Abstract
BackgroundNapabucasin is an oral NAD(P)H:quinone oxidoreductase 1 bioactivatable agent that generates reactive oxygen species, is hypothesised to affect multiple oncogenic cellular pathways, including STAT-3, and is expected to result in cancer cell death. This phase I study investigated the safety, tolerability, and pharmacokinetics of napabucasin co-administered with fluorouracil, l-leucovorin, and irinotecan (FOLFIRI) chemotherapy plus bevacizumab in Japanese patients with metastatic colorectal cancer (CRC).MethodsPatients with histologically confirmed unresectable stage IV CRC received oral napabucasin 240 mg twice daily (BID). Intravenous FOLFIRI and bevacizumab therapy was initiated on day 3 at approved doses. Unacceptable toxicity was evaluated over the first 30 days of treatment, after which treatment continued in 14-day cycles until toxicity or disease progression. Endpoints included safety, pharmacokinetics, and tumour response based on RECIST v1.1.ResultsFour patients received treatment; three were evaluable during the unacceptable toxicity period. All four patients experienced diarrhoea and decreased appetite (considered napabucasin-related in four and two patients, respectively), and three patients experienced neutrophil count decreased. No unacceptable toxicity was reported during the 30-day evaluation period. No grade 4 events, deaths, or serious adverse events were reported. The addition of FOLFIRI and bevacizumab to napabucasin did not significantly change the pharmacokinetic profile of napabucasin; however, results were variable among patients. The best overall response was stable disease in two patients (50.0%).ConclusionsNapabucasin 240 mg BID in combination with FOLFIRI and bevacizumab was tolerated, with a manageable safety profile in Japanese patients with metastatic CRC.
Highlights
Colorectal cancer (CRC) mortality continues to increase in Japan, with more than 50,000 deaths occurring in 2016 [1]
The patient who withdrew from the study during the unacceptable toxicity evaluation period received treatment with napabucasin in combination with FOLFIRI and bevacizumab for 14 days, while the three patients who completed the unacceptable toxicity evaluation period received treatment for 51–338 days (3–20 cycles)
Napabucasin 240 mg twice daily in combination with FOLFIRI and bevacizumab was tolerable in this small population, with a manageable safety profile
Summary
Colorectal cancer (CRC) mortality continues to increase in Japan, with more than 50,000 deaths occurring in 2016 [1]. Napabucasin is an oral NAD(P)H:quinone oxidoreductase 1 (NQO1) bioactivatable agent that generates reactive oxygen species; is hypothesized to affect multiple oncogenic cellular pathways, including signal transducer and activator of transcription 3 (STAT-3); and is expected to result in cancer cell death [6]. Napabucasin is an oral NAD(P)H:quinone oxidoreductase 1 bioactivatable agent that generates reactive oxygen species, is hypothesised to affect multiple oncogenic cellular pathways, including STAT-3, and is expected to result in cancer cell death. This phase I study investigated the safety, tolerability, and pharmacokinetics of napabucasin co-administered with fluorouracil, l-leucovorin, and irinotecan (FOLFIRI) chemotherapy plus bevacizumab in Japanese patients with metastatic colorectal cancer (CRC). Conclusions Napabucasin 240 mg BID in combination with FOLFIRI and bevacizumab was tolerated, with a manageable safety profile in Japanese patients with metastatic CRC
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