A Phase 1/2 Study of Olaparib in Combination With Ramucirumab in Metastatic Gastric and Gastroesophageal Junction Adenocarcinoma (10017760)
Overview
- Phase
- Phase 1
- Intervention
- Olaparib
- Conditions
- Metastatic Esophageal Carcinoma
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 51
- Locations
- 32
- Primary Endpoint
- Dose Limiting Toxicity and Maximum Tolerated Dose of Olaparib (Phase I)
- Status
- Completed
- Last Updated
- 2 months ago
Overview
Brief Summary
This phase I/II trial studies the side effects and best dose of olaparib when given together with ramucirumab and how well they work in treating patients with gastric or gastroesophageal junction cancer that has spread to other places in the body (metastatic), has come back (recurrent), or cannot be removed by surgery (unresectable). Olaparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as ramucirumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving olaparib and ramucirumab may work better in treating patients with gastric or gastroesophageal junction cancer compared to ramucirumab and paclitaxel (a chemotherapy drug) or ramucirumab alone.
Detailed Description
PRIMARY OBJECTIVES: 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). SECONDARY OBJECTIVES: 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. EXPLORATORY OBJECTIVES: 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 of each cycle and ramucirumab intravenously (IV) over 60 minutes on day 1 of each cycle. 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 if the patient has not had disease progression and every 3 months if the patient has had disease progression.
Investigators
Eligibility Criteria
Inclusion Criteria
- •The patient must have histologically confirmed, gastric carcinoma, including gastroesophageal junction (GEJ) adenocarcinoma (patients with adenocarcinoma of the distal esophagus are eligible if the primary tumor involves the GEJ)
- •The patient has metastatic disease or locally recurrent, unresectable disease
- •The patient must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1
- •The patient must have experienced disease progression during or within 4 months after the last dose of chemotherapy for metastatic disease, during or within 6 months after the last dose of adjuvant chemotherapy, or have been intolerant of previous chemotherapy
- •The patient must have experienced disease progression or intolerance as outlined above after treatment with 1 or more prior chemotherapies
- •All previous treatments are acceptable as long as they did not contain bevacizumab, ramucirumab or PARP inhibitors
- •Elevation in tumor markers without radiographic evidence of disease progression is not satisfactory for progression on previous treatment
- •The patient is \>= 18 years of age
- •The patient has a life expectancy of \>= 16 weeks
- •Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1 (Karnofsky \>= 60%)
Exclusion Criteria
- •Patients with untreated brain metastases are excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events; a scan to confirm the absence of brain metastases is not required; the patient can receive a stable dose of corticosteroids before and during the study as long as these were started at least 4 weeks prior to treatment; patients with spinal cord compression are also excluded unless considered to have received definitive treatment for this and evidence of clinically stable disease for 28 days
- •Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities \> Common Terminology Criteria for Adverse Events \[CTCAE\] grade 1 or baseline, with the exception of alopecia)
- •Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication
- •The patient has experienced any grade 3-4 gastrointestinal bleeding within 3 months prior to randomization
- •The patient has experienced any arterial thrombotic events, including but not limited to myocardial infarction, transient ischemic attack, cerebrovascular accident, or unstable angina, within 6 months prior to enrollment
- •The patient has an ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, symptomatic or poorly controlled cardiac arrhythmia, uncontrolled thrombotic or hemorrhagic disorder, or any other serious uncontrolled medical disorder in the opinion of the investigator
- •The patient has an ongoing or active psychiatric illness or social situation that would limit compliance with study requirements
- •Clinically significant peripheral vascular disease or vascular disease (abdominal aortic aneurysm \> 5 cm) or aortic dissection; if known history of abdominal aortic aneurysm with \>= 4 cm in diameter, all of the following must be met
- •An ultrasound within the last 6 months required to document that it is =\< 5 cm
- •Patient must be asymptomatic from the aneurysm
Arms & Interventions
Treatment (olaparib, ramucirumab)
Patients receive olaparib PO BID on days 1-14 of each cycle and ramucirumab IV over 60 minutes on day 1 of each cycle. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity.
Intervention: Olaparib
Treatment (olaparib, ramucirumab)
Patients receive olaparib PO BID on days 1-14 of each cycle and ramucirumab IV over 60 minutes on day 1 of each cycle. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity.
Intervention: Ramucirumab
Outcomes
Primary Outcomes
Dose Limiting Toxicity and Maximum Tolerated Dose of Olaparib (Phase I)
Time Frame: Up to 28 days
Will be assessed by National Cancer Institute (NCI) Common Terminology Criteria (CTCAE) for Adverse Events version 5.0. The safety profile and adverse event reporting were collected in an intent to treat analysis so data from all patients were included in the overall analysis and there was never any plan nor intent to evaluate or report the safety profile separately. These are not two different arms of the same study, the phase 1 part of this was a lead in to the phase 2.
Objective Response Rate (Phase II)
Time Frame: Up to 2 years
Will be defined as complete or partial response assessed by Response Evaluation Criteria in Solid Tumors version 1.1. Presented are the count of those that were considered to have responded while in treatment.
Secondary Outcomes
- Overall Survival(Up to 2 years)
- Progression Free Survival(From start of treatment to time of progression or death, whichever occurs first, assessed up to 2 years)
- Count of Participants With Adverse Events(Up to 2 years)
- BROCA-HR Status: Progression Free Survival(Up to 6 months)
- BROCA-HR Status: Overall Survival(Up to 2 years)