Janis C. Kelly

June 16, 2014

CHICAGO — The addition of bevacizumab (Avastin, Genentech, Inc) did not improve the efficacy of weekly paclitaxel in advanced angiosarcoma, according to the results from a randomized phase 2 study presented at the 2014 Annual Meeting of the American Society of Clinical Oncology (ASCO).

The study outcomes also highlight the importance of conducting phase 2 studies as randomized trials with an appropriate comparator, said lead author Nicholas Penel, MD, PhD, from the Department of General Oncology, Centre Oscar Lambret, Lille, France.

The 6-month progression-free survival rate (6-PFR), which was the study's main endpoint, was 56.7% with weekly paclitaxel and 57.6% with weekly paclitaxel plus bevacizumab.

Median overall survival (OS) as 19.5 months with weekly paclitaxel and 15.9 months with weekly paclitaxel plus bevacizumab.

"There was no difference in PFS [progression-free survival]. There was no difference in OS," Dr. Penel concluded.

The 2 study arms both included paclitaxel 90 mg/m2 on days 1, 8, and 15 in 4-week cycles for 6 cycles. The experimental arm also included bevacizumab 10 mg/kg on days 1 and 15 for 6 cycles as well as (in cases of nonprogression) maintenance with bevacizumab 15 mg/kg/3 wks until intolerance or disease progression. Twenty-four patients were enrolled in the paclitaxel arm; 25 were enrolled in the combination therapy arm.

Importance of Randomization in Phase 2 Trials

The ANGIOTAX-PLUS study was a nonblinded, randomized phase 2 trial. Patients were stratified by whether tumors were radiation induced or de novo and by whether they were visceral or soft tissue. The researchers assessed objective response at 3, 6, and 9 months as well as PFS, OS, and toxicity.

According to the statistical design, a drug would be judged "promising" if at least 8 of 24 patients achieved 6-PFR.

Eligibility criteria for the trial included histologically proven angiosarcoma, locally advanced or metastatic disease not amenable to curative intent surgery, good performance, and normal left ventricular ejection fraction. Exclusion criteria included ≥2 prior chemotherapies, contraindications to paclitaxel or bevacizumab, risk for bleeding, prior peripheral neuropathy, and brain or leptomeningeal metastasis.

"This trial illustrates the critical role of randomization and use of a comparator in phase 2 trials," Dr. Penel said. "The absence of a comparator could lead to an optimistic but erroneous conclusion, since the reported outcome is largely superior to historical data."

He noted that in the present trial, weekly paclitaxel produced PFS (6.8 vs 4.0 months) and OS (>12 vs 8 months) to a degree significantly higher than previously reported.

At ASCO, another expert further discussed the role of these early trials.

"The goal of a phase 2 trial is to inform the best phase 3. The standard phase 2 is a single-arm, small patient cohort (20-50 patients), and objective response rate [ORR] is the typical endpoint. A statistical design is often built on investigator assumptions about what would be a clinically meaningful improvement from historical controls," said Suzanne George, MD, clinical director, Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

According to Dr. George, pitfalls to the standard phase 2 approach are that single-arm studies can test only 1 question, that the small patient cohort might not be the right cohort or might include patients with different characteristics, and that historical controls might not be relevant to the current conditions.

"Randomized phase 2 designs are an effort to deal with the problems of nonrandomized phase 2 trials. Examples include comparative randomized phase 2 trials (such as Dr. Penel's), noncomparative randomized phase 2 trials, and 'pick the winner' trials," Dr. George said.

Dr. Penel also reported that there were no drug-related severe adverse events in the weekly paclitaxel arm. However, there were 10 drug-related severe adverse events in the paclitaxel/bevacizumab arm.

The study was supported by Roche-Hoffman. Dr. Penel has received research funding from Roche. Dr. George reported receiving consultant or advisory role fees from ARIAD, Bayer, Novartis, and Pfizer, and research funding from ARIAD, Bayer, Novartis, and Pfizer.

J Clin Oncol. 2014;32:5s. Abstract 10501.

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