The Combination of Brentuximab Vedotin (Bv) and Bendamustine (B) Demonstrates Marked Activity in Heavily Treated Patients with Relapsed or Refractory Hodgkin Lymphoma (HL) and Anaplastic Large T-Cell Lymphoma (ALCL): Results of an International Multi Center Phase I/II Experience
Authors: Sawas Ahmed , Connors Joseph M. , Kuruvilla John G. , Rojas Celeste , Lichtenstein Renee , Neylon Ellen , Lichtenstein Emily , Deng Changchun , Amengual Jennifer E , Villa Diego , Crump Michael , O'Connor Owen A. 
Published: October 2019

Abstract
Introduction
Patients with HL or ALCL who have relapsed post or are ineligible for autologous stem cell transplant (ASCT) remain incurable with standard therapies. The CD30 immunoconjugate Brentuximab vedotin has become the preferred treatment for such patients. Bendamustine has also demonstrated good activity and tolerability in several lymphoma subtypes including HL. This ongoing phase I/II study was designed to evaluate the safety and efficacy of the combination of brentuximab vedotin with bendamustine for the treatment of patients with relapsed or refractory HL or ALCL. We provide the phase I and II data. (ClinicalTrials.gov #NCT01657331).
Methods
Patients received an outpatient IV infusion of brentuximab vedotin on Day 1 with bendamustine 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), defined as any CTC version 4 Grade 3 or 4 toxicity 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 ongoing of the Phase 2 portion of the study, where an additional 24 patients will be accrued. In addition, plasma and serum biomarkers are being prospectively collected for correlation with toxicity and response.
Results
Forty-two patients (55% male) with a median age of 37 years (range, 30-70) were enrolled. Forty-one patients had HL and 1 ALCL; the median number of prior systemic therapies was 5 (range 1-16); with 26 patients having had prior ASCT and 14 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 were neutropenia (14%) and pneumonia (14%).
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, 36/39 patients are evaluable for response. The overall response rate was 67%, with 7 patients (19%) attaining a complete response (CR). Eight 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 67% with responses ≥ 50% in patients who had received either agent separately supporting the potential clinical synergy of the combination.
Table. Dose Cohort No. Patients Responses Complete Response Dose Cohort 1Bv = 1.2 mg/kg B = 70 mg/m2 7 4 1 Dose Cohort 2Bv = 1.2 mg/kg B = 80 mg/m2 3 3 0 Dose Cohort 3Bv = 1.8 mg/kg B = 80 mg/m2 7 5 1 Dose Cohort 4Bv = 1.8 mg/kg B = 90 mg/m2 11 5 1 Phase IIBv = 1.8 mg/kg B = 90 mg/m2 11 7 4 Total 39 (36 evaluable) 24 (67%) 7 (19%)

Disclosures
Sawas: Seattle Genetics: Research Funding; Gilead Sciences: Honoraria. Off Label Use: Bendamustine is not approved for the treatment of Hodgkin lymphoma or anaplastic large T- cell lymphoma. Connors:Roche: Research Funding; Seattle Genetics: Research Funding. Kuruvilla:Karyopharm: Honoraria, Research Funding; Roche Canada: Honoraria; Seattle Genetics: Honoraria, Research Funding. Neylon:Genentech: Speakers Bureau; Seattle Genetics: Speakers Bureau; Celgene: Speakers Bureau; Gilead: Speakers Bureau. Deng:TG Therapeutics, Inc.: Honoraria, Research Funding; Seattle Genetics: Research Funding. Amengual:Acetylon Pharmaceuticals, INC: Consultancy, Research Funding. Villa:Roche: Research Funding. Crump:Sanofi: Honoraria; Celgene: Honoraria; Seattle Genetics: Honoraria. O'Connor:Spectrum: Research Funding; Takeda Pharmaceutical Company Limited: Research Funding; Seattle Genetics: Research Funding.