The Bruton Tyrosine Kinase (Btk) Inhibitor ACP-196: Marked Activity in Relapsed/Refractory CLL with a Favorable Safety Profile

Introduction

Btk is a kinase involved in B-cell receptor (BCR) signal transduction and a critical target in chronic lymphocytic leukemia (CLL).  ACP‑196—a potent, second generation Btk inhibitor that is more selective than the first-in-class Btk inhibitor, ibrutinib (Covey AACR2015)—has demonstrated antitumor activity in preclinical CLL models (Niemann AACR2014).  Here, we present preliminary data from patients with relapsed/refractory (R/R) CLL/small lymphocytic lymphoma (SLL) enrolled in an ongoing Phase 1/2 study of single-agent ACP-196 (ClinicalTrials.gov NCT02029443).

Methods and Patients

This first-in-human study was designed to evaluate the safety, maximum tolerated dose, pharmacokinetics, pharmacodynamics and efficacy of orally administered ACP-196 in patients with R/R CLL/SLL.  Patients were continuously treated with ACP-196 at dosages ranging from 100 to 400 mg once daily (QD) as part of the dose-escalation portion of the study (4 cohorts of 6-8 patients per cohort), and 100 mg twice daily (BID) and 200 mg QD as part of the expansion portion of the study (2 cohorts). Of note, CLL patients with any degree of pancytopenia and prior exposure to PI3K inhibitors were allowed. 

CLL responses were investigator assessed per IWCLL criteria (modified Hallek 2008).  SLL responses were investigator assessed per IWG criteria (Cheson 2007).  Patients had a median age of 62 years (range 44-84), bulky lymph nodes ≥ 5 cm (47%) and median of 3 prior therapies (1-13).  High-risk prognostic factors included del(17)(p13.1) 31% (18/58), del(11)(q22.3) 29% (17/58) and unmutated IGVH genes 75% (38/51).

Results

Results are presented through 01 June 2015 for the first 61 R/R patients, including 60 evaluable for response.  The median time on study (N=61) was 10.3 (0.5-15.9) months.  ACP-196 has been well tolerated with 93% (57/61) of patients continuing on study drug. Of the 4 patients who discontinued, 1 patient each discontinued due to withdrawal of consent, physician decision, unrelated AE (pre-existing, active autoimmune hemolytic anemia) and related AE (Grade 3 dyspnea).  To date, no dose-related effect has been observed in frequency or severity of AEs or serious adverse events. No dose-limiting toxicities have occurred, and most AEs were Grade ≤ 2.  The most common Grade 1/2 AEs (≥ 15%) were headache (39%), diarrhea (33%) and URI (16%).  Grade 3/4 AEs that occurred in ≥ 3 patients were anemia (7%), pneumonia (7%) and hypertension (5%).  No major hemorrhage (including subdural hematomas), atrial fibrillation, tumor lysis syndrome or pneumonitis have occurred suggesting an improved safety profile compared with other BCR and BCL-2-targeted therapies. 

Clinical activity has been observed in patients with R/R CLL/SLL at all doses evaluated.  All patients experienced rapid reductions in lymphadenopathy.  Treatment-related lymphocytosis (defined as ≥ 50% increase from baseline and above absolute lymphocyte count [ALC] of 5 K/µL) occurred in 61% (37/61) of patients and resolved in 81% (31/37) of these patients.  In general, lymphocytosis peaked at a median of 3 weeks and resolved by a median of 19 weeks (range 1 to 58 weeks). The rapid decrease in lymphadenopathy and treatment-related lymphocytosis along with concurrent improvement in baseline cytopenias has led to a high proportion of partial responses (PRs) early in treatment (Figure 1). 

Best overall response rate including PR and PR with lymphocytosis (PR+L) was 93% (PR=70%, PR+L=23%, SD=7%, PD=0%).  For patients with del(17)(p13.1), the response rate was 100% (PR=72%, PR+L=28%).  In the 4 patients with prior idelalisib therapy, the response rate also was 100% (PR=75%, PR+L=25%).  To date, no disease progression or Richter’s transformation has occurred (Figure 2). 

Pharmacokinetic results showed exposure of ACP-196 was dose proportional with no drug accumulation.  At dosages as low as 100 mg QD, pharmacodynamic results showed low intra-patient variability, high Btk occupancy (> 90% over 24 hr) and high phospho-Btk inhibition (> 90% over 24 hr).

Conclusion

ACP-196 is a highly potent and selective oral Btk inhibitor with a favorable safety profile.  Responses occur early in treatment with no disease progression to date either in heavily pretreated patients or those with high-risk prognosis factors.  ACP-196 is currently in Phase 3 trials for TN (ClinicalTrials.gov NCT0247568) and R/R high-risk CLL (ClinicalTrials.gov NCT02477696).