The purpose of the study is to understand whether study drugs domvanalimab and zimberelimab are safe and effective in combination with standard chemotherapy for patients with operable cancer of the esophagus, stomach, or gastroesophageal junction (where the stomach meets the esophagus). All participants will receive the study treatment. Participants will receive chemotherapy and two immune therapies drugs (domvanalimab and zimberelimab) for up to 4 months before surgery. After surgery and at least a 4 week recovery, participants will receive domvanalimab and zimberelimab for up to 8 months. After completion of the study treatment, participants will be followed for up to 5 years per standard of care.
This is a single-center, phase II study evaluating the efficacy, activity and safety of domvanalimab and zimberelimab with standard chemotherapy (FLOT: fluorouracil (also called 5FU), oxaliplatin, leucovorin, docetaxel) in locally advanced, resectable, gastroesophageal adenocarcinomas. This study will enroll up to 28 participants with untreated, locally advanced, resectable adenocarcinoma of the stomach and gastroesophageal junction. Participants will receive up to 8 2-week cycles of domvanalimab , zimberelimab, and FLOT. If there is no evidence of progressive disease and participants remain good surgical candidates, they will undergo surgery 4-6 weeks after last dose of FLOT as per standard of care. Beginning 4-12 weeks after surgery, participants will receive domvanalimab + zimberelimab for up to 8 4-week cycles. Total treatment duration is approximately 12 months. Participants will remain on study unless they do not safely tolerate therapy, develop progressive disease, or withdraw consent. Participants will be followed for up to 5 years. The U.S. Food and Drug Administration (FDA) has not approved zimberelimab, domvanalimab, and FLOT in combination as a treatment for any disease. The FDA has not approved zimberelimab as a treatment for any disease. The FDA has not approved domvanalimab as a treatment for any disease. The FDA has approved FLOT (5-FU, oxaliplatin, leucovorin, and docetaxel) as approved chemotherapy drugs used to treat stomach and gastroesophageal cancers, as well as among many other cancers. Arcus Biosciences, Inc. (with Gilead Sciences) are providing study drugs zimberelimab and domvanalimab. Gateway for Cancer Research, a nonprofit organization, is providing funding for this study.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
480mg administered intravenously once every 4 weeks before surgery (up to 4 doses) and once every 4 weeks after surgery (up to 8 doses).
1600mg administered by intravenous \[IV\] infusion over about 60 minutes once every 4 weeks before surgery (up to 4 doses), and once every 4 weeks after surgery (up to 8 doses).
Administered by IV every 2 weeks before surgery for up to 8 doses. FLOT is given using a continuous IV infusion over 24 hours. FLOT will be administered according to standard clinical practice. Participants will receive FLOT before surgery but not after surgery.
Massachusetts General Hospital
Boston, Massachusetts, United States
Rate of Event-free Survival (EFS)
The primary endpoint is the rate of 24-month EFS. EFS is defined as the time from enrollment to the first of the following events: radiographic disease progression per RECIST 1.1; local or distant recurrence as assessed by computer tomography (CT) scan or biopsy if indicated (for participants who are disease free after surgery); clinical progression as evidenced by peritoneal carcinomatosis confirmed by preoperative laparoscopy or laparotomy (for participants who are confirmed to be free of peritoneal involvement by laparoscopy at screening); or death due to any cause. A second primary malignancy, or radiographic progressive disease (PD) during the neoadjuvant phase that does not preclude successful surgery (i.e., disease free after surgery), are not considered EFS events.
Time frame: From enrollment to up to 24 months after enrollment
Rate of major pathologic response (MPR)
MPR Rate is the sum of the proportions of treated participants having either a pathologic complete response (TRG1a, equivalent to pathological complete regression; no residual tumour cells) or subtotal regression with \<10% residual tumor cells (TRG1b). Tumor regression grade will be quantified using the Becker regression criteria. Pathological staging will be assessed according to the 7th edition of the TNM International Union Against Cancer (UICC) classification.
Time frame: From enrollment to surgery, up to 24 weeks
Rate of pathological complete response (pCR)
Pathologic complete response (pCR) rate is defined as the proportion of treated participants having complete pathologic response, defined as no invasive disease within an entirely submitted and evaluated gross lesion, and histologically negative nodes. Pathological staging will be according to the 7th edition of the TNM International Union Against Cancer (UICC) classification.
Time frame: From enrollment to surgery, up to 24 weeks
Disease-free survival (DFS)
DFS is assessed per RECIST 1.1 and defined as the time from surgical resection to the earlier of documented disease recurrence or death due to any cause. The follow-up of patients who neither recur nor die will be censored at the date of last follow-up. The distributions of DFS will be summarized using the method of Kaplan-Meier. 12 and 24 month DFS will be calculated.
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Time frame: From surgery through up to 24 months post surgery
Overall survival (OS)
Overall Survival (OS) is defined as the time from registration to death due to any cause or censored at date last known alive. 2 and 5 year overall survival distributions will be summarized using the method of Kaplan-Meier.
Time frame: From enrollment through up to 5 years post surgery (up to 5.5 years total)
Incidence and Severity of Adverse Events
Adverse events will be graded according to the NCI CTCAE, version 5.0. The incidence of adverse events will be evaluated for all patients combined. Adverse events, both in terms of MedDRA preferred terms and CTCAE (V5) will be listed individually. The number of patients experiencing new or worsening of each type of adverse event will be summarized according to the worst grade observed; incidence rates of adverse events and grade 3-5 adverse events will be summarized with 90% exact binomial confidence intervals.
Time frame: Day 1 of treatment through 100 days post end of treatment (up to 548 days)