Ibrutinib CLL Trial Stopped Early

After significant improvement in progression-free survival with ibrutinib over ofatumumab, an independent data monitoring board has recommended stopping a phase III trial involving patients with relapsed or refractory CLL or SLL.

An independent data monitoring board has recommended stopping a phase III trial comparing ibrutinib and ofatumumab in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL). An interim analysis showed a significant improvement in progression-free survival (PFS) with ibrutinib, with an acceptable safety profile.

The RESONATE study included 391 patients at more than 70 sites across 10 countries, and will likely now stop early. The study compared the CD20 antibody ofatumumab with ibrutinib 420 mg once daily; it is being led by Danelle James, MD, of Pharmacyclics, the drug’s manufacturer. Along with improvement in PFS, the interim analysis showed significantly better overall survival, a secondary endpoint of RESONATE. Pharmacyclics is now in discussions with both the Food and Drug Administration and the European Medicines Agency to determine the next steps for the drug.

Ibrutinib is a first-in-class drug targeting a protein known as Bruton’s tyrosine kinase (BTK). BTK is a signaling molecule of the B-cell receptor signaling complex; this pathway plays a role in the survival of malignant B cells. Ibrutinib is already approved by the FDA for treatment of mantle-cell lymphoma; it was approved in November under the Breakthrough Therapy Designation program, an FDA initiative designed to speed up the development and review of drugs for life-threatening conditions.

An earlier phase Ib/II study also showed good results with ibrutinib in CLL and SLL patients. Results published in June in the New England Journal of Medicine showed response rates of 71% with both a 420 mg and a 840 mg dose of the drug. The estimated PFS at 26 months was 75% among high-risk and relapsed/refractory patients, and 83% of patients remained alive.

Fong Clow, ScD, the senior vice president of biometrics at Pharmacyclics, said in a press release that “the results seen at the interim analysis of the RESONATE trial are robust and consistent.” Patients in the trial who were randomized to ofatumumab and experienced disease progression were evaluable for subsequent treatment with ibrutinib.

The study drug is currently being investigated in nine different phase III trials of varying malignancies including CLL, SLL, mantle-cell lymphoma, and non-Hodgkin lymphoma. The full interim analysis from the RESONATE trial will likely be presented at an upcoming conference prior to publication in a journal.