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Positive Interim Analysis Halts Phase III Idelalisib CLL Study

Silas Inman @silasinman
Published: Monday, Nov 16, 2015

Dr. Norbert W. Bischofberger

Norbert W. Bischofberger, PhD

A phase III study exploring idelalisib (Zydelig) in combination with bendamustine and rituximab (BR) for patients with previously treated chronic lymphocytic leukemia (CLL) has been stopped early following a positive interim analysis, according to a statement from Gilead Sciences, the company developing the PI3K delta inhibitor.

Following a recommendation from an independent data monitoring committee, the trial, labeled Study 115, was unblinded, allowing patients in the control arm to receive idelalisib. The recommendation to halt the study was based on a statistically significant extension in progression-free survival (PFS) and overall survival (OS) experienced by patients receiving idelalisib plus BR compared with BR alone. Findings from the study will be submitted to the FDA and European Medicines Agency early next year, according to the company.

“The clinical benefit observed in this phase III study adds to the body of evidence demonstrating the potential of Zydelig-containing treatment regimens for patients with previously treated CLL,” Norbert W. Bischofberger, PhD, executive vice president, Research and Development and chief scientific officer for Gilead, said in a statement. “We look forward to sharing the detailed scientific data with the hematology community at the upcoming ASH meeting.”

In the phase III study, 416 patients with CLL received 6 cycles of BR with idelalisib (n = 207) or placebo (n = 209). Bendamustine was administered at 70 mg/m2 on day 1 and 2 of each 28-day cycle along with rituximab at 375 mg/m2 during cycle 1 and 500 mg/m2 thereafter. Continuous idelalisib was administered at 160 mg twice daily until progression or unacceptable toxicity.

Patients in the study were primarily male (76%) and 42% were ≥65 years old. The median time since completion of prior therapy was 16 months and the median number of previous therapies was 2 (range, 1-13). A number of patients had high-risk features, including del17p (32.9%), unmutated IgHV (83.2%), and refractory disease (29.8%). The primary endpoint of the study was PFS, with OS as a secondary outcome measure.

In data from a median follow-up of 12 months published in an abstract from the 2015 ASH Annual Meeting, the median PFS with idelalisib was 23 months compared with 11 months for BR alone (HR, 0.33; 95% CI, 0.24-0.45; P <.0001). There was a 45% reduction in the risk of death with the addition of idelalisib to BR, although the median OS had not yet been reached in either arm (HR, 0.55; 95% CI, 0.36-0.86; P = .008).

The PFS benefit seen with idelalisib was consistent across subgroups. In those with del17p or TP53, the HR for PFS was 0.50. For del17p alone, the HR was 0.63. Those with neither del17p nor TP53 experienced a 78% reduction in the risk of progression or death with the addition of idelalisib (HR, 0.22; 0.14-0.35).

The most common all-grade adverse events (AEs) with idelalisib plus BR were neutropenia (63.3%), ALT abnormalities (59.9%), AST abnormalities (52.2%), and pyrexia (41.5%). The most common grade ≥3 AEs were neutropenia (59.9%), ALT abnormality (21.3%), febrile neutropenia (20.3%), and AST abnormality (15.5%).

For BR alone, the most frequent all-grade AEs were neutropenia (53.6%), nausea (34.4%), ALT abnormalities (30.6%), and AST abnormalities (27.8%). The most common grade ≥3 AEs were neutropenia (45.9%) and anemia (12%). Grade ≥3 ALT and AST abnormalities were seen in 2.9% and 3.3% of patients in the placebo arm, respectively.

Grade ≥3 diarrhea occurred in 7.2% of patients treated with idelalisib versus 1.9% of those who received placebo. Additionally, serious pneumonitis occurred in 1.4% of patients treated with idelalisib compared with 0% for the placebo arm.

The FDA initially approved Idelalisib in July 2014 in combination with rituximab for patients with high-risk relapsed or refractory CLL and as a single-agent for two types of indolent non-Hodgkin lymphoma. The agent carries a Boxed Warning and a Risk Evaluation and Mitigation Strategy (REMS) regarding fatal and serious liver toxicity, diarrhea, colitis, pneumonitis, and intestinal perforation.

In addition to these indications and findings from Study 115, data are currently with the FDA from the phase III Study 119, which showed an improvement in objective response rates and PFS with the combination of idelalisib and ofatumumab compared with the CD20 inhibitor alone in patients with previously treated CLL. 

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