Acalabrutinib Monotherapy in Patients with Ibrutinib Intolerance: Results from the Phase 1/2 ACE-CL-001 Clinical Study

Background: Bruton tyrosine kinase (BTK) is a validated target in CLL. Ibrutinib is a BTK inhibitor that has dramatically improved progression-free survival (PFS) and overall survival (OS) of CLL patients (pts) over conventional therapies used in this disease. In a subset of pts receiving ibrutinib, adverse events (AEs), such as diarrhea, rash, myalagias/arthralgias, atrial fibrillation, and bleeding occur and may be related to alternative drug targets, leading to treatment discontinuations or dose reductions. Having an alternative, more selective BTK inhibitor that is tolerable is of high priority for this pt population. Acalabrutinib, a highly selective, potent BTK inhibitor designed to minimize alternative kinase inhibition was evaluated in pts with CLL/SLL in the Phase 1/2 ACE-CL-001 clinical study (NCT02029443).

Methods: Eligibility criteria for the ibrutinib-intolerant cohort included confirmed CLL/SLL, intolerance due to ibrutinib-related AEs, Eastern Cooperative Oncology Group performance status ≤2 and age ≥18 years. Pts were treated with acalabrutinib 100 mg twice daily (n=30) or 200 mg daily (n=3) until disease progression or discontinuation for another reason. The primary objective was to determine the safety of acalabrutinib, as assessed by frequency, severity, and attribution of AEs based on CTCAE criteria. The secondary objective was to determine response rate by investigator assessment. Overall response rate (ORR), PFS, and duration of response (DOR) were calculated. Pts were defined as evaluable for response based on ≥1 response assessment after the first dose of study drug, presence of measurable disease, and established modified response criteria (Hallek et al. 2008).

Results: Thirty-three pts were treated in the ibrutinib-intolerant cohort. Results are presented through 01 June 2016. Median age was 64 years (range, 50 to 82). Pts were high risk with derived baseline Rai stage III-IV (52%), bulky lymph nodes ≥5 cm (31%), del17p in 8 of 27 patients (30%), del11q in 7 of 27 patients (26%), and unmutated IGHV(81%) at time of study entry. Median duration of prior ibrutinib treatment was 10.5 months (range, 1.0 to 62.3), and median duration from end of ibrutinib to start of acalabrutinib was 47 days (range, 3 to 331). The median follow-up period (n=33) was 9.5 months (range, 0.5 to 20.6). At the time of data cutoff, 24 pts (73%) continued on treatment. Most AEs were Grade (G) 1/2 (58%). The most common AEs (≥15% of pts) were diarrhea (42%), headache (39%), cough (24%), increased weight (24%), nausea (21%), contusion, ecchymosis, fatigue, pyrexia (each in 18%) and myalgia, rash, urinary tract infection and vomiting (each in 15%). Pneumonia (1 G3 and 1 G4) was the only serious AE occurring in ≥2 patients. There were 2 G5 events - a cerebrovascular accident and a fungal infection - both unrelated to study drug. Two cases of treatment-emergent atrial fibrillation occurred: 1 G2 in a pt with a history of paroxysmal atrial fibrillation (G2) on ibrutinib who remains on study and 1 G3 atrial fibrillation in a patient who was able to continue acalabrutinib treatment until coming off study due to disease progression. There were no major hemorrhages, including among the 6 pts who previously developed bleeding events while on ibrutinib. Treatment discontinuations occurred in 9 (27%) patients: progressive disease in 5 (15%), AEs in 2 (6%; 1 unrelated G5 fungal infection and 1 unrelated G3 metastatic endometrial cancer), and 2 (6%) by physician decision. In patients with baseline measurable disease or lymphocytosis, the ORR (CR+PR+PRL) (n=29) was 76%, with 1 CR, 14 PR, and 7 PRL. Median time to PR or better was 3.7 months (95% CI, 1.9 to 5.5). Among 15 responders, median DOR was 13 months (95% CI, 5.6 to 13) at the time of data cutoff. Median PFS has not been reached.

Conclusions: Acalabrutinib is well tolerated and effective in most ibrutinib-intolerant pts, providing a potential avenue to continue impactful BTK inhibitor therapy. An ongoing Phase 2 study (NCT02717611) is evaluating acalabrutinib monotherapy in pts with relapsed/refractory CLL and ibrutinib intolerance.