15 results on '"Erin E, Karski"'
Search Results
2. Universal Updated Phase 1 Data Highlights Role of Allogeneic Anti-BCMA ALLO-715 Therapy for Relapsed/Refractory Multiple Myeloma
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Sham Mailankody, Jeffrey V. Matous, Michaela Liedtke, Surbhi Sidana, Olalekan O. Oluwole, Meera Mohan, Jose C. Cruz, Rajneesh Nath, Faiz Anwer, Adriana Rossi, Myo Htut, Shahbaz A. Malik, Srinivas Ghatta, Myles Dillon, Wendy Ying, Lynn Navale, Erin E. Karski, Arun Balakumaran, and Shaji K. Kumar
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
3. Publisher Correction: Allogeneic BCMA-targeting CAR T cells in relapsed/refractory multiple myeloma: phase 1 UNIVERSAL trial interim results
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Sham Mailankody, Jeffrey V. Matous, Saurabh Chhabra, Michaela Liedtke, Surbhi Sidana, Olalekan O. Oluwole, Shahbaz Malik, Rajneesh Nath, Faiz Anwer, Jose Carlos Cruz, Myo Htut, Erin E. Karski, Wade Lovelace, Myles Dillon, Eric Butz, Wendy Ying, Arun Balakumaran, and Shaji K. Kumar
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General Medicine ,General Biochemistry, Genetics and Molecular Biology - Published
- 2023
4. Peripheral Blood Biomarkers Associated With Toxicity and Treatment Characteristics After 131 I- Metaiodobenzylguanidine Therapy in Patients With Neuroblastoma
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Aleksandra Olow, Kevin Campbell, Daphne A. Haas-Kogan, Ayano C. Kohlgruber, Erin E. Karski, Katherine K. Matthay, Steven G. DuBois, David A. Edmondson, and Matthew A. Coleman
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Oncology ,Cancer Research ,medicine.medical_specialty ,Radiosensitizer ,Radiation ,business.industry ,Neutropenia ,medicine.disease ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,Concomitant ,Neuroblastoma ,Toxicity ,Immunology ,Cohort ,medicine ,Radiology, Nuclear Medicine and imaging ,business ,Prospective cohort study ,Cohort study - Abstract
Purpose Few tools exist to predict clinical outcomes after radiopharmaceutical therapy. Our goal was to identify associations between blood-based biomarkers of radiation effect and clinical outcomes after 131 I-metaiodobenzylguanidine ( 131 I-MIBG) therapy in patients with neuroblastoma. Methods and Materials We conducted a prospective, single-center cohort study in children with advanced neuroblastoma treated with 131 I-MIBG as monotherapy or in combination with systemic putative radiation sensitizers. We collected serial peripheral blood samples after 131 I-MIBG infusions and quantified a panel of protein and messenger RNA markers. We plotted relative change from baseline to assess degree of modulation over time and then evaluated association of marker modulation with toxicity and response endpoints. Results The cohort included 40 patients (30 male/10 female; median age 7 years). We observed significant modulation of the majority of markers between baseline and hour 72 after 131 I-MIBG. Greater fold increase of plasma FLT3 ligand was associated with subsequent grade 4 neutropenia ( P =.039). Modulation of peripheral blood BCLXL and DDB2 was associated with grade 3+ nonhematologic toxicity ( P =.043 and .048, respectively). No markers were associated with tumor response. Greater plasma FLT3 ligand, BCLXL , and BCL2 modulation was observed in patients receiving 131 I-MIBG in combination with radiation sensitizers. Among 9 patients who received 2 courses, the degree of modulation in serum amylase was significantly lower after the second course ( P =.012). Conclusions Peripheral blood biomarkers relevant to radiation exposure are significantly modulated during the acute period after 131 I-MIBG. The degree of modulation of a subset of these markers is associated with toxicity and receipt of concomitant radiation sensitizers.
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- 2017
5. Universal: An Allogeneic First-in-Human Study of the Anti-Bcma ALLO-715 and the Anti-CD52 ALLO-647 in Relapsed/Refractory Multiple Myeloma
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Sham Mailankody, Michaela Liedtke, Parameswaran Hari, Shahbaz Malik, Arun Balakumaran, Srinand Nandakumar, Surbhi Sidana, Rajneesh Nath, Jeffrey V. Matous, Wade Lovelace, Erin E. Karski, Olalekan O. Oluwole, and Xiangdong Zhou
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CD52 ,business.industry ,Immunology ,Relapsed refractory ,Cancer research ,Medicine ,Cell Biology ,Hematology ,First in human ,business ,medicine.disease ,Biochemistry ,Multiple myeloma - Abstract
Background Allogeneic (off the shelf) chimeric antigen receptor (CAR) T cell therapy addresses the logistical challenges, availability and variable product quality of autologous CAR T therapy. ALLO-715 is a genetically modified anti-BCMA AlloCAR Ttm cell product in which the TCR alpha constant gene is disrupted to reduce the risk of graft-versus-host disease (GvHD) and the CD52 gene is disrupted with Talen® technology to permit the use of ALLO-647, an anti-CD52 mAb, for selective and prolonged host lymphodepletion (LD). Methods This is an open-label, Phase 1 trial (NCT04093596) in adults with R/R multiple myeloma who have received ≥3 prior lines of therapy including a proteasome inhibitor, immunomodulator, and anti-CD38 mAb. Patients (pts) must be refractory to their last treatment line. Patients receive LD followed by ALLO-715 at 1 of 4 dose levels (DL) in a 3+3 dose escalation design: 40, 160, 320, and 480 x 106 CAR+ T cells. Several LD regimens are being evaluated. These include: FCA (fludarabine (F) 90 mg/m2, cyclophosphamide (C) 900 mg/m2, and ALLO-647 (A) 39 mg divided over 3 days), FCA+ (same F and C but ALLO-647 (A+) dose of 90 mg divided over 3 days); as well as CA (same C and A divided over 3 days, but no F given). Results As of 08 July 2020, 19 pts had enrolled and 15 had received ALLO-715 at 3 DLs: 3 pts at DL1 (3 FCA and 0 CA); 7 pts at DL2 (4 FCA and 3 CA); 5 pts at DL3 (3 FCA and 2 CA). As of the data cutoff, no pts had received FCA+ or ALLO-715 DL4. Patients were heavily pre-treated and in advanced stage of disease with a median of 5 (range 3-11) prior lines of therapy and 31.6% ISS Stage III at screening. All but 1 had a prior autologous stem cell transplant. 52.6% (10/19) of patients had high risk cytogenetics, and 26.3% (5/19) had extramedullary disease. The most common Grade ≥3 adverse events were anemia (41.2%), neutropenia (41.2%), lymphopenia (29.4%), and thrombocytopenia (29.4%). Four episodes of Grade ≥3 infections occurred in 4 pts. Three of these were Grade 3 and included parvovirus B19, staphylococcal bacteremia, and pneumonia, which resolved with treatment. The fourth was a Grade 5 episode that occurred on day 8 post-ALLO-715 infusion in a rapidly progressing, refractory myeloma pt who, on day 1, developed a non-neutropenic fever and multifocal pneumonia with negative blood and sputum cultures. The patient progressed to respiratory failure and only comfort care was pursued. This death was considered related to conditioning (CA). No DLTs to ALLO-715 had been reported as of the data cutoff. In addition, no neurotoxicity (ICANS) or GvHD had been reported as of the data cutoff. Cytokine release syndrome was reported in 4 pts (24%). Three episodes were Grade 1 and 1 was Grade 2 (Lee Grading); all resolved without tocilizumab or corticosteroids. Fifteen pts were efficacy evaluable (defined as receiving ALLO-715, and undergoing at least one response assessment or discontinuing prior to the first response assessment), with a median follow-up of 2 months (range 0, 10 months). A higher dose of ALLO-715 (DL3) was associated with greater anti-cancer activity with 3/5 pts responding per IMWG (60%, 95% CI 14.7, 94.7). In pts who received DL3 FCA, 2/3 responded (1 sCR and 1 VGPR, Table 1). All DL3 pts who responded experienced at least a VGPR and achieved MRD negative status by local MRD testing. All responses were initially observed at day 14. Four (80%) out of the 5 responders were still in response at the time of the data cutoff. ALLO-715 cell expansion by qPCR was observed at all dose levels. Conclusions These early data suggest that ALLO-715 and ALLO-647 have a manageable safety profile. ALLO-715 shows evidence of clinical activity in the allogeneic setting in pts with R/R multiple myeloma and suggests that higher cell doses are associated with greater anti-cancer activity. Enrollment is ongoing in cohorts with higher ALLO-715 (480M CAR+ T-cells) and ALLO-647 (90mg). Updated safety, efficacy, PK/PD data will be presented. Clinical trial information: NCT04093596. Disclosures Mailankody: Physician Education Resource: Honoraria; PleXus Communications: Honoraria; Takeda Oncology: Research Funding; Janssen Oncology: Research Funding; Allogene Therapeutics: Research Funding; Juno Therapeutics, a Bristol-Myers Squibb Company: Research Funding. Matous:Bristol-Myers Squibb Company: Consultancy, Honoraria, Speakers Bureau. Liedtke:Janssen: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria. Sidana:Janssen: Consultancy. Nath:Actinium: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria. Oluwole:Bayer: Consultancy; Spectrum Pharmaceuticals: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy. Karski:Crisper Therapeutics: Current equity holder in publicly-traded company; Allogene Therapeutics: Current Employment, Current equity holder in publicly-traded company; Nektar Therapeutics: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Lovelace:Allogene Therapeutics: Current Employment, Current equity holder in publicly-traded company. Zhou:Allogene Therapeutics: Current Employment, Current equity holder in publicly-traded company. Nandakumar:Allogene Therapeutics: Current Employment, Current equity holder in publicly-traded company. Balakumaran:Allogene Therapeutics: Current Employment, Current equity holder in publicly-traded company; Merck: Ended employment in the past 24 months. Hari:BMS: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Amgen: Consultancy; GSK: Consultancy; Incyte Corporation: Consultancy.
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- 2020
6. Phase 1 study of sirolimus in combination with oral cyclophosphamide and topotecan in children and young adults with relapsed and refractory solid tumors
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Fabienne Hollinger, Kieuhoa T. Vo, Steven G. DuBois, Nicole Nasholm, Janel Long-Boyle, Katherine K. Matthay, Stephen Shiboski, Erin E. Karski, W. Clay Gustafson, and Shelly Allen
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Male ,0301 basic medicine ,Pharmacology ,Gastroenterology ,0302 clinical medicine ,Antibiotics ,Neoplasms ,Antineoplastic Combined Chemotherapy Protocols ,Epidemiology ,Child ,Stomatitis ,Cancer ,Pediatric ,Antibiotics, Antineoplastic ,Antineoplastic ,Local ,Oncology ,6.1 Pharmaceuticals ,030220 oncology & carcinogenesis ,mTOR ,Female ,medicine.drug ,Adult ,medicine.medical_specialty ,Adolescent ,Cyclophosphamide ,Oncology and Carcinogenesis ,Young Adult ,03 medical and health sciences ,topotecan ,Refractory ,Clinical Research ,Internal medicine ,medicine ,Humans ,Sirolimus ,business.industry ,Evaluation of treatments and therapeutic interventions ,medicine.disease ,Regimen ,Neoplasm Recurrence ,030104 developmental biology ,phase 1 ,Pharmacodynamics ,cyclophosphamide ,Topotecan ,Clinical Research Paper ,Neoplasm Recurrence, Local ,business - Abstract
// Kieuhoa T. Vo 1 , Erin E. Karski 1 , Nicole M. Nasholm 1 , Shelly Allen 1 , Fabienne Hollinger 1 , W. Clay Gustafson 1 , Janel R. Long-Boyle 2 , Stephen Shiboski 3 , Katherine K. Matthay 1 and Steven G. DuBois 1 1 Department of Pediatrics, UCSF Benioff Children’s Hospital, University of California, San Francisco School of Medicine, San Francisco, CA, USA 2 Department of Clinical Pharmacy, UCSF Benioff Children’s Hospital, University of California, San Francisco School of Medicine, San Francisco, CA, USA 3 Department of Epidemiology and Biostatistics, UCSF Benioff Children’s Hospital, University of California, San Francisco School of Medicine, San Francisco, CA, USA Correspondence to: Kieuhoa T. Vo, email: // Keywords : phase 1, mTOR, sirolimus, topotecan, cyclophosphamide Received : August 23, 2016 Accepted : October 13, 2016 Published : October 25, 2016 Abstract Purpose: To determine the maximum tolerated dose (MTD), toxicities, and pharmacodynamics effects of sirolimus combined with oral metronomic topotecan and cyclophosphamide in a pediatric population. Materials and Methods: Patients who were 1 to 30 years of age with relapsed/refractory solid tumors (including CNS) were eligible. Patients received daily oral sirolimus and cyclophosphamide (25-50 mg/m 2 /dose) on days 1-21 and oral topotecan (0.8 mg/m 2 /dose) on days 1-14 in 28-day cycles. Sirolimus steady-state plasma trough concentrations of 3-7.9 ng/mL and 8-12.0 ng/mL were evaluated, with dose escalation based on a 3+3 phase 1 design. Biomarkers of angiogenesis were also evaluated. Results: Twenty-one patients were treated (median age 18 years; range 9-30). Dose-limiting toxicities included myelosuppression, ALT elevation, stomatitis, and hypertriglyceridemia. The MTD was sirolimus with trough goal of 8-12.0 ng/mL; cyclophosphamide 25 mg/m 2 /dose; and topotecan 0.8 mg/m 2 /dose. No objective responses were observed. Four patients had prolonged stable disease > 4 cycles (range 4-12). Correlative biomarker analyses demonstrated reductions in thrombospondin-1 ( p =0.043) and soluble vascular endothelial growth factor receptor-2 plasma concentrations at 21 days compared to baseline. Conclusions: The combination of oral sirolimus, topotecan, and cyclophosphamide was well tolerated and biomarker studies demonstrated modulation of angiogenic pathways with this regimen.
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- 2016
7. Identification of Discrete Prognostic Groups in Ewing Sarcoma
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Mark Krailo, Linda Granowetter, Neyssa Marina, Richard B. Womer, Steven G. DuBois, Mark R. Segal, Elizabeth McIlvaine, Paul A. Meyers, Erin E. Karski, Holcombe E. Grier, and Judy Felgenhauer
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Pediatrics ,Prognostic variable ,Ifosfamide ,business.industry ,Recursive partitioning ,Hematology ,medicine.disease ,Clinical trial ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Cog ,030220 oncology & carcinogenesis ,Internal medicine ,Pediatrics, Perinatology and Child Health ,medicine ,Sarcoma ,Stage (cooking) ,business ,Etoposide ,medicine.drug - Abstract
Background Although multiple prognostic variables have been proposed for Ewing sarcoma (EWS), little work has been done to further categorize these variables into prognostic groups for risk classification. Procedure We derived initial prognostic groups from 2,124 patients with EWS in the SEER database. We constructed a multivariable recursive partitioning model of overall survival using the following covariates: age; stage; race/ethnicity; sex; axial primary; pelvic primary; and bone or soft tissue primary. Based on this model, we identified risk groups and estimated 5-year overall survival for each group using Kaplan–Meier methods. We then applied these groups to 1,680 patients enrolled on COG clinical trials. Results A multivariable model identified five prognostic groups with significantly different overall survival: (i) localized, age
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- 2015
8. Peripheral Blood Biomarkers Associated With Toxicity and Treatment Characteristics After
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Kevin, Campbell, Erin E, Karski, Aleksandra, Olow, David A, Edmondson, Ayano C, Kohlgruber, Matthew, Coleman, Daphne A, Haas-Kogan, Katherine K, Matthay, and Steven G, DuBois
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Adult ,Male ,Radiation-Sensitizing Agents ,Neutropenia ,Adolescent ,Membrane Proteins ,Pilot Projects ,3-Iodobenzylguanidine ,Neuroblastoma ,Child, Preschool ,Humans ,Female ,Prospective Studies ,Radiopharmaceuticals ,Child ,Biomarkers - Abstract
Few tools exist to predict clinical outcomes after radiopharmaceutical therapy. Our goal was to identify associations between blood-based biomarkers of radiation effect and clinical outcomes afterWe conducted a prospective, single-center cohort study in children with advanced neuroblastoma treated withThe cohort included 40 patients (30 male/10 female; median age 7 years). We observed significant modulation of the majority of markers between baseline and hour 72 afterPeripheral blood biomarkers relevant to radiation exposure are significantly modulated during the acute period after
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- 2017
9. Treatment of Hepatoblastoma With High-dose Chemotherapy and Stem Cell Rescue
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Peter J. Shaw, Emmanuel Katsanis, Weston P. Miller, Erin E. Karski, Wing Leung, Muna Qayed, Christopher C. Dvorak, and James H. Feusner
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Hepatoblastoma ,Oncology ,medicine.medical_specialty ,medicine.medical_treatment ,Population ,Appropriate use ,High dose chemotherapy ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Combined Modality Therapy ,Child ,Intensive care medicine ,education ,education.field_of_study ,Chemotherapy ,business.industry ,Liver Neoplasms ,Hematology ,Prognosis ,medicine.disease ,Bone transplantation ,Stem cell rescue ,Pediatrics, Perinatology and Child Health ,Neoplasm Recurrence, Local ,business ,Stem Cell Transplantation - Abstract
Children with high-risk or relapsed hepatoblastoma continue to represent treatment challenges. Multiple case reports have documented the use of high-dose chemotherapy with stem cell rescue (HDC) for this population; however, the efficacy and appropriate use of HDC remains unclear.A literature search was performed to identify cases of hepatoblastoma that were treated with HDC. Additional patients were identified by a query through the Pediatric Blood and Marrow Transplant Consortium. All cases were categorized as undergoing HDC as part of their initial treatment or for relapsed disease. Overall survival (OS) and event-free survival (EFS) proportions were calculated for each group. Subgroup analyses were performed looking at the effects of remission status, initial stage, and relapse site.Forty-two patients were identified. Thirty-one patients received HDC as part of their initial treatment and 55% were long-term survivors with 48% event-free. Eleven received HDC for relapsed disease and 64% were long-term survivors, 36% without events.It is difficult to draw firm conclusions from a small number of nonrandomized patients who had different stages, treatments, and events before undergoing HDC. However, our calculated EFS and OS proportions are consistent with current data using multimodal therapy without HDC, suggesting that HDC (at least as currently delivered) for hepatoblastoma may not be beneficial.
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- 2014
10. 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.
- Published
- 2019
11. Transcript Analysis for Internal Biodosimetry Using Peripheral Blood from Neuroblastoma Patients Treated with (131)I-mIBG, a Targeted Radionuclide
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Harsha Koneru, Steven G. DuBois, David A. Edmondson, Ayano C. Kohlgruber, Katherine K. Matthay, Christine L. Hartmann, Shelly Allen, Matthew A. Coleman, Leif E. Peterson, and Erin E. Karski
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0301 basic medicine ,Male ,Time Factors ,Messenger ,Medical and Health Sciences ,Neuroblastoma ,0302 clinical medicine ,Medicine ,Child ,Whole blood ,Cancer ,Pediatric ,Radiation ,Biological Sciences ,3-Iodobenzylguanidine ,030220 oncology & carcinogenesis ,Absorbed dose ,Child, Preschool ,Physical Sciences ,Female ,Whole-Body Irradiation ,Adult ,Adolescent ,education ,Biophysics ,Article ,Dose-Response Relationship ,03 medical and health sciences ,Young Adult ,Rare Diseases ,Refractory ,Biodosimetry ,Clinical Research ,Genetics ,Humans ,Radiology, Nuclear Medicine and imaging ,Oncology & Carcinogenesis ,RNA, Messenger ,Preschool ,Radiometry ,Radionuclide ,business.industry ,Dose-Response Relationship, Radiation ,medicine.disease ,Peripheral blood ,030104 developmental biology ,131i mibg ,RNA ,business ,Nuclear medicine ,Transcriptome - Abstract
Calculating internal dose from therapeutic radionuclides currently relies on estimates made from multiple radiation exposure measurements, converted to absorbed dose in specific organs using the Medical Internal Radiation Dose (MIRD) schema. As an alternative biodosimetric approach, we utilized gene expression analysis of whole blood from patients receiving targeted radiotherapy. Collected blood from patients with relapsed or refractory neuroblastoma who received (131)I-labeled metaiodobenzylguanidine ((131)I-mIBG) at the University of California San Francisco (UCSF) was used to compare calculated internal dose with the modulation of chosen gene expression. A total of 40 patients, median age 9 years, had blood drawn at baseline, 72 and 96 h after (131)I-mIBG infusion. Whole-body absorbed dose was calculated for each patient based on the cumulated activity determined from injected mIBG activity and patient-specific time-activity curves combined with (131)I whole-body S factors. We then assessed transcripts that were the most significant for describing the mixed therapeutic treatments over time using real-time polymerase chain reaction (RT-PCR). Modulation was evaluated statistically using multiple regression analysis for data at 0, 72 and 96 h. A total of 10 genes were analyzed across 40 patients: CDKN1A; FDXR; GADD45A; BCLXL; STAT5B; BAX; BCL2; DDB2; XPC; and MDM2. Six genes were significantly modulated upon exposure to (131)I-mIBG at 72 h, as well as at 96 h. Four genes varied significantly with absorbed dose when controlling for time. A gene expression biodosimetry model was developed to predict absorbed dose based on modulation of gene transcripts within whole blood. Three transcripts explained over 98% of the variance in the modulation of gene expression over the 96 h (CDKN1A, BAX and DDB2). To our knowledge, this is a novel study, which uses whole blood collected from patients treated with a radiopharmaceutical, to characterize biomarkers that may be useful for biodosimetry. Our data indicate that transcripts, which have been previously identified as biomarkers of external exposures in ex vivo whole blood and in vivo radiotherapy patients, are also good early indicators of internal exposure. However, for internal sources of radiation, the biokinetics and physical decay of the radionuclide strongly influence the gene expression.
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- 2016
12. ATRT-11. MARKED RESPONSE TO ATEZOLIZUMAB IN A PATIENT WITH RHABDOID TUMOR: A CASE STUDY FROM THE IMATRIX-ATEZOLIZUMAB TRIAL
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Erin E. Karski, Meghna Das Thaku, Guillaume Bergthold, and Franck Bourdeaut
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Cancer ,medicine.disease ,Abstracts ,03 medical and health sciences ,030104 developmental biology ,Text mining ,Atezolizumab ,Internal medicine ,medicine ,Neurology (clinical) ,Young adult ,business ,Adverse effect - Abstract
BACKGROUND: Rhabdoid tumors (RTs) are aggressive, rare tumors usually diagnosed in early childhood. They portend poor prognosis, despite multi-modality treatment. Atezolizumab targets programmed death-ligand 1 (PD-L1), leading to enhanced anti-cancer T-cell activity. The iMATRIX-Atezolizumab study (phase I/II, open-label; NCT02541604) assessed safety, pharmacokinetics, and preliminary activity of atezolizumab in pediatric/young adult patients. METHODS: Patients aged
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- 2017
13. A phase I/II study of atezolizumab in pediatric and young adult patients with refractory/relapsed solid tumors (iMATRIX-Atezolizumab)
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Tanya M. Trippett, Birgit Geoerger, Michel Zwaan, Matthew Kowgier, Steven G. DuBois, Michael Tagen, Michela Casanova, Lynley V. Marshall, Meghna Das-Thakur, Erin E. Karski, and Antonia Kwan
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Phase i ii ,Refractory ,Atezolizumab ,030220 oncology & carcinogenesis ,Internal medicine ,Medicine ,Young adult ,business - Abstract
10524 Background: Atezolizumab targets programmed death-ligand 1 (PD-L1), leading to enhanced anticancer T-cell response. The iMATRIX-Atezolizumab study (phase I/II, multicenter, open-label; NCT02541604) assessed the safety, pharmacokinetics (PK) and preliminary activity of atezolizumab in pediatric/young adult patients with refractory/relapsed solid tumors. Methods: Patients aged < 30 years with refractory/relapsed non-central nervous system solid tumors received atezolizumab every 3 weeks until loss of clinical benefit ( < 18 years old, 15mg/kg [maximum dose 1200mg]; ≥18 years old, 1200mg). Safety/PK were assessed across tumor types and initial response was assessed by tumor-type cohorts after approximately 10 patients in each cohort had been treated. Results: As of July 19 2016, 74 patients (median age 14 years; range 2–29) were enrolled: osteosarcoma, n = 12; Ewing sarcoma, n = 11; neuroblastoma, n = 11; rhabdomyosarcoma (RMS), n = 10; non-RMS soft tissue sarcoma, n = 10; Wilms tumor, n = 6; Hodgkin lymphoma (HL), n = 5; non-HL, n = 1; other tumor types, n = 8. PK data (n = 48) were similar to that in adults (geometric mean Cmin, µg/mL [cycle 2, day 1, pre-dose]: 53.6 [2– < 6 years old]; 54.1 [6– < 12 years old]; 62.0 [12– < 18 years old]; 68.0 [adult]). Most tumors, except HL, had < 1% (score 0) tumor cell [TC]/tumor-infiltrating immune cell (IC) PD-L1 expression with overall TC/IC-positive expression rates (≥1%, score 1–3) of 7% and 10%, respectively. All available HL samples had ≥5% (score 2–3) TC/IC PD-L1 expression. 67/71 patients who received atezolizumab (median cycles 2; range 1–10) had ≥1 adverse event (AE; mainly immune-related grade 1–2); 17 patients (24%) had treatment-related grade 3–4 AEs. One AE (grade 3 transaminase increase) led to study drug discontinuation. Common AEs were pyrexia (37%), fatigue (34%) and constipation (32%). 2/5 patients with HL had a partial response (PR); the only patient with atypical rhabdoid tumor (RT) had an unconfirmed PR. Conclusions: The PK and safety profile of atezolizumab in pediatric and young adult patients is similar to that in adults. Preliminary antitumor activity was seen in HL and RT; new cohorts are planned in RT and atypical teratoid RT. Clinical trial information: NCT02541604.
- Published
- 2017
14. Characteristics and outcomes of patients with Ewing sarcoma over 40 years of age at diagnosis
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John Neuhaus, Steven G. DuBois, Robert E. Goldsby, Erin E. Karski, and Katherine K. Matthay
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Male ,Cancer Research ,Pediatrics ,Aging ,Epidemiology ,Pediatric cancers ,Cohort Studies ,Surveillance, Epidemiology, and End Results ,80 and over ,Medicine ,Young adult ,Child ,Cancer ,Aged, 80 and over ,Pediatric ,Incidence (epidemiology) ,Age Factors ,Sarcoma ,Middle Aged ,Prognosis ,Survival Rate ,Oncology ,Child, Preschool ,Public Health and Health Services ,Female ,Patient Safety ,Cohort study ,Adult ,medicine.medical_specialty ,Adolescent ,Oncology and Carcinogenesis ,Bone Neoplasms ,Sarcoma, Ewing ,Article ,Young Adult ,Rare Diseases ,Age ,Clinical Research ,Internal medicine ,Ewing ,Humans ,Oncology & Carcinogenesis ,Preschool ,Survival rate ,Proportional Hazards Models ,Retrospective Studies ,Aged ,business.industry ,Proportional hazards model ,Infant, Newborn ,Infant ,Retrospective cohort study ,medicine.disease ,Newborn ,United States ,SEER ,business ,Ewing sarcoma ,SEER Program - Abstract
BackgroundThe peak incidence of Ewing sarcoma (EWS) is in adolescence, with little known about patients who are ≥40 years at diagnosis. We describe the clinical characteristics and survival of this rare group.MethodsThis retrospective cohort study utilized the Surveillance Epidemiology and End Results database. 2780 patients were identified; including 383 patients diagnosed ≥40 years. Patient characteristics between age groups were compared using chi-squared tests. Survival from diagnosis to death was estimated via Kaplan-Meier methods, compared with log-rank tests, and modeled using multivariable Cox methods. A competing risks analysis was performed to evaluate death due to cancer.ResultsPatients ≥40 years of age were more likely to have extra-skeletal tumors (66.1% vs. 31.7%; p < 0.001), axial tumors (64.0% vs. 57.2%; p = 0.01), and metastatic disease at diagnosis (35.5% vs. 30.0%; p = 0.04) compared to younger patients. Five-year survival for those age ≥40 and age
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- 2013
15. Biomarkers of radiation exposure in children with neuroblastoma treated with 131I-mIBG
- Author
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Ayona Kohlgruber, Matthew A. Coleman, Aleksandra Olow, Daphne A. Haas-Kogan, Steven G. DuBois, M. Shelly Allen, Erin E. Karski, and Katherine K. Matthay
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Oncology ,Cancer Research ,medicine.medical_specialty ,Pathology ,education.field_of_study ,business.industry ,Monocyte ,Population ,Colony-stimulating factor ,medicine.disease ,Peripheral blood mononuclear cell ,medicine.anatomical_structure ,131i mibg ,Refractory ,Internal medicine ,Neuroblastoma ,Toxicity ,medicine ,education ,business - Abstract
10060 Background: Neuroblastoma (NB) is the most common solid extra-cranial tumor of childhood. 131I-mIBG is a targeted radiopharmaceutical for patients with advanced NB and is one of the most active agents in this treatment resistant population. To date, no clinically relevant biomarkers of response or toxicity have been reported in patients treated with 131I-mIBG. Methods: Patients with relapsed or refractory NB who received 131I-mIBG at UCSF were eligible to participate in this prospective correlative study. Blood samples were obtained at baseline and 72 hours after 131I-mIBG infusion. We quantified a panel of biomarkers shown to be effected in patients receiving other forms of radiation, including: serum amylase; plasma Flt-3 ligand; plasma monocyte colony stimulating factor (MCSF); and CDKN1A mRNA in mononuclear cells. Extent of modulation of each marker was evaluated using paired t-tests at hour 0 and 72. We assessed potential differential modulation between groups based on response (PR/CR vs SD/PD), toxicity (grade 3 non-hematologic toxicity; grade 4 neutropenia or thrombocytopenia) or administration of combination therapy (131I-mIBG alone vs in combination with vincristine/irinotecan or vorinostat) using unpaired t-tests. Results: 26 patients (21 male; median age 7 years) participated and received a median 131I-mIBG dose of 18 mCi/kg. 16 patients received 131I-mIBG in combination. We observed robust modulation of amylase (median fold increase from baseline 3.1; p 131I-mIBG had more robust modulation of Flt-3 ligand (mean difference 296 pg/mL; p=0.02) compared to single agent 131I-mIBG. No correlations with clinical response or toxicity were found. Conclusions: Amylase, Flt-3 ligand, and CDKN1A mRNA all show robust modulation after 131I-mIBG treatment. Patients receiving 131I-mIBG in combination demonstrated the largest changes in plasma Flt-3 ligand. In this initial analysis, no associations were found between response or toxicity and the proposed biomarkers.
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- 2013
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