Session: 642. CLL: Therapy, excluding Transplantation: Poster III
Hematology Disease Topics & Pathways:
Biological, Leukemia, Diseases, Therapies, CLL, Non-Hodgkin Lymphoma, B-Cell Lymphoma, Lymphoid Malignancies, Clinically relevant, TKI
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.
Disclosures: Woyach: Janssen: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding; Karyopharm: Research Funding; Loxo: Research Funding; Morphosys: Research Funding; Verastem: Research Funding; AstraZeneca: Consultancy; Arqule: Consultancy. Stephens: Karyopharm: Research Funding; Gilead: Research Funding; Acerta: Research Funding. Flinn: Acerta Pharma, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karyopharm Therapeutics, Kite Pharma, Novartis, Pharmacyclics, Portola Pharmaceuticals: Research Funding; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; AbbVie, Seattle Genetics, TG Therapeutics, Verastem: Consultancy; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding. Bhat: Pharmacyclics: Consultancy; Janssen: Consultancy. Savage: ArQule, Inc.: Employment. Chai: ArQule, Inc.: Employment. Eathiraj: ArQule, Inc.: Employment. Granlund: ArQule, Inc.: Employment. Schwartz: ArQule, Inc.: Employment. Byrd: Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Genentech: Research Funding; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Genentech: Research Funding; Acerta: Research Funding; Acerta: Research Funding; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Ohio State University: Patents & Royalties: OSU-2S; BeiGene: Research Funding; Ohio State University: Patents & Royalties: OSU-2S; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau.
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