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Woyach, J.1; Stephens, D.2; Flinn, I.3; Bhat, S.1; Savage, R. E.4; Chai, F.4; Eathiraj, S.4; Granlund, L.4; Szuszkiewicz, L.1; Byrd, J.1

doi: 10.1097/01.HS9.0000562884.42743.6c
Poster Session II: Chronic lymphocytic leukemia and related disorders - Clinical

1Ohio State University, Columbus

2Huntsman Cancer Institute, Salt Lake City

3Sarah Cannon Research Institute, Nashville

4ArQule, Inc., Burlington, United States

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The BTK inhibitor ibrutinib has been approved for multiple indications based on marked treatment benefit in B cell lymphoma/leukemia. Although ibrutinib provides durable, disease control, resistance is emerging as an area of unmet medical need. ARQ 531 is a reversible ATP competitive inhibitor of BTK that inhibits both wild type and ibrutinib-resistant BTK-C481S mutant CLL cells and has demonstrated antitumor activity in CLL, Richter's transformation, and DLBCL mouse models.

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The primary objectives of the clinical study are to assess the safety and tolerability of ARQ 531, and to determine the recommended Phase 2 dose and schedule. The secondary objectives are to assess the pharmacokinetic (PK) profile, pharmacodynamic (PD) activity, and preliminary evidence of anti-tumor activity.

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This is a first in human, Phase 1 dose escalation study in patients with relapsed/refractory CLL/SLL, B-cell NHL or Waldenstrom's macroglobulinemia who received at least 2 prior lines of systemic therapy. Prior therapy must have included a 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.

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As of February 15, 2019, a total of 26 patients have been treated: CLL/SLL (n = 19), DLBCL (n = 2), FL (n = 4), MCL (n = 1). Baseline demographics were: median age 65 (48-82) years, male/female 24/2 and median number of prior lines of therapy 5 (range 2-12). Enrolled patients received ARQ 531 orally once daily in 28-day cycles at doses of 5, 10, 15, 20, 30, 45 and 65 mg QD.

Drug related TEAEs that occurred in ≥2 subjects were nausea (15.4%), neutrophil count decreased (11.5%), constipation, diarrhea, vomiting, fatigue, decreased appetite, arthralgia, dizziness, dysgeusia and headache (7.7% each). The majority of the TEAEs were grade 1 or 2. Drug related grade 3 or worse TEAEs included neutrophil count decreased (11.5%), platelet count decreased (3.8%), lipase increased (3.8%), and rash (3.8%). The only grade 3 TEAE of rash occurred in one subject treated with 65 mg QD and was a SAE and assessed as a dose limiting toxicity (DLT). The 65 mg QD cohort was expanded to enroll more subjects. The maximum tolerated dose (MTD) has not been reached.

Preliminary PK data show that cohorts receiving ≥ 45 mg QD of ARQ 531 exhibited steady-state trough concentrations (Cmin) of above 1 micromolar; the estimated plasma half-life generally ranged from 20-30 hours and was associated with complete pBTK inhibition and CCL3 suppression. Furthermore, increasing tumor suppression seen at higher dose levels was also correlated with higher Cmin concentrations.

Among the 14 subjects who have received doses ≥ 45 mg QD, either as starting dose or dose escalated, 9 were evaluable for response (on study treatment for at least one cycle and had at least one post-treatment tumor measurement). Among them, 2 patients had partial responses (1 CLL with BTK C481S mutation who had received 3 prior lines of therapy including acalabrutinib, 1 FL who had received 3 prior lines of therapy and is on study for >83 weeks) and 5 achieved stable disease with tumor reduction between 30% to 49% with median lines of prior therapy of 9.

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Based on the emerging data, ARQ 531 has a manageable safety profile and shows preliminary anti-tumor activity as a single agent in heavily treated B-cell NHL and BTK inhibitor resistant CLL patients. Dose escalation continues, updated safety, PK, biomarker and anti-tumor activity data will be presented at the meeting.

Copyright © 2019 The Authors. Published by Wolters Kluwer Health Inc., on behalf of the European Hematology Association.