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. 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). It is anticipated that the trials may escalate through 3 different dose levels of Neratinib (120 mg, 160 mg, 200 mg) and standardized approved dosing of TDxD (5.4mg/kg) in breast cancer will be used as explained in the study rationale. 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. Therefore, we are not testing the recommended single agent dose of 240mg of Neratinib with this combination. For the same reason, TDxD will not be used at the approved single agent dose of 6.4mg/kg as the safety of this dosing was established in the monotherapy setting \[33\]. 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. The Dose Limiting Toxicities (DLT) window to determine MTD for the trial will be 28 days (cycle 1) from the start of the treatment. If toxicities are experienced outside the DLT window, they would not be considered in determining the MTD but will be closely monitored by the study team as well as institutional DSMB to ensure patient safety. The 28-day window will also help determine the RP2D. At the conclusion of the safety lead in portion, the Cohort Review committee will determine the RP2D, based on MTD as well as the safety profile of the drug after careful consideration. DLT will be defined in this study as a clinically significant adverse event or abnormal laboratory value assessed as described in section 6.3. All patients will undergo screening transthoracic echocardiography or multigated acquisition scan (MUGA) prior to initiating treatment and every 12 weeks while on treatment. The same imaging tumor assessment as at the time of screening should be used (computed tomography (CT) of the chest abdomen and pelvis with IV contrast or CT of the chest without IV contrast and magnetic resonance imaging (MRI) of the abdomen/pelvis if iodinated contrast is contraindicated). Tumor assessment must be performed every 3 cycles (+/-7 days). The assessment will be conducted before day 1 of each cycle as possible. Head CT/MRI should only be done when symptoms associated with brain metastasis occur.
