SUNNYVALE, Calif.—Pharmacyclics Inc. and Raritan, N.J.-based Janssen Research & Development LLC have simultaneously announced that an independent data monitoring committee (IDMC) unanimously recommended that the Phase 3 RESONATE study (also called Study PCYC-1112-CA), a head-to-head comparison of Imbruvica (ibrutinib) vs. ofatumumab, be stopped early because the primary and a key secondary endpoint of the study have been met.
At the planned interim analysis, the Phase 3 RESONATE study demonstrated that Imbruvica showed a statistically significant improvement in progression-free survival (the primary endpoint of the study, which was evaluated by an independent review committee) in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Further, Imbruvica showed statistically significant improvement in overall survival (a key secondary endpoint of the trial). The safety profile of Imbruvica was acceptable and consistent with prior clinical experience. The IDMC recommended that the sponsor provide access to Imbruvica for subjects on the ofatumumab arm.
Pharmacyclics has informed the U.S. Food and Drug Administration of the recommendations of the IDMC. Similarly, Janssen, the co-developer of Imbruvica, has informed the European Medicines Agency. Both companies are engaging in a dialogue with the health authorities to define the next regulatory steps and anticipate providing a comprehensive RESONATE study report to them within the coming months.
“I am tremendously proud of the accomplishment of the Pharmacyclics team for their effort and execution as well as the collaboration with the clinical sites toward this high-quality study. This collaboration resulted in expeditious enrollment and rapid data collection and analysis. This global study involving 391 patients was conducted at more than 70 clinical sites in 10 countries,” said Dr. Maria Fardis, chief of oncology operations and alliances at Pharmacyclics.
“We express our appreciation to the patients, the investigators and the entire Pharmacyclics and Janssen teams for overcoming the barriers and challenges associated with this exciting scientific outcome,” added Robert Duggan, CEO and chairman of Pharmacyclics.
The RESONATE study is an international, randomized, open-label Phase 3 clinical study including 391 patients with relapsed or refractory CLL/SLL with measurable nodal disease and who were not eligible for treatment with purine analog-based therapy, who had received at least one prior therapy. Patients were randomized to receive 420 mg of ibrutinib orally once daily or intravenous doses of ofatumumab, an approved treatment for relapsed/refractory CLL, over the course of 24 weeks. Both treatments were administered until disease progression or unacceptable toxicity.
The primary endpoint of the study was progression-free survival; overall survival is a key secondary endpoint and others included overall response rate and safety. The IDMC unanimously recommended stopping the study early based on a planned interim analysis, in which statistically significant differences in progression-free survival (as assessed by an independent review committee) and overall survival were observed. The IDMC agreed that these results suggest evidence of clinical benefit as well as a tolerable safety profile in patients receiving ibrutinib as compared to intravenous doses of ofatumumab.
The study results will be presented at an upcoming medical meeting and also will be submitted for publication in a peer-reviewed journal. Until that time, the co-sponsors decline to make statements about the details of the findings.
“We’re delighted with this outcome, and look forward to sharing these results with the scientific community and health authorities,” said Dr. Peter F. Lebowitz, head of oncology therapeutics for Janssen Research & Development. “This Phase 3 randomized study provides a useful head-to-head comparison of single agent ibrutinib versus ofatumumab, and builds upon the early evidence of clinical benefit observed in the ibrutinib Phase 2 program.”
Janssen and Pharmacyclics forged their collaboration in December 2011. Under the terms of the agreement, Pharmacyclics was to receive an upfront payment of $150 million. In addition, Pharmacyclics will receive up to an additional $825 million in development and regulatory milestone payments, based upon continued development, regulatory progress and approval of the product, for total potential payments of $975 million.
Ibrutinib was approved in November 2013 in the U.S. under the tradename Imbruvica, as a single agent for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. This indication is based on overall response rate. An improvement in survival or disease-related symptoms has not been established. The drug has been submitted to the EMA for the treatment of adult patients with relapsed or refractory CLL/SLL or adult patients with relapsed or refractory MCL.
CLL is a slow-growing cancer of the white blood cells (lymphocytes), most commonly B cells. CLL is the most common adult leukemia. SLL is a slow-growing lymphoma in which too many immature white blood cells cause lymph nodes to become larger than normal.