Promising Results Halt Phase III Studies of Idelalisib

A phase III study of the PI3K-delta inhibitor idelalisib in combination with rituximab (Rituxan) has been stopped early following a positive interim analysis, according to a statement from Gilead Sciences, Inc, the company developing the drug.

The randomized trial, labeled Study 116, investigated the combination as a treatment for chemotherapy- ineligible patients with previously treated chronic lymphocytic leukemia (CLL). The decision to stop the trial early followed a recommendation from an independent data monitoring committee that found a highly statistically significant prolongation in the primary end point of progression-free survival (PFS). Subsequently, patients on the control arm receiving rituximab plus placebo are now eligible for treatment with idelalisib in an extension study.

Idelalisib, a first-in-class selective PI3K-delta inhibitor, is thought to be effective in B-cell malignancies due to the role of PI3K-delta in the activation, proliferation, and survival of B cells, a

rationale that was confirmed in earlystage trials.

“This is the first phase III study to report positive results for a new class of targeted therapies that inhibit B-cell receptor signaling as a major component of their mechanism of action, an important area of focus in the development of chemotherapy- free regimens in CLL and other B-cell malignancies,” said Norbert W. Bischofberger, PhD, executive vice president of research and development and chief scientific officer at Gilead, in the statement.

The study enrolled a total of 220 patients, all of whom had previously treated recurrent CLL with measurable lymphadenopathy. Patients in the trial were randomized in a 1:1 ratio to receive idelalisib at a 150 mg dose twice a day in combination with intravenous rituximab at an initial dose of 375-mg/m2 followed by 500 mg/m2 or rituximab and placebo. Patients who progressed were eligible to receive idelalisib therapy in a double-blind extension study.

The phase III study was launched on the basis of results from a phase I trial examining the combination of idelalisib with rituximab and/or bendamustine for patients with previously treated

CLL, presented at the 2012 meeting of the American Society of Hematology. In that study, 19 patients who had received a median of 2 prior therapies took idelalisib at 150 mg twice a day in combination with weekly rituximab at 375 mg/m2. In the intent-to-treat population, the overall response rate (ORR) was 78%, the 1-year PFS rate was 74%, and 84% of patients experienced a lymph node response (shrinkage ≥50%) resulting in marked reductions in lymphadenopathy.

The combination of idelalisib, rituximab, and bendamustine (Treanda) presented the best response, with an ORR of 87%, a 1-year PFS rate of 87%, and lymph node response in 87% of the 15 patients. A randomized phase III study examining the combination of idelalisib, rituximab, and bendamustine is recruiting patients with previously treated CLL (NCT01569295).

The early stop of the phase III trial indicates a promising treatment with the potential for regulatory approval, although early discontinuation of randomized clinical trials based on evidence

of benefit is controversial, with research suggesting an overestimation of treatment effects.

In its announcement, Gilead stated that it had informed the US Food and Drug Administration (FDA) of its decision to stop the trial. The company is engaged in conversations regarding a potential regulatory filing for idelalisib in CLL. In September 2013, Gilead submitted a New Drug Application to the FDA for approval of idelalisib for the treatment of patients with indolent

non-Hodgkin’s lymphoma (iNHL).

That submission was based on data from a single-arm, open-label phase II study of 125 patients with iNHL who were refractory to rituximab and an alkylating- agent-containing chemotherapy.

In an interim analysis of this study, single-agent idelalisib achieved an ORR of 53.6%, with a median duration of response of 11.9 months, median PFS of 11.4 months, and lymph node shrinkage experienced in 89% of patients.

Additionally, according to results from a phase II trial presented at the 2013 annual meeting of the American Society of Clinical Oncology, idelalisib plus rituximab has demonstrated promising

results in treatment-naïve patients with CLL. In that study, patients who were ≥65 years old with previously untreated CLL or small lymphocytic lymphoma received idelalisib at 150 mg twice a

day combined with weekly rituximab at 375 mg/m2. At a 24-month analysis, the combination was found to be highly active in treatment-naïve elderly patients. The trial found a Kaplan-Meier estimated PFS benefit of 93%. Moreover, the combination achieved a complete response rate of 19% and an ORR of 97%.

At the time of the presentation, the principal investigator on the study, Susan M. O’Brien, MD, Ashbel Smith Professor of Medicine in the Department of Leukemia at the University of Texas

EBO

MD Anderson Cancer Center, said, “The high overall response rate and durable disease control observed in this phase II study suggest that idelalisib in combination with rituximab could become an important therapeutic option for CLL patients new to treatment.”