A Multi-Center Phase I Trial of Neratinib and Fam-trastuzumab Deruxtecan in Advanced Refractory Gastric and Esophageal Cancer Patients
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.
• 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
• 4.1.3 Patients' tumors must have HER2-overexpressing:
∙ (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)
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• Age \> 18 years.
• ECOG performance status 0-2
• Patients must have normal organ and marrow function as defined below
‣ Leukocytes \> 3,000/mcL
⁃ Absolute neutrophil count \> 1,500/mcL
⁃ Platelets \> 90,000/mcL
⁃ Hemoglobin \> 9 gm/dl
⁃ Total bilirubin \< 2 times institutional normal limits
⁃ AST/ALT (SGOT/SGPT) \< 5 times institutional normal limits if liver metastases and \</+ 2 times institutional normal limits otherwise
⁃ Creatinine \< 2.0mg/dL OR
⁃ Creatinine clearance \> 50 Ml/min/1.73 m2 for patients with creatinine levels above institutional normal
• Left Ventricular Ejection Fraction ≥ 45% or lower limit of normal.
⁃ Chemotherapy is harmful to the human fetus. For this reason, females of childbearing potential must be willing to use an effective method of contraception, as outlined in Section 4.4, for the course of the study through at least 6 months after the last dose of study medication. Males who have women of childbearing (WOCB) partners must agree to use an effective method of contraception as outlined in Section 4.4 for the course of the study through 8 months after the last dose of study medication.
⁃ Patients should be willing and able to swallow oral tablet medications
⁃ Ability to understand and willingness to sign a written informed consent and HIPAA consent document