Phase 2 Study of Otlertuzumab (TRU-016), an Anti-CD37 ADAPTIRTM Protein, in Combination with Bendamustine Vs Bendamustine Alone in Patients with Relapsed Chronic Lymphocytic Leukemia (CLL) - Updated Results
Authors: Robak Tadeusz , Hellman Andrzej , Loscertales Javier , Lech-Maranda Ewa , Pagel John M. , Mato Anthony R. , Byrd John C. , Awan Farrukh , Hebart Holger , Garcia-Marco Jose A , Hill Brian T. , Hallek Michael , Stromatt Scott , Kloczko Janusz 
Published: October 2019

Abstract
Background: CD37 is a tetraspanin protein expressed on the surface of normal and transformed B cells across a wide range of maturational stages that mediates death signaling via SHP1. Otlertuzumab is a CD37-specific therapeutic protein built on the ADAPTIRTM (modular protein technology) platform that has shown significantly greater direct killing of CLL cells than rituximab and higher levels of Fc mediated cellular cytotoxicity of CLL cells than either alemtuzumab or rituximab in pre-clinical models. Preclinical in vitro and in vivo models showed significant activity of otlertuzumab with bendamustine (benda). In phase 1 of this study involving 12 relapsed and/or refractory CLL patients (pts), otlertuzumab plus benda was well tolerated and showed activity. This phase 2 trial was conducted to investigate the activity of this combination compared to benda alone.
Methods: Pts with relapsed-refractory CLL who had 1-3 prior treatments, adequate organ function, ECOG performance status ≤2, ANC ≥1200/μL and CrCl >40 mL/min were eligible. Pts were stratified at randomization (1:1) based on Cumulative Illness Rating Score (CIRS), CrCl, and deletion or mutation of 17p13.1. Pts in the study drug arm received otlertuzumab(20 mg/kg) weekly (1st dose split over 2 days) by IV infusion for two 28-day cycles then every 14 days for four 28-day cycles. In both arms, benda (70 mg/m2) was administered IV on Days 1 and 2 of each cycle for up to six 28-day cycles. Safety was evaluated using CTCAE, v4.03 and IWCLL 2008 Grading scale for Hematologic Toxicity in CLL Studies. Response was determined using the 1996 NCI and 2008 IWCLL Criteria.
Results: 65 pts were treated; 32 with otlertuzumab plus benda and 33 with benda alone. Pt characteristics, response, and adverse events (AEs) are shown in the table. All but 4 patients have been followed for 2 years. Overall response rate was higher in the otlertuzumab+benda arm compared to benda alone (69% vs 39%, p=0.025) and median progression-free survival (PFS) was longer (14 m vs 10 m, p=0.016) in the otlertuzumab+benda arm. The frequency of all AEs was similar between treatment arms with hematologic and infection AEs being the most frequent. The imbalance in serious AEs appeared to be driven by CLL-related events in the benda alone arm. The half-life of otlertuzumab is 10 days and there were no pts with detectable antidrug antibody in the 14 pts tested to date. Pts were followed for 18 months.
Conclusions: The combination ofotlertuzumab and bendamustine was well tolerated and significantly prolonged response rate and PFS over single agent bendamustine. The overall incidence of AEs was similar between the 2 treatment cohorts, but there was a higher incidence of pyrexia, neutropenia, and thrombocytopenia with the combination. However, the addition of otlertuzumab did not appear to increase the number of serious adverse events. The activity and safety profile of otlertuzumab warrants continued development. A trial in combination with obinutuzumab is underway and a trial in combination with a pi3k inhibitor is slated to start shortly. TableOtlertuzumab + Benda (n=32)Benda (n=33)Baseline CharacteristicsAge, median (range)65 (44-82)60 (48-79)CIRS >619%18%CrCl < 60 mL/min19%15%FIT75%67%Bulky disease*25%18%Prior rituximab81%64%Refractory16%12%≥ 2 Prior regimens63%39%del(17p13.1)13%18%TP53 mutation16%27%del(11q)47%30%Mutated IGVH25%21%Rai III/IV28%36%Efficacy IWCLL ORR**69%39%IWCLL CR9%3%IWCLL CRi3%0DOR, months (80% CI)13 (11-18)8 (7-10)PFS, months (80% CI)***14 (14-19)10 (9-11)%, All Adverse Events/All / ≥ Grade 3 Adverse EventsAny Event91/66100/76 Events in ≥5 patients in either armNeutropenia59/5639/39Any Infection59/1361/27Thrombocytopenia34/1927/15Pyrexia34/312/0Anaemia28/1333/15Nausea19/030/0Diarrhea16/321/0Fatigue16/015/3Pruritus16/03/0Upper respiratory tract infection16/09/0Cough13/021/0Bronchitis13/021/9Vomiting13/015/3Pneumonia9/615/12Headache6/015/0Constipation6/024/0Febrile neutropenia0/06/6%, Serious Adverse Events in ≥2 patientsAll serious events3146Pneumonia912Pyrexia99Febrile neutropenia06Bronchitis09 *nodes ≥7 cm or 3 adjacent/confluent nodes ≥3 cm **p=0.025 ***p=0.016 FIT = CIRS ≤6 and CrCL ≥60 mL/min, ORR = overall response rate, CR = complete response rate, Cri = CR with incomplete bone marrow recovery, PFS = median progression free survival, DOR = median duration of response

Disclosures
Robak: Emergent Product Development: Research Funding. Mato:Emegent Product Development: Honoraria. Byrd:Emergent Product Development: Research Funding. Awan:Lymphoma Research Foundation: Research Funding; Boehringer Ingelheim: Consultancy. Hill:Emergent Product Development: Research Funding. Stromatt:Emergent Product Development: Employment.