Safety Results from the United States Cohort of the Ibrutinib Early Access Treatment Protocol (EAP: MCL4001) in Patients with Relapsed or Refractory Mantle Cell Lymphoma

Background: Bruton’s tyrosine kinase (BTK) is a critical signaling molecule in the B-cell receptor pathway. Ibrutinib is a first-in-class, once daily, oral covalent inhibitor of BTK that was approved in the US (November 2013) based on an international multi-center Phase 2 study in patients with relapsed or refractory mantle cell lymphoma (MCL), with an ORR of 68% (CR 21% and PR 47%) and median progression free survival of 13.9 months (Wang et al. NEJM 2013). This EAP was conducted in a similar patient population to provide access to ibrutinib prior to market authorization and to collect additional safety data. The results of the US cohort are reported here.

Methods: This was an open-label EAP in patients with relapsed or refractory MCL, who resided in areas where ibrutinib was not available and were ineligible for ongoing ibrutinib trials. Key entry criteria were as follows: age ≥ 18 years, relapsed or refractory MCL, and no prior ibrutinib therapy. Patients received ibrutinib 560mg orally once daily in 28 day cycles until progressive disease, unacceptable toxicity, no further benefit or end of study (US approval). Adverse events (Grade ≥ 3), serious adverse events, and adverse events of interest (major hemorrhage, intracranial hemorrhage) were collected.

Results: In total,149 patients participated in the EAP at 46 US sites from May 2013 to April 2014. Median age was 68 years (range: 39-90 years) and 89% were white. Median treatment exposure was 3.65 months (range: 0.0-7.7 months), with approximately 26% of patients receiving treatment for more than 6 months. Of the 149 patients, 58.5% had refractory disease and 66.7% had received ≥3 prior lines of therapy. Adverse events grade ≥3 were reported in 59 patients (39.6%), the most common of which were neutropenia (6.7%), dyspnea (4%), anemia (3.4%) and thrombocytopenia (3.4%). Serious adverse events were reported in 46 patients (30.9%). Adverse events of interest were reported in two patients (1.3%): 1 major hemorrhage (0.7%) and 1 intracranial hemorrhage (0.7%). Ten patients (6.7%) discontinued treatment due to adverse events. The primary reason for discontinuation was progressive disease in 20 patients (13.4%) and death in 12 patients (8.1%). The majority of patients (66%) continued on therapy until the end of study (US approval).

Conclusions: The safety profile observed in this US cohort of the EAP was consistent with that observed during the registration trial for MCL. No new safety signals were observed in this predominantly refractory population of patients. Moreover, this EAP provided an important mechanism for patients to receive ibrutinib prior to US approval.