Final Results of Phase 1, Dose Escalation Study Evaluating ARQ 531 in Patients with Relapsed or Refractory B-Cell Lymphoid Malignancies

Introduction: Resistance to covalent BTK inhibitors such as ibrutinib and acalabrutinib is a common mechanism of resistance that portends a poor long-term clinical outcome. ARQ 531 is a potent, reversible inhibitor of both wild type and ibrutinib-resistant C481S-mutant BTK. ARQ 531 suppresses oncogenic BCR signaling in CLL cells resistant to ibrutinib and has demonstrated antitumor activity superior to ibrutinib in CLL, Richter's transformation, and DLBCL mouse models.

Methods: The primary objectives of the clinical study were to assess the safety and tolerability of ARQ 531, and to determine the recommended Phase 2 dose (RP2D) and schedule. The secondary objectives were to assess the pharmacokinetic (PK) profile, pharmacodynamic (PD) activity, and preliminary evidence of anti-tumor activity. Eligible patients had relapsed/refractory CLL/SLL, B-cell NHL or Waldenstrom's macroglobulinemia, had received at least 2 prior lines of systemic therapy and had good organ function including creatinine clearance ≥ 60 mL/min as estimated by the Cockcroft-Gault equation or by 24-hour urine collection, absolute neutrophil count ≥ 1000/µL, platelet count ≥ 50,000/µL and hemoglobin ≥ 8.0 g/dL. Prior therapy for CLL must have included an irreversible BTK inhibitor. Dose escalation was performed according to a 3+3 study design. Treatment emergent adverse events (TEAEs) were assessed per NCI CTCAE v.4.03. Tumor responses were evaluated per disease specific guidelines.

Results: As of July 19, 2019, a total of 40 patients have been treated: CLL/SLL (n=26), Richter's transformation (n=6), DLBCL (n=3), FL (n=4), MCL (n=1). Baseline demographics were: median age 65.5 (range 47-82) years, male/female 36/4 and median number of prior lines of therapy 4 (range 2-12). BTK-C481S mutation was documented in 22/26 (85%) CLL patients. Enrolled patients received ARQ 531 orally once daily, continuously, in 28- day cycles at doses of 5, 10, 15, 20, 30, 45, 65 and 75 mg QD. The most common drug-related TEAEs that occurred in > 2 patients were nausea (n=4), diarrhea (n=4), fatigue (n=3), neutrophil count decreased (n=3), dysgeusia (n=3) and rash (n=3). The majority of the drug-related TEAEs were grade 1 or 2. Drug-related grade 3 or 4 TEAEs included neutrophil count decreased (n=3), as well as febrile neutropenia, cellulitis, platelet count decreased, lipase increased, and rash (one each). One subject treated at 65 mg experienced a DLT of grade 3 rash. The 65 mg cohort was expanded to a total of 10 patients, and no other DLTs were observed. At the 75 mg QD dose level (n =4), drug-related grade 2 adverse events were reported which led to dose reduction to 65 mg QD (n=3) or treatment discontinuation (n=1). Preliminary PK data show that patients receiving ARQ 531 at 65 mg QD exhibit steady-state trough concentrations (Cmin) above 1 µM; the estimated plasma half-life generally ranged from 20-30 hours and was associated with complete pBTK inhibition. Clinical responses to ARQ 531 were observed in multiple patients with B-cell malignancies. Ten partial responses (PRs) were achieved mainly in the higher dose cohorts, and included patients with CLL (n=7), Richter's transformation (n=1), DLBCL (n=1) and follicular lymphoma (n=1). Of the 7 CLL patients who attained PRs, 5 were initiated at 65 mg, 1 was initiated at 45 mg and was dose escalated to 65 mg and 1 was initiated at 75 mg and dose reduced to 65 mg. Together, the safety, PK/PD and clinical activity results suggest that ARQ 531 at 65 mg QD is safe, well tolerated and has clear signs of anti-tumor efficacy. Thus, 65 mg QD dose has been selected as the RP2D in patients with B-cell malignancies.

Conclusion: ARQ 531 has a manageable safety profile and shows anti-tumor activity as single agent therapy in heavily pre-treated patients with B-cell NHL and in patients with CLL resistant to covalent BTK inhibitor. The Phase 1 dose escalation portion of this study is complete. Enrollment of patients with multiple B-cell malignancies is ongoing at 65 mg QD in the phase 1b expansion portion of the study. Updated safety, PK, biomarker and anti-tumor activity data will be presented.