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

Abstract

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.

Trial registration: ClinicalTrials.gov NCT01502800.

Conflict of interest statement

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.

Figures

Fig. 1

Efficacy of ARQ 761 according to tumour NQO1 expression. a Waterfall plot demonstrating best radiographic response in the overall study population. Dark bars indicate NQO1-high cases; light bars indicate NQO1-low cases. b Swimmer’s plot demonstrating time on therapy in the overall study population. Dark bars indicate NQO1-high cases; light bars indicate NQO1-low cases. Asterisks indicate cases for which treatment was discontinued for a reason other than disease progression. c Radiographic response among first 20 patients with both evaluable efficacy and tumour NQO1 expression data. NQO1 expression was higher among patients achieving stable disease compared to those with primary disease progression (P = 0.06). Of note, all six patients with NQO1-negative tumours had progressive disease. Based on these data, subsequent enrolment was limited to patients with NQO1-positive tumours (defined as H-score ≥ 200). PD progressive disease, RECIST, Response Evaluation Criteria in Solid Tumours, SD stable disease. d Progression-free survival according to tumour NQO1 expression. HR 0.68; 95% CI, 0.33–1.39; P = 0.3

Fig. 2

Example of minor radiographic response from ARQ 761. Patient had heavily pre-treated bladder cancer (five prior lines of therapy). Images show multiple pulmonary metastases that decreased in size after initiation of study treatment

Fig. 3

NQO1 IHC staining. a Moderately differentiated pancreatic adenocarcinoma, 3+ NQO1 staining, H-score 300. b Moderately differentiated colonic adenocarcinoma, 3+ NQO1 staining, H-score 250. c Lung adenocarcinoma, 3+ NQO1 staining, H-score 290. d High-grade invasive ductal breast carcinoma, 3+ NQO1 staining, H-score 300. e Prostate adenocarcinoma, 0+ NQO1 staining, H-score 0