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.
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.
Sequential
CA-4948
DrugProvided by Curis, Inc.
Nivolumab
Biological/Vaccine240 mg IV on Day 1 of each cycle
Pembrolizumab
Biological/Vaccine400 mg IV on Day 1 of every 3 cycles (C1D1, C4D1, C7D1,…) and dosing may continue for a max of 2 years
Trastuzumab
Drug6 mg/kg IV loading dose on Cycle 1 Day 1 and 4 mg/kg IV on Day 1 of every subsequent cycle
mFOLFOX7
DrugStandard of care
Safety of regimen as measured by number of adverse events
Expansion dose of CA-4948 in combination with FOLFOX/PD-1 inhibitor with/without trastuzumab
Progression-free rate (PFR)
* Defined as the proportion of patients who are free of disease progression/recurrence at 6-month among the evaluable patients at 6-month, where the evaluable patients include 1) patients who progressed/relapsed prior to 6-month; and 2) patients who not progressed/relapsed and followed up to 6-month * Progressive disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.
Disease control rate (DCR)
* Proportion of participants who had complete response, partial response, or stable disease by RECIST 1.1 * Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Disappearance of all non-target lesions and normalization of tumor marker level. * Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. * Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
Overall response rate (ORR) per RECIST 1.1
* Defined as number of participants with complete response, partial response, or stable disease (with a duration of stable disease for 6 months) per RECIST 1.1 guidelines. * Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Disappearance of all non-target lesions and normalization of tumor marker level. * Partial response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. * Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
Overall response rate (ORR) per iRECIST
-Defined as number of participants with complete response or partial response per iRECIST guidelines.
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Washington University School of Medicine
Lead sponsor
Curis, Inc.
Collaborator
The Foundation for Barnes-Jewish Hospital
Collaborator
