Randomized phase II study of 2nd-line FOLFIRI versus modified FOLFIRI with PARP inhibitor ABT-888 (veliparib) (NSC-737664) in metastatic pancreatic cancer (mPC): SWOG S1513.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS4147-TPS4147
Author(s):  
E. Gabriela Chiorean ◽  
Shannon McDonough ◽  
Philip Agop Philip ◽  
Elizabeth M. Swisher ◽  
Michael J. Pishvaian ◽  
...  
Keyword(s):  
Dna Repair ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Parp Inhibitor ◽  
New Drugs ◽  
Parp Inhibition ◽  
Dna Breaks ◽  
Antitumor Effects ◽  
Repair Capacity ◽  
Randomized Phase Ii

TPS4147 Background: PC is characterized by multiple DNA repair defects, including in BRCA1/ 2, and other homologous recombination (HR) genes such as FANC, ATM, ATR (Waddell N, Nature 2015). Folinic acid/5-fluorouracil/ irinotecan (FOLFIRI) is a 2nd line therapy option in mPC, but overall survival (OS) averages only 6 mos (Yoo C, Br J Cancer 2009). It is known that PARP facilitates repair from topoisomerase 1-associated DNA damage, and that preclinically PARP inhibitors (PARPi) increase DNA breaks from camptothecins, resulting in synergistic antitumor effects (Smith LM, Clin Cancer Res 2005, Davidson D, Invest New Drugs 2013). PARPi are active in mPC harboring BRCA1/2 mutations. Given the preclinical synergism between ABT-888 with irinotecan, and the safety and preliminary efficacy noted in a phase I trial (Berlin J, J Clin Oncol 2014; abstr 2574), we designed a randomized phase II study of mFOLFIRI /ABT-888 vs FOLFIRI alone for 2nd line mPC patients (pts). Blood and tumor samples are collected at baseline to retrospectively analyze biomarkers related to DNA repair capacity, including the HRD assay and BROCA-HR, a targeted multi-gene sequencing to detect alterations within the Fanconi Anemia-BRCA (HR), non-homologous end joining (NHEJ), and DNA mismatch repair pathways, and correlate with efficacy. Methods: Phase II study in 143 pts randomized (1:1) to mFOLFIRI/ABT-888 or FOLFIRI. For optimal PARP inhibition, ABT-888 is dosed Days (D) 1-7 and mFOLFIRI (no 5-FU bolus) D3-5 in 14D-cycles. In the control arm, FOLFIRI is dosed D1-3 in 14D-cycles. Primary endpoint: compare OS between treatment arms; secondary endpoints: safety, progression-free survival, response rates; translational: correlate germline/somatic BRCA1/2 mutations, and other DNA repair biomarkers with efficacy in each arm. Standard eligibility criteria apply. Assuming that the addition of ABT-888 will increase OS from 6 to 9 mos, 128 eligible pts (143 pts total) are required, based on a one-sided type 1 error of 10%, and 80% power. Kaplan-Meier methodology will be used to estimate median OS for each treatment arm. This study is open to accrual (NCT02890355). Clinical trial information: NCT02890355.

Randomized phase II study of second-line modified FOLFIRI with PARP inhibitor ABT-888 (Veliparib) (NSC-737664) versus FOLFIRI in metastatic pancreatic cancer (mPC): SWOG S1513.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4014-4014 ◽  
Author(s):  
E. Gabriela Chiorean ◽  
Katherine A Guthrie ◽  
Philip Agop Philip ◽  
Elizabeth M. Swisher ◽  
Florencia Jalikis ◽  
...  
Keyword(s):  
Dna Repair ◽  
Phase Ii ◽  
Somatic Mutations ◽  
Phase Ii Study ◽  
Parp Inhibitor ◽  
Gene Mutations ◽  
Control Treatment ◽  
Repair Gene ◽  
Randomized Phase Ii ◽  
Dna Repair Gene

4014 Background: PC is characterized by DNA Damage Repair (DDR) deficiencies, including in BRCA1/2, ATM, and FANC genes. Given preclinical synergism between veliparib with irinotecan, safety and preliminary efficacy, we designed a randomized phase II study of mFOLFIRI (no 5-FU bolus) + veliparib vs FOLFIRI alone for 2nd line mPC patients (pts). Methods: Eligible pts had mPC, adequate organ function, ECOG PS 0-1, and 1 prior non-irinotecan systemic therapy.143 pts were to be randomized (1:1) to veliparib vs control. Primary endpoint was overall survival (OS). All pts had blood and tumor biopsies at baseline to assess germline and somatic BRCA1/2 mutations (integrated), and homologous recombination (HR) or DDR biomarkers (exploratory). Results: 123 pts were accrued between 09/2016 to 12/2017, and 108 were included in this analysis. 117 pts were biomarker evaluable: 109 blood/106 tumors. 11 cancers (9%) had HR deficiency (HRD), including 4 germline ( BRCA1, BRCA2, ATM) and 7 somatic mutations ( BRCA2, PALB2, ATM, CDK12). Additional 24 cancers (20%) had germline (n = 11, e.g., FANC, BLM, SLX4, CHEK2) or somatic mutations (n = 13, e.g., FANC, BLM, POLD1, RIF1, MSH2, MSH6) in other DNA repair genes, not classified as HRD. A planned interim futility analysis at 35% of expected PFS events determined the veliparib arm was unlikely to be superior to control. Most common grade 3/4 treatment related toxicities were neutropenia (33% vs 20%), fatigue (19% vs 4%), and nausea (11% vs 4%), for veliparib vs control. Treatment exposure was similar for veliparib vs control: median 4 cycles (range 1-31 vs 1-32). Median OS was 5.1 vs 5.9 mos (HR 1.3, 95%CI 0.9-2.0, p = 0.21), and median PFS was 2.1 vs 2.9 mos (HR 1.5, 95%CI 1.0-2.2, p = 0.05) for veliparib vs control arms, respectively. Correlations of gene mutations and signatures with efficacy outcomes will be presented. Conclusions: Nearly 30% of mPC pts had DNA repair gene abnormalities, including 9% with HRD. Veliparib increased toxicity and did not improve OS when added to mFOLFIRI in biomarker unselected pts. BRCA1/2 and DDR biomarkers will be correlated with efficacy to inform patient selection for future PARP inhibitor clinical trials. Clinical trial information: NCT02890355.

Randomized Phase II Study of PARP Inhibitor Veliparib with Modified FOLFIRI versus FOLFIRI as Second Line Treatment of Metastatic Pancreatic Cancer: SWOG S1513

2021 ◽  
pp. clincanres.1789.2021
Author(s):  
E. Gabriela Chiorean ◽  
Katherine A Guthrie ◽  
Philip A Philip ◽  
Elizabeth M. Swisher ◽  
Florencia Jalikis ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Parp Inhibitor ◽  
Metastatic Pancreatic Cancer ◽  
Line Treatment ◽  
Second Line ◽  
Randomized Phase Ii

Results of a randomized phase II study of irofulven in hormone-refractory prostate cancer patients that have failed first-line docetaxel treatment

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 5068-5068
Author(s):  
E. R. Berger ◽  
T. Ciuleanu ◽  
L. Hart ◽  
K. N. Chi ◽  
J. Alexandre ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Median Number ◽  
Hormone Refractory Prostate Cancer ◽  
Antitumor Effects ◽  
Pain Status ◽  
Randomized Phase Ii ◽  
Hormone Refractory ◽  
Grade 3

5068 Background: Currently, no available treatments demonstrate an increase in survival for patients (pts) with hormone- refractory prostate cancer (HRPC) who have failed treatment with docetaxel-based regimens. Previous monotherapy and combination Phase I/II trials with irofulven (IROF) have shown antitumor effects in pts with HRPC, including those with resistance to docetaxel. A randomized phase II study was undertaken in HRPC pts with documented resistance to docetaxel to evaluate the efficacy and safety of IROF regimens compared to mitoxantrone (MITOX). Methods: Pts with metastatic HRPC with documented progression by RECIST or PSA Working Group criteria during or within 3 months of prior docetaxel were randomized to 1 of 3 arms in a 2:2:1 ratio: Arm A: IROF (0.45 mg/kg, Day [D]1, 8 every [q] 3 weeks [w]) and prednisone (PRED; 10 mg qd); Arm B: IROF (0.4 mg/kg D1, 15), capecitabine (CAPE; 2,000 mg/m2 D1–15 q4w) and PRED; Arm C: MITOX (12 mg/m2 q3w) and PRED. Pts were stratified by baseline pain status. Efficacy endpoints included time to progression (TTP), overall survival (OS), and response. Results: Enrollment of 134 treated pts was completed as of Jan 2006 (Arm A/B/C: 53/54/27). Median age: 64/66/63 years, median KPS: 80/90/80, median baseline PSA (ng/mL): 144/136/243, disease-related pain at baseline: 65%/57%/59%, and median number of metastatic sites: 1/1/2. Median pre-study PSA doubling time (days) was 42/44/50. Efficacy: As of Jan 2007, median OS (mos) was 10.1/9.5/7.4 in Arms A/B/C (based on 73% of pt deaths). Preliminary median TTP (mos) was 2.2/3.8/1.8, based mainly on PSA progression. PSA and RECIST responses were 10%/22%/0% and 10%/10%/13%, respectively. Safety: Treatment was well tolerated in all arms. The most frequent Grade 3–4 toxicities (% pts) were asthenia (8%/15%/0%), and vomiting (4%/11%/0%). Grade 3–4 hematological events included neutropenia (22%/15%/61%) and thrombocytopenia (23%/21%/4%). Conclusions: Results to date indicate longer survival, longer TTP, and greater PSA response for IROF/PRED and IROF/CAPE/PRED compared to MITOX/PRED. Based on these data, a larger randomized trial of irofulven in docetaxel resistant HRPC patients is warranted. No significant financial relationships to disclose.

Randomized phase II study of docetaxel plus vandetanib (D+V) versus docetaxel followed by vandetanib (D-V) in patients with persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma (OC): SWOG S0904.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 5015-5015 ◽  
Author(s):  
Robert L. Coleman ◽  
James Moon ◽  
Anil Sood ◽  
Donna Branham ◽  
James Edwin Delmore ◽  
...  
Keyword(s):  
Phase Ii ◽  
Kinase Inhibitor ◽  
Phase Ii Study ◽  
Single Agent ◽  
Objective Response ◽  
Primary Therapy ◽  
Antitumor Effects ◽  
Angiogenic Therapy ◽  
Randomized Phase Ii ◽  
Therapy Stratification

5015 Background: Antiangiogenesis therapy has led to antitumor effects both preclinically and clinically. Vandetanib (V) is an oral tyrosine kinase inhibitor of VEGFR-2/3, EGFR and RET. These targets are of interest in OC care, as targeting has shown anti-tumor efficacy, particularly in combination with taxanes. We explored the efficacy, safety, and toxicity of docetaxel (D) and V in women with recurrent OC. Methods: Women with resistant, refractory, or progressive/persistent OC were eligible for this randomized phase II study provided they had not received D or V for recurrent disease. Patients were allowed to receive other anti-VEGF targeted agents for primary therapy (stratification variable). Up to 3 additional cytotoxic regimens for recurrence were allowed. Patients were allocated 1:1 to D(75 mg/m2, I.V.)+V (100 mg daily, p.o.) or D(75 mg/m2). Patients receiving single agent D were allowed to crossover to V upon progression (D-V). The primary endpoint was PFS. Other objectives were: OS, objective response (ORR), and frequency/severity of adverse events. The study was designed with 84% power to detect a 1.55 PFS hazard ratio using a one-sided P of 0.1. Results: 131 patients were enrolled; 5 were excluded (1 ineligible, 4 eligible but untreated). 9% had received prior anti-angiogenic therapy. 61 patients on D+V were assessable for toxicity; 19 (31%) had treatment-related G4 events, primarily hematologic. Similarly, 17 (26%) of 65 patients receiving D alone had G4 events, primarily hematologic. 34 (52%) patients crossed over to V; no G4 events were recorded among 32 evaluable patients. G3 diarrhea was observed in 14% of D+V patients; 5% D-V patients. G3 acneiform rash occurred in 2% and 0%, respectively. The median PFS estimates were 3.0 mos (D+V) vs 3.5 (D-V); HR (PFS): 0.98 (80% CI:0.75-1.27). For OS, the median estimates were 14 mos (D+V) vs 12 mos (D-V); HR (OS):0.84 (80% CI:0.56-1.28). ORR was 14% and 17%, respectively. Crossover V response was 4% (1/27 measurable patients). Conclusions: D+V was well tolerated in this population however, did not prolong PFS with respect to D.

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