Olaparib and Ramucirumab in Treating Patients With Metastatic or Locally Recurrent Gastric or Gastroesophageal Junction Cancer That Cannot Be Removed by Surgery
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|ClinicalTrials.gov Identifier: NCT03008278|
Recruitment Status : Recruiting
First Posted : January 2, 2017
Last Update Posted : June 28, 2021
|Condition or disease||Intervention/treatment||Phase|
|Metastatic Esophageal Carcinoma Metastatic Gastric Carcinoma Metastatic Gastroesophageal Junction Adenocarcinoma Recurrent Esophageal Carcinoma Recurrent Gastric Carcinoma Recurrent Gastroesophageal Junction Adenocarcinoma Stage III Esophageal Cancer AJCC v7 Stage III Gastric Cancer AJCC v7 Stage IIIA Esophageal Cancer AJCC v7 Stage IIIA Gastric Cancer AJCC v7 Stage IIIB Esophageal Cancer AJCC v7 Stage IIIB Gastric Cancer AJCC v7 Stage IIIC Esophageal Cancer AJCC v7 Stage IIIC Gastric Cancer AJCC v7 Stage IV Esophageal Cancer AJCC v7 Stage IV Gastric Cancer AJCC v7 Unresectable Esophageal Carcinoma Unresectable Gastric Carcinoma Unresectable Gastroesophageal Junction Adenocarcinoma||Drug: Olaparib Biological: Ramucirumab||Phase 1 Phase 2|
I. To determine the safe dose of olaparib with ramucirumab, but not to exceed olaparib dose of 300 mg twice daily (tablet formulation). (Phase I) II. To determine the efficacy of olaparib plus ramucirumab as measured by the objective response rates (ORR) stratified by BROCA-HR biomarker status. (Phase II).
I. To estimate median progression-free survival (PFS) stratified by BROCA-HR biomarker status.
II. To estimate median overall survival (OS) stratified by BROCA-HR biomarker status.
III. To measure the prevalence of the BROCA-HR biomarker in our study population.
IV. To determine toxicity of olaparib and ramucirumab combination.
I. To assess the correlation between the signature 3 status, and mutations in BROCA-HR panel.
II. To evaluate the association between findings from BROCA-HR panel with response to therapy.
III. To evaluate the association between findings from BROCA-HR panel and signature 3 results with response to therapy.
IV. To determine results of immunoassay for poly-ADP-ribosylated (PAR) substrates in tumor tissue.
V. To create a PDX model to study deoxyribonucleic acid (DNA) repair in gastric tumors treated with PARP inhibitors (PARPi) from both pre-treatment biopsy and repeat biopsy after 16 weeks of treatment.
VI. Development of a novel genomic assay for BRCAness. VII. Defining T cell receptor diversity of gastric cancer patients +/- BRCAness.
VIII. Biobank additional tumor tissue for future genomic analysis. IX. Biobank peripheral blood for future genomic analysis and assessment of circulating tumor DNA.
OUTLINE: This is a phase I, dose-escalation study of olaparib followed by a phase II study.
Patients receive olaparib orally (PO) twice daily (BID) on days 1-14 and ramucirumab intravenously (IV) over 60 minutes on day 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 4 weeks and then every 6 weeks thereafter.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||49 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase 1/2 Study of Olaparib in Combination With Ramucirumab in Metastatic Gastric and Gastroesophageal Junction Adenocarcinoma (10017760)|
|Actual Study Start Date :||November 7, 2017|
|Estimated Primary Completion Date :||June 30, 2022|
|Estimated Study Completion Date :||June 30, 2022|
Experimental: Treatment (olaparib, ramucirumab)
Patients receive olaparib PO BID on days 1-14 and ramucirumab IV over 60 minutes on day 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity.
- Dose limiting toxicity and maximum tolerated dose of olaparib (Phase I) [ Time Frame: Up to 14 days ]Will be assessed by National Cancer Institute (NCI) Common Terminology Criteria (CTCAE) for Adverse Events version 5.0.
- Objective response rate (Phase II) [ Time Frame: Up to 1 year ]Will be defined as complete or partial response assessed by Response Evaluation Criteria in Solid Tumors version 1.1. Will be estimated using the 95% confidence interval (CI) based on Wilson's method. A 5% 2-sided alpha will be used. The Wilcoxon rank sum test and Fisher's exact test will be applied to study the association between the response status and the continuous and categorical variables, respectively. The generalized non-linear model and logistic regression will be applied for multivariable data analysis. The adjusted p-value and 95% CI of the odds ratio will be reported.
- Progression free survival [ Time Frame: From start of treatment to time of progression or death, whichever occurs first, assessed up to 1 year ]Will be compared for duration of response survival with Kaplan-Meier estimates and log-rank tests. The Rothman CI will be reported. In addition, the possible risk factors will be compared for survival with log-rank test. For multivariate analysis, the proportional hazards Cox model will be applied to investigate potential prognostic factors, such as age and stage of disease of the PFS data. The adjusted p-values of the hazard ratios and the adjusted 95% confidence interval will be reported.
- Overall survival [ Time Frame: Up to 1 year ]Will be compared for duration of response survival with Kaplan-Meier estimates and log-rank tests. The Rothman CI will be reported. In addition, the possible risk factors will be compared for survival with log-rank test. The adjusted p-values of the hazard ratios and the adjusted 95% confidence interval will be reported.
- BROCA-HR status [ Time Frame: Up to 1 year ]Will be compared for duration of response survival with Kaplan-Meier estimates and log-rank tests. The Rothman CI will be reported. In addition, the possible risk factors will be compared for survival with log-rank test. The adjusted p-values of the hazard ratios and the adjusted 95% confidence interval will be reported.
- Incidence of adverse events [ Time Frame: Up to 30 days of last dose administration ]Will be assessed by NCI CTCAE version 5.0. Will be tabulated by type and grade and compared to established rates for ramucirumab monotherapy. Ninety-five percent confidence intervals will be calculated for each of these.
- BROCA HR assay [ Time Frame: Up to 1 year ]The association of BROCA HR assay with Signature 3 will be assessed using a series of contingency table analyses. The association of the presence of an individual mutation from the BROCA HR panel with the signature 3 (yes/no) using Fisher's exact test. Using a Cochran Mantel Haenzel test the relationship across all three measures will be examined. Finally, the relationship of each of these measures with response will be examined. To do this multiple logistic regression models can be fit with the response (complete response/partial response vs stable disease/partial disease) considered as the outcome variable and the assay measures can be used predictors.
- Tumor cells for PDX model, and biobanked tumor tissue and peripheral blood [ Time Frame: Up to 1 year ]
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03008278
|Principal Investigator:||Michael Cecchini||Yale University Cancer Center LAO|