Details

Autor(en) / Beteiligte

• Moulder, Stacy L
• Borges, Virginia F
• Baetz, Tara
• Mcspadden, Tessa
• Fernetich, Gina
• Murthy, Rashmi K
• Chavira, Renae
• Guthrie, Kari
• Barrett, Emma
• Chia, Stephen K

Titel

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)

Ist Teil von

• Clinical cancer research, 2017-07, Vol.23 (14), p.3529-3536

Ort / Verlag

United States: American Association for Cancer Research Inc

Erscheinungsjahr

2017

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. 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). 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 ( = 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%. 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. .