Clinical Trials /

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

NCT03995017

Description:

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.

Related Conditions:
  • Adenocarcinoma of the Gastroesophageal Junction
  • Gastric Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Rucaparib Plus Ramucirumab With or Without Nivolumab in Advanced Gastric and Esophageal Adenocarcinoma
  • 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)

Clinical Trial IDs

  • ORG STUDY ID: IIT-2018-RucaRamNivo
  • NCT ID: NCT03995017

Conditions

  • Esophagus Cancer, Adenocarcinoma
  • Stomach Cancer, Adenocarcinoma

Interventions

DrugSynonymsArms
RucaparibRubracaSafety Lead In
RamucirumabCyramzaSafety Lead In
NivolumabOpdivo, Bristol- Meyers Squibb (BMS)-936558Safety Lead In

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Safety Lead InExperimentalRucaparib 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
  • Rucaparib
  • Ramucirumab
  • Nivolumab
Cohort AExperimentalRucaparib 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
  • Rucaparib
  • Ramucirumab
  • Nivolumab
Cohort BActive ComparatorRucaparib 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
  • Rucaparib
  • Ramucirumab

Eligibility 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Recommended Phase 2 Dose (RP2D)
Time Frame:Up to 28 days
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Number of participants with treatment related adverse events (TRAEs)
Time Frame:Up to 12 months
Safety Issue:
Description:Determining per CTCAE 5.0
Measure:Overall Benefit Rate (OBR)
Time Frame:Up to 12 months
Safety Issue:
Description: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
Measure:Progression free survival (PFS)
Time Frame:Up to 12 months
Safety Issue:
Description: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
Measure:Overall survival (OS)
Time Frame:Up to 12 months
Safety Issue:
Description: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.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Anwaar Saeed

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