Randomized open-label phase 2 study of MM-111 and paclitaxel (PTX) with trastuzumab (TRAS) in patients with HER2-expressing carcinomas of the distal esophagus, gastroesophageal (GE) junction, and stomach who have failed front-line metastatic or locally ad

[[abstract]]Background: HER2 overexpression occurs in ≤ 20% of GE cancers, and front-line fluoropyrimidine/platinum with TRAS increases survival in HER2+ GE junction/gastric cancer patients. Weekly PTX has activity after front-line therapy in GE cancers. HER3 is overexpressed in < 87% of GE cancers and expression is associated with poor prognosis. HER3 is activated by its ligand, heregulin, to form a potent signaling heterodimer with HER2 and is emerging as a key tumorigenic node and mediator of drug resistance. MM-111 is a novel molecule that inhibits heregulin-activated HER3 signaling in HER2+ tumors. In preclinical gastric cancer models, MM-111 potentiates the antitumor activity of TRAS and PTX, and also mitigates HER3-mediated resistance. MM-111 has been combined with PTX and TRAS in a multi-arm, dose escalation phase 1 trial. Most common dose-limiting toxicities include myelosuppression, GI toxicities, and electrolyte abnormalities. Methods: This is a randomized open-label multi-center Phase 2 study of PTX and TRAS +/- MM-111 in patients with HER2 expressing advanced GE adenocarcinoma. Arms are stratified for prior TRAS exposure, geographic region, and ECOG performance status. Patients are dosed with PTX at 80 mg/m2 on days 1, 8, and 15 of a 28 day cycle; TRAS at 4 mg/kg loading dose then 2 mg/kg/weekly and MM-111 at 20 mg/kg/weekly. Pretreatment tumor biopsies and archived tumor tissue will be collected to explore the correlation of biomarkers associated with HER2, HER3 and heregulin signaling activity (1) between archived and pretreatment samples and (2) with clinical response. The primary objective is progression-free survival. Secondary objectives are overall survival, time to treatment failure, objective response rate, duration of response, safety, and health-related quality of life. Pharmacokinetic and immunogenicity analysis of MM-111 will be performed. Enrollment is ongoing