Phase I Study of ONT-380, a HER2 Inhibitor, in Patients with HER2(+)-Advanced Solid Tumors, with an Expansion Cohort in HER2(+) Metastatic Breast Cancer (MBC).

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Moulder SL, Borges VF, Baetz T, Mcspadden T, Fernetich G, Murthy RK, Chavira R, Guthrie K, Barrett E, Chia SK

Phase I Study of ONT-380, a HER2 Inhibitor, in Patients with HER2(+)-Advanced Solid Tumors, with an Expansion Cohort in HER2(+) Metastatic Breast Cancer (MBC).

Clin Cancer Res. 2017 Jul 15;23(14):3529-3536. doi: 10.1158/1078-0432.CCR-16-1496. Epub 2017 Jan 4.

PubMed ID

28053022 [ View in PubMed

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Abstract

Purpose: ONT-380 (ARRY-380) is a potent and selective oral HER2 inhibitor. This Phase I study determined the MTD, pharmacokinetics (PK) and antitumor activity of ONT-380 in HER2-positive advanced solid tumors, with an expansion cohort of patients with HER2(+) MBC.Experimental Design: ONT-380 was administered twice daily (BID) in continuous 28-day cycles. After a modified 3+3 dose-escalation design determined the MTD, the expansion cohort was enrolled. PK properties of ONT-380 and a metabolite were determined. Response was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST).Results: Fifty patients received ONT-380 (escalation = 33; expansion = 17); 43 patients had HER2(+) MBC. Median prior anticancer regimens = 5. Dose-limiting toxicities of increased transaminases occurred at 800 mg BID, thus 600 mg BID was the MTD. Common AEs were usually Grade 1/2 in severity and included nausea (56%), diarrhea (52%), fatigue (50%), vomiting (40%) constipation, pain in extremity and cough (20% each). 5 patients (19%) treated at MTD had grade 3 AEs (increased transaminases, rash, night sweats, anemia, and hypokalemia). The half-life of ONT-380 was 5.38 hours and increases in exposure were approximately dose proportional. In evaluable HER2(+) MBC (n = 22) treated at doses >/= MTD, the response rate was 14% [all partial response (PR)] and the clinical benefit rate (PR + stable disease >/= 24 weeks) was 27%.Conclusions: ONT-380 had a lower incidence and severity of diarrhea and rash than that typically associated with current dual HER2/EGFR inhibitors and showed notable antitumor activity in heavily pretreated HER2(+) MBC patients, supporting its continued development. Clin Cancer Res; 23(14); 3529-36. (c)2017 AACR.

DrugBank Data that Cites this Article

Drugs

Tucatinib

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Tucatinib	Receptor tyrosine-protein kinase erbB-2	Protein	Humans	Unknown	Inhibitor	Details