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 gastric adenocarcinoma (including GEJ tumors) that are HER2-overexpressing (IHC 3+ or IHC2+/ISH+). 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. It is anticipated that the trials may escalate through 3 different dose levels of Neratinib (120 mg, 160 mg, 200 mg). Both drugs have GI toxicity specifically diarrhea and the combination may have risk of increased toxicity from TDxD due to increase cellular uptake of the cytotoxic payload. If the initial dose level 0 is deemed too toxic, the study investigators and DSMB can make a decision to allow dose reduction of TDxD to 4.4mg/kg (dose level -1) and reintroduction of neratinib at dose level 0, if the toxicities are felt to be related to TDxD. For cycle 1, patients will start with Neratinib lead in starting at Day -7 and TDxD will be administered on Day 1. Each future treatment cycle will comprise of Neratinib administered PO daily for a 21-day cycle with food. TDxD will be administered intravenously on day 1 of a 21-day cycle. All patients will undergo screening transthoracic echocardiography or multigated acquisition scan (MUGA) prior to initiating treatment and every 9 weeks while on treatment. Tumor assessment must be performed every 3 cycles (+/-7 days). The assessment will be conducted before day 1 of each cycle as possible.
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 gastric adenocarcinoma (including GEJ tumors) that are HER2-overexpressing (IHC 3+ or IHC2+/ISH+). Patients must have progressed or been intolerant of at least one prior line of chemotherapy + HER2 directed therapy.