CA-4948 in Combination With FOLFOX/PD-1 Inhibitor +/- Trastuzumab for Untreated Unresectable Gastric and Esophageal Cancer

Exclusion Criteria23

• Current use or anticipated need for alternative, holistic, naturopathic, or botanical formulations used for the purpose of cancer treatment. Use of medical marijuana is permitted.
• A history of other malignancy with the exception of 1) malignancies for which all treatment was completed at least 2 years before registration and the patient has no evidence of disease; 2) or known indolent malignancies that do not require treatment and will likely not alter the course of treatment of metastatic gastric, GEJ, or esophageal cancer.
• History of allogeneic organ or stem cell transplant
• Currently receiving any other investigational therapeutic agents. Investigational tracers related to imaging studies are allowed with a 7 day-washout.
• Currently have an intraluminal GI stent (gastric, esophageal, small bowel, colon). Biliary stents are allowed.
• History of clinically relevant bleeding from their tumor(s). Includes but is not limited to bleeding tumor requiring RBC transfusion, or bleeding requiring more than one endoscopic intervention.
• Untreated ulcerating tumor. Patients who are endoscopically treated must be assessed by the study PI or delegate for eligibility.
• Use of systemic therapeutic anticoagulation, including daily baby aspirin, within 5 half-lives of the anticoagulant prior to C1D1. Patients can receive heparin or alteplase flush in their ports.
• Use of anti-platelet therapies (i.e. P2Y12 inhibitors (clopidogrel, prasugrel, etc.), within 5 half-lives of the anti-platelet therapy prior to C1D1.
• Use of NSAIDs within 5 half-lives of the NSAID prior to C1D1.
• Clinically active CNS metastasis; treated and asymptomatic metastasis allowed at the discretion of the PI. Radiotherapy to the brain must be completed \> 10 days prior to planned C1D1.
• A history of allergic reactions attributed to compounds of similar chemical or biologic composition to CA-4948, FOLFOX, nivolumab, trastuzumab or other agents used in the study.
• Concomitant use of drugs with a known risk of causing prolonged QTc and/or Torsades de Pointes or a history of risk factors for Torsades de Pointes.
• Presence of interstitial lung disease or pneumonitis ≥ G2
• Administration of a live attenuated vaccine within 30 days prior to enrollment.
• QTc (Bazett) \>470ms on screening EKG
• Gastrointestinal condition which could impair absorption of CA-4948 or inability to ingest CA-4948
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia
• Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 7 days of study entry.
• Patients with HIV are eligible unless their CD4+ T-cell counts are \< 350 cells/mcL or they have a history of AIDS-defining opportunistic infection within the 12 months prior to registration. Concurrent treatment with effective ART according to DHHS treatment guidelines is recommended. Recommend exclusion of specific ART agents based on predicted drug-drug interactions (i.e., for sensitive CYP3A4 substrates, concurrent strong CYP3A4 inhibitors (ritonavir and cobicistat) or inducers (efavirenz) should be contraindicated).
• Participants with active, known or suspected autoimmune disease. Participants with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, euthyroid participants with a history of Grave's disease (participants with suspected autoimmune thyroid disorders must be negative for thyroglobulin and thyroid peroxidase antibodies and thyroid stimulating immunoglobulin prior to first dose of study treatment), psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll after discussing with the PI.
• Participants with a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone or equivalent) or other immunosuppressive medications within 14 days of study treatment except for adrenal replacement steroid doses \> 10 mg daily prednisone equivalent in the absence of active autoimmune disease. Note: treatment with a short course of steroids (\< 5 days) up to 7 days prior to initiating study treatment is permitted. Inhaled intranasal, intra-articular, and topical steroid uses are permitted.
• Patients are unwilling to adhere to the lifestyle guidance in protocol.