title: 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).
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. ©2017 AACR.
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas. smoulder@mdanderson.org.
authors.forename: Stacy L
authors.initials: SL
authors.lastname: Moulder
authors.affiliation: University of Colorado Denver, Aurora, Colorado.
authors.forename: Virginia F
authors.initials: VF
authors.lastname: Borges
authors.affiliation: Cancer Centre of Southeastern Ontario, Queen's University, Kingston, Ontario, Canada.
authors.forename: Tara
authors.initials: T
authors.lastname: Baetz
authors.affiliation: University of Colorado Denver, Aurora, Colorado.
authors.forename: Tessa
authors.initials: T
authors.lastname: Mcspadden
authors.affiliation: Cancer Centre of Southeastern Ontario, Queen's University, Kingston, Ontario, Canada.
authors.forename: Gina
authors.initials: G
authors.lastname: Fernetich
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Rashmi K
authors.initials: RK
authors.lastname: Murthy
authors.affiliation: Array BioPharma Inc., Boulder, Colorado.
authors.forename: Renae
authors.initials: R
authors.lastname: Chavira
authors.affiliation: Array BioPharma Inc., Boulder, Colorado.
authors.forename: Kari
authors.initials: K
authors.lastname: Guthrie
authors.affiliation: Array BioPharma Inc., Boulder, Colorado.
authors.forename: Emma
authors.initials: E
authors.lastname: Barrett
authors.affiliation: British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Stephen K
authors.initials: SK
authors.lastname: Chia
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018567:Breast Neoplasms, Male / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions / Q000145:classification / Q000473:pathology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009362:Neoplasm Metastasis; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D066246:ErbB Receptors; D047428:Protein Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; C512478:EGFR protein, human; C508053:ERBB2 protein, human