A Phase 1 -2 Study of Brentuximab Vedotin (Bv) and Bendamustine (B) in Patients with Relapsed or Refractory Hodgkin Lymphoma (HL) and Anaplastic Large T-Cell Lymphoma (ALCL)

Patients with relapsed or refractory HL or ALCL have few therapeutic options. Recently, brentuximab vedotin was approved for patients who have relapsed following autologous stem cell transplant (ASCT), and for patients considered ineligible for ASCT. Patients who achieve a complete response experience very durable remissions of their disease. Another agent recently established as active in patients with heavily treated HL is bendamustine, which has been demonstrated to produce a good overall response rate in this setting, though the progression free survival and duration of response are considered modest. The notion that one drug which can produce a rapid response in a majority of patients, coupled with one that can sustain a response led to the concept that a brentuximab vedotin and bendamustine combination could be an excellent salvage regimen for patients with relapsed or refractory disease especially considering their largely non-overlapping toxicity spectra. If this combination produces meaningful complete remissions, it could be used as second line therapy, sparing patient the adverse effects and inpatient stays experienced with ICE based chemotherapy.

In this Phase 1 study, we planned to explore 5 dose levels of brentuximab and bendamustine: (1) Bv = 1.2mg/kg; B = 70mg/m2; (2) Bv = 1.2mg/kg; B = 80mg/m2; (3) Bv = 1.8mg/kg; B = 80mg/m2; (4) Bv = 1.8mg/kg; B = 90; and (5) Bv = 1.8mg/kg and B = 100mg/m2. Accrual followed a classic Fibonacchi dose escalation, with 3 patients being treated at each dose level. A Dose Limiting Toxicity, defined as any CTC version 4 Grade 3 or 4 toxicity, excepting modifications for neutropenia, anemia, and thrombocytopenia, nausea and vomiting, diarrhea, alopecia and fatigue, led to expansion of the dose cohort. In brief, the study population consisted of 28 patients accrued to the Phase 1 portion of the study, of which: 18 were male; 27 had HL and 1 ALCL; the median number of prior systemic therapies was 5 (range 1-14); with 17 patients having had prior ASCT and 11 prior radiation therapy. The maximum tolerated dose (MTD) was Bv = 1.8 mg/m2 and 90 mg/m2 of bendamustine. The DLT was not reached, as the study called for only 5 dose cohorts, with the highest dose cohort being defined by the MTD of the individual drugs. To date, 27 patients were evaluable for response. Two patients (7%) experienced a complete remission, and 10 had a partial remission, for an overall response rate of 44%. Ten patients had stable disease. Interestingly, among the 9 patients who had prior Bv, 4 responded (44%) (PR=4, SD=2, POD=3), and of the 4 patients who had prior B, 2 responded (50%) (PR=2, SD=1, POD=1).

The study is now being expanded into a Phase 2 study, where an additional 37 patients will be accrued. In addition, plasma and serum was collected from every patient, which are being analyzed for a variety of immunological biomarkers which will be correlated with toxicity and response. We believe that in this very heavily treated patient population, the combination of Bv and B represents a highly promising combination for patients with relapsed or refractory HL and ALCL.

* Decision was made not to exceed the MTD of individual drugs