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



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.


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).


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).


ARQ 761 has modest single-agent activity, which appears associated with tumour NQO1 expression. Principal toxicities include anaemia and possible methemoglobinaemia.

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Data availability

The data sets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.


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The authors thank Ms. Dru Gray for assistance with manuscript preparation. This work was supported in part by a National Cancer Institute at the National Institutes of Health, Midcareer Investigator Award in Patient-Oriented Research (K24CA201543–01; to D.E.G.), a National Cancer Institute Cancer Clinical Investigator Team Leadership Award (1P30 CA142543–01 supplement; to D.E.G.), the Harold C. Simmons Comprehensive Cancer Center at the University of Texas Southwestern Medical Center (1P30 CA142543–03), and ArQule, Inc. Research reported in this publication was supported in part by the Harold C. Simmons Comprehensive Cancer Center’s Biomarker Research Core and Biostatistics and Bioinformatics Shared Resource, which are supported by NCI Cancer Center Support Grant 1P30 CA142543–03. Additionally, research reported in this publication was supported in part by Cancer Prevention Research Institute of Texas Core Facilities Support Award (RP170003; to W.C.P.).

Author information

D.E.G., F.F., and O.F. drafted the manuscript. F.F., C.C.M., R.R.K., I.S., Y.D., and V.S. performed the experiments and data analysis. R.D.L., W.C.P., V.S., O.F., X.L., Y.X., and D.E.G. performed data interpretation. All authors have contributed to conception and design of the study and are involved in the critical revision and final approval of the manuscript.

Correspondence to David E. Gerber.

Ethics declarations

Ethics approval and consent to participate

This study was approved by the UT Southwestern Institutional Review Board (IRB # STU 042011–005). All patients provided informed consent. The study was performed in accordance with the Declaration of Helsinki.

Competing interests

D.E.G. has received research funding from ArQule, Inc. B.S. is an employee of ArQule, Inc. The other authors declare no competing interests.


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