Acalabrutinib with Obinutuzumab in Relapsed/Refractory and Treatment-Naive Patients with Chronic Lymphocytic Leukemia: The Phase 1b/2 ACE-CL-003 Study

Background : Bruton tyrosine kinase (BTK) inhibitors have greatly improved the survival of patients with chronic lymphocytic leukemia (CLL). Combining BTK inhibitors with engineered CD20 antibodies, such as obinutuzumab, is hypothesized to increase rapidity and depth of response. Acalabrutinib (ACP-196) is a highly selective covalent inhibitor of BTK. The selectivity of acalabrutinib enables twice-daily dosing and potentially enhanced BTK occupancy over 24 hours. This Phase 1b/2 trial evaluated the activity and tolerability of acalabrutinib in combination with obinutuzumab in relapsed/refractory (R/R) and symptomatic, treatment-naive (TN) patients with CLL.

Methods: Key eligibility criteria included diagnosis of CLL or small lymphocytic leukemia, measurable nodal disease, Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2 and age ≥18 years. Patients were eligible for the R/R cohort if they had ≥1 prior treatment or the TN cohort if previously untreated and ≥65 years of age or <65 years of age and chemoimmunotherapy ineligible. All patients met IWCLL 2008 criteria for treatment. Previous treatment with ibrutinib or another BTK inhibitor was permitted if the patient discontinued for a reason other than on-treatment disease progression. Concomitant use of vitamin K antagonists was excluded. In 28-day cycles, acalabrutinib was administered orally at 100 mg BID or 200 mg QD (n=15, all later switched to 100 mg BID) until progressive disease (PD); obinutuzumab was administered intravenously on days 1 (100 mg), 2 (900 mg), 8 and 15 (1000 mg) of cycle 2 and day 1 (1000 mg) of cycles 3 to 7. The primary endpoints were overall response rate (ORR), defined as partial response + complete response (CR), and safety. Secondary endpoints included duration of response (DOR), time to response (TTR), progression-free survival (PFS) and pharmacodynamics.

Results: As of April 28, 2017, 19 TN and 26 R/R patients had been treated. The median age of all patients was 61 years (range, 42 to 76). Baseline characteristics in TN and R/R patients respectively included ECOG PS ≤1 (both 100%), bulky lymph nodes ≥5 cm (53% and 50%), del(17p) (4/18 [22%] and 5/26 [19%]), del11q (5/18 [28%] and 9/26 [35%]) and unmutated IGHV (9/17 [53%] and 17/26 [65%]). Higher median BTK occupancy at trough was observed with 100 mg BID vs 200 mg QD dosing on cycle 1 day 2 (96% vs 87%; p<0.0001) and on cycle 2 day 1 (97% vs 91%; p=0.001). Median follow-up was 17.8 months (range, 1.0 to 23.4) in TN patients and 21.2 months (range, 15.8 to 27.5) in R/R patients. ORR was 95% and 92% in TN and R/R patients, respectively (Table). CR was achieved in 3 (16%) TN patients and 2 (8%) R/R patients. In TN and R/R patients, median TTR was 2.8 months. Time to CR for the 3 TN patients was 5.6, 10.2, and 10.2 months, and for the 2 R/R patients was 10.2 and 15.7 months, respectively. Median DOR was not reached in TN or R/R patients; the 18-month DOR rate was 86% and 94% in TN and R/R patients, respectively. Median PFS (Figure) was not reached in either cohort. Most patients remain on treatment at the time of cut off (89% and 92% of TN and R/R patients, respectively). Study treatment was discontinued in 2/19 TN patients (11%; 1 metastatic squamous cell carcinoma which pre-existed trial therapy, and 1 Richter transformation [RT] at 15.8 months in a patient with del(17p)) and in 2/26 R/R patients (8%; both due to RT at 18.4 and 24.0 months, respectively). In all patients, the most common AEs (≥40%) of any grade were upper respiratory tract infection (69%), diarrhea (65%), nausea (62%), maculopapular rash (58%), increased weight (54%), cough, headache, and infusion-related reaction (50% each), contusion, vomiting, and constipation (42% each). Grade 3/4 AEs (≥5% of all patients) included decreased neutrophil count (24%), decreased platelet count (9%), increased weight and syncope (7% each). There were no cases of major hemorrhage, defined as Grade ≥3, serious AEs and/or any grade or seriousness of central nervous system hemorrhage, or Grade ≥3 contusion or petechiae. One patient (2%) experienced atrial fibrillation (Grade 3) which did not lead to treatment discontinuation.

Conclusions: Treatment with acalabrutinib plus obinutuzumab was well-tolerated and yielded high response rates that deepened over time in both R/R and TN patients. Most patients (41/45 [91%]) remain on treatment with a median follow-up of 21 months.

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