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A Randomized Phase II Study to Determine the Effect of 2 Different Doses of Aflibercept in Patients With Metastatic Renal Cell Carcinoma (ECOG-ACRIN [E4805]).

ABSTRACT: Aflibercept is a recombinantly produced fusion protein that has potent anti-vascular endothelial growth factor (VEGF) activity. We tested whether aflibercept has clinical activity in clear-cell renal cell carcinoma (ccRCC). The recommended phase II dose was 4 mg/kg but several patients (pts) treated at 1 mg/kg showed prolonged progression-free survival. We therefore tested both doses in a parallel group randomized trial.Eligible pts had histologically confirmed advanced or metastatic ccRCC and previous treatments included exposure to a VEGF receptor tyrosine kinase inhibitor. Pts received aflibercept (either 1 mg/kg or 4 mg/kg) on day 1 of a 14-day cycle until disease progression. Pts randomized to 1 mg/kg could crossover to 4 mg/kg at the time of disease progression. The primary end point was proportion alive and progression-free at 8 weeks. A Simon 2-stage design was used for each arm with 33 and 24 eligible pts per arm enrolled in stages 1 and 2.Ninety-four pts were enrolled, 59 and 35 to 4 mg and 1 mg doses, respectively. Seventy-two percent had 1 previous treatment most commonly sunitinib. Sixteen eligible pts crossed over at the time of disease progression to the 4-mg dose. Most common adverse events were hypertension, proteinuria, and fatigue. Only 4 pts reported Grade 4 or higher toxicity. With 36 of 59 pts (61%) progression-free at 8 weeks, the 4-mg/kg dose met protocol-specified efficacy criteria.Aflibercept is active in previously treated ccRCC and might be worthy of further study.

SUBMITTER: Pili R

PROVIDER: S-EPMC5675826 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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A Randomized Phase II Study to Determine the Effect of 2 Different Doses of Aflibercept in Patients With Metastatic Renal Cell Carcinoma (ECOG-ACRIN [E4805]).

Pili Roberto R Jegede Opeyemi O Carducci Michael A MA Manola Judith J Groteluschen David L DL Appleman Leonard L LL Liu Glenn G Shanks James C JC Dakhil Shaker R SR Dutcher Janice J DiPaola Robert S RS

Clinical genitourinary cancer 20170426 6

<h4>Background</h4>Aflibercept is a recombinantly produced fusion protein that has potent anti-vascular endothelial growth factor (VEGF) activity. We tested whether aflibercept has clinical activity in clear-cell renal cell carcinoma (ccRCC). The recommended phase II dose was 4 mg/kg but several patients (pts) treated at 1 mg/kg showed prolonged progression-free survival. We therefore tested both doses in a parallel group randomized trial.<h4>Patients and methods</h4>Eligible pts had histologica ...[more]

PMID: 28545998

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Project description:BackgroundEribulin mesylate, a synthetic analog of halichondrin B, is a novel tubulin-binding agent that inhibits cancer cell proliferation at low-nanomolar levels.MethodsIn a multicenter ECOG trial, patients with progressive metastatic CRPC, ECOG 0-2 were treated with eribulin 1.4 mg/m as an IV bolus over 5 minutes on days 1 and 8 of a 21-day cycle. This noncomparative study stratified points to either a chemonaive (CN), prior-taxane (Tax) only, or 2 prior cytotoxic (TCx) chemotherapy arm. The trial was powered to detect a 50% PSA reduction using Consensus Criteria in at least 40% versus 20% (90% power, one-sided α=0.10) for the CN stratum and 25% versus. 10% (power 87%, one-sided α=0.10) for the Tax and TCx strata.ResultsIn total, 119 pts received treatment of which 116 were eligible for the primary response determination in this study. Median age 70 years (range, 45 to 88); median number of treatment cycles 4 (range, 1 to 20+); ECOG 0-1 90%. Confirmed PSA response rates (50% decline from baseline) were 29% (90% [18.2%, 41.2%]; P=0.20), 10% (90% [5.2%, 27.1%]; P=1.00), and 4% ([0.2%, 18.3%]; P=0.59) in the chemonaive stratum, the prior-taxane stratum, and the 2-prior-chemotherapy stratum, respectively. Median progression-free survival was 3.5 months (95% CI, 2.0, 5.9), 2.3 months (95% CI, 2.0, 2.9) and 3.7 months (95% CI, 2.1, 4.2) for the chemonaive stratum, the prior-taxane stratum and the 2-prior-chemotherapy stratum, respectively. Nonhematological toxicities of any grade (mainly grade 1 and 2) were fatigue (74%), neuropathy (40%), alopecia (39%), nausea (35%), and anorexia (34%). Common hematological toxicities were decreased leukocytes (75%), decreased neutrophils (72%), and decreased hemoglobin (66%). The most common grade ≥ 3 toxicities were decreased neutrophils (55%), decreased leukocytes (42%), sensory neuropathy (13%), and fatigue (11%). Overall, there was a 4% rate of febrile neutropenia.ConclusionsIn summary, per the prespecified study endpoints, eribulin did not have adequate activity in chemotherapy naïve or chemotherapy pretreated patients with metastatic CRPC to support further study in this setting.

Project description:PurposeVeliparib, a poly (ADP ribose) polymerase inhibitor, potentiated standard chemotherapy against small-cell lung cancer (SCLC) in preclinical studies. We evaluated the combination of veliparib with cisplatin and etoposide (CE; CE+V) doublet in untreated, extensive-stage SCLC (ES-SCLC).Materials and methodsPatients with ES-SCLC, stratified by sex and serum lactate dehydrogenase levels, were randomly assigned to receive four 3-week cycles of CE (75 mg/m2 intravenously on day 1 and 100 mg/m2 on days 1 through 3) along with veliparib (100 mg orally twice per day on days 1 through 7) or placebo (CE+P). The primary end point was progression-free survival (PFS). Using an overall one-sided 0.10-level log-rank test, the study had 88% power to demonstrate a 37.5% reduction in the PFS hazard rate.ResultsA total of 128 eligible patients received treatment on protocol. The median age was 66 years, 52% of patients were men, and Eastern Cooperative Oncology Group performance status was 0 for 29% of patients and 1 for 71%. The respective median PFS for the CE+V arm versus the CE+P arm was 6.1 versus 5.5 months (unstratified hazard ratio [HR], 0.75 [one-sided P = .06]; stratified HR, 0.63 [one-sided P = .01]), favoring CE+V. The median overall survival was 10.3 versus 8.9 months (stratified HR, 0.83; 80% CI, 0.64 to 1.07; one-sided P = .17) for the CE+V and CE+P arms, respectively. The overall response rate was 71.9% versus 65.6% (two-sided P = .57) for CE+V and CE+P, respectively. There was a significant treatment-by-strata interaction in PFS: Male patients with high lactate dehydrogenase levels derived significant benefit (PFS HR, 0.34; 80% CI, 0.22 to 0.51) but there was no evidence of benefit among patients in other strata (PFS HR, 0.81; 80% CI, 0.60 to 1.09). The following grade ≥ 3 hematology toxicities were more frequent in the CE+V arm than the CE+P arm: CD4 lymphopenia (8% v 0%; P = .06) and neutropenia (49% v 32%; P = .08), but treatment delivery was comparable.ConclusionThe addition of veliparib to frontline chemotherapy showed signal of efficacy in patients with ES-SCLC and the study met its prespecified end point.

Dataset Information

A Randomized Phase II Study to Determine the Effect of 2 Different Doses of Aflibercept in Patients With Metastatic Renal Cell Carcinoma (ECOG-ACRIN [E4805]).

Publications

A Randomized Phase II Study to Determine the Effect of 2 Different Doses of Aflibercept in Patients With Metastatic Renal Cell Carcinoma (ECOG-ACRIN [E4805]).

Similar Datasets

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