Positive Data Stops Phase 3 CLL Study of Zydelig

A phase 3 study exploring Zydelig (idelalisib) in combination with Treanda (bendamustine) and Rituxan (rituximab) 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 Zydelig. 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 Zydelig plus Treanda plus Rituxan compared with Treanda plus Rituxan 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 3 study adds to the body of evidence demonstrating the potential of Zydelig-containing treatment regimens for patients with previously treated CLL,” Norbert W. Bischofberger, 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 [American Society of Hematology] meeting.”

In the phase 3 study, 416 patients with CLL received six cycles of Treanda plus Rituxan with Zydelig (207 patients) or placebo (209 patients). Treanda was administered at 70 mg/m² on day 1 and 2 of each 28-day cycle along with Rituxan at 375 mg/m² during cycle 1 and 500 mg/m² thereafter. Continuous Zydelig was administered at 160 mg twice daily until progression or unacceptable toxicity.

Patients in the study were primarily male (76 percent) and 42 percent were at least 65 years old. The median time since completion of prior therapy was 16 months and the median number of previous therapies was 2 (ranging from one to 13). A number of patients had high-risk features, including refractory disease (29.8 percent). 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 American Society of Hematology Annual Meeting, a meeting of thousands of oncologists and other oncology professionals in December, the median PFS with Zydelig was 23 months compared with 11 months for Treanda plus Rituxan alone. There was a 45 percent reduction in the risk of death with the addition of Zydelig to BR, although the median OS had not yet been reached in either arm. The PFS benefit seen with Zydelig was consistent across subgroups.

The most common all-grade adverse events (AEs) with Zydelig plus Treanda plus Rituxan were neutropenia (63.3 percent), ALT abnormalities (59.9 percent), AST abnormalities (52.2 percent) and pyrexia (41.5 percent). The most common AEs of grade 3 or greater were neutropenia (59.9 percent), ALT abnormality (21.3 percent), febrile neutropenia (20.3 percent) and AST abnormality (15.5 percent).

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

Diarrhea of grade 3 or greater occurred in 7.2 percent of patients treated with Zydelig versus 1.9 percent of those who received placebo. Additionally, serious pneumonitis occurred in 1.4 percent of patients treated with Zydelig compared with 0 for the placebo arm.

The FDA initially approved Zydelig in July 2014 in combination with Rituxan 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 3 Study 119, which showed an improvement in objective response rates and PFS with the combination of Zydelig and Arzerra (ofatumumab) compared with the CD20 inhibitor alone in patients with previously treated CLL.