126 results on '"Ute Hoch"'
Search Results
2. Bempegaldesleukin selectively depletes intratumoral Tregs and potentiates T cell-mediated cancer therapy
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Meenu Sharma, Hiep Khong, Faisal Fa’ak, Salah-Eddine Bentebibel, Louise M. E. Janssen, Brent C. Chesson, Caitlin A. Creasy, Marie-Andrée Forget, Laura Maria S. Kahn, Barbara Pazdrak, Binisha Karki, Yared Hailemichael, Manisha Singh, Christina Vianden, Srinivas Vennam, Uddalak Bharadwaj, David J. Tweardy, Cara Haymaker, Chantale Bernatchez, Shixia Huang, Kimal Rajapakshe, Cristian Coarfa, Michael E. Hurwitz, Mario Sznol, Patrick Hwu, Ute Hoch, Murali Addepalli, Deborah H. Charych, Jonathan Zalevsky, Adi Diab, and Willem W. Overwijk
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Science - Abstract
Interleukin-2 can induce an anti-tumour response, but is associated with toxicity. Here, the authors demonstrate that an engineered interleukin-2 promotes intratumoral T regulatory cell depletion while enhancing effective anti-tumour CD8+ T cell responses that result in potent tumor suppression.
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- 2020
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3. 420 Progression-free survival and biomarker correlates of response with BEMPEG plus NIVO in previously untreated patients with metastatic melanoma: results from the PIVOT-02 study
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Mario Sznol, Adi Diab, Brendan Curti, Igor Puzanov, Gregory Daniels, Jonathan Zalevsky, Ute Hoch, Mary Tagliaferri, Michael Hurwitz, Scott Tykodi, Michele Maio, Sekwon Jang, Tuan Nguyen, Wei Lin, Karl Lewis, Alexander Spira, Ewa Kalinka, Daniel Cho, Shanhong Guan, Erika Puente, and Sue Currie
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2020
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4. NKTR-214 immunotherapy synergizes with radiotherapy to stimulate systemic CD8+ T cell responses capable of curing multi-focal cancer
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William L Redmond, Ute Hoch, Melissa J Kasiewicz, Michael J McNamara, Deborah H Charych, Joshua M Walker, Annah S Rolig, Daniel C Rose, and Ian F Hilgart-Martiszus
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background High-dose radiotherapy (RT) is known to be immunogenic, but is rarely capable of driving clinically relevant abscopal antitumor immunity as monotherapy. RT is known to increase antigen presentation, type I/II interferon responses, and immune cell trafficking to irradiated tumors. Bempegaldesleukin (NKTR-214) is a CD122-preferential interleukin 2 (IL-2) pathway agonist that has been shown to increase tumor-infiltrating lymphocytes, T cell clonality, and increase PD-1 expression. NKTR-214 has increased drug half-life, decreased toxicity, and increased CD8+ T cell and natural killer cell stimulation compared with IL-2.Methods Animals bearing bilateral subcutaneous MCA-205 fibrosarcoma or CT26 colorectal tumors were treated with NKTR-214, RT, or combination therapy, and tumor growth of irradiated and abscopal lesions was assessed. Focal RT was delivered using a small animal radiation research platform. Peripheral and tumor-infiltrating immune phenotype and functional analyses were performed by flow cytometry. RNA expression profiling from both irradiated and abscopal lesions was performed using microarray.Results We demonstrate synergy between RT of a single tumor and NKTR-214 systemic therapy resulting in dramatically increased cure rates of mice bearing bilateral tumors compared with RT or NKTR-214 therapy alone. Combination therapy resulted in increased magnitude and effector function of tumor-specific CD8+ T cell responses and increased trafficking of these T cells to both irradiated and distant, unirradiated, tumors.Conclusions Given the increasing role of hypofractionated and stereotactic body RT as standard of care treatments in the management of locally advanced and metastatic cancer, these data have important implications for future clinical trial development. The combination of RT and NKTR-214 therapy potently stimulates systemic antitumor immunity and should be evaluated for the treatment of patients with locally advanced and metastatic solid tumors.
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- 2020
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5. Modeling the receptor pharmacology, pharmacokinetics, and pharmacodynamics of NKTR-214, a kinetically-controlled interleukin-2 (IL2) receptor agonist for cancer immunotherapy.
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Deborah Charych, Samira Khalili, Vidula Dixit, Peter Kirk, Thomas Chang, John Langowski, Werner Rubas, Stephen K Doberstein, Michael Eldon, Ute Hoch, and Jonathan Zalevsky
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Medicine ,Science - Abstract
Cytokines are potent immune modulating agents but are not ideal medicines in their natural form due to their short half-life and pleiotropic systemic effects. NKTR-214 is a clinical-stage biologic that comprises interleukin-2 (IL2) protein bound by multiple releasable polyethylene glycol (PEG) chains. In this highly PEG-bound form, the IL2 is inactive; therefore, NKTR-214 is a biologic prodrug. When administered in vivo, the PEG chains slowly release, creating a cascade of increasingly active IL2 protein conjugates bound by fewer PEG chains. The 1-PEG-IL2 and 2-PEG-IL2 species derived from NKTR-214 are the most active conjugated-IL2 species. Free-IL2 protein is undetectable in vivo as it is eliminated faster than formed. The PEG chains on NKTR-214 are located at the region of IL2 that contacts the alpha (α) subunit of the heterotrimeric IL2 receptor complex, IL2Rαβγ, reducing its ability to bind and activate the heterotrimer. The IL2Rαβγ complex is constitutively expressed on regulatory T cells (Tregs). Therefore, without the use of mutations, PEGylation reduces the affinity for IL2Rαβγ to a greater extent than for IL2Rβγ, the receptor complex predominant on CD8 T cells. NKTR-214 treatment in vivo favors activation of CD8 T cells over Tregs in the tumor microenvironment to provide anti-tumor efficacy in multiple syngeneic models. Mechanistic modeling based on in vitro and in vivo kinetic data provides insight into the mechanism of NKTR-214 pharmacology. The model reveals that conjugated-IL2 protein derived from NKTR-214 occupy IL-2Rβγ to a greater extent compared to free-IL2 protein. The model accurately describes the sustained in vivo signaling observed after a single dose of NKTR-214 and explains how the properties of NKTR-214 impart a unique kinetically-controlled immunological mechanism of action.
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- 2017
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6. Bempegaldesleukin plus Nivolumab in First-line Metastatic Urothelial Carcinoma: Results from PIVOT-02
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Arlene O. Siefker-Radtke, Daniel C. Cho, Adi Diab, Mario Sznol, Mehmet A. Bilen, Arjun V. Balar, Giovanni Grignani, Erika Puente, Lily Tang, David Chien, Ute Hoch, Arkopal Choudhury, Danni Yu, Sue L. Currie, Mary A. Tagliaferri, Jonathan Zalevsky, Michael E. Hurwitz, and Nizar M. Tannir
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Carcinoma, Transitional Cell ,Nivolumab ,Urinary Bladder Neoplasms ,Urology ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Interleukin-2 ,Prodrugs - Abstract
Despite recent changes in the treatment landscape, there remains an unmet need for effective, tolerable, chemotherapy-free treatments for patients with advanced/metastatic urothelial carcinoma (mUC), especially cisplatin-ineligible patients.To evaluate the immunostimulatory interleukin-2 cytokine prodrug bempegaldesleukin (BEMPEG) plus nivolumab in patients with advanced/mUC from the phase 2 multicenter PIVOT-02 study.This open-label, multicohort phase 1/2 study enrolled patients with previously untreated locally advanced/surgically unresectable or mUC (N = 41).Patients received BEMPEG 0.006 mg/kg plus nivolumab 360 mg intravenously every 3 wk.The primary objectives were safety and the objective response rate (ORR) in patients with measurable disease at baseline and at least one postbaseline tumor response assessment (response-evaluable). Secondary objectives were overall survival (OS) and progression-free survival (PFS). Exploratory biomarker analyses via univariate logistic regression were performed to test the association between potential biomarkers (CD8The ORR was 35% (13/37 evaluable patients) and the complete response rate was 19% (7/37 patients); the median duration of response was not reached. Median PFS was 4.1 mo (95% confidence interval [CI] 2.1-8.7) and median OS was 23.7 mo (95% CI 15.8-not reached). Overall, 40/41 patients (98%) experienced at least one treatment-related adverse event (TRAE); grade 3/4 TRAEs occurred in 11 patients (27%), most commonly pyrexia (4.9%; 2 patients). Exploratory biomarker analyses showed no association between biomarkers and response. Limitations include the small sample size and single-arm design.BEMPEG plus nivolumab was well tolerated and showed antitumor activity as first-line treatment in patients with locally advanced/mUC.We investigated an immune-stimulating prodrug called bempegaldesleukin plus the antibody nivolumab as the first therapy for patients with advanced or metastatic cancer of the urinary tract. This combination had manageable treatment-related side effects and was effective in a subset of patients. This trial is registered at ClinicalTrials.gov as NCT02983045.
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- 2022
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7. Treatment With Etirinotecan Pegol for Patients With Metastatic Breast Cancer and Brain Metastases: Final Results From the Phase 3 ATTAIN Randomized Clinical Trial
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Debu, Tripathy, Sara M, Tolaney, Andrew D, Seidman, Carey K, Anders, Nuhad, Ibrahim, Hope S, Rugo, Chris, Twelves, Véronique, Diéras, Volkmar, Müller, Yining, Du, Sue L, Currie, Ute, Hoch, Mary, Tagliaferri, Alison L, Hannah, Javier, Cortés, and Katherine H R, Tkaczuk
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Brain Neoplasms ,Brief Report ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Breast Neoplasms ,Female ,Middle Aged ,Heterocyclic Compounds, 4 or More Rings ,Polyethylene Glycols - Abstract
IMPORTANCE: Patients with breast cancer and brain metastases (BM) have a poor prognosis and high clinical need for novel treatments; however, historically, studies have often excluded these patients. Although the BEACON study did not meet its primary end point, treatment with etirinotecan pegol vs chemotherapy of the physician’s choice for patients with advanced breast cancer demonstrated a significant improvement in overall survival (OS) for the prespecified patient subgroup with preexisting, pretreated, and nonprogressive BM. OBJECTIVE: To compare clinical outcomes in patients with BM treated with etirinotecan pegol vs chemotherapy of the physician’s choice in a confirmatory trial. DESIGN, SETTING, AND PARTICIPANTS: This study was a phase 3, open-label, randomized clinical trial (ATTAIN) in patients with metastatic breast cancer and a history of stable pretreated BM who experienced disease progression while receiving chemotherapy in the metastatic setting. The trial took place at 47 sites in 10 countries, and patients were enrolled between March 7, 2017, and November 6, 2019. INTERVENTIONS: Patients were randomized to receive etirinotecan pegol, 145 mg/m(2), every 21 days or chemotherapy (eribulin, ixabepilone, vinorelbine, gemcitabine, paclitaxel, docetaxel, or nab-paclitaxel). MAIN OUTCOMES AND MEASURES: The primary end point was OS. Key secondary end points included progression-free survival, objective response rate, duration of response, and the clinical benefit rate. RESULTS: A total of 178 female patients (9 [5.1%] Asian, 8 [4.5%] Black or African American, and 123 [69.1] White individuals) were randomized to receive treatment with etirinotecan pegol (92 [51.7%]; median [range] age, 53 [27-79] years) or chemotherapy (86 [48.3%]; median [range] age, 52 [24-77] years). Median OS was similar in both groups (etirinotecan pegol, 7.8 months; chemotherapy, 7.5 months; hazard ratio [HR], 0.90; 95% CI, 0.61-1.33; P = .60). Median progression-free survival for non–central nervous system metastases per blinded independent central review for etirinotecan pegol vs chemotherapy was 2.8 and 1.9 months (HR, 0.72; 95% CI, 0.45-1.16; P = .18) and 3.9 vs 3.3 months, respectively, for central nervous system metastases (HR, 0.59; 95% CI, 0.33-1.05; P = .07). Safety profiles between the groups were largely comparable. CONCLUSIONS AND RELEVANCE: The results of the ATTAIN randomized clinical trial found no statistically significant difference in outcomes between treatment with etirinotecan pegol and chemotherapy in patients with BM. However, this study represents one of the largest published trials dedicated to patients with breast cancer and BM and may help to inform further research. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02915744
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- 2023
8. Data from Bempegaldesleukin (NKTR-214) plus Nivolumab in Patients with Advanced Solid Tumors: Phase I Dose-Escalation Study of Safety, Efficacy, and Immune Activation (PIVOT-02)
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Daniel C. Cho, Michael E. Hurwitz, Chantale Bernatchez, Yijie Liao, Ernesto Iacucci, Ahsan Rizwan, Christie Fanton, Sandra Aung, Ute Hoch, Alison L. Hannah, Jonathan Zalevsky, Mary A. Tagliaferri, Brendan D. Curti, Scott S. Tykodi, Mario Sznol, Scott N. Gettinger, Harriet M. Kluger, Cara Haymaker, Vassiliki Papadimitrakopoulou, Patrick Hwu, Salah-Eddine Bentebibel, Nizar M. Tannir, and Adi Diab
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This single-arm, phase I dose-escalation trial (NCT02983045) evaluated bempegaldesleukin (NKTR-214/BEMPEG), a CD122-preferential IL2 pathway agonist, plus nivolumab in 38 patients with selected immunotherapy-naïve advanced solid tumors (melanoma, renal cell carcinoma, and non–small cell lung cancer). Three dose-limiting toxicities were reported in 2 of 17 patients during dose escalation [hypotension (n = 1), hyperglycemia (n = 1), metabolic acidosis (n = 1)]. The most common treatment-related adverse events (TRAE) were flu-like symptoms (86.8%), rash (78.9%), fatigue (73.7%), and pruritus (52.6%). Eight patients (21.1%) experienced grade 3/4 TRAEs; there were no treatment-related deaths. Total objective response rate across tumor types and dose cohorts was 59.5% (22/37), with 7 complete responses (18.9%). Cellular and gene expression analysis of longitudinal tumor biopsies revealed increased infiltration, activation, and cytotoxicity of CD8+ T cells, without regulatory T-cell enhancement. At the recommended phase II dose, BEMPEG 0.006 mg/kg plus nivolumab 360 mg every 3 weeks, the combination was well tolerated and demonstrated encouraging clinical activity irrespective of baseline PD-L1 status.Significance:These data show that BEMPEG can be successfully combined with a checkpoint inhibitor as dual immunotherapy for a range of advanced solid tumors. Efficacy was observed regardless of baseline PD-L1 status and baseline levels of tumor-infiltrating lymphocytes, suggesting therapeutic potential for patients with poor prognostic risk factors for response to PD-1/PD-L1 blockade.See related commentary by Rouanne et al., p. 1097.This article is highlighted in the In This Issue feature, p. 1079
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- 2023
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9. Data from A First-in-Human Study and Biomarker Analysis of NKTR-214, a Novel IL2Rβγ-Biased Cytokine, in Patients with Advanced or Metastatic Solid Tumors
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Adi Diab, Mario Sznol, Nizar M. Tannir, Brendan D. Curti, Patrick Hwu, Sandra Aung, Christie Fanton, Ute Hoch, Jonathan Zalevsky, Mary A. Tagliaferri, Michael T. Tetzlaff, Harriet M. Kluger, Courtney W. Hudgens, Cara Haymaker, Chantale Bernatchez, Michael E. Hurwitz, and Salah-Eddine Bentebibel
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NKTR-214 (bempegaldesleukin) is a novel IL2 pathway agonist, designed to provide sustained signaling through heterodimeric IL2 receptor βγ to drive increased proliferation and activation of CD8+ T and natural killer cells without unwanted expansion of T regulatory cells (Treg) in the tumor microenvironment. In this first-in-human multicenter phase I study, NKTR-214 administered as an outpatient regimen was well tolerated and showed clinical activity including tumor shrinkage and durable disease stabilization in heavily pretreated patients. Immune activation and increased numbers of immune cells were observed in the periphery across all doses and cycles with no loss of NKTR-214 activity with repeated administration. On-treatment tumor biopsies demonstrated that NKTR-214 promoted immune cell increase with limited increase of Tregs. Transcriptional analysis of tumor biopsies showed that NKTR-214 engaged the IL2 receptor pathway and significantly increased genes associated with an effector phenotype. Based on safety and pharmacodynamic markers, the recommended phase II dose was determined to be 0.006 mg/kg every three weeks.Significance:We believe that IL2- and IL2 pathway–targeted agents such as NKTR-214 are key components to an optimal immunotherapy treatment algorithm. Based on its biological activity and tolerability, NKTR-214 is being studied with approved immuno-oncology agents including checkpoint inhibitors.See related commentary by Sullivan, p. 694.This article is highlighted in the In This Issue feature, p. 681
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- 2023
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10. CD-19-1510R1_Supplementary_Appendix.docx from Bempegaldesleukin (NKTR-214) plus Nivolumab in Patients with Advanced Solid Tumors: Phase I Dose-Escalation Study of Safety, Efficacy, and Immune Activation (PIVOT-02)
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Daniel C. Cho, Michael E. Hurwitz, Chantale Bernatchez, Yijie Liao, Ernesto Iacucci, Ahsan Rizwan, Christie Fanton, Sandra Aung, Ute Hoch, Alison L. Hannah, Jonathan Zalevsky, Mary A. Tagliaferri, Brendan D. Curti, Scott S. Tykodi, Mario Sznol, Scott N. Gettinger, Harriet M. Kluger, Cara Haymaker, Vassiliki Papadimitrakopoulou, Patrick Hwu, Salah-Eddine Bentebibel, Nizar M. Tannir, and Adi Diab
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Consolidated supplementary appendix: tables, figures, text plus legends
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- 2023
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11. Supplementary Data from A First-in-Human Study and Biomarker Analysis of NKTR-214, a Novel IL2Rβγ-Biased Cytokine, in Patients with Advanced or Metastatic Solid Tumors
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Adi Diab, Mario Sznol, Nizar M. Tannir, Brendan D. Curti, Patrick Hwu, Sandra Aung, Christie Fanton, Ute Hoch, Jonathan Zalevsky, Mary A. Tagliaferri, Michael T. Tetzlaff, Harriet M. Kluger, Courtney W. Hudgens, Cara Haymaker, Chantale Bernatchez, Michael E. Hurwitz, and Salah-Eddine Bentebibel
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Supplementary Figures, Tables, and Methods
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- 2023
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12. Figure S1 from NKTR-214, an Engineered Cytokine with Biased IL2 Receptor Binding, Increased Tumor Exposure, and Marked Efficacy in Mouse Tumor Models
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Stephen K. Doberstein, Seema S. Kantak, Theresa D. Sweeney, Jicai Huang, Yujun Wang, Chunmei Ji, Yolanda M. Kirksey, Rupesh S. Kanhere, Rhoneil L. Pena, Marina Konakova, Thomas K. Chang, Cherie F. Ali, Laurie A. VanderVeen, Paul W. Sims, Xiaofeng Liu, Dawei Sheng, Peter B. Kirk, Murali K. Addepalli, Steve R. Lee, John L. Langowski, Ute Hoch, and Deborah H. Charych
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In vitro hydrolysis of NKTR-214 under physiological conditions generating NKTR-214 released IL-2 conjugates
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- 2023
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13. Supplemental Tables and Figures from Change in Topoisomerase 1–Positive Circulating Tumor Cells Affects Overall Survival in Patients with Advanced Breast Cancer after Treatment with Etirinotecan Pegol
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Edith A. Perez, Ute Hoch, Mary Tagliaferri, Darren W. Davis, Deborah A. Zajchowski, Katie Caygill, Sherwin Sy, Lin Lu, Alison Hannah, Seock-Ah Im, Chris Twelves, Joyce O'Shaughnessy, Ahmad Awada, Javier Cortes, and Hope S. Rugo
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Supplemental Tables and Figures
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- 2023
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14. Data from NKTR-214, an Engineered Cytokine with Biased IL2 Receptor Binding, Increased Tumor Exposure, and Marked Efficacy in Mouse Tumor Models
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Stephen K. Doberstein, Seema S. Kantak, Theresa D. Sweeney, Jicai Huang, Yujun Wang, Chunmei Ji, Yolanda M. Kirksey, Rupesh S. Kanhere, Rhoneil L. Pena, Marina Konakova, Thomas K. Chang, Cherie F. Ali, Laurie A. VanderVeen, Paul W. Sims, Xiaofeng Liu, Dawei Sheng, Peter B. Kirk, Murali K. Addepalli, Steve R. Lee, John L. Langowski, Ute Hoch, and Deborah H. Charych
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Purpose: Aldesleukin, recombinant human IL2, is an effective immunotherapy for metastatic melanoma and renal cancer, with durable responses in approximately 10% of patients; however, severe side effects limit maximal dosing and thus the number of patients able to receive treatment and potential cure. NKTR-214 is a prodrug of conjugated IL2, retaining the same amino acid sequence as aldesleukin. The IL2 core is conjugated to 6 releasable polyethylene glycol (PEG) chains. In vivo, the PEG chains slowly release to generate active IL2 conjugates.Experimental Design: We evaluated the bioactivity and receptor binding of NKTR-214 and its active IL2 conjugates in vitro; the tumor immunology, tumor pharmacokinetics, and efficacy of NKTR-214 as a single agent and in combination with anti–CTLA-4 antibody in murine tumor models. Tolerability was evaluated in non-human primates.Results: In a murine melanoma tumor model, the ratio of tumor-killing CD8+ T cells to Foxp3+ regulatory T cells was greater than 400 for NKTR-214 compared with 18 for aldesleukin, supporting preferential activation of the IL2 receptor beta over IL2 receptor alpha, due to the location of PEG molecules. NKTR-214 provides a 500-fold greater exposure of the tumor to conjugated IL2 compared with aldesleukin. NKTR-214 showed efficacy as a single agent and provided durable immunity that was resistant to tumor rechallenge in combination with anti–CTLA-4 antibody. NKTR-214 was well tolerated in non-human primates.Conclusions: These data support further evaluation of NKTR-214 in humans for a variety of tumor types, adding to the repertoire of potent and potentially curative cancer immunotherapies. Clin Cancer Res; 22(3); 680–90. ©2016 AACR.
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- 2023
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15. Data from Change in Topoisomerase 1–Positive Circulating Tumor Cells Affects Overall Survival in Patients with Advanced Breast Cancer after Treatment with Etirinotecan Pegol
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Edith A. Perez, Ute Hoch, Mary Tagliaferri, Darren W. Davis, Deborah A. Zajchowski, Katie Caygill, Sherwin Sy, Lin Lu, Alison Hannah, Seock-Ah Im, Chris Twelves, Joyce O'Shaughnessy, Ahmad Awada, Javier Cortes, and Hope S. Rugo
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Purpose: Preplanned exploratory analyses were performed to identify biomarkers in circulating tumor cells (CTC) predictive of response to the topoisomerase 1 inhibitor etirinotecan pegol (EP).Experimental Design: The BEACON trial treated patients with metastatic breast cancer (MBC) with EP or treatment of physician's choice (TPC). Blood from 656 of 852 patients (77%) was processed with ApoStream to enrich for CTCs. A multiplex immunofluorescence assay measured expression of candidate response biomarkers [topoisomerase 1 (Top1), topoisomerase 2 (Top2), Ki67, RAD51, ABCG2, γH2AX, and terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling (TUNEL)] in CTCs. Patients were classified as Top1 low (Top1Lo) or Top1 high (Top1Hi) based on median CTC Top1 expression. Correlation of CTC biomarker expression at baseline, cycle 2 day 1 (C2D1), and cycle 4 day 1 with overall survival (OS) was investigated using Cox regression and Kaplan–Meier analyses.Results: Overall, 98% of samples were successfully processed, of which 97% had detectable CTCs (median, 47–63 CTCs/mL; range, 0–2,020 CTCs/mL). Top1, Top2, and TUNEL expression was detected in 52% to 90% of samples; no significant associations with OS were observed in pretreatment samples for either group. EP-treated patients with low C2D1Top1+ CTCs had improved OS compared with those with higher positivity (14.1 months vs. 11.0 months, respectively; HR, 0.7; P = 0.02); this difference was not seen in TPC-treated patients (HR, 1.12; P = 0.48). Patients whose CTCs decreased from Top1Hi to Top1Lo at C2D1 had the greatest OS benefit from EP (HR, 0.57; P = 0.01).Conclusions: CTC Top1 expression following EP treatment may identify patients with MBC most likely to have an OS benefit. Clin Cancer Res; 24(14); 3348–57. ©2018 AACR.
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- 2023
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16. Supplemental Data from NKTR-214, an Engineered Cytokine with Biased IL2 Receptor Binding, Increased Tumor Exposure, and Marked Efficacy in Mouse Tumor Models
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Stephen K. Doberstein, Seema S. Kantak, Theresa D. Sweeney, Jicai Huang, Yujun Wang, Chunmei Ji, Yolanda M. Kirksey, Rupesh S. Kanhere, Rhoneil L. Pena, Marina Konakova, Thomas K. Chang, Cherie F. Ali, Laurie A. VanderVeen, Paul W. Sims, Xiaofeng Liu, Dawei Sheng, Peter B. Kirk, Murali K. Addepalli, Steve R. Lee, John L. Langowski, Ute Hoch, and Deborah H. Charych
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Supplemental Materials and Methods. ELISA study materials; NKTR-214 chemistry; Mapping of PEGylation sites; Identification of active released IL-2 conjugates; Binding affinity to IL-2 receptors; In vivo immune cell phenotyping, In vivo immune cell phenotyping; In vivo T cell antigen staining; In vivo depletion of immune cells; Hematology parameters for evaluation of immune markers in non-human primates. Supplemental Figure Legends S1-S4. Supplemental Tables S1 and S2. Table S1: Fold change of affinity to IL-2αβ and IL-2β for NKTR-214 and its released active IL-2 conjugates compared to aldesleukin; Table S2: Activation of Primary Cynomulgus Monkey and Human T Cells in Response to IL-2 and the Active Metabolite of NKTR-214
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- 2023
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17. 1473 Mechanism of action of bempegaldesleukin (BEMPEG) plus nivolumab (NIVO) in patients with unresectable or metastatic melanoma from the phase 3 randomized open-label PIVOT IO-001 clinical trial
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Celeste Lebbe, Shruthi Ravimohan, Antara Datta, Aparna Chhibber, Eva Muñoz Couselo, Caio Pereira, Shahneen Sandhu, Ming Zhou, Brendan Curti, Nikhil Khushalani, Matthew Taylor, Alfonsus Van Den Eertwegh, Ute Hoch, Georgina Long AO, Yull Arriaga, Adi Diab, and Helen Gogas
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- 2022
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18. Bempegaldesleukin plus nivolumab in first-line renal cell carcinoma: results from the PIVOT-02 study
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Nizar M Tannir, Daniel C Cho, Adi Diab, Mario Sznol, Mehmet A Bilen, Arjun V Balar, Giovanni Grignani, Erika Puente, Lily Tang, David Chien, Ute Hoch, Arkopal Choudhury, Danni Yu, Sue L Currie, Mary A Tagliaferri, Jonathan Zalevsky, Arlene O Siefker-Radtke, and Michael E Hurwitz
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Pharmacology ,Male ,Cancer Research ,Immunology ,Kidney Neoplasms ,Nivolumab ,Oncology ,Antineoplastic Combined Chemotherapy Protocols ,Molecular Medicine ,Immunology and Allergy ,Humans ,Interleukin-2 ,Female ,Carcinoma, Renal Cell - Abstract
BackgroundImmune checkpoint inhibitor-based combinations have expanded the treatment options for patients with renal cell carcinoma (RCC); however, tolerability remains challenging. The aim of this study was to evaluate the safety and efficacy of the immunostimulatory interleukin-2 cytokine prodrug bempegaldesleukin (BEMPEG) plus nivolumab (NIVO) as first-line therapy in patients with advanced clear-cell RCC.MethodsThis was an open-label multicohort, multicenter, single-arm phase 1/2 study; here, we report results from the phase 1/2 first-line RCC cohort (N=49). Patients received BEMPEG 0.006 mg/kg plus NIVO 360 mg intravenously every 3 weeks. The primary objectives were safety and objective response rate (ORR; patients with measurable disease at baseline and at least one postbaseline tumor response assessment). Secondary objectives included overall survival (OS) and progression-free survival (PFS). Exploratory biomarker analyses: association between baseline biomarkers and ORR.ResultsAt a median follow-up of 32.7 months, the ORR was 34.7% (17/49 patients); 3/49 patients (6.1%) had a complete response. Of the 17 patients with response, 14 remained in response for >6 months, and 6 remained in response for >24 months. Median PFS was 7.7 months (95% CI 3.8 to 13.9), and median OS was not reached (95% CI 37.3 to not reached). Ninety-eight per cent (48/49) of patients experienced ≥1 treatment-related adverse event (TRAE) and 38.8% (19/49) had grade 3/4 TRAEs, most commonly syncope (8.2%; 4/49) and increased lipase (6.1%; 3/49). No association between exploratory biomarkers and ORR was observed. Limitations include the small sample size and single-arm design.ConclusionsBEMPEG plus NIVO showed preliminary antitumor activity as first-line therapy in patients with advanced clear-cell RCC and was well tolerated. These findings warrant further investigation.
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- 2022
19. 83P Evaluation of concordance between PD-L1 immunohistochemistry 28-8 and 22C3 pharmDx assays in metastatic urothelial carcinoma (mUC) in PIVOT-10
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Robert Huddart, Mary Tagliaferri, Nizar M. Tannir, Daniel C. Cho, Ute Hoch, L. Santiago, Arjun Vasant Balar, D. Yu, Jonathan Zalevsky, D. Chien, J. Novotny, Arlene O. Siefker-Radtke, S.L. Currie, Ananya Choudhury, Mehmet Asim Bilen, and Y. Loriot
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Pathology ,medicine.medical_specialty ,Metastatic Urothelial Carcinoma ,Oncology ,biology ,business.industry ,PD-L1 ,Concordance ,biology.protein ,medicine ,Immunohistochemistry ,Hematology ,business - Published
- 2021
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20. NKTR-214 immunotherapy synergizes with radiotherapy to stimulate systemic CD8+ T cell responses capable of curing multi-focal cancer
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Annah S Rolig, Ute Hoch, Deborah H. Charych, Melissa J Kasiewicz, Michael J. McNamara, Daniel Rose, Joshua M. Walker, William L. Redmond, and Ian Hilgart-Martiszus
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Cancer Research ,Combination therapy ,medicine.medical_treatment ,T cell ,Fibrosarcoma ,Immunology ,immunity, cellular ,CD8-Positive T-Lymphocytes ,T-Lymphocytes, Regulatory ,Natural killer cell ,Polyethylene Glycols ,Mice ,Immune system ,Lymphocytes, Tumor-Infiltrating ,Immunology and Allergy ,Medicine ,Cytotoxic T cell ,Animals ,RC254-282 ,T-lymphocytes ,Pharmacology ,Mice, Inbred BALB C ,Radiotherapy ,business.industry ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Basic Tumor Immunology ,Immunotherapy ,Combined Modality Therapy ,Radiation therapy ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Oncology ,Cancer research ,Molecular Medicine ,Interleukin-2 ,Female ,Sarcoma, Experimental ,business ,Colorectal Neoplasms ,CD8 - Abstract
BackgroundHigh-dose radiotherapy (RT) is known to be immunogenic, but is rarely capable of driving clinically relevant abscopal antitumor immunity as monotherapy. RT is known to increase antigen presentation, type I/II interferon responses, and immune cell trafficking to irradiated tumors. Bempegaldesleukin (NKTR-214) is a CD122-preferential interleukin 2 (IL-2) pathway agonist that has been shown to increase tumor-infiltrating lymphocytes, T cell clonality, and increase PD-1 expression. NKTR-214 has increased drug half-life, decreased toxicity, and increased CD8+T cell and natural killer cell stimulation compared with IL-2.MethodsAnimals bearing bilateral subcutaneous MCA-205 fibrosarcoma or CT26 colorectal tumors were treated with NKTR-214, RT, or combination therapy, and tumor growth of irradiated and abscopal lesions was assessed. Focal RT was delivered using a small animal radiation research platform. Peripheral and tumor-infiltrating immune phenotype and functional analyses were performed by flow cytometry. RNA expression profiling from both irradiated and abscopal lesions was performed using microarray.ResultsWe demonstrate synergy between RT of a single tumor and NKTR-214 systemic therapy resulting in dramatically increased cure rates of mice bearing bilateral tumors compared with RT or NKTR-214 therapy alone. Combination therapy resulted in increased magnitude and effector function of tumor-specific CD8+T cell responses and increased trafficking of these T cells to both irradiated and distant, unirradiated, tumors.ConclusionsGiven the increasing role of hypofractionated and stereotactic body RT as standard of care treatments in the management of locally advanced and metastatic cancer, these data have important implications for future clinical trial development. The combination of RT and NKTR-214 therapy potently stimulates systemic antitumor immunity and should be evaluated for the treatment of patients with locally advanced and metastatic solid tumors.
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- 2020
21. Bempegaldesleukin selectively depletes intratumoral Tregs and potentiates T cell-mediated cancer therapy
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Marie Andrée Forget, Barbara Pazdrak, Yared Hailemichael, Meenu Sharma, Patrick Hwu, Cara Haymaker, Adi Diab, Binisha Karki, Ute Hoch, Christina Vianden, Deborah H. Charych, Manisha Singh, Caitlin Creasy, Cristian Coarfa, Michael E. Hurwitz, Salah Eddine Bentebibel, Mario Sznol, Uddalak Bharadwaj, Hiep Khong, Kimal Rajapakshe, Chantale Bernatchez, David J. Tweardy, Jonathan Zalevsky, Murali Addepalli, Srinivas Vennam, Faisal Fa’ak, Willem W. Overwijk, Shixia Huang, Louise M.E. Janssen, Brent C. Chesson, and Laura Maria S. Kahn
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0301 basic medicine ,Cancer therapy ,medicine.medical_treatment ,General Physics and Astronomy ,CD8-Positive T-Lymphocytes ,Lymphocyte Activation ,T-Lymphocytes, Regulatory ,Polyethylene Glycols ,Cohort Studies ,Mice ,0302 clinical medicine ,Prodrugs ,Lymphocytes ,lcsh:Science ,Receptor ,Melanoma ,Multidisciplinary ,3. Good health ,Cytokine ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Monoclonal ,Tumour immunology ,Cytokines ,Drug Therapy, Combination ,Female ,Immunotherapy ,medicine.symptom ,Science ,T cell ,Antibodies, Monoclonal, Humanized ,Article ,General Biochemistry, Genetics and Molecular Biology ,Interferon-gamma ,03 medical and health sciences ,medicine ,Animals ,Humans ,Carcinoma, Renal Cell ,Tumor Necrosis Factor-alpha ,business.industry ,Cancer ,Receptors, Interleukin-2 ,General Chemistry ,medicine.disease ,Ipilimumab ,Blockade ,Mice, Inbred C57BL ,030104 developmental biology ,Mechanism of action ,Cancer research ,Interleukin-2 ,lcsh:Q ,business ,CD8 - Abstract
High dose interleukin-2 (IL-2) is active against metastatic melanoma and renal cell carcinoma, but treatment-associated toxicity and expansion of suppressive regulatory T cells (Tregs) limit its use in patients with cancer. Bempegaldesleukin (NKTR-214) is an engineered IL-2 cytokine prodrug that provides sustained activation of the IL-2 pathway with a bias to the IL-2 receptor CD122 (IL-2Rβ). Here we assess the therapeutic impact and mechanism of action of NKTR-214 in combination with anti-PD-1 and anti-CTLA-4 checkpoint blockade therapy or peptide-based vaccination in mice. NKTR-214 shows superior anti-tumor activity over native IL-2 and systemically expands anti-tumor CD8+ T cells while inducing Treg depletion in tumor tissue but not in the periphery. Similar trends of intratumoral Treg dynamics are observed in a small cohort of patients treated with NKTR-214. Mechanistically, intratumoral Treg depletion is mediated by CD8+ Teff-associated cytokines IFN-γ and TNF-α. These findings demonstrate that NKTR-214 synergizes with T cell-mediated anti-cancer therapies., Interleukin-2 can induce an anti-tumour response, but is associated with toxicity. Here, the authors demonstrate that an engineered interleukin-2 promotes intratumoral T regulatory cell depletion while enhancing effective anti-tumour CD8+ T cell responses that result in potent tumor suppression.
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- 2020
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22. Integrated population pharmacokinetics of etirinotecan pegol and its four metabolites in cancer patients with solid tumors
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Yen Lin Chia, Michael A Eldon, Toufigh Gordi, Sherwin K. B. Sy, and Ute Hoch
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0301 basic medicine ,Oncology ,Adult ,Male ,Cancer Research ,medicine.medical_specialty ,030106 microbiology ,Population ,Renal function ,Antineoplastic Agents ,Toxicology ,Irinotecan ,Heterocyclic Compounds, 4 or More Rings ,Models, Biological ,Polyethylene Glycols ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Pharmacokinetics ,Internal medicine ,Neoplasms ,medicine ,Humans ,Pharmacology (medical) ,Dosing ,Population pharmacokinetics ,Glucuronosyltransferase ,education ,Active metabolite ,Aged ,Pharmacology ,Body surface area ,Aged, 80 and over ,education.field_of_study ,Clinical Trials as Topic ,business.industry ,Cancer ,Middle Aged ,medicine.disease ,SN38 ,030220 oncology & carcinogenesis ,Original Article ,Camptothecin ,Female ,Etirinotecan pegol ,business ,medicine.drug - Abstract
Purpose Etirinotecan pegol (EP), a long-acting topoisomerase-1 inhibitor, is a polyethylene glycol conjugate of irinotecan, with an intended indication for treatment of breast cancer with brain metastases. The objective of this study was to develop a population pharmacokinetic (popPK) model of EP and four of its metabolites (irinotecan, SN38, SN38-glucuronide, and APC) and determine covariates affecting their pharmacokinetics. Methods Data from 83 cancer patients enrolled in phase 1 studies were used. The model was developed in two stages: (1) concentration–time data were analyzed with a 3-analyte model for EP, irinotecan, and SN38; and (2) a 5-analyte model developed based on expansion of 3-analyte model to include concentration–time data for SN38 glucuronide and APC with parameter values from 3-analyte model fixed. Covariate relationships with parameters were selected based on Wald’s test within the Wald’s Approximation Method approach, first for the 3-analyte model then the 5-analyte model. Results The final integrated popPK model for the five analytes was a two-compartment per analyte model that followed the metabolic cascade of EP to irinotecan, followed by metabolism of irinotecan to the previously known metabolites, but with altered exposures as compared to administration of irinotecan. With the model developed based on total dose of EP, the population estimates of EP clearance and central volume were 0.237 L/h and 5.5 L, respectively. Patient age, body surface area (BSA), and estimated glomerular filtration rate were found to correlate with EP clearance and BSA with EP central volume. Individuals who were homozygous for UGT1A1*28 genotype had modestly reduced elimination capacity of SN38 compared to heterozygous and wild-type genotypes. Simulations evaluating the clinical importance of significant covariates indicated minimal change in areas under the curve and peak concentrations of EP and SN38. Conclusions The pharmacokinetics of EP and four metabolites including the active metabolite SN38 were described by an integrated popPK model. Other than BSA, which was already accounted by a BSA-based dosing scheme, no other covariates were deemed to have clinical implications. No EP starting dose adjustment based on patient demographics and other covariates was deemed necessary. Electronic supplementary material The online version of this article (10.1007/s00280-018-3562-3) contains supplementary material, which is available to authorized users.
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- 2018
23. 59 Associations between KIR/KIR-ligand genotypes and clinical outcome for patients with advanced solid tumors receiving BEMPEG plus nivolumab combination therapy in the PIVOT-02 trial
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Danni Yu, Ute Hoch, Sara M. Tolaney, Adi Diab, Arika Feils, Arlene O. Siefker-Radtke, KyungMann Kim, Jen Birstler, Paul M. Sondel, Sue Currie, Tuan Nguyen, Amy K. Erbe, Matthew D. Hellmann, and Nizar M. Tannir
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Pharmacology ,Oncology ,Cancer Research ,medicine.medical_specialty ,Combination therapy ,business.industry ,medicine.medical_treatment ,Immunology ,Follicular lymphoma ,Cancer ,Phases of clinical research ,Dinutuximab ,Immunotherapy ,medicine.disease ,Clinical trial ,Internal medicine ,medicine ,Molecular Medicine ,Immunology and Allergy ,Nivolumab ,business - Abstract
BackgroundHigh-dose IL2 therapy has shown clinical benefit in metastatic melanoma and renal cell carcinoma, however only in a select subset of patients. Bempegaldesleukin (BEMPEG), a novel CD122-preferential IL2 pathway agonist, preferentially binds the heterodimeric IL2βγR predominantly expressed on NK and CD8 T cells and minimizes binding to the IL2αR expressed on immunosuppressive Tregs. BEMPEG monotherapy in Phase I clinical trials induced proliferation and activation of NK cells in the blood and tumor microenvironment.1 NK activation is dependent on the balance of inhibitory and excitatory signals transmitted by NK receptors, including Fc-gamma receptors (FCγRs) and killer immunoglobulin-like receptors (KIRs) along with their KIR-ligands. The repertoire of KIRs/KIR-ligands an individual inherits and the single-nucleotide polymorphisms (SNPs) of FCγRs can influence NK cell function and affect responses to immunotherapies.2–4 Thus, we sought to investigate whether distinct immunogenotypes are associated with clinical response of patients enrolled in PIVOT-02, a Phase II study of BEMPEG plus nivolumab.Methods200 patients with advanced solid tumors enrolled in PIVOT-02 who were not previously treated with immunotherapy (immunotherapy-naïve, ‘IO’) had DNA available for genotyping and clinical data for correlative analyses. All patients received 0.006mg/kg BEMPEG plus 360mg nivolumab every 3 weeks.5 KIR/KIR-ligand gene status was assessed by real-time SYBR green PCR melt-curve analyses and PCR-SSP. FCγR SNP status was determined using Taqman primers/probes for FCγR2A, and FCγR3A and FCγR2C were determined using RNaseH primers/probes.6 Clinical outcome parameters included objective response rate (ORR), progression-free survival (PFS), and tumor shrinkage (TS, defined as best objective response ResultsKIR2DL2+/C1+ IO patients observed significantly greater TS (p=0.015) and a trend towards improved ORR (p=0.060) and increased PFS (p=0.058) compared to IO patients who were not KIR2DL2+/C1+. IO patients who were KIR2DL2+/C1+/KIR3DL1+/Bw4+ showed significantly improved ORR (p=0.014) and greater TS (p=0.044) compared to IO patients who were not KIR2DL2+/C1+/KIR3DL1+/Bw4+, with no significance found for PFS in these patients. FCγR polymorphisms did not influence ORR/PFS/TS.ConclusionsNK cells may play an important role in the anti-tumor efficacy of BEMPEG plus nivolumab, and NK activation is influenced by certain immunogenotypes. Similar to previous findings,2–4 the status of KIR2DL2+/C1+ and KIR2DL2+/C1+/KIR3DL1+/Bw4+ was associated with the response to BEMPEG plus nivolumab treatment in the PIVOT-02 trial. The potential to utilize these genotypes in clinical decision-making for immunotherapy treatment requires further investigation.Trial RegistrationClinicalTrialsgov NCT02983045ReferencesBentebibel S-E, et al. A first-in-human study and biomarker analysis of NKTR-214, a Novel IL2βγ-Biased cytokine, in patients with advanced or metastatic solid tumors. Cancer Discov 2019;9:711–21.Erbe AK, et al. Follicular lymphoma patients with KIR2DL2 and KIR3DL1 and their ligands (HLA-C1 and HLA-Bw4) show improved outcome when receiving rituximab. J Immunother Cancer 2019;7(1):70.Erbe AK, et al. Neuroblastoma patients’ KIR and KIR-Ligand genotypes influence clinical outcome for dinutuximab-based immunotherapy: A report from the Children’s Oncology Group. Clin Cancer Res 2018;24(1):189–96.Erbe AK, et al. FCGR polymorphisms influence response to IL2 in metastatic renal cell carcinoma. Clin Cancer Res 2017;23(9):2159–68.Diab A, et al. Bempegaldesleukin (NKTR-214) plus nivolumab in patients with advanced solid tumors: Phase I dose-escalation study of safety, efficacy, and immune activation (PIVOT-02). Cancer Discov 2020;10:1–16.Erbe AK, et al. Genotyping single nucleotide polymorphisms and copy number variability of the FCGRs expressed on NK cells. Methods Mol Biol 2016;1441:43–56.Ethics ApprovalThe study was conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki. The Protocol (online only) was approved by independent ethics committees and the relevant institutional review board at each site. All patients provided written informed consent.
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- 2021
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24. Prolonged survival in patients with breast cancer and a history of brain metastases: results of a preplanned subgroup analysis from the randomized phase III BEACON trial
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Audrey Mailliez, Denise A. Yardley, Mary Tagliaferri, David Potter, Alison L. Hannah, Jin Seok Ahn, Edith A. Perez, Alvaro Moreno-Aspitia, Javier Cortes, Ute Hoch, Hope S. Rugo, Chris Twelves, Ahmad Awada, Seock–Ah –A Im, Patricia Gómez-Pardo, Lee S. Schwartzberg, Joyce O'Shaughnessy, Carol Zhao, and Véronique Diéras
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,NKTR-102 ,Clinical Trials and Supportive Activities ,Clinical Sciences ,Oncology and Carcinogenesis ,Population ,Subgroup analysis ,Vinorelbine ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Breast cancer ,Clinical Research ,Internal medicine ,Breast Cancer ,medicine ,Chemotherapy ,Oncology & Carcinogenesis ,education ,Cancer ,education.field_of_study ,business.industry ,Neurosciences ,Ixabepilone ,Evaluation of treatments and therapeutic interventions ,Brain metastases ,Metastatic breast cancer ,medicine.disease ,Clinical Trial ,Cancérologie ,030104 developmental biology ,Docetaxel ,chemistry ,6.1 Pharmaceuticals ,030220 oncology & carcinogenesis ,Etirinotecan pegol ,business ,medicine.drug ,Eribulin - Abstract
Purpose: Conventional chemotherapy has limited activity in patients with breast cancer and brain metastases (BCBM). Etirinotecan pegol (EP), a novel long-acting topoisomerase-1 inhibitor, was designed using advanced polymer technology to preferentially accumulate in tumor tissue including brain metastases, providing sustained cytotoxic SN38 levels. Methods: The phase 3 BEACON trial enrolled 852 women with heavily pretreated locally recurrent or metastatic breast cancer between 2011 and 2013. BEACON compared EP with treatment of physician’s choice (TPC; eribulin, vinorelbine, gemcitabine, nab-paclitaxel, paclitaxel, ixabepilone, or docetaxel) in patients previously treated with anthracycline, taxane, and capecitabine, including those with treated, stable brain metastases. The primary endpoint, overall survival (OS), was assessed in a pre-defined subgroup of BCBM patients; an exploratory post hoc analysis adjusting for the diagnosis-specific graded prognostic assessment (GPA) index was also conducted. Results: In the trial, 67 BCBM patients were randomized (EP, n = 36; TPC, n = 31). Treatment subgroups were balanced for baseline characteristics and GPA indices. EP was associated with a significant reduction in the risk of death (HR 0.51; P, SCOPUS: ar.j, info:eu-repo/semantics/published
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- 2017
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25. Abstract P1-12-05: Etirinotecan pegol: Survival advantage over standard of care drugs in a model of brain metastases of breast cancer
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Paul R. Lockman, Jessica Griffith, Afroz S. Mohammad, Emma L. Dolan, Ute Hoch, R Jagannathan, Chris E. Adkins, and Neal Shah
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Vinorelbine ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Breast cancer ,Internal medicine ,medicine ,business.industry ,Cancer ,medicine.disease ,Gemcitabine ,Surgery ,Irinotecan ,030104 developmental biology ,Docetaxel ,chemistry ,030220 oncology & carcinogenesis ,business ,medicine.drug ,Brain metastasis ,Eribulin - Abstract
BACKGROUND: Brain metastasis of breast cancer is a significant cause of death among women with disseminated breast cancer. Chemotherapy, radiation, and surgery for these metastases provide only minimal benefit with considerable toxicity. The long-acting topoisomerase I inhibitor etirinotecan pegol (EP) is a novel treatment for disseminated breast cancer. EP consists of irinotecan attached to a 20kDa branched polymer via a releasable linker. The large molecular weight of EP results in tumor accumulation, including brain metastases, providing increased and sustained exposure to cytotoxic SN38. In the Phase 3 BEACON study, EP showed a significant survival benefit (HR 0.51; 95% CI 0.30-0.86) in a prespecified subgroup of women with history of treated, stable brain metastases compared to treatment of physicians choice (TPC) consisting of one of seven approved chemotherapy drugs (median OS 10.0 vs 4.8 mo). Nektar has filed a conditional marketing authorization in Europe for EP in patients with advanced breast cancer and brain metastases. A Phase 3 trial in this patient population is being initiated to support a potential U.S. filing. To further support the biological rationale for EP in these patients, an experimental preclinical model of brain metastases of breast cancer was conducted to compare the efficacy of EP to TPC in BEACON and the planned subsequent study. METHODS: Female athymic nude mice were inoculated with 1.75x105 MDA-MB-231-BrLuc cells via intracardiac injection. Starting on day 21, gemcitabine (60 mg/kg) and eribulin (1.5 mg/kg) were dosed IP every 4 days; EP (50 mg/kg), irinotecan (50 mg/kg), paclitaxel (6 mg/kg), vinorelbine (10 mg/kg), docetaxel (10 mg/kg), and vehicle (saline or dextrose) were dosed weekly via tail vein. Efficacy was measured by tumor burden and survival. Tumor burden was determined based on twice weekly bioluminescence measurements. Animals were euthanized according to international animal care guidelines. RESULTS: Median survival for all control arm groups (docetaxel, vinorelbine, eribulin, gemcitabine, irinotecan, and paclitaxel) were 39, 43, 41, 48, 35, and 42 days, respectively, none of which were significantly different from vehicle control median survival of 40 days (p>0.05). No animals receiving these drugs survived until the end of the 90-day trial. Median survival for the EP treatment group was 86 days (p CONCLUSIONS: In this model of brain metastases, EP preferentially accumulates in brain metastases, significantly reduces tumor burden progression and significantly improves survival in brain metastases of breast cancer compared to the most active chemotherapeutic agents available for advanced breast cancer and those used in the BEACON trial and planned subsequent Phase 3 study. Citation Format: Shah N, Mohammad AS, Adkins CE, Dolan EL, Griffith J, Jagannathan R, Hoch U, Lockman PR. Etirinotecan pegol: Survival advantage over standard of care drugs in a model of brain metastases of breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-12-05.
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- 2017
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26. Bempegaldesleukin (NKTR-214) plus Nivolumab in Patients with Advanced Solid Tumors: Phase I Dose-Escalation Study of Safety, Efficacy, and Immune Activation (PIVOT-02)
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Daniel C. Cho, Harriet M. Kluger, Scott N. Gettinger, Chantale Bernatchez, Christie Fanton, Yijie Liao, Ernesto Iacucci, Mary Tagliaferri, Michael E. Hurwitz, Alison L. Hannah, Scott S. Tykodi, Cara Haymaker, Salah Eddine Bentebibel, Adi Diab, Ute Hoch, Jonathan Zalevsky, Vassiliki A. Papadimitrakopoulou, Sandra Aung, Mario Sznol, Ahsan Naqi Rizwan, Patrick Hwu, Nizar M. Tannir, and Brendan D. Curti
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0301 basic medicine ,Oncology ,Adult ,Male ,medicine.medical_specialty ,Lung Neoplasms ,medicine.medical_treatment ,Programmed Cell Death 1 Receptor ,Polyethylene Glycols ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Antineoplastic Agents, Immunological ,Lymphocytes, Tumor-Infiltrating ,Renal cell carcinoma ,Internal medicine ,Carcinoma, Non-Small-Cell Lung ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Lymphocyte Count ,Adverse effect ,Carcinoma, Renal Cell ,Immune Checkpoint Inhibitors ,Melanoma ,Aged ,business.industry ,Metabolic acidosis ,Immunotherapy ,Middle Aged ,medicine.disease ,Rash ,Kidney Neoplasms ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Nivolumab ,Treatment Outcome ,030220 oncology & carcinogenesis ,Interleukin-2 ,Female ,medicine.symptom ,business ,CD8 - Abstract
This single-arm, phase I dose-escalation trial (NCT02983045) evaluated bempegaldesleukin (NKTR-214/BEMPEG), a CD122-preferential IL2 pathway agonist, plus nivolumab in 38 patients with selected immunotherapy-naïve advanced solid tumors (melanoma, renal cell carcinoma, and non–small cell lung cancer). Three dose-limiting toxicities were reported in 2 of 17 patients during dose escalation [hypotension (n = 1), hyperglycemia (n = 1), metabolic acidosis (n = 1)]. The most common treatment-related adverse events (TRAE) were flu-like symptoms (86.8%), rash (78.9%), fatigue (73.7%), and pruritus (52.6%). Eight patients (21.1%) experienced grade 3/4 TRAEs; there were no treatment-related deaths. Total objective response rate across tumor types and dose cohorts was 59.5% (22/37), with 7 complete responses (18.9%). Cellular and gene expression analysis of longitudinal tumor biopsies revealed increased infiltration, activation, and cytotoxicity of CD8+ T cells, without regulatory T-cell enhancement. At the recommended phase II dose, BEMPEG 0.006 mg/kg plus nivolumab 360 mg every 3 weeks, the combination was well tolerated and demonstrated encouraging clinical activity irrespective of baseline PD-L1 status. Significance: These data show that BEMPEG can be successfully combined with a checkpoint inhibitor as dual immunotherapy for a range of advanced solid tumors. Efficacy was observed regardless of baseline PD-L1 status and baseline levels of tumor-infiltrating lymphocytes, suggesting therapeutic potential for patients with poor prognostic risk factors for response to PD-1/PD-L1 blockade. See related commentary by Rouanne et al., p. 1097. This article is highlighted in the In This Issue feature, p. 1079
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- 2019
27. Human Abuse Potential of Oral NKTR-181 in Recreational Opioid Users: A Randomized, Double-Blind, Crossover Study
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Michael A Eldon, Suresh Siddhanti, Jack E. Henningfield, Carlo J Di Fonzo, Mary Tagliaferri, Lin Lu, Ute Hoch, Janet Jobes, Jonathan Zalevsky, Stephen K. Doberstein, Margaret Ziola, Debra Kelsh, Bradley Vince, Sunny Xie, and Ge Xue
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Adult ,Male ,Visual analogue scale ,Administration, Oral ,Placebo ,Double-Blind Method ,Pharmacokinetics ,Recreational Drug Use ,Humans ,Medicine ,Adverse effect ,Cross-Over Studies ,Dose-Response Relationship, Drug ,business.industry ,General Medicine ,Crossover study ,Analgesics, Opioid ,Anesthesiology and Pain Medicine ,Morphinans ,Opioid ,Pharmacodynamics ,Anesthesia ,Female ,Neurology (clinical) ,business ,Oxycodone ,medicine.drug - Abstract
ObjectiveTo evaluate the human abuse potential, pharmacokinetics, pharmacodynamics, and safety of oral NKTR-181 (oxycodegol), a novel full mu-opioid receptor agonist, relative to oral oxycodone.DesignThis double-blind, randomized, single-dose, crossover human abuse potential study was conducted in healthy, adult, non–physically dependent recreational opioid users.SettingInpatient clinical research site.SubjectsSeventy-one subjects randomized (95.7% male, 65.2% African American, mean age = 31.7 years).MethodsThe primary objective was to compare two therapeutic doses of NKTR-181 (400 and 600 mg) with 40 and 60 mg of oxycodone and a supratherapeutic dose (1200 mg) of NKTR-181 with 60 mg of oxycodone using visual analog scale (VAS) ratings for Drug Liking “at this moment” (Drug Liking). Secondary objectives included VAS ratings for other subjective measures, and central nervous system (CNS) mu-opioid effects were assessed using pupillometry. Each subject received single oral doses of five treatments and matching placebo.ResultsCompared with 40 and 60 mg of oxycodone, the maximum mean Drug Liking score at 400 and 600 mg NKTR-181 was significantly lower, and the rate of onset and extent of Drug Liking for all NKTR-181 doses in the first two hours postdose were also significantly lower. Delayed attenuated Drug Liking and pupillary miosis response following administration of NKTR-181 vs oxycodone were consistent with slower NKTR-181 CNS entry kinetics and mu-opioid receptor binding. No adverse events were rated as severe, and somnolence and dizziness occurred more frequently when subjects received oxycodone.ConclusionsNKTR-181 at oral doses of 400 and 600 mg showed significantly fewer and less severe subjective effects accepted as representative of opioid abuse potential, such as lower peak Drug Liking in recreational opioid users, than 40 and 60 mg of oxycodone.
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- 2019
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28. Etirinotecan pegol administration is associated with lower incidences of neutropenia compared to irinotecan administration
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S. Kenneth Sy, Ute Hoch, Theresa D. Sweeney, Michael A. Eldon, and Chunmei Ji
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Male ,0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,Neutropenia ,NKTR-102 ,Antineoplastic Agents ,Pharmacology ,Irinotecan ,Toxicology ,Heterocyclic Compounds, 4 or More Rings ,Beagle ,Gastroenterology ,Polyethylene Glycols ,03 medical and health sciences ,Dogs ,Breast cancer ,0302 clinical medicine ,Pharmacokinetics ,Internal medicine ,medicine ,Animals ,Pharmacology (medical) ,business.industry ,Incidence ,Incidence (epidemiology) ,medicine.disease ,Etirinotecan pegol ,SN38 ,030104 developmental biology ,Oncology ,Area Under Curve ,030220 oncology & carcinogenesis ,Absolute neutrophil count ,Camptothecin ,Female ,Original Article ,business ,medicine.drug - Abstract
Purpose The relationship between incidences of neutropenia and 10-hydroxy-7-ethyl camptothecin (SN38) exposure was explored using SN38 pharmacokinetic and neutrophil count data from toxicology studies of etirinotecan pegol (EP) and irinotecan in beagle dogs. Methods Dogs received four weekly intravenous infusions of either vehicle control (n = 22), EP (6, 15, 20, 25, 40/25 mg/kg; n = 3–9 dogs/dose group/sex; n = 48), or irinotecan (20 or 25 mg/kg n = 3–4 dogs/dose group/sex; n = 14). Blood samples were collected up to 50 days post-dose for characterization of SN38 pharmacokinetics. Two separate models were created describing SN38 concentration time profiles after either irinotecan or EP administrations to project the AUC0–168h after Day 1 and Day 22 doses. The relationship between incidence of neutropenia and SN38 exposure was explored using logistic regression. Results The incidence of neutropenia in dogs receiving weekly doses of irinotecan or EP was strongly correlated with maximum plasma SN38 concentration (C max), but not SN38 area under the concentration–time curve (AUC). Neutropenia occurred in approximately 80% of dogs receiving irinotecan (mean SN38 C max of 13.5 and 26.3 ng/mL for 20 and 25 mg/kg, respectively). No neutropenia occurred in dogs receiving EP at doses up to and including 25 mg/kg (mean SN38 C max of 3.4 and 4.9 ng/mL for 20 and 25 mg/kg, respectively), despite 2.5–3.6 times greater SN38 AUC after EP compared to irinotecan at equivalent doses. Conclusions EP administration avoids both high SN38 C max values and development of dose-limiting neutropenia observed after irinotecan, while maintaining greater and sustained SN38 exposure between doses. Electronic supplementary material The online version of this article (doi:10.1007/s00280-016-3192-6) contains supplementary material, which is available to authorized users.
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- 2016
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29. Abstract P1-13-02: Early change in topoisomerase 1 (Top1) positive circulating tumor cells (CTCs) is associated with overall survival (OS) in patients with advanced breast cancer after treatment with etirinotecan pegol
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D Zajchowski, S-A Im, Darren W. Davis, Ute Hoch, S Sy, J. Cortes, Joyce A. O'Shaughnessy, Katie Caygill, E. A. Perez, L Lu, Alison L. Hannah, Chris Twelves, Ahmad Awada, and HS Rugo
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Oncology ,Cancer Research ,medicine.medical_specialty ,education.field_of_study ,Intention-to-treat analysis ,business.industry ,Population ,Cancer ,medicine.disease ,Surgery ,Cytokeratin ,Circulating tumor cell ,Breast cancer ,Pharmacodynamics ,Internal medicine ,medicine ,business ,education ,Whole blood - Abstract
Background: Etirinotecan pegol (EP) is a long-acting Top1 inhibitor providing sustained levels of active metabolite throughout the entire chemotherapy cycle. The phase 3 BEACON trial compared EP to treatment of physician's choice (TPC) in patients with advanced breast cancer, demonstrating a non-statistically significant 2.1 month difference in survival favoring EP in the intent to treat population. A novel aspect of the BEACON trial is to explore the utility of biomarkers measured in CTCs for predicting efficacy with EP. Pre- and post-treatment CTCs were isolated from blood of 77% of the 852 BEACON patients. Target-specific pharmacodynamic biomarkers for EP measured in CTCs were analyzed to identify patients most responsive to treatment with EP. Methods: Donation of blood samples for CTC analysis was voluntary. Participating BEACON patients had serial (baseline, Cycle 2 Day 1 [C2D1], Cycle 4 Day 1 [C4D1], End of Treatment) 7.5-mL whole blood samples drawn in EDTA tubes and shipped within 96 hours ambient to ApoCell (Houston, TX) for processing. PBMCs were separated by Ficoll® gradient, and CTCs were isolated using ApoStream® technology. Isolated cells were deposited on three slides and stained for DAPI, CD45, cytokeratin markers, as well as Top1, Top2, Ki67, γH2AX, Rad51, ABCG2, and TUNEL. Biomarkers were quantified by iCys® laser scanning cytometer equipped with image analysis software, and correlated with OS using Cox multiple regression and Kaplan-Meier analyses. Results: The CTC substudy yielded 611 pre-treatment, 519 C2D1, 268 C4D1, and 431 End of Treatment samples. Among the successfully processed blood samples, 98% had detectable CTCs, with a median of 63, 46, 51, and 57 CTCs/mL at baseline, C2D1, C4D1, and End of Treatment, respectively. Cox regression analyses of CTC number and percentage of Top1, Top2, Ki67, or TUNEL positive CTCs identified a correlation for post-treatment number of Top1-positive CTCs with OS in patients receiving EP. To assess the impact of Top1-positive CTCs, patients were classified as Top1-High (> median) or Top1-Low (≤ median) based on the percent of Top1-positive CTCs at baseline. Among the Top1-High patients at baseline, significantly improved OS (HR 0.54, p=0.007) was observed for those who converted to Top1-Low after their first treatment with EP (C2D1), but not TPC (HR 1.12, p=0.613). These results suggest that decreased number of Top1-positive CTCs may reflect EP target engagement with Top1, as these patients derived the most benefit from treatment. Conclusions: CTC collection and analysis was successfully incorporated into the phase 3 BEACON study, with 77% patient participation. CTC detection rate using ApoStream® was high, permitting evaluation of biomarkers at baseline and post-treatment. Significantly improved OS was observed in patients who had a decreased number of Top1-positive CTCs following cycle 1 of EP. Citation Format: Rugo HS, Cortes J, Awada A, O'Shaughnessy J, Twelves C, Im S-A, Hannah AL, Lu L, Sy S, Caygill K, Zajchowski D, Davis DW, Hoch U, Perez EA. Early change in topoisomerase 1 (Top1) positive circulating tumor cells (CTCs) is associated with overall survival (OS) in patients with advanced breast cancer after treatment with etirinotecan pegol. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-13-02.
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- 2016
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30. Abstract P4-11-08: Impact of treatment on quality of life (QOL) in the BEACON study, a randomized phase III trial of etirinotecan pegol (EP) versus treatment of physician's choice (TPC) in patients (pts) with advanced breast cancer (aBC) whose disease has progressed following anthracycline (A), taxane (T) and capecitabine (C)
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Alison L. Hannah, J Ney, S-A Im, E. A. Perez, Joyce A. O'Shaughnessy, HS Rugo, Chris Twelves, Carol Zhao, Ute Hoch, J. Cortes, and Ahmad Awada
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Oncology ,Cancer Research ,medicine.medical_specialty ,Taxane ,business.industry ,Nausea ,medicine.disease ,humanities ,Surgery ,Capecitabine ,Irinotecan ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Quality of life ,030220 oncology & carcinogenesis ,Statistical significance ,Internal medicine ,medicine ,medicine.symptom ,business ,Adverse effect ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Background: The need remains for novel agents that prolong survival and/or improve QOL in women with aBC. EP is a long-acting topoisomerase 1 inhibitor engineered to produce sustained exposure to irinotecan and its active metabolite SN38. Given previous efficacy seen in an earlier phase II trial in MBC, EP 145 mg/m2 every 3 weeks was compared to TPC (one of 7 single-agent regimens) in the randomized phase 3 BEACON study (NCT01492101). As reported at ASCO 2015 (abstract 1001), EP prolonged median overall survival by 2.1 months, although this did not reach statistical significance (12.4 vs 10.3 months; HR 0.87, p=0.08). Grade ≥ 3 adverse events were significantly less common with EP (48% vs 63% with TPC, p Methods: Patients completed validated health-related QoL (HRQoL) questionnaires, EORTC QLQ-C30 (version 3.0) and breast cancer-specific QLQ-BR23, pretreatment and every 8 weeks until progression, death or withdrawal of consent. Questionnaires were scored according to the EORTC manual. For each scale, raw scores were standardized via a linear transformation to a range from 0 to 100. Absolute scores and changes from baseline were analyzed longitudinally and categorically using a 5-point difference calculated by treatment group. Comparisons between treatment groups were conducted to evaluate the differences in global health status, functional scores and symptoms over time. Results: The majority of patients who were randomized (total: 733/852 [86%], EP: 378/429 [88%], TPC: 355/423 [84%]) completed at least one post-baseline HRQoL questionnaire. In the EORTC QLQ-C30, grade ≥ 3 AEs significantly impacted HRQoL measured by global health status and 5 additional functional domains. Of the six domains, compared to TPC in a longitudinal analysis, EP was statistically superior in the mean treatment effect through Week 32 in global health status p=0.02 and physical functioning scale p=0.01. EP was also numerically superior in all other scales. In EORTC QLQ-C30 and BR-23, a total of 13 symptoms were measured and categorically analyzed. There were no treatment differences in 7 of 13 symptom scales. EP was associated with worsening of 3 symptom scales: appetite loss, nausea/vomiting, and diarrhea. TPC was associated with worsening of 2 symptom scales: dyspnea and systemic side effects. Conclusions: In the phase 3 BEACON trial comparing EP to TPC, the more favorable toxicity profile of EP resulted in an improvement in global health status and physical function (results of the symptom scales confirmed the different toxicities of the two arms). EP remains a promising investigational therapy for aBC. Citation Format: Cortes J, Awada A, Perez EA, Rugo HS, Twelves C, Im S-A, Zhao C, Hoch U, Ney J, Hannah AL, O'Shaughnessy J. Impact of treatment on quality of life (QOL) in the BEACON study, a randomized phase III trial of etirinotecan pegol (EP) versus treatment of physician's choice (TPC) in patients (pts) with advanced breast cancer (aBC) whose disease has progressed following anthracycline (A), taxane (T) and capecitabine (C). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-11-08.
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- 2016
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31. P124 - Molecular determinants of the inherently slow entry of NKTR-181 into the brain
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Jonathan Zalevsky, Aleksandrs Odinecs, Stephen K. Doberstein, Werner Rubas, Myong Lee, Ute Hoch, Michael A. Eldon, and Laurie VanderVeen
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Pharmacology ,Pharmaceutical Science ,Pharmacology (medical) - Published
- 2020
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32. A First-in-Human Study and Biomarker Analysis of NKTR-214, a Novel IL2Rβγ-Biased Cytokine, in Patients with Advanced or Metastatic Solid Tumors
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Salah Eddine Bentebibel, Jonathan Zalevsky, Michael T. Tetzlaff, Ute Hoch, Michael E. Hurwitz, Nizar M. Tannir, Patrick Hwu, Sandra Aung, Chantale Bernatchez, Mario Sznol, Harriet M. Kluger, Christie Fanton, Courtney W. Hudgens, Mary Tagliaferri, Brendan D. Curti, Cara Haymaker, and Adi Diab
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0301 basic medicine ,Agonist ,medicine.drug_class ,medicine.medical_treatment ,chemical and pharmacologic phenomena ,Antineoplastic Agents ,CD8-Positive T-Lymphocytes ,Polyethylene Glycols ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Cell Line, Tumor ,Neoplasms ,Tumor Microenvironment ,Medicine ,Humans ,IL-2 receptor ,Tumor microenvironment ,business.industry ,Interleukin-2 Receptor alpha Subunit ,Immunotherapy ,030104 developmental biology ,Cytokine ,Treatment Outcome ,Oncology ,Tolerability ,030220 oncology & carcinogenesis ,Cancer research ,Interleukin-2 ,business ,CD8 ,Biomarkers ,Signal Transduction - Abstract
NKTR-214 (bempegaldesleukin) is a novel IL2 pathway agonist, designed to provide sustained signaling through heterodimeric IL2 receptor βγ to drive increased proliferation and activation of CD8+ T and natural killer cells without unwanted expansion of T regulatory cells (Treg) in the tumor microenvironment. In this first-in-human multicenter phase I study, NKTR-214 administered as an outpatient regimen was well tolerated and showed clinical activity including tumor shrinkage and durable disease stabilization in heavily pretreated patients. Immune activation and increased numbers of immune cells were observed in the periphery across all doses and cycles with no loss of NKTR-214 activity with repeated administration. On-treatment tumor biopsies demonstrated that NKTR-214 promoted immune cell increase with limited increase of Tregs. Transcriptional analysis of tumor biopsies showed that NKTR-214 engaged the IL2 receptor pathway and significantly increased genes associated with an effector phenotype. Based on safety and pharmacodynamic markers, the recommended phase II dose was determined to be 0.006 mg/kg every three weeks. Significance: We believe that IL2- and IL2 pathway–targeted agents such as NKTR-214 are key components to an optimal immunotherapy treatment algorithm. Based on its biological activity and tolerability, NKTR-214 is being studied with approved immuno-oncology agents including checkpoint inhibitors. See related commentary by Sullivan, p. 694. This article is highlighted in the In This Issue feature, p. 681
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- 2018
33. 33rd Annual Meeting & Pre-Conference Programs of the Society for Immunotherapy of Cancer (SITC 2018)
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Sekwon Jang, Scott S. Tykodi, Igor Puzanov, Fiore Cattaruzza, Ute Hoch, Alexander Spira, Ewa Kalinka Warzocha, Karl D. Lewis, Jonathan Zalevsky, Gregory A. Daniels, Mike Hurwitz, Brendan D. Curti, Dariusz Sawka, Alison L. Hannah, Mary Tagliaferri, Chantale Bernatchez, Wendy L. Clemens, Christie Fanton, Mario Sznol, Cara Haymaker, James Larkin, Adi Diab, Michael H. Wong, Michele Maio, Sandra Aung, Mehmet Asim Bilen, Giovanni Grignani, Daniel Cho, Salah Eddine Bentebibel, Ahsan Naqi Rizwan, Michael Imperiale, Ernesto Iaccucci, and Paul Lorigan
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Pharmacology ,Oncology ,0303 health sciences ,Cancer Research ,medicine.medical_specialty ,business.industry ,Immunology ,Immune monitoring ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Stage iv melanoma ,Molecular Medicine ,Immunology and Allergy ,Nivolumab ,business ,030304 developmental biology - Published
- 2018
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34. Abstract P3-10-03: Etirinotecan pegol target-specific pharmacodynamic biomarkers in circulating tumor cells from patients with metastatic breast cancer in the phase 3 BEACON study
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Alison L. Hannah, H Rugo, Katie Caygill, Edith A. Perez, Ahmad Awada, Chris Twelves, Kenna Anderes, Javier Cortes, Ute Hoch, Seock-Ah Im, Joyce A. O'Shaughnessy, and Darren W. Davis
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Oncology ,Cancer Research ,medicine.medical_specialty ,Pathology ,education.field_of_study ,medicine.diagnostic_test ,business.industry ,Population ,Phases of clinical research ,medicine.disease ,Metastatic breast cancer ,Circulating tumor cell ,Breast cancer ,Interquartile range ,Internal medicine ,Pharmacodynamics ,Biopsy ,medicine ,education ,business - Abstract
Background: Etirinotecan pegol (EP) is the first long-acting topoisomerase 1-inhibitor providing sustained level of active metabolite that concentrate in the tumor for an entire chemotherapy cycle. In a Phase 2 study (Lancet Oncology 2013), EP demonstrated a 29% overall response rate in patients with metastatic breast cancer, leading to the Phase 3 global BEACON study in this population. Detection of circulating tumor cells (CTCs) using immunomagnetic EpCAM-based methods have been conceptually accepted as a "liquid tumor biopsy". To circumvent the limited recovery of CTCs these methods provide for molecular profiling applications, we isolated CTCs based on an antibody-independent, continuous flow dielectrophoresis (DEP) technology (ApoStream®). We developed quantitative multiplex immunofluorescent assays for target-specific pharmacodynamics (PD) biomarkers for EP in CTCs isolated pre- and post-treatment. Here we present the distribution of the PD biomarkers in CTC samples collected from BEACON patients. Methods: Donation of blood samples for CTC analysis was voluntary. BEACON patients participating in the substudy had serial (pre-dose, Cycle 2 Day 1, Cycle 4 Day 1, End of Treatment) 7.5-mL whole blood samples drawn in EDTA tubes and shipped ambient to ApoCell (Houston, TX) within 96 hrs for processing. PBMCs were separated by Ficoll® gradient, and CTCs were isolated using ApoStream® technology. Isolated cells were deposited on three slides and stained for DAPI, CD45, and cytokeratin markers, as well as 2-3 of the seven PD markers, and analyzed by iCys® laser scanning cytometer equipped with image analysis software. CTC count, mean fluorescence intensity (MFI) of PD biomarkers, and % marker-positive cells were analyzed for their distribution. Results: 75% of the 852 BEACON patients participated in the CTC substudy, yielding 649 pre-treatment CTC samples. As of Mar14, 538 Cycle 2 Day 1, 281 Cycle 4 Day 1, and 394 End of Treatment samples were collected. 98% of pre-treatment blood samples were successfully processed. 97% had detectable CTCs, with a median of 504 CTCs (interquartile range: 128-1432). PD markers could be analyzed in 83-92% of samples after implementing a minimum requirement of 10 CTCs analyzed. Staining was positive for Top1, Top2, μH2Ax, Rad51, ABCG2, Ki67, and TUNEL in 82%, 71%, 14%, 30%, 20%, 56%, and 94% of samples, respectively. Percent of marker-positive cells varied from 0.2-69%, with 6- to 37-fold interquartile ranges. Median MFI in these cells varied between 25x103 and 100x103, with 1.2- to 1.6-fold interquartile ranges. Conclusions: CTC collection was successfully incorporated into the BEACON study, with 75% patient participation. CTC detection rate using ApoStream® was high, permitting evaluation of biomarkers at baseline and over time. EP target-specific PD biomarkers can be measured in CTCs isolated from patients participating in BEACON and will be assessed for their potential to predict clinical response. Final BEACON efficacy and safety results are expected in early 2015, which will allow further analysis of CTCs with patient outcome (response, PFS, OS) and change in CTCs at time of progression. Citation Format: Edith A Perez, Katie Caygill, Alison L Hannah, Javier Cortes, Ahmad Awada, Joyce O'Shaughnessy, Christopher Twelves, Hope Rugo, Seock-Ah Im, Kenna Anderes, Darren W Davis, Ute Hoch. Etirinotecan pegol target-specific pharmacodynamic biomarkers in circulating tumor cells from patients with metastatic breast cancer in the phase 3 BEACON study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-10-03.
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- 2015
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35. Change in Topoisomerase 1-Positive Circulating Tumor Cells Affects Overall Survival in Patients with Advanced Breast Cancer after Treatment with Etirinotecan Pegol
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Sherwin K. B. Sy, Deborah D.A. Zajchowski, Ahmad Awada, Javier Cortes, Seock–Ah –A Im, Ute Hoch, Edith A. Perez, Darren W. Davis, Mary Tagliaferri, Lin Lu, Hope S. Rugo, Joyce O'Shaughnessy, Alison L. Hannah, Chris Twelves, and Katie Caygill
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0301 basic medicine ,Oncology ,Adult ,Cancer Research ,medicine.medical_specialty ,Breast Neoplasms ,Kaplan-Meier Estimate ,Immunofluorescence ,Heterocyclic Compounds, 4 or More Rings ,Polyethylene Glycols ,03 medical and health sciences ,0302 clinical medicine ,Circulating tumor cell ,Internal medicine ,medicine ,Overall survival ,Humans ,Topoisomerase II Inhibitors ,Neoplasm Metastasis ,Aged ,Neoplasm Staging ,Aged, 80 and over ,biology ,medicine.diagnostic_test ,Proportional hazards model ,business.industry ,Topoisomerase ,Cancer ,Middle Aged ,medicine.disease ,Neoplastic Cells, Circulating ,Prognosis ,Metastatic breast cancer ,Molecular Imaging ,030104 developmental biology ,Treatment Outcome ,DNA Topoisomerases, Type I ,030220 oncology & carcinogenesis ,biology.protein ,Biomarker (medicine) ,Female ,business ,Biomarkers - Abstract
Purpose: Preplanned exploratory analyses were performed to identify biomarkers in circulating tumor cells (CTC) predictive of response to the topoisomerase 1 inhibitor etirinotecan pegol (EP). Experimental Design: The BEACON trial treated patients with metastatic breast cancer (MBC) with EP or treatment of physician's choice (TPC). Blood from 656 of 852 patients (77%) was processed with ApoStream to enrich for CTCs. A multiplex immunofluorescence assay measured expression of candidate response biomarkers [topoisomerase 1 (Top1), topoisomerase 2 (Top2), Ki67, RAD51, ABCG2, γH2AX, and terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling (TUNEL)] in CTCs. Patients were classified as Top1 low (Top1Lo) or Top1 high (Top1Hi) based on median CTC Top1 expression. Correlation of CTC biomarker expression at baseline, cycle 2 day 1 (C2D1), and cycle 4 day 1 with overall survival (OS) was investigated using Cox regression and Kaplan–Meier analyses. Results: Overall, 98% of samples were successfully processed, of which 97% had detectable CTCs (median, 47–63 CTCs/mL; range, 0–2,020 CTCs/mL). Top1, Top2, and TUNEL expression was detected in 52% to 90% of samples; no significant associations with OS were observed in pretreatment samples for either group. EP-treated patients with low C2D1Top1+ CTCs had improved OS compared with those with higher positivity (14.1 months vs. 11.0 months, respectively; HR, 0.7; P = 0.02); this difference was not seen in TPC-treated patients (HR, 1.12; P = 0.48). Patients whose CTCs decreased from Top1Hi to Top1Lo at C2D1 had the greatest OS benefit from EP (HR, 0.57; P = 0.01). Conclusions: CTC Top1 expression following EP treatment may identify patients with MBC most likely to have an OS benefit. Clin Cancer Res; 24(14); 3348–57. ©2018 AACR.
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- 2017
36. Health-related quality of life in patients with locally recurrent or metastatic breast cancer treated with etirinotecan pegol versus treatment of physician’s choice: Results from the randomised phase III BEACON trial
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Javier Cortes, Alison L. Hannah, Mary Tagliaferri, Hope S. Rugo, Ahmad Awada, David Potter, Chris Twelves, Edith A. Perez, Carol Zhao, Jin Seok Ahn, Ute Hoch, Patricia Gómez-Pardo, Seock–Ah –A Im, Audrey Mailliez, Lee S. Schwartzberg, Joyce O'Shaughnessy, Véronique Diéras, Denise A. Yardley, and Alvaro Moreno-Aspitia
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0301 basic medicine ,Oncology ,Cancer Research ,Lung Neoplasms ,Health Status ,Docetaxel ,Disease ,Deoxycytidine ,Polyethylene Glycols ,0302 clinical medicine ,Quality of life ,Sleep Initiation and Maintenance Disorders ,Activities of Daily Living ,Fatigue ,Aged, 80 and over ,Brain Neoplasms ,Liver Neoplasms ,Nausea ,Vinorelbine ,Cancer Pain ,Ketones ,Middle Aged ,Metastatic breast cancer ,humanities ,Anorexia ,Reproductive Health ,030220 oncology & carcinogenesis ,Advanced breast cancer ,Female ,Taxoids ,Etirinotecan pegol ,Adult ,medicine.medical_specialty ,Paclitaxel ,Anthracycline ,Vomiting ,NKTR-102 ,Antineoplastic Agents ,Bone Neoplasms ,Breast Neoplasms ,Vinblastine ,Heterocyclic Compounds, 4 or More Rings ,03 medical and health sciences ,Breast cancer ,Albumins ,Internal medicine ,Body Image ,medicine ,Humans ,Furans ,Aged ,Taxane ,business.industry ,Cancer ,medicine.disease ,Gemcitabine ,Cancérologie ,Dyspnea ,030104 developmental biology ,Epothilones ,Quality of Life ,Physical therapy ,business - Abstract
Background Health-related quality of life (HRQoL) enhances understanding of treatment effects that impact clinical decision-making. Although the primary end-point was not achieved, the BEACON (BrEAst Cancer Outcomes with NKTR-102) trial established etirinotecan pegol, a long-acting topoisomerase-1 (TOP1) inhibitor, as a promising therapeutic for patients with advanced/metastatic breast cancer (MBC) achieving clinically meaningful benefits in median overall survival (OS) for patients with stable brain metastases, with liver metastases or ≥ 2 sites of metastatic disease compared to treatment of physician's choice (TPC). Reported herein are the findings from the preplanned secondary end-point of HRQoL. Patients and methods HRQoL, assessed by European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) (version 3.0) supplemented by the breast cancer-specific Quality of Life Questionnaire (QLQ-BR23), was evaluated post randomisation in 733 of 852 patients with either anthracycline-, taxane- and capecitabine-pretreated locally recurrent or MBC randomised to etirinotecan pegol (n = 378; 145 mg/m2 every 3 weeks (q3wk)) or single-agent TPC (n = 355). Patients completed assessments at screening, every 8 weeks (q8wk) during treatment, and end-of-treatment. Changes from baseline were analysed, and the proportions of patients achieving differences (≥5 points) in HRQoL scores were compared. Results Differences were seen favouring etirinotecan pegol up to 32 weeks for global health status (GHS) and physical functioning scales (P, SCOPUS: ar.j, info:eu-repo/semantics/published
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- 2017
37. Erratum to: Prolonged survival in patients with breast cancer and a history of brain metastases: results of a preplanned subgroup analysis from the randomized phase III BEACON trial
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Mary Tagliaferri, Edith A. Perez, Ahmad Awada, Audrey Mailliez, Véronique Diéras, Denise A. Yardley, Patricia Gómez-Pardo, Javier Cortes, Alison L. Hannah, Lee S. Schwartzberg, Joyce O'Shaughnessy, Hope S. Rugo, Carol Zhao, David Potter, Jin Seok Ahn, Chris Twelves, Alvaro Moreno-Aspitia, Seock–Ah –A Im, and Ute Hoch
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Oncology ,Cancer Research ,medicine.medical_specialty ,Breast cancer ,business.industry ,Internal medicine ,medicine ,In patient ,Subgroup analysis ,Erratum ,business ,medicine.disease - Abstract
Conventional chemotherapy has limited activity in patients with breast cancer and brain metastases (BCBM). Etirinotecan pegol (EP), a novel long-acting topoisomerase-1 inhibitor, was designed using advanced polymer technology to preferentially accumulate in tumor tissue including brain metastases, providing sustained cytotoxic SN38 levels.The phase 3 BEACON trial enrolled 852 women with heavily pretreated locally recurrent or metastatic breast cancer between 2011 and 2013. BEACON compared EP with treatment of physician's choice (TPC; eribulin, vinorelbine, gemcitabine, nab-paclitaxel, paclitaxel, ixabepilone, or docetaxel) in patients previously treated with anthracycline, taxane, and capecitabine, including those with treated, stable brain metastases. The primary endpoint, overall survival (OS), was assessed in a pre-defined subgroup of BCBM patients; an exploratory post hoc analysis adjusting for the diagnosis-specific graded prognostic assessment (GPA) index was also conducted.In the trial, 67 BCBM patients were randomized (EP, n = 36; TPC, n = 31). Treatment subgroups were balanced for baseline characteristics and GPA indices. EP was associated with a significant reduction in the risk of death (HR 0.51; P 0.01) versus TPC; median OS was 10.0 and 4.8 months, respectively. Improvement in OS was observed in both poorer and better GPA prognostic groups. Survival rates at 12 months were 44.4% for EP versus 19.4% for TPC. Consistent with the overall BEACON population, fewer patients on EP experienced grade ≥3 toxicity (50 vs. 70%).The significant improvement in survival in BCBM patients provides encouraging data for EP in this difficult-to-treat subgroup of patients. A phase three trial of EP in BCBM patients is underway (ClinicalTrials.gov NCT02915744).
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- 2017
38. Modeling the receptor pharmacology, pharmacokinetics, and pharmacodynamics of NKTR-214, a kinetically-controlled interleukin-2 (IL2) receptor agonist for cancer immunotherapy
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Vidula Dixit, Michael A. Eldon, Ute Hoch, Jonathan Zalevsky, Stephen K. Doberstein, John L. Langowski, Samira Khalili, Deborah H. Charych, Peter Kirk, Thomas Chang, and Werner Rubas
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0301 basic medicine ,Receptor complex ,Physiology ,lcsh:Medicine ,CD8-Positive T-Lymphocytes ,Pharmacology ,Immune Receptors ,Biochemistry ,T-Lymphocytes, Regulatory ,Polyethylene Glycols ,White Blood Cells ,0302 clinical medicine ,Animal Cells ,Neoplasms ,Medicine and Health Sciences ,STAT5 Transcription Factor ,Tumor Microenvironment ,Cytotoxic T cell ,Prodrugs ,IL-2 receptor ,Post-Translational Modification ,Phosphorylation ,Receptor ,lcsh:Science ,Mice, Inbred BALB C ,Mice, Inbred C3H ,Immune System Proteins ,Multidisciplinary ,T Cells ,ZAP70 ,Chemical Reactions ,hemic and immune systems ,Regulatory T cells ,Body Fluids ,Cell biology ,Chemistry ,Blood ,030220 oncology & carcinogenesis ,Physical Sciences ,Female ,Immunotherapy ,Cellular Types ,Anatomy ,medicine.symptom ,Coreceptors ,Algorithms ,Research Article ,Signal Transduction ,Interleukin Receptor Common gamma Subunit ,Chemical Dissociation ,Immune Cells ,Immunology ,Cytotoxic T cells ,chemical and pharmacologic phenomena ,Biology ,Blood Plasma ,03 medical and health sciences ,In vivo ,Cell Line, Tumor ,medicine ,Animals ,Transplantation, Homologous ,Blood Cells ,lcsh:R ,Interleukin-2 Receptor alpha Subunit ,Biology and Life Sciences ,Proteins ,CD coreceptors ,Receptors, Interleukin-2 ,Cell Biology ,Pegylation ,Models, Theoretical ,T Cell Receptors ,Interleukin-2 Receptor beta Subunit ,Mice, Inbred C57BL ,Drug Liberation ,Kinetics ,stomatognathic diseases ,030104 developmental biology ,Mechanism of action ,PEGylation ,Interleukin-2 ,lcsh:Q - Abstract
Cytokines are potent immune modulating agents but are not ideal medicines in their natural form due to their short half-life and pleiotropic systemic effects. NKTR-214 is a clinical-stage biologic that comprises interleukin-2 (IL2) protein bound by multiple releasable polyethylene glycol (PEG) chains. In this highly PEG-bound form, the IL2 is inactive; therefore, NKTR-214 is a biologic prodrug. When administered in vivo, the PEG chains slowly release, creating a cascade of increasingly active IL2 protein conjugates bound by fewer PEG chains. The 1-PEG-IL2 and 2-PEG-IL2 species derived from NKTR-214 are the most active conjugated-IL2 species. Free-IL2 protein is undetectable in vivo as it is eliminated faster than formed. The PEG chains on NKTR-214 are located at the region of IL2 that contacts the alpha (α) subunit of the heterotrimeric IL2 receptor complex, IL2Rαβγ, reducing its ability to bind and activate the heterotrimer. The IL2Rαβγ complex is constitutively expressed on regulatory T cells (Tregs). Therefore, without the use of mutations, PEGylation reduces the affinity for IL2Rαβγ to a greater extent than for IL2Rβγ, the receptor complex predominant on CD8 T cells. NKTR-214 treatment in vivo favors activation of CD8 T cells over Tregs in the tumor microenvironment to provide anti-tumor efficacy in multiple syngeneic models. Mechanistic modeling based on in vitro and in vivo kinetic data provides insight into the mechanism of NKTR-214 pharmacology. The model reveals that conjugated-IL2 protein derived from NKTR-214 occupy IL-2Rβγ to a greater extent compared to free-IL2 protein. The model accurately describes the sustained in vivo signaling observed after a single dose of NKTR-214 and explains how the properties of NKTR-214 impart a unique kinetically-controlled immunological mechanism of action.
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- 2017
39. Nonclinical pharmacokinetics and activity of etirinotecan pegol (NKTR-102), a long-acting topoisomerase 1 inhibitor, in multiple cancer models
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Michael A. Eldon, Randall K. Johnson, Ute Hoch, and Carl-Michael Staschen
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Male ,Cancer Research ,Mice, Nude ,Antineoplastic Agents ,Mice, SCID ,Topoisomerase-I Inhibitor ,Pharmacology ,Irinotecan ,Toxicology ,Heterocyclic Compounds, 4 or More Rings ,Anticancer activity ,Polyethylene Glycols ,Rats, Sprague-Dawley ,Topoisomerase 1 inhibition ,Mice ,Dogs ,Species Specificity ,Pharmacokinetics ,medicine ,Animals ,Humans ,Pharmacology (medical) ,business.industry ,Neoplasms, Experimental ,Xenograft Model Antitumor Assays ,humanities ,Rats ,Etirinotecan pegol ,SN38 ,Treatment Outcome ,Long acting ,Oncology ,Pharmacodynamics ,Topoisomerase 1 inhibitor ,Original Article ,Camptothecin ,Female ,Topoisomerase I Inhibitors ,business ,medicine.drug - Abstract
Purpose The aim of the study was to demonstrate the activity of etirinotecan pegol, a polymer conjugate of irinotecan, in multiple human tumor models and to establish both the pharmacokinetic/pharmacodynamics (PK/PD) relationship and clinical relevance of the findings. Experimental design Anti-tumor activity was evaluated in mouse models of human lung, colorectal, breast, ovarian, and gastric cancers. Etirinotecan pegol was administered intravenously (once or every 3–7 days) to animals with established tumors. Activity was assessed by tumor growth delay (TGD) and regression. Mice bearing established colorectal and lung tumors were treated with etirinotecan pegol or irinotecan, and serial blood and tumor samples were collected at planned times between 0 and 60 days post-treatment for quantitation of etirinotecan pegol and SN38. For PK analysis, analyte concentration–time data were fit with compartmental models; PK/PD analysis was based on an inhibitory Emax response model. Results Etirinotecan pegol was active in all tumor models. TGD was sustained for 2–10 weeks after last dose, while conventional irinotecan resulted in little suppression of tumor growth. Etirinotecan pegol was eliminated very slowly from the tumor (t1/2 = 17 days), achieving higher and more sustained tumor exposure when compared with conventional irinotecan. The increased tumor exposure following etirinotecan pegol correlated with strong and prolonged suppression of tumor growth. Sustained plasma exposure to active SN38 was consistently observed across nonclinical species (including mouse, rat, and dog) and translated to cancer patients. Conclusions Etirinotecan pegol is the first long-acting topoisomerase 1 inhibitor that provides sustained exposure, which results in prolonged anti-tumor activity in a wide variety of cancer models. Electronic supplementary material The online version of this article (doi:10.1007/s00280-014-2577-7) contains supplementary material, which is available to authorized users.
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- 2014
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40. Baseline tumor-immune signatures associated with response to bempegaldesleukin (NKTR-214) and nivolumab
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Mario Sznol, Tuan Nguyen, Harriet M. Kluger, Daniel C. Cho, Arjun Vasant Balar, Michael E. Hurwitz, Mary Tagliaferri, Willem W. Overwijk, Brendan D. Curti, Ute Hoch, Yi Liu, Adi Diab, Christie Fanton, Arlene O. Siefker-Radtke, Chantale Bernatchez, Ernesto Iacucci, and Jonathan Zalevsky
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Agonist ,Oncology ,Cancer Research ,medicine.medical_specialty ,medicine.drug_class ,business.industry ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,In patient ,Nivolumab ,business ,030215 immunology - Abstract
2623 Background: PIVOT-02 is an ongoing phase 1/2 study of bempegaldesleukin (NKTR-214), a CD122-preferential IL-2 pathway agonist, plus nivolumab in patients with advanced solid tumors. Bempegaldesleukin (NKTR-214) increases proliferative tumor infiltrating lymphocytes (TIL) and cell surface PD-1 on immune cells and PD-L1 on tumor cells, demonstrating potential synergy with anti-PD-1 therapy. Pre-treatment tumor biopsies from metastatic 1L melanoma (MEL) and urothelial carcinoma (UC) patients were analyzed to correlate baseline immune phenotype to response. Methods: Pre-treatment TIL (CD8+ T cells/mm2 and %CD3+ by IHC; 29 MEL; 22 UC) were measured and divided into high and low groups based on median values. PD-L1 (% PD-L1 on tumor cells by IHC [28-8 PharmDx]; 33 MEL; 23 UC) was scored negative (2, respectively. Response rate correlations were 67% and 20% with IFNG high and low, 79% and 29% with CD3-TIL high and low, 79% and 33% with CD8-TIL high and low, and 68% and 43% with PD-L1 positive and negative. Most importantly, responses were observed in patients with the least favorable tumor microenvironment, characterized as both PD-L1 negative and TIL low, with responses of 17% (1/6 CD8-TIL), and 25% (2/8 CD3-TIL), respectively. Similar correlative trends were observed in UC, with 50% (4/8 CD8-TIL) and 38% (3/8 CD3-TIL) responses in patients with least favorable microenvironment. Conclusions: The biomarker program included in PIVOT-02 identified baseline immune signatures correlated with response for MEL and UC. The response rates observed in both the favorable and unfavorable tumor microenvironments indicate the potential of this combination and support its broad development. Clinical trial information: NCT02983045.
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- 2019
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41. Phase Ib: Preliminary clinical activity and immune activation for NKTR-262 [TLR 7/8 agonist] plus NKTR-214 [CD122-biased agonist] in patients (pts) with locally advanced or metastatic solid tumors (REVEAL Phase Ib/II Trial)
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Sandra P. D'Angelo, Shilpa Gupta, Brian Kotzin, Jonathan Zalevsky, Mario Q. Marcondes, Ute Hoch, Yunfeng Li, Evidio Domingo Musibay, Erkut Borazanci, Mary Tagliaferri, Fiore Cattaruzza, Brendan D. Curti, James Brugarolas, Mehmet Asim Bilen, Andrew S. Brohl, Anthony P. Conley, and Adi Diab
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Agonist ,Cancer Research ,business.industry ,medicine.drug_class ,Antigen presentation ,Prodrug ,Tumor antigen ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Medicine ,In patient ,business ,CD8 ,030215 immunology ,Immune activation - Abstract
26 Background: NKTR-262 is a novel intratumoral prodrug designed to promote tumor antigen release, an immune stimulatory environment, and antigen presentation. NKTR-214 increases CD8+ T cells and NK cells in the tumor microenvironment. The combination of NKTR-262 with NKTR-214 accesses innate and adaptive immunity to provide an abscopal response and systemic tumor immunity. The Phase 1b/2 REVEAL trial is enrolling. Methods: In a 3+3 Phase 1 design, pts who are relapsed/refractory to ≥1 CPI receive escalating doses of intratumoral (IT) NKTR-262 followed by combined q3w treatment of IT NKTR-262 and fixed-dose intravenous (IV) NKTR-214 (0.006 mg/kg). Phase 1 will evaluate PK, safety, efficacy, and determine recommended Phase 2 dose. Scans are conducted every 9 wks (± 1 wk). Peripheral blood (PB) and tumor tissue are collected to measure biomarkers of immune activation. In Phase 2 expansion, NKTR-262 + NKTR-214 ± IV nivolumab (360 mg) will be assessed in specific tumor cohorts of IO-naïve and experienced pts. Results: As of 06 Nov 2018, 11 pts had received at least one cycle of NKTR-262 + NKTR-214 therapy. 7/11 pts were efficacy evaluable with at least one on-treatment scan (4 MEL, 2 SARC, 1 CRC). 2/4 R/R melanoma pts had uPRs with 100% (scan 2) and 40% (scan 1) reductions in target lesions per RECIST 1.1, respectively. Both patients remain on treatment. Two SARC pts had stable disease at scan 1. No pts experienced G3 or higher TRAEs or immune-related adverse events (AEs). Most common G1-2 AEs were transient flu-like symptoms. Gene expression analysis of tumor and PB show dose-dependent induction (4 to 16-fold) of TLR target genes. Consistent with the mechanism of action for NKTR-214, PB flow cytometry shows an average 13-fold increase from baseline in Ki67+ CD8+T cells in 6 pts. Conclusions: NKTR-262 + NKTR-214 engage the immune activation cascade from local tumor antigen production to anti-tumor T cell response. Initial dose levels of NKTR-262 with fixed-dose NKTR-214 were well-tolerated with early evidence of clinical activity. These data support continued evaluation of the combination +/- nivolumab. Clinical trial information: NCT03435640.
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- 2019
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42. NKTR-214 + nivolumab in first-line advanced/metastatic urothelial carcinoma (mUC): Updated results from PIVOT-02
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Ahsan Naqi Rizwan, Arjun Vasant Balar, Giovanni Grignani, Mayer Fishman, Ute Hoch, Mehmet Asim Bilen, Alison L. Hannah, Jonathan Zalevsky, Jianjun Gao, Arlene O. Siefker-Radtke, Mary Tagliaferri, Adi Diab, and Erin E. Karski
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Cisplatin ,Oncology ,Cancer Research ,medicine.medical_specialty ,Metastatic Urothelial Carcinoma ,business.industry ,First line ,Immune checkpoint inhibitors ,Unmet needs ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Nivolumab ,business ,030215 immunology ,medicine.drug - Abstract
388 Background: Single-agent checkpoint inhibitors have changed the mUC treatment landscape; however, unmet need remains in first-line (1L) cisplatin ineligible mUC, particularly for PD-L1 negative (–) patients (pts). NKTR-214 is a CD122-biased agonist designed to provide sustained signaling through the IL-2 βγ receptor. PIVOT-02 is an ongoing study of NKTR-214 + nivolumab (nivo) in pts with advanced cancers, including mUC. Methods: Pts with mUC who were 1L cisplatin ineligible or refused standard of care (SOC) received NKTR-214 IV 0.006 mg/kg + nivo IV 360 mg q3w. Responses were assessed every 8 wks. Matched blood and tumor biopsies were evaluated for biomarkers including PD-L1 expression (assessed by Dako 28-8 PharmaDx IHC; PD-L1+ defined as ≥ 1% tumor cell staining). Results: As of 11 Oct. 2018, 34 pts received ≥ 1 dose of treatment (cisplatin ineligible [n=22]; refused SOC [n=12]). Median age was 70. Of 34 pts, 23 were efficacy evaluable (defined per protocol as having ≥ 1 post-treatment scan), 7 were pending a first scan, 1 pt was excluded for non-eligibility (no target lesion), and 3 discontinued prior to first scan. Thresholds for efficacy were exceeded in all 1L mUC cohorts under a pre-specified Fleming ORR analysis. In the efficacy evaluable population, overall ORR was 48% (11/23; 95% CI 27–69%) with a 17% CR rate (4/23) and 70% (16/23) DCR. The ORR was 50% in PD-L1– pts (5/10; 95% CI 19–81%) and 56% in PD-L1+ pts (5/9; 95% CI 21–86%). PD-L1 status was unknown in 4 efficacy-evaluable pts. The most common treatment-related AEs (TRAE, >30%) were fatigue (59%), pyrexia (38%), chills (32%), and flu-like symptoms (32%). Grade ≥ 3 TRAEs occurred in 18% of pts and 8.8% discontinued due to TRAEs. No G4/G5 TRAEs occurred. 22 pts had available baseline PD-L1 results (PD-L1+ [n=11]; PD-L1– [n=11]). 10 of the 11 PD-L1– baseline samples had matched wk 3 biopsies. Of these, 6/10 (60%) converted to PD-L1+ at wk 3. Updated results will be presented. Conclusions: NKTR-214 + nivo showed encouraging clinical activity, including CRs, and an acceptable preliminary safety profile in pts with mUC. Efficacy appears independent of PD-L1 status with a similar ORR in PD-L1– and + tumors. These data support further evaluation of the combination. Clinical trial information: NCT02983045.
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- 2019
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43. A Multicenter, Phase I, Dose-Escalation Study to Assess the Safety, Tolerability, and Pharmacokinetics of Etirinotecan Pegol in Patients with Refractory Solid Tumors
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Stephen P. Anthony, Daniel D. Von Hoff, Carlos Alemany, Erica White, Lee S. Rosen, Michael A Eldon, Robert A. Medve, Katrina Schroeder, Raoul Tibes, Allen Lee Cohn, Ioana Hinshaw, Ramesh K. Ramanathan, Glen J. Weiss, Robert M. Jotte, Gayle S. Jameson, John T. Hamm, Mitesh J. Borad, Michele Basche, and Ute Hoch
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Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Phases of clinical research ,Antineoplastic Agents ,Pharmacology ,Heterocyclic Compounds, 4 or More Rings ,Gastroenterology ,Drug Administration Schedule ,Article ,Polyethylene Glycols ,Pharmacokinetics ,Refractory ,Neoplasms ,Internal medicine ,medicine ,Clinical endpoint ,Humans ,Dosing ,Adverse effect ,Aged ,Aged, 80 and over ,business.industry ,Middle Aged ,Irinotecan ,Treatment Outcome ,Oncology ,Tolerability ,Female ,Topoisomerase I Inhibitors ,business ,medicine.drug - Abstract
Purpose: This study was designed to establish the maximum tolerated dose (MTD) and to evaluate tolerability, pharmacokinetics, and antitumor activity of etirinotecan pegol. Experimental Design: Patients with refractory solid malignancies were enrolled and assigned to escalating-dose cohorts. Patients received 1 infusion of etirinotecan pegol weekly 3 times every 4 weeks (w × 3q4w), or every 14 days (q14d), or every 21 days (q21d), with MTD as the primary end point using a standard 3 + 3 design. Results: Seventy-six patients were entered onto 3 dosing schedules (58–245 mg/m2). The MTD was 115 mg/m2 for the w × 3q4w schedule and 145 mg/m2 for both the q14d and q21d schedules. Most adverse events related to study drug were gastrointestinal disorders and were more frequent at higher doses of etirinotecan pegol. Late onset diarrhea was observed in some patients, the frequency of which generally correlated with dose density. Cholinergic diarrhea commonly seen with irinotecan treatment did not occur in patients treated with etirinotecan pegol. Etirinotecan pegol administration resulted in sustained and controlled systemic exposure to SN-38, which had a mean half-life of approximately 50 days. Overall, the pharmacokinetics of etirinotecan pegol are predictable and do not require complex dosing adjustments. Confirmed partial responses were observed in 8 patients with breast, colon, lung (small and squamous cell), bladder, cervical, and neuroendocrine cancer. Conclusion: Etirinotecan pegol showed substantial antitumor activity in patients with various solid tumors and a somewhat different safety profile compared with the irinotecan historical profile. The MTD recommended for phase II clinical trials is 145 mg/m2 q14d or q21d. Clin Cancer Res; 19(1); 268–78. ©2012 AACR.
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- 2013
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44. Safety and tolerability of etirinotecan pegol in advanced breast cancer: analysis of the randomized, phase 3 BEACON trial
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Ute Hoch, Alison L. Hannah, Ahmad Awada, Seock–Ah –A Im, Carol Zhao, Javier Cortes, Hope S. Rugo, Denise Tomkinson, Joyce O'Shaughnessy, Edith A. Perez, Chris Twelves, James Buchanan, and Mary Tagliaferri
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Anthracycline ,Population ,Clinical Trials and Supportive Activities ,Chemotherapy safety ,Neutropenia ,Capecitabine ,Vaccine Related ,03 medical and health sciences ,0302 clinical medicine ,Clinical Research ,Internal medicine ,Breast Cancer ,medicine ,education ,Cancer ,education.field_of_study ,Multidisciplinary ,Taxane ,business.industry ,Research ,Evaluation of treatments and therapeutic interventions ,medicine.disease ,Metastatic breast cancer ,Surgery ,030104 developmental biology ,Tolerability ,030220 oncology & carcinogenesis ,6.1 Pharmaceuticals ,Technologie de la sécurité ,Patient Safety ,Etirinotecan pegol ,business ,Chemotherapy side effects ,medicine.drug - Abstract
Purpose: New treatments with novel mechanisms of action and non-overlapping toxicities are needed for patients with metastatic breast cancer. Etirinotecan pegol (EP) is a long-acting topoisomerase-I inhibitor with a unique toxicity profile. The randomized phase 3 BEACON study that compared EP to treatment of physician’s choice (TPC) demonstrated its clinical activity. We now present detailed safety data from the BEACON trial. Methods: Patients with locally recurrent or metastatic breast cancer who had received at least two prior cytotoxic regimens for advanced disease were randomized to EP or TPC. Prior treatment with an anthracycline, a taxane and capecitabine was required. The frequencies of treatment-emergent AEs (TEAEs) and serious TEAEs were evaluated for the safety population, comprising all patients who received at least one dose of assigned treatment. Results: A total of 831 patients were evaluated (n = 425, EP; n = 406, TPC). Compared with TPC, EP was associated with a slightly higher median relative dose intensity (98.3 vs. 92.8 %, respectively) and significantly fewer grade ≥3 toxicities (48.0 vs. 63.1 %, P, SCOPUS: ar.j, info:eu-repo/semantics/published
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- 2016
45. 31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016): part two
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Casey Ager, Matthew Reilley, Courtney Nicholas, Todd Bartkowiak, Ashvin Jaiswal, Michael Curran, Tina C. Albershardt, Anshika Bajaj, Jacob F. Archer, Rebecca S. Reeves, Lisa Y. Ngo, Peter Berglund, Jan ter Meulen, Caroline Denis, Hormas Ghadially, Thomas Arnoux, Fabien Chanuc, Nicolas Fuseri, Robert W. Wilkinson, Nicolai Wagtmann, Yannis Morel, Pascale Andre, Michael B. Atkins, Matteo S. Carlino, Antoni Ribas, John A. Thompson, Toni K. Choueiri, F. Stephen Hodi, Wen-Jen Hwu, David F. McDermott, Victoria Atkinson, Jonathan S. Cebon, Bernie Fitzharris, Michael B. Jameson, Catriona McNeil, Andrew G. Hill, Eric Mangin, Malidi Ahamadi, Marianne van Vugt, Mariëlle van Zutphen, Nageatte Ibrahim, Georgina V. Long, Robyn Gartrell, Zoe Blake, Ines Simoes, Yichun Fu, Takuro Saito, Yingzhi Qian, Yan Lu, Yvonne M. Saenger, Sadna Budhu, Olivier De Henau, Roberta Zappasodi, Kyle Schlunegger, Bruce Freimark, Jeff Hutchins, Christopher A. Barker, Jedd D. Wolchok, Taha Merghoub, Elena Burova, Omaira Allbritton, Peter Hong, Jie Dai, Jerry Pei, Matt Liu, Joel Kantrowitz, Venus Lai, William Poueymirou, Douglas MacDonald, Ella Ioffe, Markus Mohrs, William Olson, Gavin Thurston, Cristian Capasso, Federica Frascaro, Sara Carpi, Siri Tähtinen, Sara Feola, Manlio Fusciello, Karita Peltonen, Beatriz Martins, Madeleine Sjöberg, Sari Pesonen, Tuuli Ranki, Lukasz Kyruk, Erkko Ylösmäki, Vincenzo Cerullo, Fabio Cerignoli, Biao Xi, Garret Guenther, Naichen Yu, Lincoln Muir, Leyna Zhao, Yama Abassi, Víctor Cervera-Carrascón, Mikko Siurala, João Santos, Riikka Havunen, Suvi Parviainen, Akseli Hemminki, Angus Dalgleish, Satvinder Mudan, Mark DeBenedette, Ana Plachco, Alicia Gamble, Elizabeth W. Grogan, John Krisko, Irina Tcherepanova, Charles Nicolette, Pooja Dhupkar, Ling Yu, Eugenie S. Kleinerman, Nancy Gordon, Italia Grenga, Lauren Lepone, Sofia Gameiro, Karin M. Knudson, Massimo Fantini, Kwong Tsang, James Hodge, Renee Donahue, Jeffrey Schlom, Elizabeth Evans, Holm Bussler, Crystal Mallow, Christine Reilly, Sebold Torno, Maria Scrivens, Cathie Foster, Alan Howell, Leslie Balch, Alyssa Knapp, John E. Leonard, Mark Paris, Terry Fisher, Siwen Hu-Lieskovan, Ernest Smith, Maurice Zauderer, William Fogler, Marilyn Franklin, Matt Thayer, Dan Saims, John L. Magnani, Jian Gong, Michael Gray, George Fromm, Suresh de Silva, Louise Giffin, Xin Xu, Jason Rose, Taylor H. Schreiber, Sofia R. Gameiro, Paul E. Clavijo, Clint T. Allen, James W. Hodge, Kwong Y. Tsang, Jane Grogan, Nicholas Manieri, Eugene Chiang, Patrick Caplazi, Mahesh Yadav, Patrick Hagner, Hsiling Chiu, Michelle Waldman, Anke Klippel, Anjan Thakurta, Michael Pourdehnad, Anita Gandhi, Ian Henrich, Laura Quick, Rob Young, Margaret Chou, Andrew Hotson, Stephen Willingham, Po Ho, Carmen Choy, Ginna Laport, Ian McCaffery, Richard Miller, Kimberly A. Tipton, Kenneth R. Wong, Victoria Singson, Chihunt Wong, Chanty Chan, Yuanhiu Huang, Shouchun Liu, Jennifer H. Richardson, W. Michael Kavanaugh, James West, Bryan A. Irving, Ritika Jaini, Matthew Loya, Charis Eng, Melissa L. Johnson, Alex A. Adjei, Mateusz Opyrchal, Suresh Ramalingam, Pasi A. Janne, George Dominguez, Dmitry Gabrilovich, Laura de Leon, Jeannette Hasapidis, Scott J. Diede, Peter Ordentlich, Scott Cruickshank, Michael L. Meyers, Matthew D. Hellmann, Pawel Kalinski, Amer Zureikat, Robert Edwards, Ravi Muthuswamy, Nataša Obermajer, Julie Urban, Lisa H. Butterfield, William Gooding, Herbert Zeh, David Bartlett, Olga Zubkova, Larissa Agapova, Marina Kapralova, Liudmila Krasovskaia, Armen Ovsepyan, Maxim Lykov, Artem Eremeev, Vladimir Bokovanov, Olga Grigoryeva, Andrey Karpov, Sergey Ruchko, Alexandr Shuster, Danny N. Khalil, Luis Felipe Campesato, Yanyun Li, Adam S. Lazorchak, Troy D. Patterson, Yueyun Ding, Pottayil Sasikumar, Naremaddepalli Sudarshan, Nagaraj Gowda, Raghuveer Ramachandra, Dodheri Samiulla, Sanjeev Giri, Rajesh Eswarappa, Murali Ramachandra, David Tuck, Timothy Wyant, Jasmin Leshem, Xiu-fen Liu, Tapan Bera, Masaki Terabe, Birgit Bossenmaier, Gerhard Niederfellner, Yoram Reiter, Ira Pastan, Leiming Xia, Yang Xia, Yangyang Hu, Yi Wang, Yangyi Bao, Fu Dai, Shiang Huang, Elaine Hurt, Robert E. Hollingsworth, Lawrence G. Lum, Alfred E. Chang, Max S. Wicha, Qiao Li, Thomas Mace, Neil Makhijani, Erin Talbert, Gregory Young, Denis Guttridge, Darwin Conwell, Gregory B. Lesinski, Rodney JM Macedo Gonzales, Austin P. Huffman, Ximi K. Wang, Ran Reshef, Andy MacKinnon, Jason Chen, Matt Gross, Gisele Marguier, Peter Shwonek, Natalija Sotirovska, Susanne Steggerda, Francesco Parlati, Amani Makkouk, Mark K. Bennett, Ethan Emberley, Tony Huang, Weiqun Li, Silinda Neou, Alison Pan, Jing Zhang, Winter Zhang, Netonia Marshall, Thomas U. Marron, Judith Agudo, Brian Brown, Joshua Brody, Christopher McQuinn, Matthew Farren, Hannah Komar, Reena Shakya, Thomas Ludwug, Y. Maurice Morillon, Scott A. Hammond, John W. Greiner, Pulak R. Nath, Anthony L. Schwartz, Dragan Maric, David D. Roberts, Aung Naing, Kyriakos P. Papadopoulos, Karen A. Autio, Deborah J. Wong, Manish Patel, Gerald Falchook, Shubham Pant, Patrick A. Ott, Melinda Whiteside, Amita Patnaik, John Mumm, Filip Janku, Ivan Chan, Todd Bauer, Rivka Colen, Peter VanVlasselaer, Gail L. Brown, Nizar M. Tannir, Martin Oft, Jeffrey Infante, Evan Lipson, Ajay Gopal, Sattva S. Neelapu, Philippe Armand, Stephen Spurgeon, John P. Leonard, Rachel E. Sanborn, Ignacio Melero, Thomas F. Gajewski, Matthew Maurer, Serena Perna, Andres A. Gutierrez, Raphael Clynes, Priyam Mitra, Satyendra Suryawanshi, Douglas Gladstone, Margaret K. Callahan, James Crooks, Sheila Brown, Audrey Gauthier, Marc Hillairet de Boisferon, Andrew MacDonald, Laura Rosa Brunet, William T. Rothwell, Peter Bell, James M. Wilson, Fumi Sato-Kaneko, Shiyin Yao, Shannon S. Zhang, Dennis A. Carson, Cristina Guiducci, Robert L. Coffman, Kazutaka Kitaura, Takaji Matsutani, Ryuji Suzuki, Tomoko Hayashi, Ezra E. W. Cohen, David Schaer, Yanxia Li, Julie Dobkin, Michael Amatulli, Gerald Hall, Thompson Doman, Jason Manro, Frank Charles Dorsey, Lillian Sams, Rikke Holmgaard, Krishnadatt Persaud, Dale Ludwig, David Surguladze, John S. Kauh, Ruslan Novosiadly, Michael Kalos, Kyla Driscoll, Hardev Pandha, Christy Ralph, Kevin Harrington, Brendan Curti, Wallace Akerley, Sumati Gupta, Alan Melcher, David Mansfield, David R. Kaufman, Emmett Schmidt, Mark Grose, Bronwyn Davies, Roberta Karpathy, Darren Shafren, Katerina Shamalov, Cyrille Cohen, Naveen Sharma, James Allison, Tala Shekarian, Sandrine Valsesia-Wittmann, Christophe Caux, Aurelien Marabelle, Brian M. Slomovitz, Kathleen M. Moore, Hagop Youssoufian, Marshall Posner, Poonam Tewary, Alan D. Brooks, Ya-Ming Xu, Kithsiri Wijeratne, Leslie A. A. Gunatilaka, Thomas J. Sayers, John P. Vasilakos, Tesha Alston, Simon Dovedi, James Elvecrog, Iwen Grigsby, Ronald Herbst, Karen Johnson, Craig Moeckly, Stefanie Mullins, Kristen Siebenaler, Julius SternJohn, Ashenafi Tilahun, Mark A. Tomai, Katharina Vogel, Eveline E. Vietsch, Anton Wellstein, Martin Wythes, Stefano Crosignani, Joseph Tumang, Shilpa Alekar, Patrick Bingham, Sandra Cauwenberghs, Jenny Chaplin, Deepak Dalvie, Sofie Denies, Coraline De Maeseneire, JunLi Feng, Kim Frederix, Samantha Greasley, Jie Guo, James Hardwick, Stephen Kaiser, Katti Jessen, Erick Kindt, Marie-Claire Letellier, Wenlin Li, Karen Maegley, Reece Marillier, Nichol Miller, Brion Murray, Romain Pirson, Julie Preillon, Virginie Rabolli, Chad Ray, Kevin Ryan, Stephanie Scales, Jay Srirangam, Jim Solowiej, Al Stewart, Nicole Streiner, Vince Torti, Konstantinos Tsaparikos, Xianxian Zheng, Gregory Driessens, Bruno Gomes, Manfred Kraus, Chunxiao Xu, Yanping Zhang, Giorgio Kradjian, Guozhong Qin, Jin Qi, Xiaomei Xu, Bo Marelli, Huakui Yu, Wilson Guzman, Rober Tighe, Rachel Salazar, Kin-Ming Lo, Jessie English, Laszlo Radvanyi, Yan Lan, Michael Postow, Yasin Senbabaoglu, Billel Gasmi, Hong Zhong, Cailian Liu, Daniel Hirschhorhn-Cymerman, Yuanyuan Zha, Gregory Malnassy, Noreen Fulton, Jae-Hyun Park, Wendy Stock, Yusuke Nakamura, Hongtao Liu, Xiaoming Ju, Rachelle Kosoff, Kimberly Ramos, Brandon Coder, Robert Petit, Michael Princiotta, Kyle Perry, Jun Zou, Ainhoa Arina, Christian Fernandez, Wenxin Zheng, Michael A. Beckett, Helena J. Mauceri, Yang-Xin Fu, Ralph R. Weichselbaum, Whitney Lewis, Yanyan Han, Yeting Wu, Chou Yang, Jing Huang, Dongyun Wu, Jin Li, Xiaoling Liang, Xiangjun Zhou, Jinlin Hou, Raffit Hassan, Thierry Jahan, Scott J. Antonia, Hedy L. Kindler, Evan W. Alley, Somayeh Honarmand, Weiqun Liu, Meredith L. Leong, Chan C. Whiting, Nitya Nair, Amanda Enstrom, Edward E. Lemmens, Takahiro Tsujikawa, Sushil Kumar, Lisa M. Coussens, Aimee L. Murphy, Dirk G. Brockstedt, Sven D. Koch, Martin Sebastian, Christian Weiss, Martin Früh, Miklos Pless, Richard Cathomas, Wolfgang Hilbe, Georg Pall, Thomas Wehler, Jürgen Alt, Helge Bischoff, Michael Geissler, Frank Griesinger, Jens Kollmeier, Alexandros Papachristofilou, Fatma Doener, Mariola Fotin-Mleczek, Madeleine Hipp, Henoch S. Hong, Karl-Josef Kallen, Ute Klinkhardt, Claudia Stosnach, Birgit Scheel, Andreas Schroeder, Tobias Seibel, Ulrike Gnad-Vogt, Alfred Zippelius, Ha-Ram Park, Yong-Oon Ahn, Tae Min Kim, Soyeon Kim, Seulki Kim, Yu Soo Lee, Bhumsuk Keam, Dong-Wan Kim, Dae Seog Heo, Shari Pilon-Thomas, Amy Weber, Jennifer Morse, Krithika Kodumudi, Hao Liu, John Mullinax, Amod A. Sarnaik, Luke Pike, Andrew Bang, Tracy Balboni, Allison Taylor, Alexander Spektor, Tyler Wilhite, Monica Krishnan, Daniel Cagney, Brian Alexander, Ayal Aizer, Elizabeth Buchbinder, Mark Awad, Leena Ghandi, Jonathan Schoenfeld, Elizabeth Lessey-Morillon, Lisa Ridnour, Neil H. Segal, Manish Sharma, Dung T. Le, Robert L. Ferris, Andrew D. Zelenetz, Ronald Levy, Izidore S. Lossos, Caron Jacobson, Radhakrishnan Ramchandren, John Godwin, A. Dimitrios Colevas, Roland Meier, Suba Krishnan, Xuemin Gu, Jaclyn Neely, John Timmerman, Claire I. Vanpouille-Box, Silvia C. Formenti, Sandra Demaria, Erik Wennerberg, Aranzazu Mediero, Bruce N. Cronstein, Michael P. Gustafson, AriCeli DiCostanzo, Courtney Wheatley, Chul-Ho Kim, Svetlana Bornschlegl, Dennis A. Gastineau, Bruce D. Johnson, Allan B. Dietz, Cameron MacDonald, Mark Bucsek, Guanxi Qiao, Bonnie Hylander, Elizabeth Repasky, William J. Turbitt, Yitong Xu, Andrea Mastro, Connie J. Rogers, Sita Withers, Ziming Wang, Lam T. Khuat, Cordelia Dunai, Bruce R. Blazar, Dan Longo, Robert Rebhun, Steven K. Grossenbacher, Arta Monjazeb, William J. Murphy, Scott Rowlinson, Giulia Agnello, Susan Alters, David Lowe, Nicole Scharping, Ashley V. Menk, Ryan Whetstone, Xue Zeng, Greg M. Delgoffe, Patricia M. Santos, Jian Shi, Greg Delgoffe, Misako Nagasaka, Ammar Sukari, Miranda Byrne-Steele, Wenjing Pan, Xiaohong Hou, Brittany Brown, Mary Eisenhower, Jian Han, Natalie Collins, Robert Manguso, Hans Pope, Yashaswi Shrestha, Jesse Boehm, W. Nicholas Haining, Kyle R. Cron, Ayelet Sivan, Keston Aquino-Michaels, Marco Orecchioni, Davide Bedognetti, Wouter Hendrickx, Claudia Fuoco, Filomena Spada, Francesco Sgarrella, Gianni Cesareni, Francesco Marincola, Kostas Kostarelos, Alberto Bianco, Lucia Delogu, Jessica Roelands, Sabri Boughorbel, Julie Decock, Scott Presnell, Ena Wang, Franco M. Marincola, Peter Kuppen, Michele Ceccarelli, Darawan Rinchai, Damien Chaussabel, Lance Miller, Andrew Nguyen, J. Zachary Sanborn, Charles Vaske, Shahrooz Rabizadeh, Kayvan Niazi, Steven Benz, Shashank Patel, Nicholas Restifo, James White, Sam Angiuoli, Mark Sausen, Sian Jones, Maria Sevdali, John Simmons, Victor Velculescu, Luis Diaz, Theresa Zhang, Jennifer S. Sims, Sunjay M. Barton, Angela Kadenhe-Chiweshe, Filemon Dela Cruz, Andrew T. Turk, Christopher F. Mazzeo, Andrew L. Kung, Jeffrey N. Bruce, Darrell J. Yamashiro, Eileen P. Connolly, Jason Baird, Marka Crittenden, David Friedman, Hong Xiao, Rom Leidner, Bryan Bell, Kristina Young, Michael Gough, Zhen Bian, Koby Kidder, Yuan Liu, Emily Curran, Xiufen Chen, Leticia P. Corrales, Justin Kline, Ethan G. Aguilar, Jennifer Guerriero, Alaba Sotayo, Holly Ponichtera, Alexandra Pourzia, Sara Schad, Ruben Carrasco, Suzan Lazo, Roderick Bronson, Anthony Letai, Richard S. Kornbluth, Sachin Gupta, James Termini, Elizabeth Guirado, Geoffrey W. Stone, Christina Meyer, Laura Helming, Nicholas Wilson, Robert Hofmeister, Natalie J. Neubert, Laure Tillé, David Barras, Charlotte Soneson, Petra Baumgaertner, Donata Rimoldi, David Gfeller, Mauro Delorenzi, Silvia A. Fuertes Marraco, Daniel E. Speiser, Tara S. Abraham, Bo Xiang, Michael S. Magee, Scott A. Waldman, Adam E. Snook, Wojciech Blogowski, Ewa Zuba-Surma, Marta Budkowska, Daria Salata, Barbara Dolegowska, Teresa Starzynska, Leo Chan, Srinivas Somanchi, Kelsey McCulley, Dean Lee, Nico Buettner, Feng Shi, Paisley T. Myers, Stuart Curbishley, Sarah A. Penny, Lora Steadman, David Millar, Ellen Speers, Nicola Ruth, Gabriel Wong, Robert Thimme, David Adams, Mark Cobbold, Remy Thomas, Mariam Al-Muftah, Michael KK Wong, Michael Morse, Joseph I. Clark, Howard L. Kaufman, Gregory A. Daniels, Hong Hua, Tharak Rao, Janice P. Dutcher, Kai Kang, Yogen Saunthararajah, Vamsidhar Velcheti, Vikas Kumar, Firoz Anwar, Amita Verma, Zinal Chheda, Gary Kohanbash, John Sidney, Kaori Okada, Shruti Shrivastav, Diego A. Carrera, Shuming Liu, Naznin Jahan, Sabine Mueller, Ian F. Pollack, Angel M. Carcaboso, Alessandro Sette, Yafei Hou, Hideho Okada, Jessica J. Field, Weiping Zeng, Vincent FS Shih, Che-Leung Law, Peter D. Senter, Shyra J. Gardai, Nicole M. Okeley, Jennifer G. Abelin, Abu Z. Saeed, Stacy A. Malaker, Jeffrey Shabanowitz, Stephen T. Ward, Donald F. Hunt, Pam Profusek, Laura Wood, Dale Shepard, Petros Grivas, Kerstin Kapp, Barbara Volz, Detlef Oswald, Burghardt Wittig, Manuel Schmidt, Julian P. Sefrin, Lars Hillringhaus, Valeria Lifke, Alexander Lifke, Anna Skaletskaya, Jose Ponte, Thomas Chittenden, Yulius Setiady, Eva Sivado, Vincent Thomas, Meddy El Alaoui, Sébastien Papot, Charles Dumontet, Mike Dyson, John McCafferty, Said El Alaoui, Praveen K. Bommareddy, Andrew Zloza, Frederick Kohlhapp, Ann W. Silk, Sachin Jhawar, Tomas Paneque, Jenna Newman, Pedro Beltran, Felicia Cao, Bang-Xing Hong, Tania Rodriguez-Cruz, Xiao-Tong Song, Stephen Gottschalk, Hugo Calderon, Sam Illingworth, Alice Brown, Kerry Fisher, Len Seymour, Brian Champion, Emma Eriksson, Jessica Wenthe, Ann-Charlotte Hellström, Gabriella Paul-Wetterberg, Angelica Loskog, Ioanna Milenova, Magnus Ståhle, Justyna Jarblad-Leja, Gustav Ullenhag, Anna Dimberg, Rafael Moreno, Ramon Alemany, Sharad Goyal, Ann Silk, Janice Mehnert, Nashat Gabrail, Jennifer Bryan, Daniel Medina, Leah Mitchell, Kader Yagiz, Fernando Lopez, Daniel Mendoza, Anthony Munday, Harry Gruber, Douglas Jolly, Steven Fuhrmann, Sasa Radoja, Wei Tan, Aldo Pourchet, Alan Frey, Ian Mohr, Matthew Mulvey, Robert H. I. Andtbacka, Merrick Ross, Sanjiv Agarwala, Kenneth Grossmann, Matthew Taylor, John Vetto, Rogerio Neves, Adil Daud, Hung Khong, Stephanie M. Meek, Richard Ungerleider, Scott Welden, Maki Tanaka, Matthew Williams, Sigrun Hallmeyer, Bernard Fox, Zipei Feng, Christopher Paustian, Carlo Bifulco, Sadia Zafar, Otto Hemminki, Simona Bramante, Lotta Vassilev, Hongjie Wang, Andre Lieber, Silvio Hemmi, Tanja de Gruijl, Anna Kanerva, Tameem Ansari, Srividya Sundararaman, Diana Roen, Paul Lehmann, Anja C. Bloom, Lewis H. Bender, Ian B. Walters, Jay A. Berzofsky, Fanny Chapelin, Eric T. Ahrens, Jeff DeFalco, Michael Harbell, Amy Manning-Bog, Alexander Scholz, Danhui Zhang, Gilson Baia, Yann Chong Tan, Jeremy Sokolove, Dongkyoon Kim, Kevin Williamson, Xiaomu Chen, Jillian Colrain, Gregg Espiritu Santo, Ngan Nguyen, Wayne Volkmuth, Norman Greenberg, William Robinson, Daniel Emerling, Charles G. Drake, Daniel P. Petrylak, Emmanuel S. Antonarakis, Adam S. Kibel, Nancy N. Chang, Tuyen Vu, Dwayne Campogan, Heather Haynes, James B. Trager, Nadeem A. Sheikh, David I. Quinn, Peter Kirk, Murali Addepalli, Thomas Chang, Ping Zhang, Marina Konakova, Katsunobu Hagihara, Steven Pai, Laurie VanderVeen, Palakshi Obalapur, Peiwen Kuo, Phi Quach, Lawrence Fong, Deborah H. Charych, Jonathan Zalevsky, John L. Langowski, Yolanda Kirksey, Ravi Nutakki, Shalini Kolarkar, Rhoneil Pena, Ute Hoch, Stephen K. Doberstein, John Cha, Zach Mallon, Myra Perez, Amanda McDaniel, Snjezana Anand, Darrin Uecker, Richard Nuccitelli, Eva Wieckowski, Ravikumar Muthuswamy, Roshni Ravindranathan, Ariana N. Renrick, Menaka Thounaojam, Portia Thomas, Samuel Pellom, Anil Shanker, Duafalia Dudimah, Alan Brooks, Yu-Lin Su, Tomasz Adamus, Qifang Zhang, Sergey Nechaev, Marcin Kortylewski, Spencer Wei, Clark Anderson, Chad Tang, Jonathan Schoenhals, Efrosini Tsouko, John Heymach, Patricia de Groot, Joe Chang, Kenneth R. Hess, Adi Diab, Padmanee Sharma, David Hong, James Welsh, Andrea J. Parsons, Jardin Leleux, Stephane Ascarateil, Marie Eve Koziol, Dina Bai, Peihong Dai, Weiyi Wang, Ning Yang, Stewart Shuman, Liang Deng, Patrick Dillon, Gina Petroni, David Brenin, Kim Bullock, Walter Olson, Mark E. Smolkin, Kelly Smith, Carmel Nail, Craig L. Slingluff, Meenu Sharma, Faisal Fa’ak, Louise Janssen, Hiep Khong, Zhilan Xiao, Yared Hailemichael, Manisha Singh, Christina Vianden, Willem W. Overwijk, Andrea Facciabene, Pierini Stefano, Fang Chongyung, Stavros Rafail, Michael Nielsen, Peter Vanderslice, Darren G. Woodside, Robert V. Market, Ronald J. Biediger, Upendra K. Marathi, Kevin Hollevoet, Nick Geukens, Paul Declerck, Nathalie Joly, Laura McIntosh, Eustache Paramithiotis, Magnus Rizell, Malin Sternby, Bengt Andersson, Alex Karlsson-Parra, Rui Kuai, Lukasz Ochyl, Anna Schwendeman, James Moon, Weiwen Deng, Thomas E. Hudson, Bill Hanson, Chris S. Rae, Joel Burrill, Justin Skoble, George Katibah, Michele deVries, Peter Lauer, Thomas W. Dubensky, Xin Chen, Li Zhou, Xiubao Ren, Charu Aggarwal, Drishty Mangrolia, Roger Cohen, Gregory Weinstein, Matthew Morrow, Joshua Bauml, Kim Kraynyak, Jean Boyer, Jian Yan, Jessica Lee, Laurent Humeau, Sandra Oyola, Susan Duff, David Weiner, Zane Yang, Mark Bagarazzi, Douglas G. McNeel, Jens Eickhoff, Robert Jeraj, Mary Jane Staab, Jane Straus, Brian Rekoske, Glenn Liu, Marit Melssen, William Grosh, Nikole Varhegyi, Nadejda Galeassi, Donna H. Deacon, Elizabeth Gaughan, Maurizio Ghisoli, Minal Barve, Robert Mennel, Gladice Wallraven, Luisa Manning, Neil Senzer, John Nemunaitis, Masahiro Ogasawara, Shuichi Ota, Kaitlin M. Peace, Diane F. Hale, Timothy J. Vreeland, Doreen O. Jackson, John S. Berry, Alfred F. Trappey, Garth S. Herbert, Guy T. Clifton, Mark O. Hardin, Anne Toms, Na Qiao, Jennifer Litton, George E. Peoples, Elizabeth A. Mittendorf, Lila Ghamsari, Emilio Flano, Judy Jacques, Biao Liu, Jonathan Havel, Vladimir Makarov, Timothy A. Chan, Jessica B. Flechtner, John Facciponte, Stefano Ugel, Francesco De Sanctis, George Coukos, Sébastien Paris, Agnes Pottier, Laurent Levy, Bo Lu, Federica Cappuccini, Emily Pollock, Richard Bryant, Freddie Hamdy, Adrian Hill, Irina Redchenko, Hussein Sultan, Takumi Kumai, Valentyna Fesenkova, Esteban Celis, Ingrid Fernando, Claudia Palena, Justin M. David, Elizabeth Gabitzsch, Frank Jones, James L. Gulley, Mireia Uribe Herranz, Hiroshi Wada, Atsushi Shimizu, Toshihiro Osada, Satoshi Fukaya, Eiji Sasaki, Milad Abolhalaj, David Askmyr, Kristina Lundberg, Ann-Sofie Albrekt, Lennart Greiff, Malin Lindstedt, Dallas B. Flies, Tomoe Higuchi, Wojciech Ornatowski, Jaryse Harris, Sarah F. Adams, Todd Aguilera, Marjan Rafat, Laura Castellini, Hussein Shehade, Mihalis Kariolis, Dadi Jang, Rie vonEbyen, Edward Graves, Lesley Ellies, Erinn Rankin, Albert Koong, Amato Giaccia, Reham Ajina, Shangzi Wang, Jill Smith, Mariaelena Pierobon, Sandra Jablonski, Emanuel Petricoin, Louis M. Weiner, Lorcan Sherry, John Waller, Mark Anderson, Alison Bigley, Chantale Bernatchez, Cara Haymaker, Harriet Kluger, Michael Tetzlaff, Natalie Jackson, Ivan Gergel, Mary Tagliaferri, Patrick Hwu, Mario Snzol, Michael Hurwitz, Theresa Barberi, Allison Martin, Rahul Suresh, David Barakat, Sarah Harris-Bookman, Charles Drake, Alan Friedman, Sara Berkey, Stephanie Downs-Canner, Robert P. Edwards, Tyler Curiel, Kunle Odunsi, Tullia C. Bruno, Brandon Moore, Olivia Squalls, Peggy Ebner, Katherine Waugh, John Mitchell, Wilbur Franklin, Daniel Merrick, Martin McCarter, Brent Palmer, Jeffrey Kern, Dario Vignali, Jill Slansky, Anissa S. H. Chan, Xiaohong Qiu, Kathryn Fraser, Adria Jonas, Nadine Ottoson, Keith Gordon, Takashi O. Kangas, Steven Leonardo, Kathleen Ertelt, Richard Walsh, Mark Uhlik, Jeremy Graff, Nandita Bose, Ravi Gupta, Nitin Mandloi, Kiran Paul, Ashwini Patil, Rekha Sathian, Aparna Mohan, Malini Manoharan, Amitabha Chaudhuri, Yu Chen, Jing Lin, Yun-bin Ye, Chun-wei Xu, Gang Chen, Zeng-qing Guo, Andrey Komarov, Alex Chenchik, Michael Makhanov, Costa Frangou, Yi Zheng, Carla Coltharp, Darryn Unfricht, Ryan Dilworth, Leticia Fridman, Linying Liu, Milind Rajopadhye, Peter Miller, Fernando Concha-Benavente, Julie Bauman, Sumita Trivedi, Raghvendra Srivastava, James Ohr, Dwight Heron, Uma Duvvuri, Seungwon Kim, Heather Torrey, Toshi Mera, Yoshiaki Okubo, Eva Vanamee, Rosemary Foster, Denise Faustman, Edward Stack, Daisuke Izaki, Kristen Beck, Dan Tong Jia, Paul Armenta, Ashley White-Stern, Douglas Marks, Bret Taback, Basil Horst, Laura Hix Glickman, David B. Kanne, Kelsey S. Gauthier, Anthony L. Desbien, Brian Francica, Justin L. Leong, Leonard Sung, Ken Metchette, Shailaja Kasibhatla, Anne Marie Pferdekamper, Lianxing Zheng, Charles Cho, Yan Feng, Jeffery M. McKenna, John Tallarico, Steven Bender, Chudi Ndubaku, Sarah M. McWhirter, Elena Gonzalez Gugel, Charles J. M. Bell, Adiel Munk, Luciana Muniz, Nina Bhardwaj, Fei Zhao, Kathy Evans, Christine Xiao, Alisha Holtzhausen, Brent A. Hanks, Nathalie Scholler, Catherine Yin, Pien Van der Meijs, Andrew M. Prantner, Cecile M. Krejsa, Leia Smith, Brian Johnson, Daniel Branstetter, Paul L. Stein, Juan C. Jaen, Joanne BL Tan, Ada Chen, Timothy Park, Jay P. Powers, Holly Sexton, Guifen Xu, Steve W. Young, Ulrike Schindler, Wentao Deng, David John Klinke, Hannah M. Komar, Gregory Serpa, Omar Elnaggar, Philip Hart, Carl Schmidt, Mary Dillhoff, Ming Jin, Michael C. Ostrowski, Madhuri Koti, Katrina Au, Nichole Peterson, Peter Truesdell, Gillian Reid-Schachter, Charles Graham, Andrew Craig, Julie-Ann Francis, Beatrix Kotlan, Timea Balatoni, Emil Farkas, Laszlo Toth, Mihaly Ujhelyi, Akos Savolt, Zoltan Doleschall, Szabolcs Horvath, Klara Eles, Judit Olasz, Orsolya Csuka, Miklos Kasler, Gabriella Liszkay, Eytan Barnea, Collin Blakely, Patrick Flynn, Reid Goodman, Raphael Bueno, David Sugarbaker, David Jablons, V. Courtney Broaddus, Brian West, Paul R. Kunk, Joseph M. Obeid, Kevin Winters, Patcharin Pramoonjago, Edward B. Stelow, Todd W. Bauer, Osama E. Rahma, Adam Lamble, Yoko Kosaka, Fei Huang, Kate A. Saser, Homer Adams, Christina E. Tognon, Ted Laderas, Shannon McWeeney, Marc Loriaux, Jeffery W. Tyner, Brian J. Druker, Evan F. Lind, Zhuqing Liu, Shanhong Lu, Lawrence P. Kane, Gulidanna Shayan, Julia Femel, Ryan Lane, Jamie Booth, Amanda W. Lund, Anthony Rodriguez, Victor H. Engelhard, Alessandra Metelli, Bill X. Wu, Caroline W. Fugle, Rachidi Saleh, Shaoli Sun, Jennifer Wu, Bei Liu, Zihai Li, Zachary S. Morris, Emily I. Guy, Clinton Heinze, Jasdeep Kler, Monica M. Gressett, Lauryn R. Werner, Stephen D. Gillies, Alan J. Korman, Hans Loibner, Jacquelyn A. Hank, Alexander L. Rakhmilevich, Paul M. Harari, Paul M. Sondel, Erica Huelsmann, Joseph Broucek, Dorothee Brech, Tobias Straub, Martin Irmler, Johannes Beckers, Florian Buettner, Elke Schaeffeler, Matthias Schwab, Elfriede Noessner, Alison Wolfreys, Andre Da Costa, John Silva, Andrea Crosby, Ludovicus Staelens, Graham Craggs, Annick Cauvin, Sean Mason, Alison M. Paterson, Andrew C. Lake, Caroline M. Armet, Rachel W. O’Connor, Jonathan A. Hill, Emmanuel Normant, Ammar Adam, Detlev M. Biniszkiewicz, Scott C. Chappel, Vito J. Palombella, Pamela M. Holland, Annette Becker, Manmohan R. Leleti, Eric Newcomb, Joanne B. L. Tan, Suthee Rapisuwon, Arash Radfar, Kellie Gardner, Geoffrey Gibney, Michael Atkins, Keith R. Rennier, Robert Crowder, Ping Wang, Russell K. Pachynski, Rosa M. Santana Carrero, Sarai Rivas, Figen Beceren-Braun, Scott Anthony, Kimberly S. Schluns, Deepali Sawant, Maria Chikina, Hiroshi Yano, Creg Workman, Elise Salerno, Ileana Mauldin, Donna Deacon, Sofia Shea, Joel Pinczewski, Thomas Gajewski, Stefani Spranger, Brendan Horton, Akiko Suzuki, Pamela Leland, Bharat H. Joshi, Raj K. Puri, Randy F. Sweis, Riyue Bao, Jason Luke, Marie-Nicole Theodoraki, Frances-Mary Mogundo, Haejung Won, Dayson Moreira, Chan Gao, Xingli Zhao, Priyanka Duttagupta, Jeremy Jones, Massimo D’Apuzzo, and Sumanta Pal
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0301 basic medicine ,Pharmacology ,Cancer Research ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Immunology ,Cancer ,Immunotherapy ,medicine.disease ,3. Good health ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,Family medicine ,Molecular Medicine ,Immunology and Allergy ,Medicine ,business - Abstract
O1 IL-15 primes an mTOR-regulated gene-expression program to prolong anti-tumor capacity of human natural killer cells #### Andreas Lundqvist1, Vincent van Hoef1, Xiaonan Zhang1, Erik Wennerberg2, Julie Lorent1, Kristina Witt1, Laia Masvidal Sanz1, Shuo Liang1, Shannon Murray3, Ola Larsson1
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- 2016
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46. NKTR-214, an Engineered Cytokine with Biased IL2 Receptor Binding, Increased Tumor Exposure, and Marked Efficacy in Mouse Tumor Models
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Rhoneil Pena, Seema S. Kantak, Stephen Doberstein, Yolanda Kirksey, Marina Konakova, Paul Sims, Jicai Huang, Yujun Wang, Murali Addepalli, Peter Kirk, Chunmei Ji, Dawei Sheng, Chang Thomas, Laurie Vanderveen, Cherie F. Ali, Ute Hoch, Theresa D. Sweeney, Xiaofeng Liu, Deborah H. Charych, Steve R. Lee, John L. Langowski, and Rupesh S. Kanhere
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0301 basic medicine ,Male ,Models, Molecular ,Cancer Research ,medicine.medical_treatment ,Recombinant Fusion Proteins ,Melanoma, Experimental ,Molecular Conformation ,chemical and pharmacologic phenomena ,Antineoplastic Agents ,Biology ,Pharmacology ,CD8-Positive T-Lymphocytes ,T-Lymphocytes, Regulatory ,Polyethylene Glycols ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Lymphocytes, Tumor-Infiltrating ,In vivo ,Aldesleukin ,Cell Line, Tumor ,Neoplasms ,medicine ,Animals ,Humans ,CTLA-4 Antigen ,Prodrugs ,IL-2 receptor ,Melanoma ,Cancer ,FOXP3 ,Drug Synergism ,Receptors, Interleukin-2 ,Immunotherapy ,medicine.disease ,Recombinant Proteins ,Tumor Burden ,Disease Models, Animal ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Interleukin-2 ,Female ,Immunologic Memory ,CD8 ,Protein Binding - Abstract
Purpose: Aldesleukin, recombinant human IL2, is an effective immunotherapy for metastatic melanoma and renal cancer, with durable responses in approximately 10% of patients; however, severe side effects limit maximal dosing and thus the number of patients able to receive treatment and potential cure. NKTR-214 is a prodrug of conjugated IL2, retaining the same amino acid sequence as aldesleukin. The IL2 core is conjugated to 6 releasable polyethylene glycol (PEG) chains. In vivo, the PEG chains slowly release to generate active IL2 conjugates. Experimental Design: We evaluated the bioactivity and receptor binding of NKTR-214 and its active IL2 conjugates in vitro; the tumor immunology, tumor pharmacokinetics, and efficacy of NKTR-214 as a single agent and in combination with anti–CTLA-4 antibody in murine tumor models. Tolerability was evaluated in non-human primates. Results: In a murine melanoma tumor model, the ratio of tumor-killing CD8+ T cells to Foxp3+ regulatory T cells was greater than 400 for NKTR-214 compared with 18 for aldesleukin, supporting preferential activation of the IL2 receptor beta over IL2 receptor alpha, due to the location of PEG molecules. NKTR-214 provides a 500-fold greater exposure of the tumor to conjugated IL2 compared with aldesleukin. NKTR-214 showed efficacy as a single agent and provided durable immunity that was resistant to tumor rechallenge in combination with anti–CTLA-4 antibody. NKTR-214 was well tolerated in non-human primates. Conclusions: These data support further evaluation of NKTR-214 in humans for a variety of tumor types, adding to the repertoire of potent and potentially curative cancer immunotherapies. Clin Cancer Res; 22(3); 680–90. ©2016 AACR.
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- 2016
47. Abstract P3-06-31: Etirinotecan pegol in patients with metastatic breast cancer (mBC): Modeling CA27.29 response and its correlation with tumor response
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Alison L. Hannah, Michael A. Eldon, Ute Hoch, and YL Chia
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Oncology ,Cancer Research ,medicine.medical_specialty ,Taxane ,business.industry ,Cancer ,Phases of clinical research ,medicine.disease ,Metastatic breast cancer ,Surgery ,Pharmacokinetics ,Tumor progression ,Internal medicine ,medicine ,Dosing ,business ,Tumor marker - Abstract
Background: Etirinotecan pegol (NKTR-102) is a unique topoisomerase 1 inhibitor that provides continuous exposure to SN38. In a Phase 2 study in pts with mBC whose disease had failed prior taxane-based treatment (Tx) etirinotecan pegol given q14d or q21d demonstrated a 29% overall response rate (J Clin Oncol 29: 2011 (suppl; abstr 1034)). Here we present the relationship between the dynamics of serum tumor marker CA27.29, etirinotecan pegol pharmacokinetics, and tumor response. Methods: Data from 45 pts with at least two CA27.29 measurements (pre- & post-first dose), were fitted with a PK/PD model developed to correlate CA27.29 dynamics with SN38 exposure predicted from individual pt dosing history: d[CA27.29]/dt = Kin*exp(beta*t)*(1−[SN38]/(IC50+[SN38]))-Kout*[CA27.29]. Correlation of CA27.29 and RECIST response was investigated; % change of CA27.29 from baseline was also correlated with progression-free survival (PFS). Results: CA27.29 vs time profiles were well described by the model, with a population mean plasma SN38 IC50 of 1.6 ng/mL. Typical minimum/maximum SN38 concentrations during Tx were 1.5/ 3 ng/mL for q14d and 0.9/ 2.4 ng/mL for q21d, indicating that both schedules resulted in SN38 exposure near the IC50. The half-life of CA27.29 decline was 15 days. 41 pts had pre- and post-Tx tumor measurements for correlation of CA27.29 response with tumor size. Of the 15 pts with RECIST CR or PR, 14 (93%) exhibited at least 10% declines in CA27.29 during Tx; all 5 pts with RECIST SD ≥ 6 months (mths) also manifested ≥10% declines, whereas only 45% (5/11) of pts with SD < 6 mths showed ≥10% decline in CA27.29. Among the 10 pts with RECIST progressive disease (PD), 80% showed ≥10% CA27.29 elevations during Tx. The median maximum % reduction in observed CA27.29 from baseline during the course of Tx ranged from −55% to +30% and correlated with responder status as tabulated below. To investigate whether response in CA27.29 can serve as early indicator of Tx outcome, we assessed the impact of a reduction of ≥25% after 6 weeks (wks) of Tx (2 or 3 Tx cycles for q21d and q14d schedules, respectively) on PFS. Among the 26 pts who had not had tumor progression or discontinued Tx by wk 6, median PFS for pts with ≥ 25% reduction in CA27.29 (n = 9) was 12 mths. Pts with Conclusions: The PK/PD model described CA27.29 dynamics well and provides a tool to predict response based on etirinotecan pegol pharmacokinetic data. 25% reduction in CA27.29 at wk 6, may constitute an early marker for Tx response to etirinotecan pegol. A Phase 3 global pivotal study (BEACON) utilizing the q21 day dosing schedule is underway in pts with advanced breast cancer. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-06-31.
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- 2012
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48. Discovery and Development of Potent LFA-1/ICAM-1 Antagonist SAR 1118 as an Ophthalmic Solution for Treating Dry Eye
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Marc J. Evanchik, Thomas R. Gadek, Jeffrey A. Silverman, Minna Bui, Michelle R. Arkin, John Burnier, Ute Hoch, Wang Shen, Min Zhong, Johan D. Oslob, Hanan Emily, Chul Yu, Jasmin Wright, Saileta Prabhu, W. Mike Flanagan, Jiang Zhu, Kenneth J. Barr, and Jennifer Hyde
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ICAM-1 ,business.industry ,Organic Chemistry ,Antigen presentation ,Antagonist ,Pharmacology ,Biochemistry ,Leukocyte extravasation ,Immunological synapse ,Immune system ,THIQ ,Drug Discovery ,medicine ,business ,Cell adhesion ,medicine.drug - Abstract
LFA-1/ICAM-1 interaction is essential in support of inflammatory and specific T-cell regulated immune responses by mediating cell adhesion, leukocyte extravasation, migration, antigen presentation, formation of immunological synapse, and augmentation of T-cell receptor signaling. The increase of ICAM-1 expression levels in conjunctival epithelial cells and acinar cells was observed in animal models and patients diagnosed with dry eye. Therefore, it has been hypothesized that small molecule LFA-1/ICAM-1 antagonists could be an effective topical treatment for dry eye. In this letter, we describe the discovery of a potent tetrahydroisoquinoline (THIQ)-derived LFA-1/ICAM-1 antagonist (SAR 1118) and its development as an ophthalmic solution for treating dry eye.
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- 2012
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49. PIVOT-02: A phase 1/2, open-label, multicenter, dose escalation and dose expansion study of NKTR-214 and nivolumab in patients with select, locally advanced or metastatic solid tumor malignancies
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Mario Sznol, M. Wong, Brendan D. Curti, Mary Tagliaferri, Cara Haymaker, Adi Diab, Chantale Bernatchez, I. Gergel, H. Kluger, Michael E. Hurwitz, Daniel C. Cho, Nizar M. Tannir, Salah-Eddine Bentebibel, Scott S. Tykodi, Sandra Aung, Igor Puzanov, Ute Hoch, Jonathan Zalevsky, M. Imperiale, and Patrick Hwu
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,business.industry ,Locally advanced ,Cancer ,Hematology ,medicine.disease ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Dose escalation ,In patient ,Nivolumab ,Open label ,business ,Solid tumor - Published
- 2017
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50. Structure–activity relationship (SAR) of the α-amino acid residue of potent tetrahydroisoquinoline (THIQ)-derived LFA-1/ICAM-1 antagonists
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Michelle R. Arkin, Ute Hoch, Minna Bui, Jennifer Hyde, Kumar Paulvannan, Kenneth J. Barr, Jasmin Wright, Saileta Prabhu, Jose R. Martell, Johan D. Oslob, Marc J. Evanchik, Jeffrey A. Silverman, Jiang Zhu, Wang Shen, Hanan Emily, W. Mike Flanagan, Chul Yu, and Min Zhong
- Subjects
Male ,Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Biochemistry ,Rats, Sprague-Dawley ,Structure-Activity Relationship ,chemistry.chemical_compound ,Residue (chemistry) ,Tetrahydroisoquinolines ,Drug Discovery ,medicine ,Animals ,Structure–activity relationship ,Moiety ,Potency ,Amino Acids ,Amino acid residue ,Molecular Biology ,ICAM-1 ,Chemistry ,Tetrahydroisoquinoline ,Organic Chemistry ,Intercellular Adhesion Molecule-1 ,Lymphocyte Function-Associated Antigen-1 ,Rats ,THIQ ,beta-Alanine ,Molecular Medicine ,medicine.drug - Abstract
This letter describes the structure-activity relationship (SAR) of the 'right-wing' α-amino acid residue of potent tetrahydroisoquinoline (THIQ)-derived LFA-1/ICAM-1 antagonists. Novel (S)-substituted heteroaryl-bearing α-amino acids have been identified as replacements of the 'right-wing' (S)-2,3-diaminopropanoic acid (DAP) moiety. Improvement of potency in the Hut-78 assay in the presence of 10% human serum has also been achieved.
- Published
- 2011
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