Neratinib + Trastuzumab Deruxtecan

Patients will be enrolled in cohorts of 3 at each dose level of Neratinib (120 mg, 160 mg, 200 mg) daily (days 1 through 21)

standard dosing of TDxD (5.4mg/m2) on day 1of a 21 day treatment cycle

Patients must have progressed or been intolerant of at least one prior line of chemotherapy + HER2 directed therapy. A total of 18 patients will be enrolled with the plan to reach MTD and enroll any remaining patients at the RP2D to further define the toxicities and preliminary efficacy to help define the future studies with this combination. Patients will be enrolled in cohorts of 3 at each dose level (see SCHEMA).

This is Phase 1 dose finding trial with potential dose expansion to evaluate the safety, toxicity, recommended phase 2 dose (RP2D), and maximum tolerated dose (MTD) of Neratinib plus TDxD using a standard 3+3 dose escalation design in patients with metastatic or unresectable gastro-esophageal cancer that are HER2-overexpressing (IHC 3+ or IHC2+/ISH+) and any other gastrointestinal cancer with HER2 expression with IHC3+.

Patients must have progressed or been intolerant of at least one prior line of chemotherapy + HER2 directed therapy.

Live record on ClinicalTrials.gov →

• Patients must have been diagnosed with histologically or cytologically confirmed gastrointestinal cancer (esophagus, stomach, colon, biliary, pancreas or unknown primary likely GI), and been deemed unresectable or have at least one site of metastatic disease
• Patients must have evaluable or measurable disease by RECIST 1.1 criteria
• (IHC 3+ or IHC2+/ISH+) advanced gastroesophageal cancer (including gastroesophageal junction adenocarcinoma).
• IHC 3+ for other GI cancers
• Patients must have received at least one prior line of HER2 directed therapy for metastatic/unresectable disease and completed treatment at least 2 weeks prior to C1D1 (only for Gastroesohageal cancers, not for other GI cancers)

Inclusion criteria as written on the registry, trimmed. The full list, with exclusions, is on the live record.