Phase 1 study of ARQ 761, a β-lapachone analogue that promotes NQO1-mediated programmed cancer cell necrosis

David E. Gerber, M. Shaalan Beg, Farjana Fattah, Arthur E. Frankel, Oluwatomilade Fatunde, Yull Arriaga, Jonathan E. Dowell, Ajit Bisen, Richard D. Leff, Claudia C. Meek, William C. Putnam, Raja Reddy Kallem, Indhumathy Subramaniyan, Ying Dong, Joyce Bolluyt, Venetia Sarode, Xin Luo, Yang Xie, Brian Schwartz, David A. Boothman

Research output: Contribution to journalArticlepeer-review

52 Scopus citations


Background: NAD(P)H:quinone oxidoreductase 1 (NQO1) is a two-electron oxidoreductase expressed in multiple tumour types. ARQ 761 is a β-lapachone (β-lap) analogue that exploits the unique elevation of NQO1 found in solid tumours to cause tumour-specific cell death. Methods: We performed a 3+3 dose escalation study of 3 schedules (weekly, every other week, 2/3 weeks) of ARQ 761 in patients with refractory advanced solid tumours. Tumour tissue was analysed for NQO1 expression. After 20 patients were analysed, enrolment was restricted to patients with NQO1-high tumours (H-score ≥ 200). Results: A total of 42 patients were treated. Median number of prior lines of therapy was 4. Maximum tolerated dose was 390 mg/m2 as a 2-h infusion every other week. Dose-limiting toxicity was anaemia. The most common treatment-related adverse events were anaemia (79%), fatigue (45%), hypoxia (33%), nausea (17%), and vomiting (17%). Transient grade 3 hypoxia, reflecting possible methemoglobinaemia, occurred in 26% of patients. Among 32 evaluable patients, best response was stable disease (n = 12); 6 patients had tumour shrinkage. There was a trend towards improved efficacy in NQO1-high tumours (P = 0.06). Conclusions: ARQ 761 has modest single-agent activity, which appears associated with tumour NQO1 expression. Principal toxicities include anaemia and possible methemoglobinaemia.

Original languageEnglish (US)
Pages (from-to)928-936
Number of pages9
JournalBritish journal of cancer
Issue number8
StatePublished - Oct 16 2018

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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