Acalabrutinib with Obinutuzumab in Relapsed/Refractory and Treatment-Naïve Patients with CLL: The Phase 1b/2 ACE-CL-003 Study

Conference Correspondent - ASH 2017 - Chronic Lymphocytic Leukemia

Bruton’s 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. Thus, the authors presented the results of a phase 1b/2 trial evaluating the activity and tolerability of acalabrutinib, a highly selective covalent inhibitor of BTK, in combination with obinutuzumab in relapsed/refractory (R/R) and symptomatic, treatment-naive (TN) patients with CLL.1

Patients with R/R or TN, symptomatic CLL or small lymphocytic lymphoma with measurable nodal disease were treated in 28-day cycles with acalabrutinib administered orally at 100 mg twice daily or 200 mg once daily (n = 15; all later switched to 100 mg twice daily) until disease progression. Obinutuzumab was administered intravenously on days 1 (100 mg), 2 (900 mg), 8 (1000 mg), and 15 (1000 mg) of cycle 2, and on day 1 (1000 mg) of cycles 3 through 7. The primary end points were overall response rate (ORR), defined as partial response + complete response (CR), and safety. Secondary end points included duration of response (DOR), time to response (TTR), progression-free survival (PFS), and pharmacodynamics.

As of this presentation, 19 TN and 26 R/R patients had been treated. Key characteristics in TN and R/R patients, respectively, included del(17p) (4/18 [22%] and 5/26 [19%]), del(11q) (5/18 [28%] and 9/26 [35%]), and unmutated IGHV (9/17 [53%] and 17/26 [65%]). Median follow-up was 17.8 months in TN patients and 21.2 months in R/R patients.

The ORR was 95% and 92% in TN and R/R patients, respectively. 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 the TN or R/R patients. The 18-month DOR rate was 86% and 94% in TN and R/R patients, respectively. Median PFS was not reached in either cohort.

Study treatment was discontinued in 2/19 TN patients (11%; 1 metastatic squamous-cell carcinoma that preexisted trial therapy, and 1 Richter’s 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 adverse events (AEs) of any grade were upper respiratory tract infection, maculopapular rash, increased weight, diarrhea, cough, nausea, headache, infusion-related reaction, contusion, dizziness, arthralgia, vomiting, constipation, and hypertension. Grade 3/4 AEs (≥5% of all patients) included decreased neutrophil count, decreased platelet count, increased weight, and syncope.

The authors concluded that 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 of the 45 patients (91%) remain on treatment after median follow-up of 21 months.


  1. Woyach JA, et al. ASH 2017. Abstract 432.
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