127 results on '"dose finding"'
Search Results
2. Initial results from a dose finding study of TNO155, a SHP2 inhibitor, in adults with advanced solid tumors
- Author
-
Thomas Hengelage, Melissa Lynne Johnson, Daniel Shao-Weng Tan, Debbie Robbrecht, Helena Alexandra Yu, Kun Xu, Maria Jove, Geoffrey I. Shapiro, Irene Brana, Kelly Biette, Hironobu Minami, Lillian L. Siu, Eugene Tan, Neeltje Steeghs, and Susan Moody
- Subjects
MAPK/ERK pathway ,Cancer Research ,Dose finding ,Oncology ,biology ,Downstream (manufacturing) ,business.industry ,Allosteric regulation ,biology.protein ,Medicine ,business ,Receptor tyrosine kinase ,Cell biology - Abstract
3005 Background: SHP2 transduces signals from activated receptor tyrosine kinases to downstream pathways including MAPK. TNO155 is a selective, allosteric, oral inhibitor of SHP2. Methods: CTNO155X2101 (NCT03114319) is an ongoing first-in-human, open-label dose escalation/expansion trial of TNO155 in adults with advanced solid tumors. The primary objective is to characterize the safety and tolerability of TNO155 and identify regimen(s) for future study. Secondary assessments included pharmacokinetics, pharmacodynamics, and preliminary clinical efficacy. Here we present data from TNO155 single agent escalation. Results: As of 10/26/2020, 118 patients received TNO155 in variable schedules: once (QD; 1.5–70 mg; n = 55) or twice daily (BID; 30–50 mg; n = 25) in a 2 weeks on/1 week off (2w/1w) cycle; or QD in a 3w/1w cycle (30–60 mg; n = 32), or continuously (40 or 50 mg QD; n = 6). The most common cancer diagnoses treated were colorectal (54%), gastrointestinal stromal tumor (16%), non-small cell lung (12%), and head & neck (8%). The median number of prior antineoplastic therapies was 4 (range 1–10). Overall 109 patients (92%) have discontinued study treatment, 94 (80%) for progressive disease and 6 (5%) for adverse events (AEs). TNO155 showed rapid absorption (median day 1 Tmax ̃1.1 hours), an effective median T½ of ̃34 hours, and near dose-proportional exposure at day 14 (power model: AUCτ beta = 1.09 [90% CI 1.02–1.16]). AEs were mostly Grade 1/2 and generally consistent with on-target effects of SHP2 inhibition. The most common treatment-related AEs (all grades) were increased blood creatine phosphokinase (n = 33, 28%), peripheral edema (n = 31, 26%), diarrhea (n = 31, 26%), and acneiform dermatitis (n = 27, 23%). The most common treatment-related Grade ≥3 AEs were decreased platelets (n = 5, 4%), increased aspartate aminotransferase, diarrhea, and decreased neutrophils (each n = 4, 3%). The best observed response was stable disease (SD) per RECIST 1.1, reported in 24 (20%) patients, with a median duration of SD of 4.9 months (range 1.7–29.3). Evidence of SHP2 inhibition, as measured by change in DUSP6 expression by qPCR in paired pre- vs. on-treatment tumor samples, was seen in the majority of patients treated with TNO155 doses ≥20 mg/day (≥25% reduction, 38/42 [90%]; ≥50% reduction, 25/42 [60%]). Analysis of tumor whole-transcriptome RNA sequencing data is ongoing. Conclusions: TNO155 shows favorable pharmacokinetic properties and promising early safety and tolerability data at doses with evidence of target inhibition. The optimal dose using several schedules is still under evaluation. Studies of TNO155 in combination with other agents, including nazartinib (mutant-selective EGFR inhibitor[i]), adagrasib (KRAS G12Ci), spartalizumab (anti-PD-1 antibody), ribociclib (CDK4/6i), and dabrafenib (BRAFi) with LTT462 (ERKi), are ongoing (NCT03114319, NCT04330664, NCT04000529, NCT04294160). Clinical trial information: NCT03114319.
- Published
- 2021
3. Trastuzumab deruxtecan (T-DXd) combinations in patients with HER2-positive advanced or metastatic breast cancer: A phase 1b/2, open-label, multicenter, dose-finding and dose-expansion study (DESTINY-Breast07)
- Author
-
Celina M. D'Cruz, Tinghui Yu, Sherene Loi, Fabrice Andre, Carey K. Anders, Komal Jhaveri, Peter Schmid, Erika Hamilton, Sarice Boston, and P. Herbolsheimer
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Improved survival ,medicine.disease ,Metastatic breast cancer ,Dose finding ,Trastuzumab ,Internal medicine ,medicine ,In patient ,Open label ,business ,medicine.drug - Abstract
TPS1096 Background: HER2-targeted therapies have improved survival in patients (pts) with HER2+ advanced/metastatic breast cancer (mBC) but challenges remain, including resistance to current HER2-targeted therapies. Also, additional treatment options are needed in pts with brain metastases (BM). In the phase 2 DESTINY-Breast01 trial, T-DXd demonstrated efficacy, with an objective response rate (ORR) of 61.4% and median progression-free survival (mPFS) of 19.4 mo in pts with previously treated HER2+ advanced/mBC (Modi SABCS 2020); data from an earlier cutoff of this trial supported approval of T-DXd in the US, Europe, and Japan. In a subgroup analysis of 24 pts with stable BM, T-DXd showed preliminary efficacy, with mPFS of 18.1 mo (Jerusalem ESMO Breast Cancer 2020). Here, we describe a phase 1b/2 trial evaluating the safety and preliminary antitumor activity of T-DXd monotherapy and combinations in pts with HER2+ advanced/mBC, including pts with stable and active BM. Methods: DESTINY-Breast07 (NCT04538742) is a global, multicenter, open-label, phase 1b/2 trial designed to evaluate the safety, tolerability, and preliminary antitumor activity of T-DXd monotherapy and combinations in pts with HER2+ advanced/mBC. This study consists of a T-DXd monotherapy module (module 0) and 5 combination modules of T-DXd plus (1) durvalumab, (2) pertuzumab, (3) paclitaxel, (4) durvalumab + paclitaxel, or (5) tucatinib, all in pts with no or stable BM. Two additional modules consisting of (6) T-DXd + tucatinib and (7) T-DXd monotherapy will include pts with untreated BM not requiring local therapy or previously treated BM that have progressed since local therapy (active BM). The need for chronic steroids or local therapy to manage BM symptoms is exclusionary. Modules 2 to 5 will each consist of 2 parts: dose finding (part 1) and dose expansion (part 2). Modules 0, 1, 6, and 7 will include part 2 only. Part 1 of individual modules will enroll pts who have had disease progression while receiving ≥1 prior line of therapy in the metastatic setting. In part 2, pts who have received no prior therapy (modules 0 to 5) or ≤1 prior therapy (modules 6 to 7) for metastatic disease will be randomized to receive a T-DXd combination regimen or monotherapy. The primary endpoints are determination of the recommended phase 2 doses (part 1 only) and safety and tolerability of T-DXd and combinations (parts 1 and 2). Secondary endpoints include ORR, PFS, PFS2, duration of response (DoR), and overall survival (all assessed in part 2 only) and pharmacokinetics and immunogenicity (parts 1 and 2). To assess central nervous system (CNS) activity, exploratory endpoints were added, including CNS-ORR, CNS-DoR, and CNS-PFS (by RECIST version 1.1 and RANO-BM criteria) as well as cognitive and symptom assessment using CANTAB, MDASI-BT, and NANO. Clinical trial information: NCT04538742 .
- Published
- 2021
4. First-in-human dose-finding study of venadaparib (IDX-1197), a potent and selective PARP inhibitor, in patients with advanced solid tumors
- Author
-
Yong Man Kim, Kyun-Seop Bae, Eun-Jihn Roh, Kyungun Kim, Nam Seok Baek, Won Sik Lee, Sung-Bae Kim, and Chan Young Ock
- Subjects
chemistry.chemical_classification ,Cancer Research ,biology ,business.industry ,Poly ADP ribose polymerase ,DNA replication ,First in human ,Dose finding ,Enzyme ,Oncology ,chemistry ,PARP inhibitor ,biology.protein ,Cancer research ,Medicine ,In patient ,business ,Polymerase - Abstract
3107 Background: Poly ADP-ribose polymerase (PARP) is an enzyme that is central to the repair of DNA replication errors known as single-strand breaks (SSBs). PARP inhibitors are currently approved for ovary, breast, pancreatic and prostate cancers which harbor germline or somatic BRCA1/2 mutations (g/sBRCAmt) and/or homologous recombinant repair mutation (g/sHRRmt). In this phase 1 dose finding study of venadaparib, we determined the maximum tolerated dose for venadaparib monotherapy and explored the safety, tolerability, pharmacokinetics, pharmacodynamics and anticancer efficacy of venadaparib in patients with advanced solid tumor which progressed after an attempt of standard-of-care therapy and for which effective therapy does not exist. Methods: Subjects who satisfied all of the inclusion/exclusion criteria and provided written informed consent were enrolled in this study. The investigational product was administered orally once daily continuously in a 3 weekly cycle. Enrolled subjects were assessed for safety and evaluated on tumor response using RECIST 1.1. The study was carried out in a conventional 3+3 design, starting from 2 mg up to 240 mg. Dose limiting toxicities (DLTs) and pharmacokinetics were assessed during the first cycle. Results: As of 08 Feb 2021, enrollment is completed with 32 patients enrolled. Most common tumor types enrolled are breast cancer (16 patients) and ovarian cancer (11 patients). Other tumor types include cancers of endometrium, fallopian tube, uterus and prostate. No DLTs were observed up to the maximum tested dose of 240 mg. Frequently observed adverse drug reactions were as follows – Anemia (56%), nausea (38%) and neutropenia (25%). Overall objective response rate (ORR) was 16% and clinical benefit rate (CBR) was 47%. Partial response was observed starting from 40 mg and clinical benefit was observed from the lowest dose of 2 mg. From optional tumor tissue samples, venadaparib exhibited ≥ 90% PAR inhibitory effect in pharmacodynamic analysis from 10 mg. For patients with known germline or somatic BRCA status either from local lab results or examined at a central lab retrospectively, ORR and CBR was 22% and 44% respectively for BRCAm(+) (9) patients. Interestingly, clinical efficacy was observed in BRCAm(-) (18) patients also, with ORR and CBR of 17% and 50% respectively. Conclusions: Safety and tolerability of the venadaparib monotherapy was confirmed with preliminary efficacy signals observed, even in BRCAm(-) patients. Clinical benefit was observed from the lowest tested dose, suggesting the potential to combine with other chemotherapeutic agents. Further studies to explore efficacy and safety of venadaparib in other tumor types and combinations, as well as to explore adequate biomarkers are warranted. Clinical trial information: NCT03317743.
- Published
- 2021
5. Triplet therapy with pembrolizumab (PEM), encorafenib (ENC) and binimetinib (BIN) in advanced, BRAF V600 mutant melanoma: Final results from the dose-finding phase I part of the IMMU-Target trial
- Author
-
Dietrich Trebing, Erwin S. Schultz, Dirk Schadendorf, Angela M. Krackhardt, Elisabeth Livingstone, Daniela Goeppner, Lisa Zimmer, and Chalid Assaf
- Subjects
MAPK/ERK pathway ,Cancer Research ,business.industry ,Melanoma ,Immune checkpoint inhibitors ,Mutant ,Medizin ,Binimetinib ,Pembrolizumab ,medicine.disease ,chemistry.chemical_compound ,Dose finding ,Oncology ,chemistry ,Encorafenib ,Cancer research ,Medicine ,business - Abstract
9532 Background: Survival of BRAF-mutated melanoma profoundly improved since the introduction of immune checkpoint inhibitors (ICI) and MAPK pathway inhibitors (MAPKi). Response kinetics of ICI and MAPKi are complementary, mechanistic evidence indicates that MAPKi may affect the tumor immune microenvironment. Combined use of both drug classes may further enhance clinical benefit. IMMU-Target was set-up as a prospective, open-label, phase I/II trial, with a safety phase I part followed by a randomized phase II part, to study the tolerability and clinical activity of PEM, ENC and BIN triplet therapy. Methods: Treatment naïve adult patients (pts) with stage IIIB-IV (AJCC 2017), BRAF V600 mutant melanoma with measurable disease but no active brain metastasis were eligible. The dose finding part used a 3+3 design, starting with a dose level (DL) 0 applying the clinically recommended doses of PEM (200 mg Q3W), ENC (450 mg QD) and BIN (45 mg BID). In case of ≥2 dose-limiting toxicities (DLT), a reduction of the ENC and BIN doses (300 mg QD and 30 mg BID at DL-1, 200 mg QD and 30 mg BID at DL -2) was foreseen. Primary endpoints of the phase I part were safety and tolerability. Results: From April 2018 until May 2020, 14 pts with BRAF V600 mutations were enrolled. 2 of 3 pts at DL 0 developed DLT (creatine phosphokinase (CPK) elevations grade 3 plus cytokine release syndrome grade 4; gamma glutamyl transferase (GGT) elevations grade 3), and had to stop therapy early. Therefore, 3+3 further pts at DL -1 were included with no DLT observed in these 6 pts. One (isolated GGT elevations grade 3) of the 2 DLT observed in the 3 pts of DL 0 enrolled initially was questionable as DLT, as the patient had further episodes of isolated GGT elevations without therapy. As a result, further 5 pts were enrolled at DL 0: here no DLT-matching treatment-related adverse event (TRAE) occurred. In total, 12 out of 14 pts (86%) experienced a TRAE and 7 (50%) experienced a grade ≥3 TRAE; there were no fatal AE or TRAE-related deaths. Increases in alanine and in aspartate aminotransferases, GGT and CPK elevations (6 of 14 pts) were the most common grade 3-4 TRAE. In median, pts at DL 0 (n=8) received triplet therapy for 18 weeks (IQR 7.5-29), at DL-1 (n=6) for 46 weeks (IQR 27-102). The overall response rate was 64% (95% CI=35-87). At a median follow-up of 10.0 months at DL 0 and 27.0 months at DL-1, progression-free survival at 12 months was 37.5% (95% CI 9- 67) and 60% (95% CI 13-88), respectively. Conclusions: Triplet therapy was feasible and safe at both dose levels leading to clinically meaningful disease control. The phase II part was not initiated, since the clinical efficacy of PEM plus ENC and BIN is currently investigated in STARBOARD ( NCT04657991 ), a prospective, randomized, placebo-controlled (PEM mono), double-blinded phase III trial. Clinical trial information: NCT02902042.
- Published
- 2021
6. Final analysis of dose-finding and single-arm confirmatory study (phase I/II study) of definitive chemoradiotherapy (dCRT) with S-1/mitomycin-C (MMC) in patients (pts) with clinical (c) Stage II/III squamous cell carcinoma of the anal canal (SCCA): JCOG0903
- Author
-
Gen Iinuma, Makoto Kinouchi, Atsuo Takashima, Takahisa Matsuda, Manabu Shiozawa, Fumio Ishida, Masayuki Ohue, Junki Mizusawa, Takeshi Kodaira, Hiroshi Katayama, Hirohisa Miura, Fumihiko Fujita, Yukihide Kanemitsu, Haruhiko Fukuda, Yoshinori Ito, Tetsuya Hamaguchi, Yasuhiro Shimada, Yoshihisa Saida, and Kohei Murata
- Subjects
Cancer Research ,medicine.medical_specialty ,business.industry ,Standard treatment ,Mitomycin C ,Definitive chemoradiotherapy ,Stage ii ,Anal canal ,Gastroenterology ,Dose finding ,medicine.anatomical_structure ,Oncology ,Internal medicine ,Medicine ,In patient ,Radiosensitivity ,business - Abstract
3521 Background: dCRT with 5-FU/MMC is a standard treatment for cStage II/III SCCA. S-1 is an oral fluoropyrimidine and has a greater effect on radiosensitivity. We conducted this trial of dCRT with S-1/MMC to determine the recommended dose (RD) of S-1 in dose-finding (phase I) part and to evaluate the efficacy and safety in confirmatory (phase II) part for cStage II/III SCCA. We reported the RD of S-1 and the 3-year survival at 2019 Gastrointestinal Cancers Symposium. We report the final data after 5-year follow-up. Methods: Eligibility criteria included histologically proven SCCA, cStage II/III (UICC 6th), PS 0-1, and age 20-80 years. dCRT consisted of MMC (10 mg/m2 on days 1, 29) and S-1 (60 mg/m2/d in level 0 and 80 mg/m2/d in level 1 on days 1-14, 29-42) with concurrent radiotherapy of 59.4 Gy/33fr. The dose-finding part adopted the 3+3 cohort design. The primary endpoint of confirmatory part was 3-year event-free survival (EFS). The sample size was 65 in the confirmatory part, with one-sided alpha of 5% and power of 80%, threshold and expected 3-year EFS as 60% and 75%. Key secondary endpoints were overall survival (OS) and progression-free survival (PFS) and colostomy-free survival (CFS), and adverse events. Final analysis was planned after 5-year follow-up for all pts. Results: From Feb/2010 to Mar/2015, 69 pts (3 in level 0 and 66 [7 in phase I and 59 in phase II] in level 1) were enrolled. Pts characteristics for level 1 were as follows: M/F, 12/54; Age, median 64 (range 33-80); cStage II/IIIA/IIIB, 29/9/28. Three in level 1 were ineligible and 63 eligible assigned to level 1 were included in efficacy analysis. In the dose-finding part, RD of S-1 was determined as 80 mg/m2/d. The complete response rate was 81% (95% CI, 69.1-90.0%) on central review. With a median follow-up of 5.4 years, 3- and 5-year EFS was 65.0% (90% CI 54.1-73.9%) and 63.4% (95% CI 50.2-73.9%). 5-year OS, PFS, and CFS were 84.1% (95% CI 72.5-91.1%), 84.1% (95% CI 72.4-91.1%), and 73.0% (95% CI 60.2-82.3%), respectively. In a univariable analysis, male sex (p = 0.045) prognosticated for poor OS and cT3 or T4 (p = 0.001), male sex (p = 0.019) and, PS 1 (p = 0.048) prognosticated for poor CFS. Nine (14.3%) of 63 pts at a dose level 1 developed recurrence or disease progression. Locoregional recurrence only and distant metastasis were observed in 1 pts (1.6%) and 8 pts (12.7%) respectively. Among all treated 65 pts, only 5 pts (7.7%) showed grade 3 late toxicities including jejunum obstruction, jejunum ulcer, proctitis, lower gastrointestinal hemorrhage, anal pain, radiation dermatitis, and ureteral stenosis. No Grade 4 or 5 late toxicities were observed. Conclusions: dCRT with S-1/MMC showed acceptable toxicities and favorable 5-year survival and could be a possible treatment option for pts with locally advanced SCCA. Clinical trial information: jRCTs031180002.
- Published
- 2021
7. Derazantinib (DZB) in combination with atezolizumab (AZB) in patients with solid tumors: Results from the dose-finding phase Ib substudy of FIDES-02
- Author
-
Michalina Marszewska, Stephan Braun, Anna Patrikidou, Raghad Muhsin Abdul-Karim, Mikael Saulay, Damien Pouessel, Frederique Cantero, Yohann Loriot, Arvind Chaudhry, Hyo Jin Lee, Fabricio Racca, Rodryg Ramlau, Jean-Laurent Deville, and Alejandro Gonzalez
- Subjects
Antitumor activity ,Cancer Research ,Dose finding ,Oncology ,Kinase ,Atezolizumab ,business.industry ,Cancer research ,Medicine ,In patient ,business - Abstract
437 Background: DZB is an oral small-molecule FGFR1/2/3 kinase inhibitor, which demonstrated antitumor activity in preclinical and clinical studies (in cholangiocarcinoma patients [pts] with FGFR2-driven tumors and in FGFR1-3-driven urothelial cancer [UC] PDX models). In CSF1-stimulated mouse bone-marrow derived macrophages, DZB reduced CSF1R phosphorylation with a maximal effect similar to the selective CSF1R inhibitor BLZ945, suggesting DZB could have an effect on tumor-associated macrophage regulation. Thus, DZB+AZB is a rationale combination to be investigated in immunogenic and FGFR-driven tumors like UC. Methods: FIDES-02 is a multi-cohort open-label Phase 1b/2 study evaluating the effect of DZB as monotherapy and DZB+AZB in combination. To determine the RP2D of DZB+AZB, a total of 26 pts with UC (N = 4) and other solid tumors (N = 22), of whom 7 pts carried various FGFR genetic aberrations (GA), were enrolled at 2 dose levels (DL) (1200 mg AZB Q3W + 200 mg [DL1] / 300 mg [DL2] DZB QD) and treated until disease progression or unacceptable toxicity. Both DLs were divided into MTD (endpoint: dose-limiting toxicity [DLT] at D21) and expansion cohorts to investigate both acute and delayed adverse events (AEs) per CTCAE v5. Results: In the MTD cohorts of both DL1 (N = 7) and DL2 (N = 6) no DLTs were observed, and the DL1 and DL2 expansion cohorts subsequently enrolled 7 and 6 pts, respectively. The most frequent treatment-emergent AEs across both DLs were fatigue (31%), nausea (27%), diarrhea (23%), the most frequent laboratory abnormalities were increased ALT (58%), and AST (50%). Non-DLT grade (G) ≥ 3 treatment-related AEs (TRAE) across both DLs were G3 diarrhea (4%), G3 nausea (4%), G3 asthenia (4%), oral fungal infection (4%) and one case of immune-related G4 nephritis (4%). Dose interruptions / reductions and discontinuations due to TRAEs occurred in 19% and 8%, respectively. Pharmacokinetic analyses demonstrated that DZB exposure parameters and AZB serum concentrations in pts treated with DZB+AZB were similar to those assessed in pts under DZB / AZB monotherapy. At data cut-off, 2 of 14 (DL1) and 7 of 12 pts (DL2) were still on treatment. Median duration of treatment in DL1 was 9.7 weeks (range, 9-25), and best overall response per investigator assessment was SD in 4 of 10 efficacy-evaluable DL1 pts. DL2 efficacy analysis was uninformative at cutoff. The combination of 1200 mg AZB Q3W with both 200 mg and 300 mg QD DZB was found to be safe and tolerable. Conclusions: The combination of DZB+AZB is safe at both investigated DLs, the RP2D has been determined as 300 mg DZB QD+1200 mg AZB Q3W. DZB can be safely dosed at its monotherapy RP2D in this novel combination with AZB. The anti-tumor efficacy of DZB+AZB is currently being investigated in adequately designed cohorts of FIDES-02 with enrichment for UC pts with FGFR GA. Clinical trial information: NCT04045613.
- Published
- 2021
8. A new radio-enhancer, PEP503 (NBTXR3), in combination with concurrent chemoradiation in locally advanced or unresectable rectal cancer: The dose-finding part of a phase I/II trial
- Author
-
Hsiang-Yao Shih, Jaw-Yuan Wang, You-Hsin Chiu, Wen-Hung Hsu, Ming-Yii Huang, Jeffrey Yung-Chuan Chao, Chou-Pin Chen, Ching-Wen Huang, Huang-Ming Hu, and Chiao-Yun Chen
- Subjects
Cancer Research ,medicine.medical_specialty ,business.industry ,Colorectal cancer ,medicine.medical_treatment ,Locally advanced ,Concurrent chemoradiation ,medicine.disease ,Hafnium oxide ,Radiation therapy ,Dose finding ,Phase i ii ,Oncology ,medicine ,Radiology ,business - Abstract
66 Background: PEP503 (as known as NBTXR3) is a novel radio-enhancer composed of functionalized hafnium oxide nanoparticles for a higher energy deposit by radiotherapy comparing to radiotherapy alone without it. A prior phase 3 study for soft tissue sarcoma has demonstrated the clinical benefit. The phase 1b part of the study aimed to test the feasibility of PEP503 intra-tumor injection and examine the safety profile of various dose levels of PEP503 in combination with concurrent chemo-radiation (CCRT) for locally advanced rectal cancers. Methods: Patients who had rectal adenocarcinoma of T3-4 or locally unresectable disease suitable for neoadjuvant CCRT were eligible. A single administration of PEP503 intra-tumor injection with multiple needle punctures was applied 24 to 72 hours before the start of IMRT or IMAT at 50 Gy in 25 fractions in combination with capecitabine or infusion 5-FU over 5~6 weeks. Dose escalation of 4 levels of PEP503 injected volume was based on 5%, 10%, 15%, and 22% of the baseline tumor volume by MRI. Intra-tumor dispersion of nanoparticles was inspected by CT-scan and the body kinetics evaluation was performed. The total mesorectal excision was planned around 8~12 weeks later after the completion of CCRT. Preliminary efficacy including tumor response after CCRT and the pathological response with tumor regression grade (TRG) after surgery was collected. Results: Twenty patients were enrolled, with 7, 4, 3, and 6 patients at 5%, 10%, 15%, and 22% dose levels, respectively. An injection procedure-related dose-limiting toxicity of urinary tract infection with sepsis was reported in the first treated patient at 5%. There was no adverse event (AE) or serious AE directly caused by PEP503. The most frequently reported AEs related to CCRT across all dose levels were diarrhea (~45%), WBC decreased (~40%), and dermatitis (~25%), but all were grade 1 or 2. The safety profile of CCRT with PEP503 was similar to it of CCRT without PEP503 for rectal cancer patients. The CT scans, before and after CCRT, displayed the dispersion of PEP503 among different tumor shapes and contours without leakage to the surrounding healthy tissues. In most patients, hafnium was not detected in the circulation in 60 minutes after PEP503 injection and not found in urine. Around 70% of patients showed tumor response after the CCRT and half of the patients receiving surgery achieved good tumor regression (AJCC TRG 0 or TRG 1). In the small phase 1b dose-escalation part of the trial, the dose-dependency of the efficacy endpoints could not be assessed. Conclusions: Intra-tumor injection of PEP503/NBTXR3 with CCRT is feasible without additional toxicities for rectal cancer patients. The extension phase 2 of the trial to investigate the clinical benefits of PEP503 at 22% of tumor volume is ongoing in Taiwan. Clinical trial information: NCT02465593.
- Published
- 2021
9. Phase I dose-finding study of oral ERK1/2 inhibitor LTT462 in patients (pts) with advanced solid tumors harboring MAPK pathway alterations
- Author
-
Elena Elez, Martin Schuler, Helen Evans, Filip Janku, Gopa Iyer, Anastasios Stathis, Abdelkader Seroutou, Noboru Yamamoto, A. Mais, Daniel Shao-Weng Tan, and Uz M. Stammberger
- Subjects
MAPK/ERK pathway ,Cancer Research ,business.industry ,Medizin ,Small molecule ,03 medical and health sciences ,Dose finding ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,Medicine ,In patient ,business ,030215 immunology - Abstract
3640 Background: LTT462 is an investigational small molecule inhibitor of ERK1/2, which has demonstrated preclinical activity in multiple MAPK activated cancer cells and xenograft models. This first-in-human study was designed to evaluate the safety and tolerability of LTT462 in advanced solid tumors harboring MAPK pathway alterations (NCT02711345). Methods: The dose-escalation part of this Phase I, open-label study, enrolled adult and adolescent pts with advanced solid tumors harboring ≥1 documented MAPK pathway alteration with progressive disease (PD) despite standard therapy, or for whom there is no effective standard treatment. Oral LTT462 was given once daily (QD) at 45–600 mg or twice daily (BID) at 150 mg or 200 mg. Objectives were to determine the maximum tolerated dose (MTD) using a Bayesian hierarchical logistic regression model guided by escalation with overdose control, and characterize safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of LTT462. Results: Sixty-five pts (median age 60 years) including 1 pt aged 15 were enrolled in the dose-escalation; most pts (22%) had 3 prior therapies. Most common primary sites for cancer were in the colon (n = 21; 32%), ovary (n = 9; 14%), and pancreas (n = 7; 11%). All pts discontinued, the majority due to PD (n = 44; 68%). Eleven pts experienced DLTs; 6 pts experienced Grade 3 eye disorder DLTs (4 pts retinopathy, 2 pts chorioretinopathy). Treatment-related adverse events (TRAEs) were reported for 89% of pts, most commonly ( > 30%) diarrhea (n = 25; 38%) and nausea (n = 22; 34%). Grade 3/4 TRAEs were reported in 29% of pts; most common was retinopathy (n = 4; 6%). MTD of LTT462 was 400 mg QD and 150 mg BID. Overall, 8 pts (12%) had stable disease (SD) and 35 pts (54%) had PD. An unconfirmed partial response was reported in a pt with cholangiocarcinoma with BRAF mutation; best change in sum of target lesions per RECIST 1.1 was -33.9%. LTT462 increased plasma peak drug concentration and drug exposure at increasing doses between 45–450 mg QD. Exposure at LTT462 600 mg QD was lower than anticipated, indicating potential saturation of absorption at this dose. LTT462 inhibited ERK1/2 and reduced DUSP6 expression relative to baseline in most pts evaluated. Conclusions: LTT462 is well tolerated. Limited clinical activity was reported with single agent LTT462; best overall response was SD. An ongoing study is investigating LTT462 in combination with the RAF inhibitor, LXH254, in NSCLC and melanoma. Clinical trial information: NCT02711345 .
- Published
- 2020
10. Phase Ib trial combining rapid determination of drug-drug interaction (DDI) followed by a dose finding period to assess safety and preliminary efficacy of fimepinostat plus venetoclax in patients with aggressive B-cell lymphoma
- Author
-
Anas Younes, Stefan K. Barta, Connie Lee Batlevi, Tycel Phillips, Jason R. Westin, Sven de Vos, Krish Patel, John M. Pagel, Dena Grayson, Vikram Kansra, Sonali M. Smith, and Jonathon B. Cohen
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Venetoclax ,business.industry ,Period (gene) ,Drug-drug interaction ,medicine.disease ,Lymphoma ,Dose finding ,chemistry.chemical_compound ,Pooled analysis ,chemistry ,Internal medicine ,medicine ,In patient ,B-cell lymphoma ,business - Abstract
8056 Background: Fimepinostat (F), a dual inhibitor of PI3K (α, β, δ) and HDACs type 1/2, causes suppression of MYC levels (Shulman et al., 2017). A pooled analysis of diffuse large B-cell lymphoma (DLBCL) pts treated with F in two Ph 1/2 trials revealed an objective response rate in evaluable/ITT MYC-altered DLBCL pts of 29%/23%, respectively (Landsburg et al., 2018). Based on compelling preclinical activity of F in combination with venetoclax (V) (a Bcl2 inhibitor), we initiated a Ph 1b/2 study of F + V in pts with relapsed or refractory (R/R) DLBCL or high-grade B-cell lymphoma (HGBL), with or without MYC alteration. V is metabolized primarily by CYP3A, and preclinical studies showed that F may inhibit CYP3A4 (IC50 of 13.58 and 0.28 µM for midazolam and testosterone, respectively), suggesting F could cause DDI with V. Methods: Cohorts of patients received increasing dose levels of F administered on a 5-days-on/2-days-off (5/2) schedule in combination with daily V in 21-day cycles (Cohort 1: F 30 mg QD 5/2 + V 400 mg QD; Cohort 2: F 60 mg QD, 5/2 + V 400 mg QD; Cohort 3: F 60 mg QD 5/2 + V 800 mg QD). A potential DDI was assessed during Cycle 0 (Table), where PK for V (10 mg) monotherapy was compared to that for V (10 mg) in the presence of F. Patient PK samples were collected, analyzed and reviewed in < 10 days to determine the final ramp-up dose level of V. Results: As of 1-Feb-2020, 16 pts have been enrolled in 2 dose cohorts. Intensive PK analysis of 13 pts showed only mild (≤ 2-fold) to no increase in V exposure in the presence of F. In Cohort 1 (n = 6), the mean AUC increased 1.6-fold, and mean Cmax by 1.5-fold. In Cohort 2 (n = 7), no increase in mean AUC (0.9-fold) or Cmax (1.0-fold) was observed. Accordingly, all pts ramped up V to 100% of the target dose (400 mg) upon entering Cycle 1; rapid escalation of V was well tolerated. DLT was observed in 1 pt (Grade 3 diarrhea) in Cohort 2. Overall, 75% of TEAEs have been mild or moderate (Grade 1/2), and most were of limited duration. 11 pts (69%) experienced SAEs; 4 pts (25%) had SAEs considered related to either F or V. Conclusions: Real-time PK evaluation showed that F had only a mild to no DDI with V. F + V is well tolerated at clinically active dose levels, and evaluation of higher dose-level cohorts was ongoing. Enrollment in Cohort 2 remains on-going. Clinical trial information: NCT01742988 . [Table: see text]
- Published
- 2020
11. TAS-116, an oral HSP90 inhibitor, in combination with nivolumab in patients with colorectal cancer and other solid tumors: An open-label, dose-finding, and expansion phase Ib trial (EPOC1704)
- Author
-
Yasutoshi Kuboki, Miki Fukutani, Daisuke Kotani, Hiroyoshi Nishikawa, Kenichi Harano, Noboru Yamamoto, Hikari Shima, Mitsuko Suzuki, Masashi Wakabayashi, Kohei Shitara, Tsukiko Higuchi, Akihiro Sato, Yoichi Naito, Akihito Kawazoe, Shogo Nomura, and Hiroya Taniguchi
- Subjects
Cancer Research ,Antitumor immunity ,Colorectal cancer ,business.industry ,Expansion phase ,medicine.disease ,digestive system diseases ,Hsp90 inhibitor ,03 medical and health sciences ,Dose finding ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,medicine ,Cancer research ,In patient ,Open label ,Nivolumab ,business ,030215 immunology - Abstract
4044 Background: Regulatory T cells (Tregs) potentially induce the resistance of anti-PD1/PD-L1 inhibitors (A-PD1). TAS-116, a novel HSP90 inhibitor, enhanced antitumor immunity via reducing Tregs in vitro and in vivo. Combination of TAS-116 plus A-PD1 showed a superior tumor growth suppression compared with either treatment alone in vivo. Based on the above, we investigated safety and efficacy of TAS-116 in combination with nivolumab in patients with solid tumors. Methods: Enrolled patients received TAS-116 plus nivolumab in a dose-finding part to estimate the maximum tolerated dose and the recommended phase 2 dose (RP2D). Additional patients were enrolled in a dose-expansion part. TAS-116 monotherapy (orally once daily, 80mg on level 1, 120mg on level 2, and 160mg on level 3) was administrated for 2 weeks followed by the combination with nivolumab (intravenously every 2 weeks, 3 mg/kg). The primary endpoint was dose-limiting toxicities (DLTs) during the first cycle (4 weeks). PD-L1 combined positive score (CPS) and tumor mutation burden (TMB) were assessed. We also conducted biomarker research using paired samples from repeated tumor biopsies and blood collections. Results: A total of 44 patients with colorectal cancer (CRC, n = 29), gastric cancer (GC, n = 8), sarcoma (n = 5), non-small cell lung cancer (NSCLC, n = 1) and melanoma (n = 1) after standard of cares were enrolled. One patient had MSI-H CRC, but all other patients had MSS tumors. No DLTs were observed at all levels and TAS-116 160 mg was determined as RP2D. The common grade 3 or worse treatment-related adverse included AST/ALT increased (7%), creatinine increased (5%) and platelet count decreased (5%). Objective tumor response was observed in 6 patients including 4 MSS CRC, 1 MSI-H CRC and 1 sarcoma, resulting in objective response rate (ORR) of 16% in MSS CRC without prior A-PD-1. PD-L1 CPS and TMB could be evaluated in 18 and 17 MSS CRC without prior A-PD-1, respectively. ORR was 27% in patients with CPS ≥1 and 0% in patients with CPS < 1. ORR was 33% with TMB-high (median as the cut-off) and 12% with TMB-low. Analysis of tumor-infiltrating lymphocytes before treatment and after TAS-116 monotherapy demonstrated reduction of FoxP3hiCD45RA−Tregs fraction in the tumor microenvironment. Conclusions: The combination of TAS-116 160mg plus nivolumab had manageable safety profiles and anti-tumor activity especially for MSS CRC patients, which warrants further investigations in a large cohort. Clinical trial information: UMIN000032801 .
- Published
- 2020
12. SAF-189s in previously treated patients with advanced ALK-rearranged non-small cell lung cancer (NSCLC): Results from the dose-finding portion in a single-arm, first-in-human phase I/II study
- Author
-
Jianying Zhou, Ai-Min Hui, Zhuli Wu, Yi-Long Wu, Nong Yang, Juan Sun, and Jin-Ji Yang
- Subjects
Cancer Research ,Crizotinib ,business.industry ,medicine.drug_class ,non-small cell lung cancer (NSCLC) ,macromolecular substances ,First in human ,medicine.disease ,carbohydrates (lipids) ,ALK inhibitor ,stomatognathic diseases ,03 medical and health sciences ,Dose finding ,0302 clinical medicine ,Phase i ii ,Oncology ,030220 oncology & carcinogenesis ,otorhinolaryngologic diseases ,medicine ,Cancer research ,Non small cell ,Previously treated ,business ,030215 immunology ,medicine.drug - Abstract
e21689 Background: Patients(pts) with ALK-rearranged non-small cell lung cancer (NSCLC) are sensitive but progress in 8–11 months with treatment of ALK inhibitor crizotinib, with leading progression in brain metastasis. SAF-189s is a novel and selective ALK inhibitor, can penetrate through blood brain barrier, and overcome multiple resistance mutation. This study aimed to explore the safety, efficacy, and pharmacokinetic properties of SAF-189s in patients with advanced ALK-rearranged NSCLC. Methods: In this multicenter I/II study, SAF-189s was orally administered under fasting condition at doses ranging from 20–210 mg once daily in a 21-day cycle to 36 pts with advanced ALK-positive NSCLC who had failed to prior systemic therapy. In this analysis report, anti-tumor activity of SAF-189s was evaluated in 34 pts received 40(n = 6), 80(n = 8), 120(n = 8), 160(n = 9) and 210(n = 3) mg doses daily. Safety was evaluated in all 36 pts who received ≥1 treatment. This study is registered with clinicaltrials.gov, NCT04237805. Results: 36 pts were enrolled in total, 22 pts had CNS metastases at baseline and 26 pts had progressed to prior TKIs therapy. There was no treatment-related SAE among the 36 pts. The most common drug-related events were nausea (14 [38.9%] of 36 pts), vomiting (10[27.8%] of 36 pts), QT prolongation (9 [25.0%] of 36 pts), sinus bradycardia (7 [19.4%] of 36 pts), ALT increase (10 [27.8%] of 36 pts), diarrhea (6 [16.7%] of 36 pts). Only one DLT of grade 3 blood glucose increase occurred at 210 mg out of the first 3 pts, so another 3 pts will be enrolled to determine RP2D/MTD. SAF-189s had shown response in the starting dose of 20mg, with 1of 2 pts achieving partial response (PR) over 43 cycles until clinical data cut off. All 34 pts in efficacy analysis set had achieved tumor shrinkage, with 17 confirmed PR (50%) (95% CI, 32.4–67.6%) and 4 unconfirmed PR (11.7%). 11 (45.8%) pts had confirmed PR among 24 pts who had failed to Crizotinib or Ceritinib and 10 (47.6%) pts had confirmed PR among 21pts who had CNS metastases. PFS data is pre-mature, with only median PFS of the 80 mg cohort being inferred as 19.42 months. Conclusions: In the dose-escalation portion of this study, SAF-189s was safe, very tolerable, and demonstrated both systemic and intracranial activity in pts with advanced ALK-positive NSCLC who had failed to at least 1 prior systemic therapy. Therefore, this study warrants further investigation to prove SAF-189s as an effective therapeutic option for pts who have ALK+ NSCLC. Clinical trial information: NCT04237805.
- Published
- 2020
13. A phase Ib study of TAK-079, an investigational anti-CD38 monoclonal antibody (mAb) in patients with relapsed/ refractory multiple myeloma (RRMM): Preliminary results
- Author
-
Qing Li, Krina K. Patel, Deborah Berg, Parameswaran Hari, Keith Stockerl-Goldstein, Ruben Niesvizky, Amrita Krishnan, Sundar Jagannath, Kristina Allikmets, and Rebecca Silbermann
- Subjects
Cancer Research ,business.industry ,medicine.drug_class ,Multiple modes ,CD38 ,medicine.disease ,Monoclonal antibody ,03 medical and health sciences ,Dose finding ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,Relapsed refractory ,medicine ,Cancer research ,In patient ,business ,Multiple myeloma ,030215 immunology - Abstract
8539 Background: TAK-079 is a subcutaneously (SC) administered mAb with multiple modes of action for killing target cells. Here we report data from an ongoing dose finding study of TAK-079 monotherapy in patients with RRMM (NCT03439280). Methods: Pt were eligible after ≥ 3 lines of therapy and previous exposure to immunomodulatory drug (IMiD), proteasome inhibitor (PI), alkylating agent, and corticosteroid; prior anti-CD38 therapy allowed. Patients were refractory or intolerant to at least 1 PI and 1 IMiD. TAK-079 given as a SC injection weekly for 8 doses, every other week for 8 doses, then monthly until disease progression (PD) or unacceptable toxicity. SC injection was 2 mL administered in ≤ 1 minute. Results: 34 patients were enrolled across 5 fixed dose cohorts (TAK-079 45-135-300-600-1200 mg SC) as of 09 December 2019. Median age was 65 (50–81) years. At study entry, 65% were refractory to both an IMiD and PI; 82% refractory to last line of therapy, 21% of patients were previously exposed to at least 1 anti-CD38 monoclonal antibody. Median number of prior therapies was 4 (2,12). No ≥ Grade 1 early or late systemic infusion reactions (IRR) reported. Three ( < 1%) injection site reactions described in > 1200 injections administered; 2 mild pruritis and 1 moderate swelling. Drug related adverse events (AEs), any grade, occurring in at least 10% of patients were: fatigue (21%), anemia (18%), neutropenia (18%), leukopenia (15%). Neutropenia was the only drug related grade 3 AEs in 2 or more patients (n = 2); only drug related SAE was 1 Grade 3 diverticulitis. No drug-related grade 4 AEs, AEs leading to study discontinuation, or on-study deaths reported. Recommended phase 2 dose (RP2) is to be 600 mg based on no reported DLTs, no MTD identified, and preliminary efficacy (PFS and response [ORR]). At the RP2 dose, 9 patients received at least 6 cycles of therapy by the data cutoff; their ORR was 33%, median duration of response was not estimable. The clinical benefit rate (minimal response or better) in all 12 patients enrolled at the RP2 dose was 67%. At a median follow-up of 7.5 months, PFS not estimable at the RP2 dose. Conclusions: TAK-079 monotherapy is safe, generally well tolerated, and active in patients with RRMM through tested doses. Clinical activity occurred early and was durable. With no MTD identified, no IRRs, no significant hematologic toxicity, the RP2 dose is 600 mg. PFS, with a median FU of 7.5 months at the data-cut off, is not estimable at the RP2 dose. Updated safety and efficacy data will be presented. Clinical trial information: NCT03439280 .
- Published
- 2020
14. First-in-human study of the cancer peptide vaccine, TAS0313, in patients with advanced solid tumors: Phase I dose-finding part results
- Author
-
Takafumi Koyama, Noboru Yamamoto, Toshio Shimizu, Satoru Iwasa, Kan Yonemori, Shunsuke Kondo, and Jun Sato
- Subjects
Cancer Research ,business.industry ,Cancer ,medicine.disease ,Epitope ,Dose finding ,CTL ,Oncology ,medicine ,Cancer research ,Peptide vaccine ,Cytotoxic T cell ,In patient ,Cancer vaccine ,business - Abstract
73 Background: TAS0313 is a cancer vaccine cocktail containing three long peptides, with a total of 12 cytotoxic T lymphocyte (CTL) epitope peptides. These peptides were derived from eight cancer-associated antigens that are highly expressed in various cancers. We report the results of a phase I part examining the tolerability, safety, potential efficacy, and immunological responses of 9 and 27 mg TAS0313 in patients (pts) with advanced solid tumors. Methods: The enrolled pts had at least one of the following HLA types: HLA-A*02:01, -A*02:06, -A*02:07, -A*11:01, -A*24:02, -A*31:01, or -A*33:03. TAS0313 was subcutaneously administered on Days 1, 8, and 15 of Cycles 1 and 2 and on Day 1 of Cycle 3 or later in 21-day cycles until disease progression, or unacceptable toxicity. Tolerability was assessed in at least six pts during the first cycle. Tumor response was evaluated using RECIST v1.1. The antigen specific CTL and IgG were analyzed post treatment by blood samples. Optional serial tumor biopsies were performed for tumor infiltrating leukocyte (TIL) analysis. CTL, IgG, and TIL were measured by ELISPOT assay, Luminex assay, and IHC (CD8 positive), respectively. Results: Seventeen pts were enrolled in 9mg (n = 10) and 27mg (n = 7) groups. There was no serious adverse drug reaction (ADR) in any patient. All ADRs were of grade 1 or 2, with the most frequent being dermatological injection site reaction, in 7/10 (70%) and 6/7 (86%) pts and pyrexia, in 1/10 (10%) and 2/7 (29%) for the 9 and 27mg groups, respectively. The best overall response was stable disease, in 2/10 (20%) and 2/7 (28%) pts. One patient with cancer of unknown origin received prolonged administration (over 10 months) of the 9mg dose. Increment of CTL and IgG by treatment were detected in 9 and 27mg groups. TIL counts were increased in 2/3(67%) and 3/4(75%) in 9 and 27mg groups compared with pre-treatment samples, respectively. Conclusions: TAS0313 demonstrated safety, tolerability, and immunological responses in pts with advanced solid tumors in the 9 and 27mg groups. A phase II part, evaluating the efficacy of combination therapy with pembrolizumab in pts with urothelial carcinoma and monotherapy in glioblastoma pts, is currently underway. Clinical trial information: JapicCTI-183824.
- Published
- 2020
15. Safety and tolerability of oxaliplatin based pressurized intraperitoneal aerosol chemotherapy (PIPAC) for patients with peritoneal carcinomatosis: A phase I dose-finding study in Asian patients
- Author
-
Guowei Kim, Siok Chin Teo, Hon Lyn Tan, Koy Min Chue, Cheng Ean Chee, Jimmy Bok Yan So, C. Jang, Chia Hui Tai, Raghav Sundar, Lingzhi Wang, Bettina Lieske, Corissa Yi Juan Chee, Asim Shabbir, and Wei Peng Yong
- Subjects
Drug ,Cancer Research ,Chemotherapy ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,media_common.quotation_subject ,Intraperitoneal chemotherapy ,Gastroenterology ,Peritoneal carcinomatosis ,Oxaliplatin ,03 medical and health sciences ,Dose finding ,0302 clinical medicine ,Oncology ,Tolerability ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Hyperthermic intraperitoneal chemotherapy ,business ,030215 immunology ,media_common ,medicine.drug - Abstract
360 Background: PIPAC is a novel, laparoscopic intraperitoneal chemotherapy delivery technique which aims to improve on hyperthermic intraperitoneal chemotherapy (HIPEC), ameliorating drug distribution and tissue penetration. Thus far, PIPAC has been conducted with oxaliplatin chemotherapy in Europe, at an arbitrary dose of 92mg/m2; 150mg/m2 was found to be intolerable. We conducted a dose-escalation phase 1 study to establish the safety, tolerability and recommended phase 2 dose (RP2D) for PIPAC in Asian patients. Methods: This phase 1 study of oxaliplatin administered via PIPAC was designed as a traditional 3+3 dose escalation study for patients with predominant peritoneal metastasis from a gastrointestinal primary tumor, after failure of standard therapies. Dose levels were planned at 45, 60, 90 and 120mg/m2. Repeat doses of PIPAC were permitted, 6 weeks apart. Dose limiting toxicities (DLT) were defined as any clinically relevant grade 3 adverse events occurring within 28 days after PIPAC. Results: This study included 16 patients (25 PIPAC procedures; 8 gastric, 4 colorectal and 1 gallbladder, pancreas and appendix cancer each). Median age was 62 years, with a median peritoneal carcinomatosis index (PCI) score of 17 (range 1 - 39). Two patients developed pancreatitis (grade 2 and 3) on day 6 and day 9 after PIPAC administration at the dose cohort of 45mg/m2, necessitating cohort expansion to 6 patients. One patient was noted to have asymptomatic grade 3 hyperamylasemia (90mg/m2 cohort). There were no other DLTs and all 3 patients in the highest dose cohort (120mg/m2) tolerated PIPAC well. Nine patients who underwent a 2nd PIPAC procedure had a decrease in PCI score from 18.4 to 15.5; one patient at 120mg/m2 had an improvement in PCI from 30 to 12. Conclusions: The RP2D of PIPAC with oxaliplatin is 120mg/m2. Single agent PIPAC is well tolerated, and future studies with PIPAC must consider a bi-directional approach with the incorporation of systemic therapy, with either chemotherapy or immunotherapy to improve efficacy. Clinical trial information: NCT03172416.
- Published
- 2020
16. Adaptive Dose-Finding Studies: A Review of Model-Guided Phase I Clinical Trials
- Author
-
Alexia Iasonos and John O'Quigley
- Subjects
Cancer Research ,medicine.medical_specialty ,Clinical Trials, Phase I as Topic ,Dose-Response Relationship, Drug ,Maximum Tolerated Dose ,business.industry ,MEDLINE ,Antineoplastic Agents ,Phase (combat) ,Study Characteristics ,Clinical trial ,Dose finding ,Oncology ,Sample size determination ,Neoplasms ,Dose escalation ,Humans ,Medicine ,Medical physics ,business ,Review Articles ,Practical implications - Abstract
Purpose We provide a comprehensive review of adaptive phase I clinical trials in oncology that used a statistical model to guide dose escalation to identify the maximum-tolerated dose (MTD). We describe the clinical setting, practical implications, and safety of such applications, with the aim of understanding how these designs work in practice. Methods We identified 53 phase I trials published between January 2003 and September 2013 that used the continual reassessment method (CRM), CRM using escalation with overdose control, or time-to-event CRM for late-onset toxicities. Study characteristics, design parameters, dose-limiting toxicity (DLT) definition, DLT rate, patient-dose allocation, overdose, underdose, sample size, and trial duration were abstracted from each study. In addition, we examined all studies in terms of safety, and we outlined the reasons why escalations occur and under what circumstances. Results On average, trials accrued 25 to 35 patients over a 2-year period and tested five dose levels. The average DLT rate was 18%, which is lower than in previous reports, whereas all levels above the MTD had an average DLT rate of 36%. On average, 39% of patients were treated at the MTD, and 74% were treated at either the MTD or an adjacent level (one level above or below). Conclusion This review of completed phase I studies confirms the safety and generalizability of model-guided, adaptive dose-escalation designs, and it provides an approach for using, interpreting, and understanding such designs to guide dose escalation in phase I trials.
- Published
- 2014
17. IOLite: Multipart, phase 1b, dose-finding study of the PD-1 inhibitor dostarlimab in combination with the PARP inhibitor niraparib ± bevacizumab (bev), or with platinum-based chemotherapy ± bev for advanced cancer
- Author
-
Bruce J. Dezube, Sharon Lu, Erika Hamilton, Jordi Rodon Ahnert, Manish R. Patel, Jasgit C. Sachdev, Alberto Bessudo, Lena Evilevitch, Nashat Y. Gabrail, Meghan Duncan, Wei Guo, and Timothy A. Yap
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Chemotherapy ,biology ,Bevacizumab ,business.industry ,medicine.medical_treatment ,Advanced cancer ,03 medical and health sciences ,Dose finding ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,Programmed cell death 1 ,PARP inhibitor ,medicine ,biology.protein ,In patient ,business ,neoplasms ,Standard therapy ,030215 immunology ,medicine.drug - Abstract
2560 Background: Novel combinations of drugs may overcome resistance in patients (pts) with solid tumors who had progressed on standard therapy. Methods: IOLite (NCT03307785) is a multicenter, open label, multipart study to determine dosing and evaluate safety and efficacy of dostarlimab in combination with approved therapies in pts with advanced solid tumors. Pts were enrolled in each part based on tumor histology, prior treatment (tx) history, and physician preference. Primary endpoint is dose-limiting toxicities (DLTs) deemed as tx-related per investigator, and safety and tolerability of the combination. Tumor responses were assessed per RECIST v1.1. Results: Parts A-D (see Table) are fully enrolled. One complete response was reported in part B (endometrial); confirmed partial responses in part A (ovarian, small cell lung [SCLC], gastrointestinal stromal [GIST]); part B (breast [2], bladder, SCLC); part C (prostate, fallopian tube), and part D (endometrial, non-SCLC). Stable disease was reported in part A (colorectal, prostate [2], breast, GIST, gastric); part B (SCLC, squamous cell, head and neck, prostate); part C (pancreatic, ovarian, GIST, breast [2], liver, endometrial); part D (ovarian, head & neck, cholangiocarcinoma). At data cutoff, 24 pts remain on treatment. PK’s of dostarlimab and niraparib (nir) were not altered by any of the combination agents tested. Conclusions: Dostarlimab is well tolerated in combination with nir ± bev, or carbo-pac ± bev. Preliminary efficacy data show responses in various histologies. No new safety signals were identified. Clinical trial information: NCT03307785. [Table: see text]
- Published
- 2019
18. S1206: A dose-finding study followed by a phase II randomized placebo-controlled trial of chemoradiotherapy (CRT) with or without veliparib in stage III non-small cell lung cancer (NSCLC)
- Author
-
Ding Wang, Megan E. Daly, Bryan A. Faller, Jieling Miao, Roy H. Decker, Allen M. Chen, Karen Kelly, Marianna Koczywas, Scott N. Gettinger, Jacob Sands, Athanassios Argiris, Mihaela C. Cristea, Ronald Yanagihara, Mary W. Redman, Linda L. Garland, David R. Gandara, Lauren Averett Byers, and Kathy S. Albain
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Veliparib ,business.industry ,Stage III NSCLC ,Placebo-controlled study ,Newly diagnosed ,Stage III Non-Small Cell Lung Cancer ,03 medical and health sciences ,chemistry.chemical_compound ,Dose finding ,0302 clinical medicine ,chemistry ,030220 oncology & carcinogenesis ,Internal medicine ,PARP inhibitor ,medicine ,business ,Chemoradiotherapy ,030215 immunology - Abstract
8523 Background: Veliparib (V), a PARP inhibitor, may potentiate the antitumor effect of CRT in NSCLC. Methods: Eligibility included newly diagnosed unresectable stage III NSCLC. Patients were randomized to receive concurrent CRT with weekly carboplatin (AUC 2) and paclitaxel (45 mg/m2) with V at 120 mg or placebo (P) twice daily during CRT followed by 2 cycles (every 21 days) of consolidation carboplatin (AUC 6), paclitaxel (200 mg/m2) with V at 80 mg or P (per randomized arm) orally on days 1-7 of each cycle. Progression-free survival (PFS) was the primary endpoint. The accrual goal was 132 patients. Results: The dose-finding study results were previously presented (ASCO 2016;A8537). V 120 mg twice daily was the recommended phase II dose. A total of 31 eligible and evaluable patients were enrolled in the phase II randomized trial: 17 on V and 13 on P (1 patient in the V arm withdrew prior to starting any treatment, thus was not evaluable). The study was closed to accrual early due to the positive results from the PACIFIC trial that changed standard practice. Median follow-up among alive patients was 16 months. During CRT, the following grade (G) 3-4 adverse events (AE) were seen with V vs P: any G3 AE (6 vs 6), any G4 AE (2 vs 3), G3 pneumonitis (0 vs 1), G3 esophagitis (1 vs 1), G3 oral mucositis (1 vs 0), G3 anorexia (1 vs 1), G3 hyponatremia (0 vs 3), G3 anemia (1 vs 0), G3 neutropenia (3 vs 1), G3 thrombocytopenia (1 vs 0), G4 hypoglycemia (0 vs 1). Also, 2 patients per arm had G4 lymphopenia. During consolidation (11 evaluable patients with V; 10 with P), G3 anemia (1 vs 0), G3 anorexia (1 vs 0), G3 weight loss (0 vs 1), G3 dehydration (1 vs 0), G3 dysphagia (2 vs 0), G3 fatigue (1 vs 0), G3 hypomagnesemia (0 vs 1), G3 nausea (1 vs 0), G4 hyperglycemia (0 vs 1), G3-4 neutropenia (3 vs 0), G3 thrombocytopenia (1 vs 0), G3-4 lymphopenia (2 vs 1); a G5 pneumonitis occurred in the P arm. Response rates were 56% (95% CI, 31-78%) and 69% (95% CI, 38-91%) on the V and P arms, respectively. PFS at 1 year was 47% (95% CI, 23% - 68%) with V and 46% (95% CI, 19% - 70%) with P. Overall survival (OS) at 1 year was 89% (95% CI, 61%-97%) with V and 54% (95% CI, 25%-76%) with P. Adding the 6 patients treated at 120 mg in the phase I part, 1-year with V was 91% (95% CI, 69%-98%). Conclusions: V in combination with CRT was tolerable with expected toxicities that relate to the backbone regimen. In the small number of randomized patients there was a suggestion of promising survival with V that may provide rationale for future trials of PARP inhibitors with CRT. Clinical trial information: NCT01386385.
- Published
- 2019
19. Randomized, optimal dose-finding, phase II study of tri-weekly nab-paclitaxel in patients with metastatic breast cancer (ABROAD)
- Author
-
Tsutomu Takashima, Kosuke Kashiwabara, Junji Tsurutani, Yuichiro Kikawa, Yoshie Hasegawa, Naruto Taira, Tsutomu Iwasa, Hiroaki Kato, Tsuyoshi Saito, Yoichi Naito, Masahiro Kitada, Hirofumi Mukai, Masato Takahashi, Tomohiko Aihara, Eiko Sakata, and Fumikata Hara
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Phases of clinical research ,medicine.disease ,Metastatic breast cancer ,03 medical and health sciences ,chemistry.chemical_compound ,Dose finding ,0302 clinical medicine ,Paclitaxel ,chemistry ,Chemotherapy-induced peripheral neuropathy ,030220 oncology & carcinogenesis ,Internal medicine ,Medicine ,In patient ,business ,030215 immunology ,Nab-paclitaxel - Abstract
1070 Background: Although nab-paclitaxel (nab-PTX) has shown superior efficacy compared to conventional paclitaxel in metastatic breast cancer (MBC), chemotherapy induced peripheral neuropathy (CIPN) was more frequently observed in nab-PTX. In a single arm Phase 2 trail (CA002-0LD), low dose nab-PTX (175mg/m2) every 3 weeks (q3w) demonstrated a good objective response rate (39.5%) without grade 3 or higher CIPN. Herein, we conducted multicenter randomized controlled study to evaluate optimal dose of nab-PTX comparing lower dose (LD or MD) to standard dose (SD). Methods: This study compared three different doses of q3w nab-PTX (SD: 260 mg/m2 vs. MD: 220 mg/m2 vs. LD: 180 mg/m2) in patients with HER2 negative metastatic breast cancer. Primary endpoint was progression-free survival (PFS). Grade 3/4 neuropathy rates in the three doses are estimated by the logistic regression. Optimal dose was selected by 2 step selection. At first, if hazard ratio (HR) for PFS was less than 0.75 or more than 1.33, the inferior dose was dropped. Then, if estimated incidence rate of grade 3/4 neurotoxicity exceed10%, that dose was also dropped. This trial is registered with the University Hospital Medical Information Network (UMIN), Japan (protocol ID C000012429). Results: In this study, 141 patients were randomly assigned to SD (n = 47), MD (n = 46) or LD (n = 48). Median PFS was 6.66 vs 7.34 vs 6.82 months, respectively. HR was 0.73 (95% confidence interval (CI): 0.42-1.28) in MD vs SD. SD was dropped due to inferiority to MD. HR was 0.77 (95%CI 0.47-1.28) in LD vs SD, and 0.96 (95%CI 0.56-1.66) in LD vs MD. LD and MD were carried over to next step due to equivalence. Overall survival was not different among all dose arms. Rate of dose reduction by treatment course was significantly higher in SD arm. Estimated incidence of grade 3/4 neurotoxicity rate was 29.5% in SD, 14.0% in MD and 5.9% in LD. Final selected dose was LD 180mg/m2. HR-QOL results will be presented. Conclusions: Low dose nab-PTX at 180 mg/m2/3 weeks could be an optimal dose with good clinical efficacy and tolerability for patients with MBC. Clinical trial information: C000012429.
- Published
- 2019
20. Regorafenib plus nivolumab in patients with advanced gastric (GC) or colorectal cancer (CRC): An open-label, dose-finding, and dose-expansion phase 1b trial (REGONIVO, EPOC1603)
- Author
-
Hiroyoshi Nishikawa, Takashi Kojima, Yuichi Mikamoto, Shogo Nomura, Akihito Kawazoe, Takako Yoshii, Kohei Shitara, Akihiro Sato, Hitomi Tamura, Yosuke Togashi, Daisuke Kotani, Ayako Sugama, Naoki Takahashi, Masako Asayama, Shota Fukuoka, Masashi Wakabayashi, and Hiroki Hara
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Colorectal cancer ,Expansion phase ,medicine.disease ,03 medical and health sciences ,chemistry.chemical_compound ,Dose finding ,0302 clinical medicine ,Immune system ,chemistry ,030220 oncology & carcinogenesis ,Regorafenib ,Internal medicine ,Medicine ,In patient ,Nivolumab ,Open label ,business ,030215 immunology - Abstract
2522 Background: Immune suppressive cells such as regulatory T cells (Tregs) or tumor-associated macrophages (TAMs) may contribute to resistance to anti-PD-1/PD-L1 inhibitors (A-PD1). Regorafenib, a potent inhibitor of angiogenic and oncogenic kinases, reduced TAMs in tumor models. The combination of regorafenib plus A-PD1 exhibited superior tumor growth suppression compared to either treatment alone in murine models. Methods: In this study, we enrolled patients (pts) with previously treated, advanced GC or CRC. The pts received regorafenib plus nivolumab in a dose-finding phase to estimate the maximum tolerated dose (MTD). Additional pts were enrolled in a dose-expansion phase to further establish the safety and determine the preliminary efficacy. Regorafenib of 80 to 160 mg was administered once daily for 21 on 7 days off with intravenous nivolumab 3 mg/kg every 2 weeks. The primary endpoint was dose-limiting toxicity (DLT) during cycle one (4 weeks) to estimate the MTD and the recommended dose. Results: Fifty pts were enrolled (25 GC; 25 CRC) until October 2018. The median prior treatment line was 3 (range 2-8). During dose-escalation, 3 DLTs were observed with regorafenib 160 mg, including grade (G) 3 maculopapular rash, mucositis and proteinuria, while there was no DLT with 80 or 120 mg. In the dose expansion cohort with regorafenib 120 mg, the dose was reduced to 80 mg owing to frequent G3 skin toxicities. Grade ≥ 3 treatment related adverse events occurred in 17 pts; the common events ( > 5%) being rash (14%), palmar-plantar erythrodysesthesia (10%), and proteinuria (8%). Objective tumor response was observed in 19 pts (38%) including 11 MSS GC, 7 MSS CRC and 1 MSI-H CRC for response rates of 44% in GC and 29% in MSS CRC. Three of the 7 A-PD1 pretreated GC pts achieved a partial response. The pre- and post-treatment tumor samples showed a reduction of FoxP3hiCD45RA-Tregs fraction at the tumor response. Conclusions: The combination of regorafenib 80mg plus nivolumab had a manageable safety profiles and encouraging anti-tumor activity in MSS GC and CRC pts, which warrants further investigations in a larger cohort. Updated biomarker analysis will be presented. Clinical trial information: NCT03406871.
- Published
- 2019
21. A dose-finding study of the SMAC mimetic Debio 1143 when given in combination with avelumab to patients with advanced solid malignancies
- Author
-
Diane Arndt, Scott A. Laurie, Glenwood D. Goss, Natalie Andrews Wright, Sergio Szyldergemajn, Rosalyn A. Juergens, Grégoire Vuagniaux, Frank Brichory, Peter M. Ellis, Daniela Purcea, Elisabeth Rouits, Michael B. Sawyer, Quincy Chu, Christian Kollmannsberger, Daniel J. Renouf, Elaine McWhirter, John Hilton, Bruno Gavillet, and Karen A. Gelmon
- Subjects
Cancer Research ,biology ,Activator (genetics) ,business.industry ,Smac mimetics ,Avelumab ,03 medical and health sciences ,Dose finding ,0302 clinical medicine ,Immune system ,Oncology ,Apoptosis ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,Medicine ,business ,Gene ,Caspase ,030215 immunology ,medicine.drug - Abstract
2599 Background: Second mitochondria-derived activator of caspase (SMAC) mimetics regulate apoptosis and modulate NFκB signaling which drives the expression of genes involved in immune and inflammatory responses. In patient (pt) tumors, Debio 1143 increased PD-1/PD-L1 expression and tumor infiltrating lymphocytes. In pre-clinical models, it synergizes in vitro and in vivo with PD1/PD-L1 checkpoint inhibitors (CPIs). Methods: In a phase I study, using a mCRM model, avelumab (10 mg/kg i.v. on D1&15 q4w) was combined with escalating doses of Debio 1143 (100 mg/d to 250 mg/d orally, D1-10 & D15-24 q4w) to define the RP2D. Consenting adult pts with advanced solid tumors, normal organ function, and PS-ECOG = 0-1 were eligible provided none received prior CPI. Dose-limiting toxicities (DLTs), efficacy, safety, PK, PD and biomarkers were assessed. Results: As of DEC’18, 16 pts were treated; M/F: 8/8; ECOG = 0 in 6 (38%); median age = 58 (28-79); 5 pts had NSCLC, 2 MPM, 2 ovarian and 7 had other tumors (n = 1 each). Common AEs were: nausea (69%); fatigue (62%); vomiting (50%); cough, dyspnea, myalgia (44% each); diarrhea, anorexia (38% each); pruritus and constipation (31% each). These were generally grade 1-2, occasionally grade 3. One pt had a DLT at 250 mg/d dose: a grade 3 AST/ALT increase. No treatment-related AEs grade 4 or higher occurred. No dose-relationships for laboratory abnormalities were observed, except for ALT/AST increases, which at 200 mg/d were all grade 1 and asymptomatic. Maximal tolerated dose was not reached and there were no dose reductions. In 15 evaluable pts, 1 PR (NSCLC) and 5 SD (RECIST v1.1) were observed. Tumor shrinkage > 15% was seen in 2 other NSCLC pts. PK showed high interpatient variability and dose-proportional increase. TNFα and IFNγ peaked in plasma following Debio 1143 dose on D1 after 8 hrs, and on D17/22, in a dose-proportional manner. Four pts developed anti-avelumab antibodies. Conclusions: Debio 1143 at 200 mg/d can be safely combined with avelumab. Toxicity was predictable and mild. Clinical activity was observed in NSCLC pts. PK was linear; no drug interaction was suspected. PD and biomarker analysis is ongoing. Expansion at this RP2D is ongoing in NSCLC. Clinical trial information: NCT03270176.
- Published
- 2019
22. Results of the dose-finding phase of ARST 1321 from the Children's Oncology Group and NRG Oncology: Neoadjuvant chemoradiation or radiation therapy +/- pazopanib in non-rhabdomyosarcoma soft tissue sarcomas
- Author
-
Dian Wang, Douglas S. Hawkins, Yueh-Yun Chi, R.L. Randall, Mark Kayton, Eduardo Zambrano, Yen-Lin Chen, Sheri L. Spunt, Andrew Ostrenga, Jennifer M. Black, Thomas J. Scharschmidt, Aaron R. Weiss, Scott H. Okuno, Simon C. Kao, Stephanie A. Terezakis, and Edwin Choy
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,medicine.drug_class ,medicine.medical_treatment ,Soft tissue ,medicine.disease ,Tyrosine-kinase inhibitor ,Radiation therapy ,Pazopanib ,03 medical and health sciences ,Dose finding ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,Medicine ,Cooperative group ,business ,Rhabdomyosarcoma ,030215 immunology ,medicine.drug - Abstract
11070 Background: Pazopanib is a tyrosine kinase inhibitor approved globally for advanced soft tissue sarcomas. The dose finding phase of this cooperative group trial assessed the dose limiting toxicities (DLT) and the maximally tolerated dose (MTD) of adding pazopanib to neoadjuvant chemoradiation or radiation therapy in children and adults with unresected intermediate/high-risk trunk and extremity non-rhabdomyosarcoma soft tissue sarcomas (NRSTS). Methods: ARST1321, a jointly designed intergroup study lead by Children's Oncology Group and NRG Oncology opened for enrollment in July 2014. Eligible adult and pediatric patients with newly diagnosed, unresected trunk/extremity NRSTS with plans for primary tumor resection were enrolled into either the Chemotherapy Cohort (those with chemosensitive NRSTS > 5 cm, grade 3, including all synovial sarcoma) or the Non-Chemotherapy Cohort (those with chemotherapy insensitive NRSTS of any size, grade 2/3, or any chemosensitive NRSTS for whom no chemotherapy was planned per discretion of patients and treatment teams). In the Chemotherapy Cohort, pazopanib was given with ifosfamide (7.5 grams/m2) and doxorubicin (75 mg/m2) plus 45 Gy preoperative RT starting after cycle 2. Primary tumor was resected at week 13, followed by chemotherapy and pazopanib to week 25. In the Non-Chemotherapy Cohort, pazopanib was given with 50 Gy preoperative RT, primary tumor was resected at week 10, and pazopanib continued to week 25. Feasibility was assessed through week 6 of therapy to determine pazopanib dose escalation/de-escalation based on DLT, total doses of pazopanib, and overall adverse event profile. Results: In the Chemotherapy Cohort, MTD was reached at Dose Level 1 (350 mg/m2 peds; 600 mg adults) with two DLTs (1 grade 3 ALT rise, 1 intolerability to therapy) in 10 patients. In the Non-Chemotherapy Cohort, 11 patients enrolled at Dose Level 1 (350 mg/m2 peds; 600 mg adults) without any observed DLTs and all received ≥75% of prescribed total pazopanib dose; MTD was reached at Dose Level 2 (450 mg/m2 peds; 800 mg adults) with 2 DLTs in ten patients enrolled (1 grade 3 dermatitis and 1 intolerability to therapy) and 9/10 receiving ≥75% of full dose. Conclusions: Pazopanib in combination with chemoradiation or radiation therapy alone was found to be safe in children and adults with NRSTS. Following this finding, ARST1321 opened in both arms using the newly determined pazopanib MTDs. Clinical trial information: NCT02180867.
- Published
- 2019
23. A phase I dose-finding and pharmacokinetics study of CPC634 (nanoparticle entrapped docetaxel) in patients with advanced solid tumors
- Author
-
Florence Atrafi, Herlinde Dumez, Jo Costermans, Ron H.J. Mathijssen, Ferry A.L.M. Eskens, Rob Hanssen, Cristianne J.F. Rijcken, Catharina Wilhelmina Menke, and Patrick Schöffski
- Subjects
Cancer Research ,business.industry ,Nanoparticle ,Pharmacology ,03 medical and health sciences ,Dose finding ,0302 clinical medicine ,Oncology ,Pharmacokinetics ,Docetaxel ,030220 oncology & carcinogenesis ,Phase (matter) ,medicine ,In patient ,business ,030215 immunology ,medicine.drug - Abstract
3026 Background: CPC634 is a novel product with docetaxel temporarily entrapped within stabilized CriPec nanoparticles. We performed the first-in-human study with CPC634 (NCT02442531). Methods: Patients (≥18 years) received CPC634 intravenously either 3-weekly (Q3W) (part 1, 15-100 mg/m2), 2-weekly (Q2W) (part 2, 45 mg/m2) or Q3W with dexamethasone premedication (part 3) following a 3+3 design. Primary objectives were to assess safety, establish the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), and to evaluate the pharmacokinetic (PK) profile of CPC634. Results: Thirty-three patients (part 1; n = 24, part 2; n = 3, part 3; n = 6) were treated. Skin toxicity was dose limiting at doses > 60 mg/m2 in part 1, and at a 45 mg/m2 dose in part 2. Skin toxicity was cumulative but resolved after ceasing treatment. The MTD in part 1 was set at 70 mg/m2. In part 3, the 60 mg/m2 was explored which resulted in improved skin tolerability even after repeated administrations without dose limiting toxicities. The RP2D was therefore set at 60 mg/m2 with dexamethasone premedication. Grade ≥3 adverse events (CTCAE version 4.03) were skin toxicity (21%), fatigue (8%), neutropenia (6%), peripheral sensory (8%) and motor neuropathy (4%), stomatitis (4%), infections (4%) and hypomagnesemia (3%). Alopecia grade 1 was reported in 15% of patients. CPC634 exhibited a dose-proportional PK profile. One partial response and sixteen cases of stable disease (RECIST 1.1) were confirmed in part 1 and in part 3 as best response. Conclusions: CPC634 could be administered safely but showed cumulative, though reversible skin toxicity at high doses. The RP2D was set at 60 mg/m2 Q3W with dexamethasone premedication. Additional studies assessing the intratumoral exposure to CPC634 (NCT0371243) and a phase II efficacy study of CPC634 in patients with platinum resistant ovarian cancer (NCT03742713) is currently ongoing. Clinical trial information: NCT02442531.
- Published
- 2019
24. Mortality and survival rates in children and adolescents enrolled in early phase trials with a dose-finding/dose-confirmation component: An innovative therapies for children with cancer (ITCC) study
- Author
-
Ajla Wasti, Loredana Amoroso, Gerard Millen, Francisco Bautista, Franca Fagioli, Marta Cortes, Lynley V. Marshall, Luca Bergamaschi, Aurore Surun, Gabriel Revon-Riviere, Gilles Vassal, Fernando Carceller, Jasper Van der Lugt, Alicia Castañeda, Antonio Juan Ribelles, Michel Zwaan, Quentin Campbell Hewson, Birgit Geoerger, Andrew D.J. Pearson, and Lucas Moreno
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Cancer ,Phase i trials ,medicine.disease ,Dose finding ,Innovative Therapies ,Internal medicine ,medicine ,Early phase ,business ,Inclusion (education) - Abstract
e21509 Background: Participation of children with advanced solid cancers in phase I trials raises ethical and logistic dilemmas. Life-expectancy beyond 8-12 weeks is a common inclusion criterion, but it can be difficult to gauge. This multicentric European study assessed the mortality and survival rates in pediatric phase I trials. Methods: Retrospective study of patients aged < 18 years with solid tumors enrolled in phase I trials in ITCC centres between 2015-2017. Outcome variables were described and prognostic factors analysed. Results: 256 patients across 12 centres in 5 countries were eligible. Median age 11.8 years (range, 0.5-17.9). Female:Male ratio 1:1.9. Tumor location: central nervous system (CNS) 66% vs extra-CNS 34%. Main diagnoses: 22% soft tissue sarcomas, 13% high grade gliomas, 11% osteosarcomas. Most frequent therapy: single targeted agent (63%). Ten cases (4%) were not evaluable for response and 128 (50%) had progressive disease at first evaluation. Best responses were complete in 12 cases (5%), partial in 29 (11%) and stable disease in 77 (30%). Median follow-up 7 months (range, 0.5-42.4). Median Time On Study (TOS) 2.1 months (range, 0.2-38.1). The 30 and 90-day mortality on trial were 3% (8/256) and 21% (54/256), respectively. The 90-day survival (95%CI) for patients with CNS vs extra-CNS tumors was 88% (78-93) vs 76% (68-82), respectively. One-year Overall Survival (95%CI) for the whole sample was 40% (33-46). No toxic deaths on trial were reported. Twenty-five cases (10%) survived ≥365 days on trial. Median TOS 21.5 months (range, 12.3-38.1). Compared to patients who died within 365 days from Cycle1-Day1, those on trial ≥365 days had lower rates of metastatic disease (74% vs 28%, respectively, p < 0.001), higher objective response rates (13% vs 44%, respectively, p < 0.001) and higher disease stabilization (27% vs 56%, respectively, p < 0.001). Conclusions: Currently few patients die within the first cycle of treatment. However a fifth of all patients died within 3 months from trial initiation. Patients with CNS tumors have comparable survival rates to those with extra-CNS and should not be excluded from phase I trials solely because of their diagnosis. The survival rates beyond one year remain modest.
- Published
- 2019
25. A phase II, dose finding, placebo-controlled, study of zuclomiphene citrate to amerliorate the frequency and severity of hot flashes caused by androgen deprivation in men with advanced prostate cancer
- Author
-
Robert H. Getzenberg, Fisch Harry, Michael L. Hancock, D. Rodriguez, and Mitchell S. Steiner
- Subjects
ZUCLOMIPHENE CITRATE ,Cancer Research ,medicine.medical_specialty ,business.industry ,medicine.drug_class ,Placebo-controlled study ,medicine.disease ,Androgen ,Androgen deprivation therapy ,Prostate cancer ,Dose finding ,Endocrinology ,Oncology ,Estrogen ,Internal medicine ,Medicine ,business ,Testosterone - Abstract
TPS338 Background: Androgen deprivation therapy (ADT) is the mainstay of treatment for advanced prostate cancer. ADT not only lowers testosterone, but also decreases estrogen levels which can cause significant side effects including hot flashes, loss of bone and bone fractures, and decreases in libido. Up to 80% of the men on ADT report hot flashes and 30-40% of men have moderate to severe hot flashes. Concern over hot flashes make patients less likely to begin ADT and can lead to early discontinuation of ADT. While the off-label use of potent steroidal estrogens has demonstrated efficacy, the appropriate dose as well as dosing route or schedule of these potent estrogens, has not been established. Furthermore, the potential for safety issues with potent steroidal estrogens remains a significant limitation to their clinical utility. Zuclomiphene citrate, is novel weak nonsteroidal estrogenic agent that should ameliorate hot flashes caused by ADT, and as one of the isomers of clomiphene, has a 50 year safety history of being well tolerated in men. Methods: The Phase 2, placebo controlled, dose finding clinical trial (V72203) evaluating zuclomiphene citrate (VERU-944) capsules, oral daily dosing, for the treatment of moderate to severe hot flashes in men with prostate cancer on ADT is in progress. Men are randomized to daily doses of placebo or zuclomiphene 10mg, 50mg or 100mg. V72203 is enrolling approximately 36 men per arm in 10 sites in the United States. The primary efficacy endpoint is the mean change in frequency of moderate and/or severe hot flashes from baseline to week 4 and maintained until week 12. Secondary endpoints include changes from baseline in bone turnover markers, free and total testosterone, SHBG, PSA, and safety. Hot flashes are being measured in real time utilizing an electronic data capture device (ePRO) provided to each subject. We anticipate completion of enrollment by the end of 2018 with study results by second quarter of 2019. Clinical trial information: NCT03646162.
- Published
- 2019
26. Dose-finding and single-arm confirmatory study of definitive chemoradiotherapy (dCRT) with S-1/mitomycin-C (MMC) in patients (pts) with clinical (c) stage II/III squamous cell carcinoma of the anal canal (SCCA): JCOG0903
- Author
-
Yukihide Kanemitsu, Hiroshi Katayama, Manabu Shiozawa, Takeshi Kodaira, Fumio Ishida, Atsuo Takashima, Takahisa Matsuda, Masahiko Watanabe, Yasuhiro Shimada, Yoshinori Ito, Makoto Kinouchi, Haruhiko Fukuda, Kohei Murata, Tetsuya Hamaguchi, Yoshihisa Saida, Fumihiko Fujita, Yoshihiro Moriya, Gen Iinuma, Masayuki Ohue, and Junki Mizusawa
- Subjects
Cancer Research ,medicine.medical_specialty ,business.industry ,Standard treatment ,Mitomycin C ,Definitive chemoradiotherapy ,Anal canal ,Stage ii ,Gastroenterology ,03 medical and health sciences ,Dose finding ,0302 clinical medicine ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,In patient ,Radiosensitivity ,business ,030215 immunology - Abstract
686 Background: dCRT with 5-FU/MMC is a standard treatment for cStage II/III SCCA. S-1 is an oral fluoropyrimidine and has a greater effect on radiosensitivity. We conducted this trial of dCRT with S-1/MMC to determine the recommended dose (RD) of S-1 in phase I part (P I) and to evaluate the efficacy and safety in phase II part (P II) for cStage II/III SCCA. When the primary endpoint in P II part is proven to be satisfactory, we can regard this combined treatment as the new standard treatment. Methods: Eligibility criteria included histologically proven SCCA, cStage II/III (UICC 6th), PS 0-1, and age 20-80 years. dCRT consisted of MMC (10 mg/m2 on days 1, 29) and S-1 (60 mg/m2/d in level 0 and 80 mg/m2/d in level 1 on days 1-14, 29-42) with concurrent 3-dimensional RT of 59.4 Gy/33fr. The P I adopted the 3+3 cohort design. The primary endpoint of P II was proportion of 3-year event-free survival (% 3-year-EFS). The sample size was 65 in the P II, with one-sided alpha of 5% and power of 80%, threshold and expected % 3-year EFS as 60% and 75%. Results: From Feb/2010 to Mar/2015, 69 pts (3 in level 0 and 66 [7 in P I and 59 in P II] in level 1) were enrolled. Pts’s backgrounds for level 1 were as follows: M/F, 12/54; Age, median 64 (range 33-80); cStage II/IIIA/IIIB, 29/9/28. Three in level 1 were ineligible and 63 eligible assigned to level 1 were included in efficacy analysis. In the P I, considering the details of DLTs, RD of S-1 was determined as 80 mg/m2/d. In the 63 eligible of level 1, %3-year EFS was 65.0% (90% CI 54.1-73.9%). % 3-year OS, PFS, and colostomy-free survival were 87.3% (95% CI 76.2-93.4%), 85.7% (74.3-92.3%), and 76.2% (63.7-84.9%), respectively. The complete response rate was 81% on central review. Among 65 pts receiving level 1 dCRT, common grade 3 or 4 acute toxicities were leukopenia (63.1%), neutropenia (40%), diarrhea (20%), radiation dermatitis (15.4%), and febrile neutropenia (3.1%). Only 6 (9.2%) showed grade 3 late toxicities. No treatment-related deaths were observed. Conclusions: Although dCRT with S-1/MMC showed acceptable toxicities and favorable 3-year survival, this study did not meet its primary endpoint. Clinical trial information: UMIN000003237.
- Published
- 2019
27. A dose-finding study for irinotecan, cisplatin, and S-1 (IPS) in patients with advanced gastric cancer (OGSG 1106)
- Author
-
Yukinori Kurokawa, Masahiro Goto, Tetsuji Terazawa, Hiroki Yukami, Hitoshi Nishitani, Toshio Shimokawa, Yoshihiro Matsubara, Toshifumi Yamaguchi, Taroh Satoh, Daisuke Sakai, Fukutaro Shimamoto, Hisato Kawakami, and Takayuki Kii
- Subjects
Oncology ,Cisplatin ,Cancer Research ,medicine.medical_specialty ,business.industry ,Advanced gastric cancer ,Irinotecan ,First line treatment ,Dose finding ,Internal medicine ,medicine ,In patient ,business ,medicine.drug - Abstract
144 Background: In Japan, S-1 plus cisplatin is regarded as one of the standard first line treatment of advanced gastric cancer (AGC). However, the prognosis of AGC remains dismal. The development of more effective chemotherapeutic regimen is thus warranted. A combination of irinotecan, cisplatin, and S-1 (IPS) can be a promising triplet therapy for advanced gastric cancer. We conducted a phase I study of IPS to determine the dose-limiting toxicity (DLT), maximum-tolerated dose (MTD) and recommended dose (RD), and to assess its safety and antitumor activity in patients with AGC. Methods: This phase I study was designed and conducted in a 3 + 3 manner to determine the recommended dose (RD) of IPS for the subsequent phase II study. Patients received an escalating dose of intravenous irinotecan (level 1: 100/level 2: 125/level 3: 150 mg/m²) on day 1, a fixed dose of intravenous cisplatin (60 mg/m²) on day 1, a fixed dose of S-1 (80 mg/m² b.i.d.) orally on days 1-14, every 4 weeks. Results: Twelve patients were enrolled between June 2013 and February 2017. During the first cycle, one of the six patients in level 1 and two of six patients in level 2 developed the DLT (grade 4 leucocytopenia and grade 3 febrile neutropenia). The MTD of irinotecan was 125 mg/m 2 (level 2) and the RD of irinotecan was considered to be 100 mg/m² (level 1). The most common grade 3 or 4 adverse events included neutropenia 75 % (9/12), anemia 25% (3/12), anorexia 8% (1/12), and febrile neutropenia 17% (2/12). Among six patients with measurable lesions, the response rate was 66.7% (4/6) [95% CI, 33.3-90.7%]. Two patients were performed R0 resection after IPS, with one patient achieved pathological complete response. The median survival time is under analysis. Conclusions: RD of IPS was determined to be 100 mg/m² of irinotecan, 60 mg/m² of cisplatin, and 80 mg/m² of S-1. Our data showed that this regimen provided acceptable antitumor activity and a favorable toxicity profile. Further evaluation of this regimen is warranted. Clinical trial information: UMIN000006864.
- Published
- 2019
28. Preliminary results of the first-in-human, dose-finding PROCLAIM-CX-072 trial of the PD-L1 Probody therapeutic CX-072 as monotherapy in patients (pts) with advanced solid tumors
- Author
-
Mark Stroh, Karen A. Autio, Matthias Will, Rachel Humphrey, Beiyao Zheng, Valentina Boni, James Strauss, Johanna C. Bendell, Luc R. Desnoyers, Amy Weise, Naiyer A. Rizvi, Bert H. O'Neil, Alexander I. Spira, Nataliya Volodymyrivna Uboha, Lori Carman, Anthony B. El-Khoueiry, Aung Naing, and Hendrik-Tobias Arkenau
- Subjects
Cancer Research ,biology ,business.industry ,First in human ,030226 pharmacology & pharmacy ,Programmed cell death ligand 1 ,03 medical and health sciences ,Dose finding ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,PD-L1 ,biology.protein ,Cancer research ,Medicine ,In patient ,Antibody ,business - Abstract
3071Background: In single-agent trials, antibodies (Abs) targeting programmed cell death ligand 1 (PD-L1) improve survival in many cancers but are associated with immune-related toxicities (most co...
- Published
- 2018
29. Phase I dose finding study for melatonin in paediatric oncology patients with relapsed solid tumors
- Author
-
Donna L. Johnston, Darcy Nicksy, Susan Zupanec, Rebecca J. Deyell, Sylvain Baruchel, Yvan Samson, Daniel A. Morgenstern, and Aru Narendran
- Subjects
Oncology ,endocrine system ,Cancer Research ,medicine.medical_specialty ,business.industry ,Paediatric oncology ,Advanced cancer ,Melatonin ,03 medical and health sciences ,Dose finding ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,030212 general & internal medicine ,business ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug - Abstract
e22514Background: Melatonin is a natural health product currently used for the treatment of sleep disturbances and fatigue. In preliminary studies of adults with advanced cancer, melatonin at a dos...
- Published
- 2018
30. Single-agent expansion cohort of lenvatinib (LEN) and combination dose-finding cohort of LEN + etoposide (ETP) + ifosfamide (IFM) in patients (pts) aged 2 to ≤25 years with relapsed/refractory osteosarcoma (OS)
- Author
-
Corina E. Dutcus, Michela Casanova, Quentin Campbell-Hewson, Claudia Rossig, Silvija Kraljevic, Adela Cañete, Soledad Gallego Melcon, Sandra J. Strauss, Isabelle Aerts, Bruce Morland, Seiichi Hayato, Marion Gambart, Francisco José Bautista Sirvent, Nathalie Gaspar, Stefan S. Bielack, Cixin He, Perrine Marec-Berard, Estelle Thebaud, Franco Locatelli, and Rajkumar Venkatramani
- Subjects
0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Ifosfamide ,business.industry ,medicine.disease ,03 medical and health sciences ,chemistry.chemical_compound ,Dose finding ,030104 developmental biology ,0302 clinical medicine ,chemistry ,030220 oncology & carcinogenesis ,Internal medicine ,Cohort ,Relapsed refractory ,medicine ,Osteosarcoma ,In patient ,Lenvatinib ,business ,Etoposide ,medicine.drug - Abstract
11527Background: LEN is a multikinase inhibitor of VEGFR1-3, FGFR1-4, PDGFRα, KIT, and RET. In human pediatric OS xenograft models, LEN enhanced the antitumor activity of IFM + ETP. In a phase (Ph)...
- Published
- 2018
31. Dose finding study of varlitinib ± trastuzumab with carboplatin/paclitaxel in advanced solid tumors
- Author
-
Lingzhi Wang, Matilda Lee, Raghav Sundar, Andrea Li Ann Wong, Cheng Ean Chee, Joline Si Jing Lim, Siew Eng Lim, David Shao Peng Tan, Ying-Chen Chen, Valerie Heong, Ross A. Soo, Wei Peng Yong, Samuel Guan Wei Ow, Boon Cher Goh, and Soo-Chin Lee
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,animal structures ,business.industry ,VARLITINIB ,Carboplatin/paclitaxel ,Dose finding ,Trastuzumab ,Internal medicine ,medicine ,business ,medicine.drug - Abstract
2588Background: Varlitinib (V) is a reversible inhibitor of HER1/HER2/HER4. This is a phase 1b dose confirmation study to determine safety and early efficacy signals of V ± T combined with weekly P...
- Published
- 2018
32. FIGHT: A phase 3 randomized, double-blind, placebo controlled study evaluating (bemarituzumab) FPA144 and modified FOLFOX6 (mFOLFOX6) in patients with previously untreated advanced gastric and gastroesophageal cancer with a dose finding phase 1 lead-in
- Author
-
Aaron Scott, Anteneh Tesfaye, Eric Cheung, Mohamedtaki Abdulaziz Tejani, Neyssa Marina, Janine Powers, Peter D. Eisenberg, Peter C. Enzinger, Daniel V.T. Catenacci, Charlie Zhang, and Clarence Eng
- Subjects
Cancer Research ,medicine.medical_specialty ,business.industry ,Placebo-controlled study ,Cancer ,medicine.disease ,Gastroenterology ,FGFR2 Gene Amplification ,Double blind ,03 medical and health sciences ,Dose finding ,0302 clinical medicine ,Gastroesophageal cancer ,Oncology ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,In patient ,030223 otorhinolaryngology ,business ,Lead (electronics) - Abstract
TPS4135Background: FGFR2b overexpression and FGFR2 gene amplification occurs in approximately 10% of patients with gastric cancer (GC) and is associated with a poor prognosis and the presence of me...
- Published
- 2018
33. A phase 1/2 study of relacorilant + nab-paclitaxel (nab-pac) in patients (pts) with solid tumors: The dose-finding phase
- Author
-
Gini F. Fleming, Stacie Peacock Shepherd, Jasgit C. Sachdev, Pamela N. Munster, and Thaddeus Block
- Subjects
Cancer Research ,business.industry ,fungi ,Antagonist ,food and beverages ,030226 pharmacology & pharmacy ,03 medical and health sciences ,Dose finding ,0302 clinical medicine ,Glucocorticoid receptor ,Oncology ,030220 oncology & carcinogenesis ,parasitic diseases ,Cancer research ,Medicine ,In patient ,business ,Chemotherapy resistance ,Nab-paclitaxel - Abstract
2554Background: Glucocorticoid receptor (GR) expression has been linked with chemotherapy resistance. Nonclinical and clinical studies have suggested that a GR antagonist (GRA) can enhance the effi...
- Published
- 2018
34. A phase I dose-finding study of metformin in combination with concurrent cisplatin and radiation in patients with locally advanced head and neck squamous cell carcinoma
- Author
-
J. Silvio Gutkind, Shuchi Gulati, Nooshin Hashemi Sadraei, Sarah Palackdharry, Changchun Xie, Muhammad Kashif Riaz, Vinita Takiar, Michelle Mierzwa, Pankaj B. Desai, Trisha Wise-Draper, Benyamin Yaniv, and John C. Morris
- Subjects
Oncology ,Cisplatin ,Cancer Research ,medicine.medical_specialty ,business.industry ,Locally advanced ,medicine.disease ,Head and neck squamous-cell carcinoma ,Metformin ,Dose finding ,Internal medicine ,Locally advanced disease ,medicine ,In patient ,business ,medicine.drug - Abstract
6074Background: Up to 60% of HNSCC present as locally advanced disease (LAHNSCC). Although prognosis has improved significantly, 3 year PFS and OS remain at 62%, and 73% respectively (RTOG 0522) de...
- Published
- 2018
35. Preliminary interim results of the first-in-human, dose-finding PROCLAIM-CX-072 trial of the PD-L1 Probody therapeutic (Pb-Tx) CX-072 in combination with ipilimumab (ipi) in patients (pts) with advanced solid tumors
- Author
-
Rachel Humphrey, Fiona C Thistlethwaite, Beiyao Zheng, Elisabeth G.E. de Vries, Javier Garcia Corbacho, Anthony B. El-Khoueiry, Matthias Will, Karen A. Autio, Rachel E. Sanborn, Morganna Freeman, Elizabeth Ruth Plummer, Vanessa Huels, Nataliya Volodymyrivna Uboha, Catharina Wilhelmina Menke, Patricia LoRusso, Hendrik-Tobias Arkenau, and Jerzy Wydmański
- Subjects
Cancer Research ,Proteases ,biology ,business.industry ,Ipilimumab ,Healthy tissue ,First in human ,030226 pharmacology & pharmacy ,Programmed cell death ligand 1 ,03 medical and health sciences ,Dose finding ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,PD-L1 ,Cancer research ,biology.protein ,Medicine ,In patient ,business ,medicine.drug - Abstract
3072Background: CX-072 is a Pb-Tx directed against programmed cell death ligand 1 (PD-L1), designed to be preferentially activated by tumor-associated proteases but not in healthy tissue. Preclinic...
- Published
- 2018
36. Pilot trial of ibrutinib plus nivolumab in patients (pts) with metastatic renal cell cancer (mRCC): Results from a dose-finding cohort
- Author
-
Daniel Robles, Mamta Parikh, Chong-Xian Pan, Primo N. Lara, Frances Lara, and Frederick J. Meyers
- Subjects
0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Immune checkpoint inhibitors ,Pilot trial ,030232 urology & nephrology ,03 medical and health sciences ,chemistry.chemical_compound ,Dose finding ,030104 developmental biology ,0302 clinical medicine ,chemistry ,Ibrutinib ,Internal medicine ,Cohort ,medicine ,In patient ,Nivolumab ,Metastatic renal cell cancer ,business - Abstract
600 Background: Immune checkpoint inhibitor therapy (CPI) has transformed the management of pts with mRCC, with a fraction experiencing durable tumor responses. However, most eventually develop disease progression after either an initial response to CPI or while on CPI. Newer agents that modulate immune response can possibly potentiate CPI therapy. The ITK/ETK/BTK inhibitor ibrutinib has been reported to inhibit myeloid derived suppressor cells in preclinical models and to potentiate CPI. We conducted an investigator-initiated pilot trial of ibrutinib plus the PD1 inhibitor nivolumab in mRCC pts, particularly in those previously exposed to CPI. Here we report initial safety and efficacy results from the dose-finding cohort. Methods: Pts with mRCC of any histologic subtype and who have completed at least one line of prior systemic therapy including prior CPI were eligible. Pts must have acceptable end-organ function and Zubrod PS of 0-2. Treatment consisted of nivolumab 240 mg IV q2 weeks plus ibrutinib 560 mg (dose level 0) or 420 mg (dose level -1) orally once daily. Cycle length was 28 days. Dose limiting toxicity (DLT) was defined as any Grade(Gr) 3+ adverse event (AE) attributable to therapy. Results: As of 9/18/17, 12 pts have been enrolled, six to each dose level. Patient characteristics: Mean age = 62 years (range 44-78); Male sex = 7 (58%); White race = 9 (75%); Prior CPI = 11 (92%). Three pts experienced one DLT each in dose level 0 (all Gr3): elevated lipase, hypoalbuminemia, & nausea. Only 1 DLT has been seen thus far in dose level -1 (Gr3 infection). The most common Gr3+ AEs include anemia (n = 5), ALT elevation (4), AST elevation (3), nausea (3), hypoalbuminemia (2), esophagitis, infection, lipase increase, and vomiting (1 each). Two pts with prior CPI had partial tumor response (1 confirmed, 1 unconfirmed). Conclusions: Ibrutinib at a dose of 420mg orally once daily in combination with nivolumab 240mg IV q 2 weeks appears feasible and tolerable in mRCC patients. No unique immune-related AEs have been seen thus far. Anti-tumor activity was seen in 2 pts previously exposed to PD1-targeted therapy. Further evaluation of this combination is warranted. (Supported by Pharmacyclics and UCDCCC). Clinical trial information: NCT02899078.
- Published
- 2018
37. Downstaging of unresectable intrahepatic or hilar cholangiocellular carcinoma by selective intra-arterial floxuridine and systemic cisplatin and gemcitabine. A dose finding single center phase IIa study
- Author
-
Heike Pietge
- Subjects
0301 basic medicine ,Cisplatin ,Cancer Research ,medicine.medical_specialty ,Poor prognosis ,business.industry ,Single Center ,Gemcitabine ,03 medical and health sciences ,Dose finding ,030104 developmental biology ,0302 clinical medicine ,Oncology ,Cholangiocellular carcinoma ,Floxuridine ,medicine ,Intra arterial ,030211 gastroenterology & hepatology ,Radiology ,business ,medicine.drug - Abstract
478 Background: Patients with unresectable cholangiocarcinomas (CCC) have a poor prognosis even if palliative systemic chemotherapy is offered. A combined approach of systemic and intrahepatic chemotherapy may improve local control rates and allow downstaging. The aim of the study was to determine the maximum tolerated dose (MTD) of systemic intravenous gemcitabine in combination with intravenous cisplatin and hepatic arterial infusion with floxuridine in patients with unresectable intrahepatic or hilar CCC. Safety, toxicity, response rates and resectability rates after 3 months of combination treatment are reported. Methods: 12 patients were treated within a 3+3 dose escalation algorithm with 600, 800 or 1000 mg/m2 gemcitabine and a fixed dose of cisplatin 25 mg/m2 systemic chemotherapy on day 1, 8 every 3 weeks for 4 cycles and floxuridine 0,2 mg/kg on day 1-14 continous hepatic intra-arterial chemotherapy every 4 weeks for 3 cycles. PET/CT and/or CT scan was performed after 12 weeks. Results: The MTD of gemcitabine was 800 mg/m2 in this setting. Dose-limiting toxicities were recurrent biliary tract infections (n = 1) and neutropenic fever (n = 1). Response rates were: 27% partial remission and 73% stable disease. Although none of the patients achieved resectability after 3 months, 3-year-overall survival (OS) was 33%, median OS 21,9 months (1-49) and median progression-free survival 10,5 months (2-40). Conclusions: Combination of systemic gemcitabine and cisplatin plus intraarterial floxuridine is feasible and appears effective in disease control, but achievement of resectability seems challenging. Randomized trials comparing this combination to gemcitabine/cisplatin alone are warranted. Clinical trial information: NCT01692704.
- Published
- 2018
38. Pharmacodynamic-Guided Modified Continuous Reassessment Method–Based, Dose-Finding Study of Rapamycin in Adult Patients With Solid Tumors
- Author
-
Heather A. Jacene, Michelle A. Rudek, Antonio Jimeno, Ming Zhao, Sharyn D. Baker, Daniel A. Laheru, Peter Kulesza, Ross C. Donehower, Manuel Hidalgo, Wells A. Messersmith, Jenna Wheelhouse, Anna Howard, Yasmin Khan, Elizabeth Garrett-Mayer, and Wen Wee Ma
- Subjects
Adult ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Maximum Tolerated Dose ,Pharmacology ,Drug Administration Schedule ,Dose finding ,Pharmacokinetics ,Neoplasms ,Internal medicine ,medicine ,Humans ,Aged ,Aged, 80 and over ,Sirolimus ,Antibiotics, Antineoplastic ,Dose-Response Relationship, Drug ,medicine.diagnostic_test ,Adult patients ,business.industry ,Middle Aged ,Phase I and Clinical Pharmacology ,Clinical trial ,Positron emission tomography ,Positron-Emission Tomography ,Pharmacodynamics ,Toxicity ,Leukocytes, Mononuclear ,Female ,business ,medicine.drug - Abstract
Purpose Pharmacodynamic studies are frequently incorporated into phase I trials, but it is uncommon that they guide dose selection. We conducted a dose selection study with daily rapamycin (sirolimus) in patients with solid tumors employing a modified continuous reassessment method (mCRM) using real-time pharmacodynamic data as primary dose-estimation parameter. Patients and Methods We adapted the mCRM logit function from its classic toxicity-based input data to a pharmacodynamic-based input. The pharmacodynamic end point was skin phospho-P70 change after 28 days. Pharmacodynamic effect was defined as at least 80% inhibition from baseline. The first two dose levels (2 and 3 mg) were evaluated before implementing the mCRM, and the data used to estimate the next dose level based on statistical modeling. Toxicity-based boundaries limited the escalation steps. Other correlates analyzed were positron emission tomography (PET) and computed tomography, pharmacokinetics, phospho-P70 in peripheral-blood mononuclear cells, and tumor biopsies in patients at the maximum-tolerated dose (MTD). Results Twenty-one patients were enrolled at doses between 2 and 9 mg. Pharmacodynamic effect occurred across dose levels, and toxicity boundaries ultimately drove dose selection. The MTD of daily oral rapamycin was 6 mg. Toxicities in at least 20% were hyperglycemia, hyperlipidemia, elevated transaminases, anemia, leucopenia, neutropenia, and mucositis. Pharmacokinetics were consistent with prior data, and exposure increased with dose. No objective responses occurred, but five previously progressing patients received at least 12 cycles. PET showed generalized stable or decreased glucose uptake unrelated to antitumor effect. Conclusion mCRM-based dose escalation using real-time pharmacodynamic assessment was feasible. However, the selected pharmacodynamic end point did not correlate with dose. Toxicity ultimately drove dose selection. Rapamycin is a well-tolerated and active oral anticancer agent.
- Published
- 2008
39. Novel phase 1a/1b dose-finding study design of CWP232291 (CWP291) in relapsed or refractory myeloma (MM)
- Author
-
Robert S Hauptschein, Elisabet E. Manasanch, Chang-Ki Min, Sung-Soo Yoon, Jae Kwang Chun, Jin Seok Kim, and Jeongeun Choi
- Subjects
0301 basic medicine ,Cancer Research ,business.industry ,Peptidomimetic ,Wnt signaling pathway ,Inhibitory postsynaptic potential ,Small molecule ,03 medical and health sciences ,Dose finding ,030104 developmental biology ,0302 clinical medicine ,Cyclin D1 ,Oncology ,Refractory ,030220 oncology & carcinogenesis ,Cancer research ,Medicine ,business ,Gene - Abstract
TPS8058 Background: CWP291, a novel peptidomimetic small molecule, has potent, selective inhibitory activity on a Wnt gene reporter, decreasing expression of β-catenin target genes, cyclin D1 and survivin. With broad anti-cancer efficacy in vitro, it significantly outperforms lenalidomide as a single agent combination in MM bone marrow engraftment models. Methods: This Phase 1a/1b study (NCT #02426723) was designed to define a well-tolerated dose of CWP291 as a single agent in subjects with R/R MM. CWP291 was administered IV over ≥30 minutes 2x weekly for 3 weeks out of a 4-week cycle, with standard 3+3 dose escalation design. But an important objective in terms of patient benefit and further clinical development was to explore activity of a combination regimen with lenalidomide. Thus, a novel study design allowed initiation of the Phase 1b as soon as CWP291 achieved a well-tolerated dose as a single agent. Combination therapy would start at one dose level lower. Enrollment of patients onto each arm was guided by Safety Review Committee assessments, including baseline laboratory values, performance status, extent of prior therapy, or prior adverse events related to lenalidomide. Results: Initiated September 2015, the starting dose was based on a prior Phase 1 study in AML, 198 mg/m2. There were 4 sites involved, and 11 patients enrolled over 12 months. Approval of the new design by regulatory authorities and IRBs was completed by November 2016. A well-tolerated single agent dose (297 mg/m2) was identified, allowing initiation of the Phase 1b at a dose of 198 mg/m2(one dose level lower) combined with lenalidomide. Four subjects were enrolled in ~2 months to the Phase 1b. Enrollment to both arms is continuing and the status of this study will be updated at presentation. Conclusions: The ability to consider combination therapy with a novel drug is clearly a motivation for patient participation in clinical trials; especially true in MM, as multiple new therapies are available. This trial design was approved and allowed based on assessment of individual patient safety and potential benefit. Rapid enrollment in the combination therapy arm may significantly foster development of novel agents with this study design. Clinical trial information: NCT #02426723.
- Published
- 2017
40. Dose finding study of the intratumoral administration of the oncolytic polio/rhinovirus recombinant (PVSRIPO) against WHO grade IV malignant glioma (MG)
- Author
-
Darell D. Bigner, Allan H. Friedman, Matthias Gromeier, James E. Herndon, John H. Sampson, Gordana Vlahovic, Frances McSherry, Katherine B. Peters, Annick Desjardins, Stevie Threatt, Henry S. Friedman, Denise Lally-Goss, Susan Boulton, Eric S. Lipp, Dina Randazzo, Elizabeth S Miller, and Chevelle Bullock
- Subjects
Cancer Research ,business.industry ,Heterologous ,Who grade ,medicine.disease ,medicine.disease_cause ,Virology ,law.invention ,Poliomyelitis ,Oncolytic virus ,Dose finding ,Oncology ,law ,Glioma ,Recombinant DNA ,medicine ,Rhinovirus ,business - Abstract
e13533 Background: The live attenuated oral poliovirus vaccine was modified to contain a heterologous internal ribosomal entry site stemming from human rhinovirus type 2, creating PVSRIPO. PVSRIPO recognizes CD155, an oncofetal cell adhesion molecule and tumor antigen widely expressed ectopically in malignancy. We report results of the dose finding trial evaluating PVSRIPO delivered intratumorally by convection-enhanced delivery (CED). Methods: Eligible patients were adults with recurrent supratentorial WHO grade IV MG; solitary tumor 1-5.5cm in diameter; ≥4 weeks after chemotherapy, bevacizumab or study drug; adequate organ function; KPS≥70%; and positive anti-polio titer. The original two-step continual reassessment method dose escalation was amended to decrease to dose level(DL) -1 and DL -2 after observing prolonged steroid use in patients treated on higher DLs. Results: As of 2/01/2017, 52 pts were treated on study (1 each at DL1 and DL3, 7 at DL2, 2 at DL4, 4 at DL5, 24 at DL -1 and 13 at DL -2). Only one DLT was observed, a grade 4 intracranial hemorrhage at the time of catheter removal on DL5. Grade 3 or higher adverse events possibly, probably or definitely related to PVSRIPO include: lymphopenia (grade 3, n = 1), steroid myopathy (grade 3, n = 1), cerebral edema (grade 4, n = 1), headache (grade 3, n = 1), dystonia (grade 3, n = 1), pyramidal tract syndrome (grade 3, n = 6), seizure (grade 3, n = 1; grade 4, n = 1), delusions (grade 3, n = 1), hypertension (grade 3, n = 1), and thromboembolic events (grade 3, n = 2). At a median follow-up of 20.1 months, 20.8% of pts remain alive at 36-month post PVSRIPO infusion, compared to 4% of an historical control. Four pts remain alive more than 22 months post treatment without having received any additional intervention following PVSRIPO at 57.5+, 56.4+, 27.9+ and 23.2+ months. Conclusions: Infusion of PVSRIPO via CED is safe and encouraging efficacy results are observed. The dose finding study is now completed and we are initiating clinical trials evaluating combination of PVSRIPO with other therapies. Clinical trial information: NCT01491893.
- Published
- 2017
41. Single-agent dose-finding cohort of a phase 1/2 study of lenvatinib (LEN) in children and adolescents with refractory or relapsed solid tumors
- Author
-
Di Li, Maria Soledad Gallego Melcon, Nathalie Gaspar, Isabelle Aerts, Michela Casanova, Estelle Thebaud, Charlotte Rigaud, Silvija Kraljevic, Corina E. Dutcus, Hina Maniar, Seiichi Hayato, Rajkumar Venkatramani, Franco Locatelli, Stefan S. Bielack, Samuel Abbou, Quentin Campbell Hewson, Bruce Morland, and Marion Gambart
- Subjects
Cancer Research ,business.industry ,010501 environmental sciences ,030226 pharmacology & pharmacy ,01 natural sciences ,Vascular endothelial growth factor ,03 medical and health sciences ,chemistry.chemical_compound ,Dose finding ,0302 clinical medicine ,Oncology ,chemistry ,Growth factor receptor ,Refractory ,Fibroblast growth factor receptor ,Cohort ,Cancer research ,Medicine ,Receptor ,business ,Lenvatinib ,0105 earth and related environmental sciences - Abstract
10544 Background: LEN is an inhibitor of vascular endothelial growth factor (VEGF) receptors 1‒3, fibroblast growth factor receptors 1‒4, platelet-derived growth factor receptor α, RET, and KIT. LEN is approved in adults for radioiodine-refractory differentiated thyroid cancer (DTC) and in combination with everolimus in patients (pts) with advanced renal cell carcinoma. We show results from the single-agent LEN dose-finding part of a phase 1/2 study in children and adolescents with solid tumors. Methods: Pts had any relapsed or refractory solid tumor, evaluable or measurable disease, were aged 2 to ≤18 years, had < 2 prior VEGF-targeted therapies, and adequate organ function. A starting dose of LEN 11 mg/m2was escalated with a time-to-event continual reassessment method. The primary endpoint was to determine the LEN recommended dose (RD). Secondary objectives included best overall response (BOR), objective response rate, safety, and pharmacokinetics (PK). Results: 23 pts enrolled (11 mg/m2: n = 5, 14 mg/m2: n = 11, 17 mg/m2: n = 7). The most common tumors were rhabdomyosarcoma (n = 5), Ewing sarcoma (n = 4), and neuroblastoma (n = 3). 3 Dose-limiting toxicities occurred in cycle 1 at 14 mg/m2 (increased alanine aminotransferase: 1; hypertension: 2). All pts had any-grade treatment-emergent adverse events (TEAEs; grade 3/4: 65%). Most common any-grade TEAEs were vomiting (52%), abdominal pain (48%), decreased appetite (48%), diarrhea (44%), and hypothyroidism (44%). 1 Pt discontinued LEN due to a LEN-related TEAE (hypertension). BOR was stable disease (n = 10). Effect of age on oral clearance and central volume of distribution was not significant. Exposure was similar to that in adults. LEN 14 mg/m2/day was therefore identified as the RD. Updated cohort 1 data will be shown. Conclusions: The LEN RD in children and adolescents was similar to the adult dose and showed a reasonable safety profile. PK in these pts did not differ significantly from that in adults. The phase 1b dose-finding study of LEN in combination with chemotherapy in osteosarcoma (OS) and phase 2 LEN monotherapy (RD 14 mg/m2) parts in DTC and OS are ongoing. Clinical trial information: NCT02432274.
- Published
- 2017
42. Clinical Trial Designs for Cytostatic Agents: Are New Approaches Needed?
- Author
-
Richard Kaplan, Edward L. Korn, Michaele C. Christian, Richard M. Simon, James M. Pluda, and Susan G. Arbuck
- Subjects
Cancer Research ,medicine.medical_specialty ,End point ,Clinical Trials, Phase I as Topic ,business.industry ,Tumor shrinkage ,Cytostatic agents ,Antineoplastic Agents ,Bioinformatics ,Preclinical data ,Surgery ,Clinical trial ,Double blind study ,Dose finding ,Clinical Trials, Phase II as Topic ,Oncology ,Research Design ,Sample Size ,Drug Evaluation ,Humans ,Medicine ,Tumor growth inhibition ,business - Abstract
ABSTRACT: Preclinical data suggest that some new anticancer agents directed at novel targets demonstrate tumor growth inhibition but not tumor shrinkage. Such cytostatic agents may offer clinical benefits for patients in the absence of tumor shrinkage. In addition, lower doses of some of these agents may be just as effective as higher doses, implying that toxicity may not be an ideal end point for dose finding. Because of these factors, the sequence and design of traditional phase I, II, and III trials used for cytotoxic agents (which typically shrink tumors and in a dose-dependent manner) may not be appropriate for cytostatic agents. This article discusses options for modifying trial designs to accommodate cytostatic agents. Examples are given where these options have been tried or are currently being tried. Recommendations given for choosing among the trial designs depend on what is known preclinically about the agents (eg, does one have a validated and reproducible biologic end point that can be used to guide a dose escalation?), what is known about the patient population being studied (eg, does one have a well-documented historical progression-free survival rate at 1 year for comparison with the experience of the new agent?), and the numbers of agents and patients available for participation in trials. Planned and ongoing trials will test the utility of some of these new approaches.
- Published
- 2001
43. A phase I/Ib, open-label, dose-finding study to evaluate safety, pharmacodynamics, and efficacy of pembrolizumab (MK-3475) in combination with vorinostat in patients with advanced renal or urothelial cell carcinoma
- Author
-
Charles G. Drake, Roberto Pili, Theodore F. Logan, David I. Quinn, Noah M. Hahn, and Costantine Albany
- Subjects
0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Entinostat ,business.industry ,Pembrolizumab ,03 medical and health sciences ,chemistry.chemical_compound ,Dose finding ,030104 developmental biology ,0302 clinical medicine ,chemistry ,Urothelial cell carcinoma ,030220 oncology & carcinogenesis ,Pharmacodynamics ,Internal medicine ,medicine ,In patient ,Open label ,business ,Vorinostat ,medicine.drug - Abstract
TPS4581Background: Novel strategies to enhance the activity of immune-checkpoint inhibitors are under development. Our group has reported that the HDAC inhibitor entinostat suppresses regulatory T ...
- Published
- 2016
44. Dose-finding study of vinblastine in combination with nilotinib in children, adolescents and young adults with refractory or recurrent low-grade glioma: Results of the ITCC/SIOPE-Brain VINILO phase I trial (NCT01887522)
- Author
-
P. Leblond, Birgit Geoerger, Christelle Dufour, Emilie De Carli, Karsten Nysom, Gilles Vassal, Anne Pagnier, Isabelle Aerts, Francisco Bautista, Jacques Grill, Claire Berger, Katty Malekzadeh, Angelo Paci, Gwénaël Le Teuff, Fanny Fouyssac, Samuel Abbou, Anne-Isabelle Bertozzi, Frédéric Millot, and Marie-Cécile Le Deley
- Subjects
0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Chemotherapy ,business.industry ,medicine.medical_treatment ,Vinblastine ,03 medical and health sciences ,Dose finding ,030104 developmental biology ,0302 clinical medicine ,Nilotinib ,Refractory ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Early adolescents ,Young adult ,business ,Adjuvant ,medicine.drug - Abstract
10555Background: Chemotherapy (CT) is frequently used as first adjuvant treatment for low-grade gliomas (LGG) when surgery cannot be completed. Relapses are frequent and new rescue regimens are nee...
- Published
- 2016
45. Phase 1/2 study of weekly nab-paclitaxel (nab-P) in pediatric patients (pts) with recurrent/refractory solid tumors (STs): Dose-finding and pharmacokinetics (PK)
- Author
-
Soledad Gallego Melcon, Gilles Vassal, Julia L. Glade Bender, Pooja Hingorani, Nicolas U. Gerber, Gianni Bisogno, Mathew Simcock, Ruta Slepetis, Lucas Moreno, Pablo Berlanga, Carla Manzitti, Isabelle Aerts, Sylvain Baruchel, Ileana Elias, Birgit Geoerger, Julia C. Chisholm, Pascal Chastagner, Michela Casanova, Franca Fagioli, and Christophe Bergeron
- Subjects
Cancer Research ,business.industry ,Neurotoxicity ,macromolecular substances ,Pharmacology ,medicine.disease ,carbohydrates (lipids) ,stomatognathic diseases ,03 medical and health sciences ,Dose finding ,chemistry.chemical_compound ,0302 clinical medicine ,Oncology ,Refractory ,Pharmacokinetics ,Paclitaxel ,chemistry ,030225 pediatrics ,030220 oncology & carcinogenesis ,otorhinolaryngologic diseases ,medicine ,bacteria ,business ,Nab-paclitaxel - Abstract
10551Background: Although solvent-based paclitaxel has demonstrated activity in adult pts with STs, solvents produce significant neurotoxicity in pediatric pts. nab-P is an albumin–bound paclitaxel...
- Published
- 2016
46. A next-generation statistical tool for phase I dose finding trials
- Author
-
Yuan Ji
- Subjects
Cancer Research ,medicine.medical_specialty ,Dose finding ,Oncology ,business.industry ,Phase (waves) ,Medicine ,Medical physics ,business - Abstract
e14037Background: There are no consensus results for assessing different statistical designs for phase I dose finding trials. Despite previous findings in the literature that recommend against the ...
- Published
- 2016
47. SWOG S1206: A dose-finding study of veliparib (ABT-888) added to chemoradiotherapy (CRT) with carboplatin (C) and paclitaxel (P) for unresectable stage III non-small cell lung cancer (NSCLC)
- Author
-
Linda L. Garland, Megan E. Daly, Karen Kelly, Allen M. Chen, Jieling Miao, Marianna Koczywas, Athanassios Argiris, Roy H. Decker, David R. Gandara, Ding Wang, James C. Moon, and Mihaela C. Cristea
- Subjects
Cancer Research ,Veliparib ,business.industry ,Carboplatin ,Stage III Non-Small Cell Lung Cancer ,03 medical and health sciences ,chemistry.chemical_compound ,Dose finding ,0302 clinical medicine ,Oncology ,chemistry ,Paclitaxel ,030220 oncology & carcinogenesis ,PARP inhibitor ,Cancer research ,Medicine ,business ,Cytotoxicity ,030217 neurology & neurosurgery ,Chemoradiotherapy - Abstract
8537Background: Preclinical studies of the PARP inhibitor velaparib (V) demonstrated synergistic effects when combined with various cytotoxic agents and radiation (RT). S1206 is a phase I trial of ...
- Published
- 2016
48. Updated data from a phase II dose finding trial of single agent isatuximab (SAR650984, anti-CD38 mAb) in relapsed/refractory multiple myeloma (RRMM)
- Author
-
Jesús F. San Miguel, Stephen A. Strickland, Joshua R. Richter, Thomas G. Martin, Meletios A. Dimopoulos, Eric Charpentier, Joseph R. Mikhael, Parameswaran Hari, Jonathan L. Kaufman, Ravi Vij, Djordje Atanackovic, Craig E. Cole, Corina Oprea, Nikoletta Lendvai, Shaji Kumar, Enrique M. Ocio, Todd M. Zimmerman, Jeffrey A. Zonder, Cristina Gasparetto, and William I. Bensinger
- Subjects
0301 basic medicine ,Isatuximab ,Cancer Research ,medicine.drug_class ,business.industry ,Cell ,CD38 ,Monoclonal antibody ,medicine.disease ,03 medical and health sciences ,Dose finding ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Immune system ,Oncology ,030220 oncology & carcinogenesis ,Relapsed refractory ,medicine ,Cancer research ,business ,Multiple myeloma - Abstract
8005Background: Isatuximab (ISA) is a humanized anti-CD38 monoclonal antibody with multiple modes of action for killing tumor cells through direct tumor targeting and immune cell engagement. Here, ...
- Published
- 2016
49. Preliminary results of the phase I/IIa dose finding trial of a folate binding protein vaccine (E39+GM-CSF) in ovarian and endometrial cancer patients to prevent recurrence
- Author
-
John C. Elkas, Timothy J. Vreeland, Doreen O. Jackson, John S. Berry, George L. Maxwell, Chad A. Hamilton, Julia M. Greene, George E. Peoples, Kathleen M. Darcy, Diane F. Hale, Alfred F. Trappey, Mark O. Hardin, Erika J Schneble, and Guy T. Clifton
- Subjects
Cancer Research ,endocrine system diseases ,business.industry ,Endometrial cancer ,medicine.disease ,Folate-binding protein ,female genital diseases and pregnancy complications ,Serous fluid ,Dose finding ,Oncology ,medicine ,Cancer research ,business ,Ovarian cancer - Abstract
5576Background: Folate binding protein (FBP) is an immunogenic protein over-expressed in serous endometrial (EC) and ovarian cancer (OC). We’ve conducted a phase I/IIa trial using E39 (GALE-301, FB...
- Published
- 2015
50. A phase I/II study of Enadenotucirev, an oncolytic Ad11/Ad3 chimeric group B adenovirus, administered intraperitoneally (IP): Dose finding and proof of concept in platinum-resistant epithelial ovarian cancer
- Author
-
Rosalind Glasspool, Mazhar Ajaz, Kerry D. Fisher, Richard J. C. Brown, Chris Twelves, Ourania Xeniou, Iain A. McNeish, C. Blanc, Agnieszka Michael, and R. Morrison
- Subjects
Cancer Research ,Pathology ,medicine.medical_specialty ,Enadenotucirev ,endocrine system diseases ,business.industry ,medicine.disease ,female genital diseases and pregnancy complications ,Group B ,Oncolytic virus ,Dose finding ,Phase i ii ,Oncology ,medicine ,Cancer research ,Epithelial ovarian cancer ,Ovarian cancer ,business ,Platinum resistant - Abstract
TPS5611 Background: Enadenotucirev (EnAd) is a tumor selective Ad11/Ad3 group B adenovirus that has demonstrated preclinical activity in a model of platinum-resistant ovarian cancer. Synergy has al...
- Published
- 2015
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.