Phase 1b Study of Otlertuzumab (TRU-016), an Anti-CD37 ADAPTIRTM Protein, in Combination with Rituximab in Patients with Chronic Lymphocytic Leukemia (CLL)
Authors: Maddocks Kami J. , Pagel John , Byrd John C. , Stromatt Scott , Awan Farrukh 
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. This phase 1b trial was conducted to evaluate the safety and efficacy of otlertuzumab in combination with rituximab in patients with CLL.
Methods: Eligibility included CLL patients with adequate organ function, ECOG ≤2, and absolute neutrophil count ≥800/μL. Three cohorts have been enrolled. In the 1st cohort, 24 patients previously untreated patients who were considered ineligible for standard chemotherapy based on age, comorbidity or patient preference (naive) were enrolled and received IV infusion of otlertuzumab weekly for two 28-day cycles then once a month for 4 months. The first dose was 10 mg/kg and all subsequent doses were 20 mg/kg. In the 2nd cohort, 16 relapsed patients who had received 1-3 prior therapies were treated on the same dose and schedule as the 1st cohort except the first dose was 6 mg/kg. In the 3rd cohort, 16 naive patients received 6 mg/kg on Day 1 and 10 mg/kg on Days 8 and 15 and then monthly for 5 months. In all cohorts, rituximab (375 mg/m2 the first dose then 500 mg/m2) was administered after otlertuzumab by on the same schedule. Safety was evaluated using CTCAE and IWCLL 2008 Grading scale for Hematologic Toxicity in CLL Studies. Response was determined using the 1996 NCI and the 2008 IWCLL Criteria.
Results: Patient characteristics and adverse events are shown in the table. All but 9 patients completed all cycles of therapy: 3 discontinued early due to progressive disease; 3 due to lack of response, and 3 due to AEs (reaction to allopurinol, systemic inflammatory response, and rash). Grade 3/4 neutropenia was reported in 9% of patients; the incidence of severe infections was low (9%). Serious adverse events occurred in 61% of pts and included infusion related reaction (28 pts, 2 grade 3, 26 ≤grade 2), febrile neutropenia (4 patients), infection (2 pneumonia and 1 each sinusitis and diverticulitis), pyrexia (2 patients), and deep vein thrombosis, lymph node pain, grade 1 acute coronary syndrome, atrial fibrillation, small intestinal obstruction, systemic inflammatory response syndrome, and hyperkalemia in 1 pt each. For the 20 mg/kg previously untreated patients (n=24) IWCLL response rate is 54% (8% CR); 1 patient is not yet evaluable. NCI response rate is 96% (38% CR). Median progression-free survival is 16 months. In the other 2 cohorts, patients have been followed from 1 to 5 months after end of treatment and response results will be presented at the meeting.
Conclusions: The preliminary response rate with otlertuzumab in combination with rituximab is promising. This study is ongoing. The results for cohort 2 and 3 will be updated. The fourth cohort is currently being treated with otlertuzumab in combination with obinutuzumab instead of rituximab. Tablel 1Basic characteristics, therapeutic efficacy and CTCAE grade III/IV toxicity. Baseline Characteristics NaiveRelapsed20 mg/kg (n=24)10 mg/kg (n=16)20 mg/kg (n=16)Age, median (range)65 (27-85)62 (48-88)63(47-74)Male, n (%)13 (54)10 (63)9 (56)Β2 Microglobulin, mg/dL, median (range)3.5 (2-6)2.9 (1-6)4..0 (2-10)CIRS ≤6, n (%)14 (58)10 (63)11 (69)Rai III/IV, n (%)5 (21)5 (31)11 (69)del17p, n (%)2 (8)1 (6)5 (31)del11q, n (%)7 (29)2 (13)2 (13)del13q, n (%)13 (54)5 (31)7 (44)Trisomy 12, n (%)9 (38)4 (25)0Adverse Events, %Any Event10094100Any Grade 3/4 Event462563Any Serious Event756338Nonhematologic Events in ≥10% of patients*Infusion-related reaction67*5619Any infection583125Nausea331325Diarrhea331331Headache17625Hypertension171913*Cough13196Pyrexia131913MyelosuppressionNeutropenia*13019Thrombocytopenia000Anemia4019 *All grade 1/2 except 2 patients with Grade 3/4 infusion related reaction, 1 with Grade 3/4 hypertension, and 5 with Grade 4 neutropenia

Disclosures
Off Label Use: Ibrutinib is approved for previously treated MCL but was used as first-line therapy in 2 patients in this report.. Byrd:Emergent Product Development: Research Funding. Stromatt:Emergent Product Development: Employment. Awan:Lymphoma Research Foundation: Research Funding; Boehringer Ingelheim: Consultancy.