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

NCT03995017 | Unknown Phase 1 DMC FDA Drug

• 1 other identifier: IIT-2018-RucaRamNivo
• Study Type: interventional
• Target: 34
• Locations: 1 country
• Sites: 8

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.

Conditions

Esophagus Cancer, Adenocarcinoma; Stomach Cancer, Adenocarcinoma

Outcome Measures

Primary Outcomes (2)

• Recommended Phase 2 Dose (RP2D)

  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.

  Up to 28 days

• Overall Response Rate (ORR)

  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

  up to 12 months

Secondary Outcomes (4)

• Number of participants with treatment related adverse events (TRAEs)

  Up to 12 months

• Overall Benefit Rate (OBR)

  Up to 12 months

• Progression free survival (PFS)

  Up to 12 months

• Overall survival (OS)

  Up to 12 months

Study Arms (3)

Safety Lead In

EXPERIMENTAL

* 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; Drug: Ramucirumab; Drug: Nivolumab

Cohort A

EXPERIMENTAL

* 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; Drug: Ramucirumab; Drug: Nivolumab

Cohort B

ACTIVE COMPARATOR

* 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; Drug: Ramucirumab

Interventions

Rucaparib DRUG

Rucaparib tablet

Also known as: Rubraca

Cohort A; Cohort B; Safety Lead In

Ramucirumab DRUG

Ramucirumab intravenous solution

Also known as: Cyramza

Cohort A; Cohort B; Safety Lead In

Nivolumab DRUG

Nivolumab intravenous solution

Also known as: Opdivo, Bristol- Meyers Squibb (BMS)-936558

Cohort A; Safety Lead In

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Kansas Medical Center: lead
• Bristol-Myers Squibb: collaborator
• Clovis Oncology, Inc.: collaborator

Study Sites (8)

University of Chicago Medical Center

Chicago, Illinois, 60637, United States

Location

KU Cancer Center

Fairway, Kansas, 66205, United States

Location

University of Kansas Cancer Center - CRC

Fairway, Kansas, 66205, United States

Location

University of Kansas Cancer Center - West

Kansas City, Kansas, 66112, United States

Location

The University of Kansas Cancer Center, Westwood Campus

Kansas City, Kansas, 66205, United States

Location

University of Kansas Cancer Center - Overland Park

Overland Park, Kansas, 66210, United States

Location

University of Kansas Cancer Center - North

Kansas City, Missouri, 64154, United States

Location

University of Kansas Cancer Center - Lee's Summit

Lee's Summit, Missouri, 64064, United States

Location

MeSH Terms

Conditions

Adenocarcinoma Of Esophagus; Stomach Neoplasms; Adenocarcinoma

Interventions

rucaparib; Ramucirumab; Nivolumab

Condition Hierarchy (Ancestors)

Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Stomach Diseases; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Anwaar Saeed, MD

  Kansas University Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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).

Study Record Dates

• First Submitted: June 19, 2019
• First Posted: June 21, 2019
• Study Start: January 9, 2020
• Primary Completion: October 19, 2022
• Study Completion: December 1, 2024
• Last Updated: February 1, 2023

Record last verified: 2023-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (8)