Background: P is a fully human monoclonal antibody against human epidermal growth factor receptor 3. P blocks activation by the ligand, heregulin (HRG), inducing receptor internalization. Evidence is growing that HRG presence determines disease progression and survival; in a phase 2 study in non–small-cell lung cancer, P + erlotinib increased progression-free survival (PFS) in high HRG mRNA expression (HRG-high) patients. A phase 1b study in SCCHN demonstrated safety, tolerability and tumor response of P + C + cisplatin or carboplatin and informed the P phase 2 dose. January 2016 (N = 15) response rate = 47%; best responses = 3 complete response (CR), 4 partial response (PR) and 8 stable disease (SD). This phase 2 study (NCT02633800) evaluates first-line P + C + platinum (P arm) vs. PBO + C + platinum (PBO arm) in recurrent and/or metastatic (R/M) SCCHN. The primary objective is to evaluate PFS in the HRG-high population (P vs. PBO arms). Methods: This is arandomized, controlled, double-blind first-line study in Europe. Patients aged ≥ 18 years with confirmed R/M SCCHN, ECOG performance status ≤ 1 and documented HRG expression (per archived or fresh biopsies) are eligible. The primary efficacy endpoint is PFS. Secondary endpoints include overall survival, overall response rate, pharmacokinetics and safety (including human antihuman antibody incidence). Approximately 105 patients will be stratified 2:1 by HRG status (70 high; 35 low), and then randomized 1:1 to the P or PBO arm. All patients will receive either intravenous P (18mg/kg loading dose [LD]; 9mg/kg maintenance dose [MD] every 3 weeks [q3w]) or PBO, and C (400mg/m² LD; 250mg/m² MD weekly) + ≤ 6 cycles of cisplatin (100mg/m² q3w) or carboplatin (area under the curve of 5). Patients demonstrating CR, PR or SD will be treated with P/PBO + C + ≤ 6 cycles platinum for the study duration (until all patients have died or ≥ 13 months postrandomization of last patient); those benefiting may continue treatment uninterrupted in an open-label extension phase until progressive disease, toxicity or withdrawal. Survival status will be obtained ≥ 13 months after discontinuation. The first patient was dosed December 2015 and enrollment is open. Clinical trial information: NCT02633800