Background: Over expression and aberrant function of ErbB receptor tyrosine kinases (EGFR, HER2, HER3 and HER4) contributes to tumorigenesis. Multiple drugs targeting EGFR or HER2 are already approved for various cancers. In spite of clinical successes with EGFR or HER2 inhibitors, single-agents are prone to drug resistance due to aberrant or compensatory activation of additional downstream signaling pathways. We sought to determine whether neratinib, a potent irreversible pan-HER tyrosine kinase inhibitor, would be safe and efficacious in combination with approved inhibitors of mTOR, CDK4/6, or MEK. Methods: This is an investigator-initiated, single-center, non-randomized, multi-arm phase I trial of subjects ≥18 years old with measurable advanced solid tumors with no curative therapeutic options and whose tumors harbor somatic mutations or amplifications in ErbB genes. Prior HER2 or EGFR directed therapy are allowed. The study will have 3-arms: Arm 1: neratinib + everolimus, Arm 2: neratinib + palbociclib, Arm 3: neratinib + trametinib. Patients are selected for each arm at investigator’s discretion based on tumor type and molecular aberrations present. A standard 3 + 3 dose-escalation design will be utilized and patients will be recruited into five dose levels for each arm of the study. Additional subjects will be treated in dose-expansion cohort(s) once the MTD has been established. A treatment cycle is 28 days. Primary endpoint is determination of the maximum tolerated dose and dose limiting toxicities for each treatment arm. Secondary endpoints include pharmacokinetic and pharmacodynamic analysis along with preliminary anti-tumor efficacy. Prophylactic use of antidiarrheal medication is mandatory during first cycle. Imaging will be performed at 8 week intervals and response will assessed by RECIST v1.1. Enrollment to the study has already commenced. Clinical trial information: NCT03065387