Patients with HL or ALCL who relapsed post or are ineligible for autologous stem cell transplant (ASCT) are incurable with standard therapies. The anti-CD30 ADC BV is approved for such patients. B is also active and tolerable HL. This phase I/II study evaluated the safety and efficacy of brentuximab vedotin with bendamustine for patients with R/R HL or ALCL. (ClinicalTrials.gov #NCT01657331).
Methods
Patients received IV BV on Day 1 with B on Days 1 and 2 of a 3-week cycle for up to 6 cycles. In the Phase 1 portion 4 dose levels were evaluated: (1) Bv = 1.2mg/kg; B = 70mg/m2; (2) Bv = 1.2mg/kg; B = 80mg/m2; (3) Bv = 1.8mg/kg; B = 80mg/m2; and (4) Bv = 1.8mg/kg; B = 90. Accrual followed a classic Fibonacci dose escalation, with 3 patients being treated at each dose level. Dose Limiting Toxicity (DLT) led to expansion of the dose cohort. The recommended phase II dose was Bv 1.8 mg/kg on Day 1 and B 90 mg/m2 on Days 1 and 2. Response was assessed by the investigator per Cheson 2007 after cycles 2 and 6. Enrollment is nearly complete (n = 3 remaining) . In addition, plasma and serum biomarkers are being prospectively collected for correlation with toxicity and response.
Results
Sixty-one patients (66% male) with a median age of 36 years (range, 18-70) were enrolled. Fifty-nine patients had HL and 2 ALCL; the median number of prior systemic therapies was 5 (range 1-16); with 36 patients having had prior ASCT and 25 patients receiving prior radiation therapy.
The predominant all grade toxicity observed with the combination was nausea (62%, grade 1-2). The observed grade 3-4 toxicities in the phase I were: neutropenia (19%), thrombocytopenia (19%), anemia (15%) and rash (11%). The observed phase II grade 3-4 toxicities include neutropenia (8%).
No DLT was observed at dose level 4 (Bv 1.8 mg/m2 and B 90 mg/m2). The maximum tolerated dose (MTD) was not reached. A decision was made not to explore further doses that exceeded the standard single agent doses of both drugs. Patient’s received a median of 6 cycles (range, 1-6).
To date, 52/59 patients are evaluable for response. The overall response rate is 73%, with 10 patients (19%) attaining a complete response (CR). Nine patients had stable disease. Among the 11 patients who received prior Bv, 6 responded (55%) (CR= 2, PR=4, SD=3, PD=2), and of the 4 patients who had prior B, 2 responded (50%) (PR=2, SD=1, PD=1). Two patients had received both Bv and B as single agents prior to initiation of study; one patient achieved a PR and the other experienced PD. The ALCL patient achieved a PR.
Conclusion
In this heavily treated population of HL and ALCL, the combination of brentuximab vedotin 1.8 mg/kg on Day 1 with bendamustine 90 mg/m2 on Days 1 and 2 of 3-week cycles represents a very effective and tolerable outpatient regimen. The regimen has an ORR of 73% with responses ≥ 50% in patients who had received either agent separately supporting the potential clinical synergy of the combination.