This is an open label, phase II, multi-site trial evaluating the efficacy and safety of the combination of 5-FU, oxaliplatin, nal-IRI, and immunotherapy (plus trastuzumab for HER2-positive tumors) as first-line therapy for participants with advanced Esophageal and Gastric Adenocarcinoma (EGA). The investigators hypothesize that this drug combination will be better tolerated than current first-line chemotherapy combinations for this disease.
Written informed consent and HIPAA authorization for release of personal health information.
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2.
Histological or cytological confirmed locally advanced or metastatic EGA. Known HER2 status prior to treatment initiation required. Known PDL1 CPS status prior to treatment initiation.
Measurable disease according to RECIST v1.1.
Known hypersensitivity to 5-FU, oxaliplatin or other platinum agents, or any of the components of nal-IRI and other liposomal products.
Known dihydropyrimidine dehydrogenase (DPD) deficiency (testing not required prior to enrollment).
Other active malignancy requiring treatment within the last 2 years. Exceptions include subjects with non-melanoma skin cancer, non-invasive/in situ cancer or low-risk prostate cancer requiring hormonal therapy only.
Current therapy with other investigational agents or participation in another clinical study (supportive care and nontherapeutic trial participation allowed if not receiving an investigational drug). Participants may participate in prescreening for other therapeutic trials (prescreening of biologic sample for specific mutations, receptors, etc.)
Single group
Nal-IRI
Drugchemotherapy drug
Oxaliplatin
Drugchemotherapy drug
5-FU
Drugchemotherapy drug
Trastuzumab
Drugimmunotherapy
Pembrolizumab
Drugimmunotherapy
Nivolumab
Drugimmunotherapy
Cohort 1: Objective Response Rate (ORR)
ORR will be calculated by combining the number of participants who achieve complete response and partial response per RECIST 1.1 criteria, from the start of treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the start of treatment). An ORR of 40% or less for proposed combination of 5-Fluorouracil, Oxaliplatin and nal-IRI during 1st line treatment of advanced esophageal and gastric adenocarcinoma in HER2-negative subjects will be considered as unacceptably low. The number and frequencies of objectives responses will be summarized in tabular format. The ORR will be reported along with the corresponding one-sided 90% confidence intervals.
Cohort 3: Objective Response Rate (ORR)
ORR will be calculated by combining the number of participants who achieve complete response and partial response per RECIST 1.1 criteria, from the start of treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the start of treatment). An ORR of 45% or less for proposed combination of 5-Fluorouracil, Oxaliplatin, nal-IRI and Nivolumab during 1st line treatment of advanced esophageal and gastric adenocarcinoma in HER2-negative subjects will be considered as unacceptably low. The number and frequencies of objectives responses will be summarized in tabular format. The ORR will be reported along with the corresponding one-sided 90% confidence intervals.
Cohorts 2 and 4: Incidence of Adverse Events
The primary objective of cohorts 2 and 4 (HER2-positive EGA) is to evaluate safety and tolerability of the studied drug combination. Toxicities and adverse events will be summarized by type and severity in tabular format.
Progression Free Survival (PFS)
PFS will be defined from the date study enrollment to the date of progression event or death. If a participant does not experience a progression event at the end of the follow-up period, then the PFS will be censored at the last assessment date. PFS will be analyzed using the Kaplan-Meier method. Median PFS will be reported along with the corresponding 90% confidence interval which will be constructed using the nonparametric Brookmeyer-Crooley method.
Disease Control Rate (DCR)
The DCR is the proportion of all participants with stable disease (SD) for 8 weeks, or partial response (PR), or complete response (CR) according to RECIST 1.1, from the start of treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the start of treatment).DCR will be reported along with the corresponding 90% confidence intervals which will be constructed using the Wilson score method.
Progression Free Survival at 6 months
PFS will be defined from the date study enrollment to the date of progression event or death. If a participant does not experience a progression event at the end of the follow-up period, then the PFS will be censored at the last assessment date. PFS will be analyzed using the Kaplan-Meier method. Median PFS will be reported along with the corresponding 90% confidence interval which will be constructed using the nonparametric Brookmeyer-Crooley method.
Progression Free Survival at 12 months
PFS will be defined from the date study enrollment to the date of progression event or death. If a participant does not experience a progression event at the end of the follow-up period, then the PFS will be censored at the last assessment date. PFS will be analyzed using the Kaplan-Meier method. Median PFS will be reported along with the corresponding 90% confidence interval which will be constructed using the nonparametric Brookmeyer-Crooley method.
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University of Wisconsin, Madison
Lead sponsor
Ipsen
Collaborator
