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 announced October 10.
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). As a result of the stoppage, patients on the control arm receiving rituximab plus placebo are now eligible for treatment with idelalisib in an extension study.
Idelalisib is a first-in-class selective PI3K-delta inhibitor. This mechanism of action 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. Prior to the phase III investigation, the treatment was explored in early-stage trials, which seemed to confirm this rationale.
“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, the executive vice president of research and development and chief scientific officer at Gilead, in the statement.
The phase III study enrolled a total of 220 patients, approximately 20 patients more than expected. All patients enrolled on the trial 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 daily 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.
Data from the interim analysis are likely to be presented later this year. “Given the significant unmet medical need in CLL, particularly in this population of patients who are not fit for chemotherapy, we are pleased that idelalisib has shown a clinically meaningful benefit for patients,” said Bischofberger in a statement.
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. Results from this analysis were 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 daily in combination with weekly rituximab at 375 mg/m2. In the intent-to-treat to population, the overall response rate (ORR) was 78%. Moreover, 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 highest level of response in this trial was experienced with the combination of idelalisib, rituximab, and bendamustine (Treanda). This portion of the trial contained 15 patients and found an ORR of 87%, a 1-year PFS rate of 87%, and lymph node response in 87% of patients. A randomized phase III study examining the combination of idelalisib, rituximab, and bendamustine is recruiting patients with previously previously treated CLL (NCT01569295).
The early stop of the phase III trial indicates a promising treatment with the potential for regulatory approval. However, controversy exists in medical research regarding stopping randomized clinical trials early based on evidence of benefit. In many cases, evidence suggests that trials that stop early overestimate treatment effects Moreover, an analysis published in BMJ in 2012 found that large overestimates of benefits were common when less than 200 events were analyzed. Most recently, a large phase III trial analyzing abiraterone acetate for men with metastatic castration-resistant prostate cancer before chemotherapy fell under scrutiny after the trial was halted early following an interim analysis.
As a result of this early unblinding, many questioned the authenticity of the survival advantage experienced in the trial, since statistical significance had not been met. Despite this, the US Food and Drug Administration (FDA) approved abiraterone based on results from this study. In its announcement, Gilead stated that it has informed the 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 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. Additionally, median PFS was 11.4 months with lymph node shrinkage experienced in 89% of patients.
In addition to previously treated patients with CLL and iNHL, idelalisib plus rituximab has demonstrated promising results in treatment-naïve patients with CLL, according to results from a phase II trial that was presented at the 2013 ASCO Annual Meeting. In that study, patients who were ≥65 years old with previously untreated CLL or small lymphocytic lymphoma received idelalisib at 150 mg BID 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 lead author, Susan M. O’Brien, MD, 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.” O’Brien is the Ashbel Smith Professor of Medicine in the Department of Leukemia at the University of Texas MD Anderson Cancer Center in Houston and was a principal investigator of the phase II study.