TY - JOUR
T1 - Phase 1 study of ARQ 761, a β-lapachone analogue that promotes NQO1-mediated programmed cancer cell necrosis
AU - Gerber, David E.
AU - Beg, M. Shaalan
AU - Fattah, Farjana
AU - Frankel, Arthur E.
AU - Fatunde, Oluwatomilade
AU - Arriaga, Yull
AU - Dowell, Jonathan E.
AU - Bisen, Ajit
AU - Leff, Richard D.
AU - Meek, Claudia C.
AU - Putnam, William C.
AU - Kallem, Raja Reddy
AU - Subramaniyan, Indhumathy
AU - Dong, Ying
AU - Bolluyt, Joyce
AU - Sarode, Venetia
AU - Luo, Xin
AU - Xie, Yang
AU - Schwartz, Brian
AU - Boothman, David A.
N1 - Publisher Copyright:
© 2018, Cancer Research UK.
PY - 2018/10/16
Y1 - 2018/10/16
N2 - 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.
AB - 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.
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U2 - 10.1038/s41416-018-0278-4
DO - 10.1038/s41416-018-0278-4
M3 - Article
C2 - 30318513
AN - SCOPUS:85054923462
SN - 0007-0920
VL - 119
SP - 928
EP - 936
JO - British journal of cancer
JF - British journal of cancer
IS - 8
ER -