FDA lymphoma drug approval based on MD Anderson-led clinical trial

The U.S. Food and Drug Administration today approved ibrutinib for treatment of patients with mantle cell lymphoma who have received at least one other form of therapy.

Approval came under the FDA's accelerated approval program for potential breakthrough drugs based on a single-arm pivotal phase II clinical trial led by Michael Wang, M.D., professor of Lymphoma/Myeloma.

"This is excellent news for mantle cell lymphoma patients," Wang says. "Ibrutinib is an oral drug taken once daily that has shown better response rates for patients than existing combination chemotherapy regimens and with much milder side effects."

Wang and colleagues reported clinical trial results in the New England Journal of Medicine on June 19.

The FDA announcement noted that the international clinical trial enrolled 111 patients and demonstrated a 66% overall response rate, with 17% of patients achieving a complete response and 49% partial responses. Median response duration was 17.5 months. Approval was based on overall response rate; a survival advantage has not yet been established.

Seventy-seven patients had stage 4 disease entering the trial and the median number of previous treatments received was three. Ibrutinib attacks malignant B cells Pharmacyclics, Inc., developed ibrutinib, which has been renamed IMBRUVICA. Mantle cell lymphoma is an aggressive B cell subtype that accounts for 6% of non-Hodgkin lymphoma cases.

B cells are white blood cells (leukocytes) that, when activated by the immune system, produce antibodies against invading pathogens. Ibrutinib targets the Bruton's tyrosine kinase -- an essential component of the B cell receptor pathway that is critical for B cell lymphomas -- causing cell death and reducing migration and adhesion of malignant B cells.

Under terms of the accelerated approval, the FDA requires Pharmacyclics to submit 24-month follow-up data for all patients in the single-arm trial. The company also will submit the results of a randomized controlled phase III trial comparing ibrutinib in combination with bendamustine plus rituximab to bendamustine plus rituximab in patients with newly diagnosed mantle cell lymphoma.

MD Anderson is enrolling patients in the combination study, led here by Jorge Romaguera, M.D., professor of lymphoma/myeloma. Click here for more information.

Reduced toxicity compared to chemotherapy The phase I clinical trial for ibrutinib was led by Nathan Fowler, M.D., associate professor of Lymphoma/Myeloma. The safety and dose-setting trial tested ibrutinib in a variety of B cell malignancies, including chronic lymphocytic leukemia and multiple lymphoma types.

Phase I results foreshadowed response rates in the mantle cell clinical trial, with objective responses in 60% of 50 patients, including complete responses in 16%.

Patients with indolent lymphoma and aggressive large cell lymphomas also responded, Fowler notes "With its activity across B cell malignancies and its relative lack of toxicity, ibrutinib represents a major breakthrough for lymphoma treatment," Fowler says.

The FDA is considering an application by Pharmacyclics for approval of the drug for chronic lymphocytic leukemia.

Mantle cell lymphoma has been treated with combination chemotherapy regimens that have good response rates but high rates of relapse and harsh side effects.

While less burdensome, ibrutinib also has side effects. The most common adverse reactions reported in the clinical trial (occurring in greater than or equal to 20% of patients) were low platelet counts, diarrhea, low white blood cell counts, anemia, fatigue, musculoskeletal pain, swelling, upper respiratory infection, nausea, bruising, shortness of breath, constipation, rash, abdominal pain, vomiting, and decreased appetite.

Five percent of patients had grade 3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding, and blood in the urine). Bleeding events, including bruising of any grade, occurred in 48% of patients. Treatment-related grade 3 or 4 low blood cell counts occurred in 41% of patients. Twenty-five percent had grade 3 or higher infections.

Additional information FDA announcement New England Journal of Medicine article and MD Anderson news release Phase I results in the Journal of Clinical Oncology