Phase I Trial of CA-4948 in Combination With FOLFOX/PD-1 Inhibitor +/- Trastuzumab for Untreated Unresectable Gastric and Esophageal Cancer
This is a phase I trial of CA-4948 in combination with FOLFOX/PD-1 inhibitor with or without trastuzumab for unresectable gastric, GEJ, and esophageal cancer. During the Dose Escalation portion of the study, different dose levels of CA-4948 in combination with FOLFOX/nivolumab will be evaluated by BOIN algorithm. Dose Expansion will include Cohorts A and B. Expansion Cohort A will enroll up to 12 patients with HER2 negative gastric, GEJ, and esophageal cancer at the expansion dose of CA-4948 determined during Dose Escalation and will use the same treatment regimen of FOLFOX/nivolumab. Expansion Cohort B will investigate CA-4948 at the dose determined during Dose Escalation in combination with FOLFOX/pembrolizumab and trastuzumab in up to 12 patients with HER2 positive disease; however, the initial 6 patients will be considered safety lead-in to confirm the safety and tolerability of this combination; if determined to be safe, an additional 6 patients will be enrolled for a total of 12 in Cohort B.
• Advanced unresectable or metastatic histologically or cytologically confirmed adenocarcinoma or squamous cell carcinoma of the stomach, gastroesophageal junction, or esophagus
• Measurable or evaluable disease defined by RECIST 1.1.
• Lesions amenable to research biopsy. This criteria can be waived by the PI after documented discussion with the treating physician.
• Known HER2 status if histology is adenocarcinoma prior to enrollment; results from local CLIA laboratory is acceptable.
‣ For Dose Escalation, patients are required to have documented HER2 negative cancer.
⁃ For Dose Expansion, patients will be enrolled to either HER2 positive or negative cohorts at the time of enrollment
• No prior systemic treatment for unresectable/advanced gastric, GEJ, or esophageal cancer.
‣ Neoadjuvant or adjuvant systemic therapy is allowed; however, surgical resection and adjuvant chemotherapy should have been \> 3 months from planned C1D1.
⁃ Up to two prior cycles of FOLFOX is allowed.
⁃ Definitive chemoradiation is allowed if the last date of chemotherapy or radiation (whichever is more recent) is \> 3 months from planned C1D1.
⁃ Prior palliative radiation therapy, including brain radiation, in the unresectable setting is allowed, but the last treatment date should be \>10 days from planned C1D1.
• At least 18 years of age
• ECOG performance status 0 or 1
• Normal bone marrow and organ function as defined below:
‣ Absolute neutrophil count ≥ 1.5 K/cumm
⁃ Platelets ≥ 100 K/cumm
⁃ Hemoglobin ≥ 9.0 g/dL
⁃ Total bilirubin ≤ 1.5 x IULN or ≤ 3 x IULN in patients with documented Gilbert's syndrome
⁃ AST(SGOT)/ALT(SGPT) ≤ 2.0 x IULN, unless there are liver metastases in which case AST and ALT ≤ 5.0 x IULN
⁃ Creatinine clearance ≥ 35 mL/min by Cockcroft-Gault
• Creatinine phosphokinase (CPK) elevation at screening \< Grade 2 (CPK \< 2.5 x IULN)
• Patients on a cholesterol lowering statin must be on a stable dose with no dose changes within 3 weeks prior to study start.
• Expansion Cohort B patients only: LVEF above LLN as assessed by MUGA or ECHO
• The effects of CA-4948 on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of the study, and 3 months after completion of the study
• Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).