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FDA Approval for Ibrutinib

Brand name: Imbruvica

  • Approved for chronic lymphocytic leukemia after previous treatment
  • Approved for mantle cell lymphoma after previous treatment

Full prescribing information is available, including clinical trial information, safety, dosing, drug-drug interactions, and contraindications.

Approved for chronic lymphocytic leukemia after previous treatment

On February 12, 2014, the U. S. Food and Drug Administration granted accelerated approval to ibrutinib (IMBRUVICA, Pharmacyclics, Inc.) for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy.  Ibrutinib previously received accelerated approval on November 13, 2013, for the treatment of patients with mantle cell lymphoma who have received at least one prior therapy.

The approval in CLL was based on the results of a multicenter single-arm trial of 48 patients with previously treated CLL. The median age of the patients was 67 years (range, 37 to 82 years), and 71 percent were male. All patients had a baseline ECOG performance status of 0 or 1. The median time since diagnosis was 6.7 years, and the median number of prior treatments was 4 (range, 1 to 12 treatments).  Ibrutinib was administered orally at 420 mg once daily until disease progression or unacceptable toxicity.

The efficacy results demonstrated a 58.3 percent overall response rate (95 percent CI: 43.2 to 72.4) as assessed by an independent review committee. No complete responses were observed. The response duration ranged from 5.6 months to more than 24.2 months; the median was not reached.

The safety profile of ibrutinib for patients with previously treated CLL was consistent with observations in the mantle cell lymphoma clinical trial.  The most common adverse reactions reported in the CLL clinical trial (occurring in at least 20 percent of patients) were thrombocytopenia, diarrhea, bruising, neutropenia, anemia, upper respiratory tract infection, fatigue, musculoskeletal pain, rash, fever, constipation, peripheral edema, joint pain, nausea, stomatitis, sinusitis, and dizziness.

As a condition of this accelerated approval, the FDA required that the sponsor submit results of randomized clinical trial(s). In January 2014, Pharmacyclics notified FDA of the early stopping of the RESONATE trial by the Data Monitoring Committee, based on favorable results of a planned interim analysis. RESONATE, a phase III clinical trial, randomly assigned patients with previously treated CLL or small lymphocytic lymphoma (SLL) who were not considered candidates for treatment with purine analogue-based treatments to either ibrutinib or ofatumumab.  The trial was reported to demonstrate an improvement in progression-free survival and overall survival.  

The recommended dose and schedule of ibrutinib for patients with CLL is 420 mg (three 140 mg capsules) taken orally once daily.

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Approved for mantle cell lymphoma after previous treatment

On November 13, 2013, the Food and Drug Administration (FDA) granted accelerated approval to ibrutinib (Imbruvica, made by Pharmacyclics, Inc.) for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.   

The approval was based on the results of a multi-center international single-arm trial enrolling 111 patients with previously treated mantle cell lymphoma. The primary endpoint was overall response rate (ORR).

The efficacy results demonstrated a 66 percent ORR (95 percent CI 56.2, 74.5). Seventeen percent of patients achieved complete responses and 49 percent achieved partial responses. The median response duration was 17.5 months (95 percent CI 15.8, not reached).   

Safety was evaluated in the 111 patients with previously treated MCL who received ibrutinib 560 mg daily. The most common adverse reactions reported in the clinical trial (occurring in at least 20 percent of patients) were thrombocytopenia, diarrhea, neutropenia, anemia, fatigue, musculoskeletal pain, peripheral edema, upper respiratory infection, nausea, bruising, dyspnea, constipation, rash, abdominal pain, vomiting, and decreased appetite.

Five percent of patients had grade 3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding, and hematuria). Bleeding events, including bruising of any grade, occurred in 48 percent of patients. Treatment-emergent grade 3 or 4 cytopenias occurred in 41 percent of patients. Twenty-five percent had grade 3 or higher infections. 

As a condition of this accelerated approval, FDA requires that the sponsor submit 24-month follow-up data for all patients in the single-arm trial and submit the results of a randomized controlled trial comparing ibrutinib in combination with bendamustine plus rituximab to bendamustine plus rituximab in patients with newly diagnosed MCL. 

The recommended dose and schedule for ibrutinib is 560 mg (four 140 mg capsules) taken orally once daily.

This summary was provided by Richard Pazdur, M.D., director of the FDA's Division of Oncology Drug Products.
The FDA is the division of the U.S. Department of Health and Human Services charged with ensuring the safety and effectiveness of new drugs and other products. (See "Learn How Drugs and Devices Get Approved.") The FDA's mission is to promote and protect the public health by helping safe and effective products to reach the market in a timely way, and monitoring products for continued safety after they are in use.

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  • Posted: November 19, 2013