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Rucaparib Plus Ramucirumab With or Without Nivolumab in Advanced Gastric and Esophageal Adenocarcinoma (RiME)

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ClinicalTrials.gov Identifier: NCT03995017
Recruitment Status : Recruiting
First Posted : June 21, 2019
Last Update Posted : November 10, 2020
Sponsor:
Collaborators:
Bristol-Myers Squibb
Clovis Oncology, Inc.
Information provided by (Responsible Party):
Anwaar Saeed, University of Kansas Medical Center

Brief Summary:
The study population is advanced gastric, gastroesophageal, and esophageal adenocarcinoma participants who have failed upfront standard of care chemotherapy. The goal is to demonstrate that Rucaparib plus Ramucirumab with or without Nivolumab has a higher response rate than what has been reported for Ramucirumab in previously treated patients. Trial will be a phase 1/2 trial. The Phase 1 portion will determine the recommended Phase 2 treatment dose for the combination of Rucaparib plus Ramucirumab and Nivolumab and enroll approximately 6-9 participants. The Phase 2 portion of the study will involve 52 participants allocated between two treatment groups comparing Rucaparib plus Ramucirumab with or without Nivolumab. The participants will be selected based on the results of a screening HRD gene panel.

Condition or disease Intervention/treatment Phase
Esophagus Cancer, Adenocarcinoma Stomach Cancer, Adenocarcinoma Drug: Rucaparib Drug: Ramucirumab Drug: Nivolumab Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 61 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:

Phase 1 - Safety Lead In - Enroll 6-9 molecularly unselected participants to determine the safety of the triplet combination of Rucaparib plus Ramucirumab and Nivolumab. One level dose de-escalation of Rucaparib will be planned based on dose limiting toxicity (DLT) signal of the first 6 participants run in phase.

Phase 2 - Parallel - Enroll 52 participants (26 in each cohort), open label, two treatment cohorts design evaluating Rucaparib plus Ramucirumab with or without Nivolumab. 50 percent (%) of participants enrollment to each treatment cohort will represent molecularly unselected population and the remaining 50% will be selected based on integrated screening tumor Homologous Recombination Deficiency (HRD) gene panel. The primary objective is efficacy by measuring the Overall Response Rate (ORR).

Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Trial of Rucaparib in Combination With Ramucirumab With or Without Nivolumab in Previously Treated Patients With Advanced Gastric and Esophageal Adenocarcinoma (RiME)
Actual Study Start Date : January 9, 2020
Estimated Primary Completion Date : October 2021
Estimated Study Completion Date : December 2024

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Safety Lead In
  • Rucaparib 600 milligrams twice daily
  • Ramucirumab 8 milligrams per kilogram intravenous every 2 weeks
  • Nivolumab 480 milligrams intravenous every 4 weeks
  • Treatment will continue until disease progression, unacceptable toxicity or the patient desires to discontinue this therapy
  • One dose level decrease of Rucaparib will be planned if toxicity develops in the first 6 patients
  • 1 cycle= 28 days
Drug: Rucaparib
Rucaparib tablet
Other Name: Rubraca

Drug: Ramucirumab
Ramucirumab intravenous solution
Other Name: Cyramza

Drug: Nivolumab
Nivolumab intravenous solution
Other Names:
  • Opdivo
  • Bristol- Meyers Squibb (BMS)-936558

Experimental: Cohort A
  • Rucaparib 600 milligrams twice daily
  • Ramucirumab 8 milligrams per kilogram intravenous every 2 weeks
  • Nivolumab 480 milligrams intravenous every 4 weeks
  • Treatment will continue until disease progression, unacceptable toxicity or the patient desires to discontinue this therapy
  • 1 cycle= 28 days
Drug: Rucaparib
Rucaparib tablet
Other Name: Rubraca

Drug: Ramucirumab
Ramucirumab intravenous solution
Other Name: Cyramza

Drug: Nivolumab
Nivolumab intravenous solution
Other Names:
  • Opdivo
  • Bristol- Meyers Squibb (BMS)-936558

Active Comparator: Cohort B
  • Rucaparib 600 milligrams twice daily
  • Ramucirumab 8 milligrams per kilogram intravenous every 2 weeks
  • Treatment will continue until disease progression, unacceptable toxicity or the patient desires to discontinue this therapy
  • 1 cycle= 28 days
Drug: Rucaparib
Rucaparib tablet
Other Name: Rubraca

Drug: Ramucirumab
Ramucirumab intravenous solution
Other Name: Cyramza




Primary Outcome Measures :
  1. Recommended Phase 2 Dose (RP2D) [ Time Frame: Up to 28 days ]
    Defined as the highest dose studied for which the observed incidence of dose limiting toxicities (DLT) is less than 33%. DLTs will be measured per the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

  2. Overall Response Rate (ORR) [ Time Frame: up to 12 months ]
    Defined as the proportion of participants with overall response to therapy. Overall response is defined as the best response recorded, (including Complete Response (CR) and Partial Response (PR)), from the start of the treatment until the end of treatment. ORR will be measured per the Modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria


Secondary Outcome Measures :
  1. Number of participants with treatment related adverse events (TRAEs) [ Time Frame: Up to 12 months ]
    Determining per CTCAE 5.0

  2. Overall Benefit Rate (OBR) [ Time Frame: Up to 12 months ]
    Defined as the proportion of participants with overall benefit to therapy. Overall benefit is defined as the best response recorded, (including complete Response (CR), Partial Response (PR), and Stable Disease (SD)), from the start of the treatment until the end of treatment. Determine overall benefit of therapy using modified RECIST version 1.1

  3. Progression free survival (PFS) [ Time Frame: Up to 12 months ]
    Reported as the proportion of participants that achieve PFS. PFS is defined as the time from the start of treatment until the first documentation of disease progression or death due to any cause, whichever occurs first. Measured per modified RECIST version 1.1

  4. Overall survival (OS) [ Time Frame: Up to 12 months ]
    Defined as the time from the start of treatment until death due to any cause, reported as the mean of all participants' OS. Measured per the medical record.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Half of the study population in phase 2 must have a deleterious tumor alteration in at least one protocol specified gene
  • Gastric or gastroesophageal junction adenocarcinoma
  • Advanced stage 4 or locally unresectable stage 3 disease
  • Must have measurable disease
  • Must consent to have a biopsy if archival tissue is not available or not enough for molecular testing
  • Must show evidence of progression or intolerance to at least one previous standard of care systemic therapy (not more than 2 lines of prior therapy)
  • Patients with human epidermal growth factor receptor 2 (HER2) positive disease must show progression on prior HER2 targeted therapy
  • Toxicities related to prior treatment should be recovered to baseline or less than grade 2 according to CTCAE
  • Adequate organ and marrow function
  • Absence of active autoimmune disease that has required systemic treatment in the past 2 years
  • Absence of conditions requiring systemic treatment with either corticosteroids or other immunosuppressive medications within 14 days of study drug administration. 10mg or less of prednisone or equivalent is acceptable
  • Evidence of post-menopausal status or negative serum pregnancy test for female pre-menopausal patients
  • Women of child-bearing potential and men with partners of child-bearing potential must agree to practice sexual abstinence, or to use two forms of adequate contraception prior to study entry, for the duration of study participation, and for 6 months following completion of therapy
  • Men of child-bearing potential must not father a child or donate sperm while on this study and for 7 months after their last study treatment

Exclusion Criteria:

  • Prior treatment with a programmed cell death protein 1 (PD1) or programmed death- ligand 1 (PD-L1) inhibitors
  • Prior treatment with poly-(ADP-Ribose)polymerase (PARP)
  • Patients with microsatellite instability (MSI) high or mismatch repair (MMR) deficient tumors
  • Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess within 6 months before first dose
  • Evidence of active peptic ulcer disease, inflammatory bowel disease, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis, acute obstruction of the pancreatic duct or common bile duct, or gastric outlet obstruction
  • Inability to swallow tablets
  • Uncontrollable ascites or pleural effusion
  • Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease manifestation
  • Clinically significant hematuria, hematemesis, or hemoptysis, or other history of significant bleeding within 12 weeks
  • Lesions invading any major blood vessels
  • Receipt of the last dose of anticancer therapy less than 28 days prior to the first dose of study drug
  • Major surgery within 8 weeks before first dose of study treatment
  • History of allogenic organ transplantation
  • Active infection including tuberculosis, hepatitis B, hepatitis C, or human immunodeficiency virus. Patients with a past or resolved hepatitis B virus (HBV) infection are eligible. Patients positive for hepatitis C antibody are eligible only if polymerase chain reaction is negative for hepatitis C virus (HCV) RNA
  • Receipt of live attenuated vaccine within 30 days prior to the first dose of study drug
  • Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, or serious chronic gastrointestinal conditions
  • Uncontrolled hypertension defined as sustained blood pressure (BP) > 150 mm Hg systolic or > 100 mm Hg diastolic despite optimal antihypertensive treatment
  • Prolonged baseline QT interval corrected for heart rate greater than 470 ms
  • Brain metastases or spinal cord compression. Patients whose brain metastases have been treated may participate provided they show radiographic stability
  • Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients
  • Current or anticipated use of other investigational agents while participating in this study
  • History of another primary malignancy except for:

    • Malignancy treated with curative intent and with no known active disease before the first dose of investigational product (IP) and of low potential risk for recurrence
    • Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
    • Adequately treated carcinoma in situ without evidence of disease
  • Psychiatric illness/social situations that would limit compliance with study requirements
  • Pregnant or breast feeding

Information from the National Library of Medicine

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): NCT03995017


Contacts
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Contact: KUCC Navigation 913-588-3671 kucc_navigation@kumc.edu

Locations
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United States, Illinois
University of Chicago Medical Center Recruiting
Chicago, Illinois, United States, 60637
Contact: Jennifer Mitchell    773-702-0405    jmitchel@medicine.bsd.uchicago.edu   
Contact: Tamika Harrs    773-702-4367    tharris@bsd.uchicago.edu   
Principal Investigator: Daniel Catenacci, MD         
United States, Kansas
KU Cancer Center Recruiting
Fairway, Kansas, United States, 66205
Contact: KUCC Navigation    913-588-3671    kucc_navigation@kumc.edu   
University of Kansas Cancer Center - CRC Recruiting
Fairway, Kansas, United States, 66205
Contact: KUCC Navigation    913-588-3671    kucc_navigation@kumc.edu   
Hays Medical Center Recruiting
Hays, Kansas, United States, 67601
Contact: Josette Klaus, RN    785-623-5761    josette.klaus@haysmed.com   
Contact: Shawn Mulkey, RN    785-623-5774    shawn.mulkey@hays.com   
University of Kansas Cancer Center - West Recruiting
Kansas City, Kansas, United States, 66112
Contact: KUCC Navigation    913-588-3671    kucc_navigation@kumc.edu   
The University of Kansas Cancer Center, Westwood Campus Recruiting
Kansas City, Kansas, United States, 66205
Contact: KUCC Navigation    913-588-3671    kucc_navigation@kumc.edu   
Olathe Medical Center Recruiting
Olathe, Kansas, United States, 66061
Contact: Jeni Wakefield, RN    913-791-3500 ext 4096      
University of Kansas Cancer Center - Overland Park Recruiting
Overland Park, Kansas, United States, 66210
Contact: KUCC Navigation    913-588-3671    kucc_navigation@kumc.edu   
Via Christi Cancer Center Recruiting
Pittsburg, Kansas, United States, 66762
Contact: Melinda Adair, RN    620-235-7906      
Salina Regional Health Recruiting
Salina, Kansas, United States, 67401
Contact: Melanie Leepers, RN    785-452-7038      
St. Francis Comprehensive Cancer Center Recruiting
Topeka, Kansas, United States, 66606
Contact: Michelle Kipp    785-270-5198      
United States, Missouri
Truman Medical Center Recruiting
Kansas City, Missouri, United States, 64108
University of Kansas Cancer Center - North Recruiting
Kansas City, Missouri, United States, 64154
Contact: KUCC Navigation    913-588-3671    kucc_navigation@kumc.edu   
University of Kansas Cancer Center - Lee's Summit Recruiting
Lee's Summit, Missouri, United States, 64064
Contact: KUCC Navigation    913-588-3671    kucc_navigation@kumc.edu   
Sponsors and Collaborators
Anwaar Saeed
Bristol-Myers Squibb
Clovis Oncology, Inc.
Investigators
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Principal Investigator: Anwaar Saeed, MD Kansas University Cancer Center
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Responsible Party: Anwaar Saeed, Principal Investigator, University of Kansas Medical Center
ClinicalTrials.gov Identifier: NCT03995017    
Other Study ID Numbers: IIT-2018-RucaRamNivo
First Posted: June 21, 2019    Key Record Dates
Last Update Posted: November 10, 2020
Last Verified: November 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Adenocarcinoma
Stomach Neoplasms
Esophageal Neoplasms
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Stomach Diseases
Head and Neck Neoplasms
Esophageal Diseases
Nivolumab
Ramucirumab
Rucaparib
Antineoplastic Agents, Immunological
Antineoplastic Agents
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action