Rucaparib and Ramucirumab with or without Nivolumab for the Treatment of Stage III-IV Gastric, Esophageal, or Esophageal Adenocarcinoma
- Ability of participant OR Legally Authorized Representative (LAR) to understand this study, and participant or LAR willingness to sign a written informed consent
- Eastern Cooperative Oncology Group (ECOG) performance status 0-1
- 50% of the study population in phase 2 must have a deleterious tumor alteration in at least one of the following genes: * ARID1A * ATM * ATRX * BAP1 * BLM * BRCA1 * BRCA2 * BRIP1 * CHEK2 * FANCA * FANCC * MRE11A * NBN * PALB2 * RAD50 * BAR51C * RAD51D
- Histologically confirmed diagnosis of either of the following: gastric, esophageal or gastroesophageal junction adenocarcinoma
- Have advanced (stage 4) or locally unresectable (stage III) disease
- Must have measurable disease per modified Response Evaluation Criteria in Solid Tumors (RECIST). Previously irradiated lesion cannot be considered as target lesion (TL) except in cases of documented progression of the lesion since the completion of radiation therapy
- Must consent to undergo a required screening baseline biopsy procedure if archival tissue is not available or not enough for molecular testing. If the participant’s tumor tissue has already been tested using foundation one CDx panel, repeat testing is not necessary. If the previous comprehensive tumor molecular testing was completed through non Foundation One CDx panel, contact sponsor for approval
- 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 HER2 positive disease must show progression on prior HER2 targeted therapy
- Recovery to baseline or < grade 2 Common Terminology Criteria for Adverse Events (CTCAE) from toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy
- Absolute neutrophil count ANC >= 1.5 x 10 K/UL
- Hemoglobin >= 9.0 g/dl (transfusion assistance acceptable)
- Platelet count >= 100 x 10 K/UL
- Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) =< 3.0 x institutional upper limit of normal (ULN) unless liver metastases are present, in which case it must be =< 5 x ULN
- Bilirubin =< 1.5 x ULN; < 2 x ULN if hyperbilirubinemia is due to Gilbert’s syndrome
- Prothrombin time (PT)/international normalized ratio (INR) or partial thromboplastin time (PTT) test < 1.5 x ULN within 7 days before the first dose of study treatment
- Serum albumin >= 2.8 g/dl
- Measured or calculated creatinine clearance (CrCL) >= 30 mL/min. For calculated CrCL, the Cockcroft Gault formula or institutional standard formula can be used
- Urine protein/creatinine ratio (UPCR) =< 1 mg/mg (=< 113.2 mg/mmol)
- Absence of active autoimmune disease that has required systemic treatment in the past 2 years
- Absence of Conditions requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration
- Evidence of post-menopausal status or negative serum pregnancy test (24 hours prior to study drug initiation and every 4 weeks while on study treatment) for female premenopausal 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 (hormonal AND barrier method of birth control) prior to study entry, for the duration of study participation, and for 6 months following completion of therapy. If a woman becomes pregnant or suspects she is pregnant while participating in this study, she should inform her treating physician immediately
- 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
- Prior treatment with a PD1 or PD-L1 inhibitors
- Prior treatment with PARP or VEGF inhibitors
- Primary refractory disease to platinum based regimen (defined as disease progression on first evaluation of tumor response for advanced stage disease or disease recurrence within 6 months of completing platinum based chemo-radiation for resectable/ locally advanced disease)
- Patients with microsatellite instability (MSI) high or mismatch repair (MMR) deficient tumors
- Abdominal fistula, gastrointestinal (GI) perforation, bowel obstruction, or intra-abdominal abscess within 6 months before first dose. Note: Complete healing of an intra-abdominal abscess must be confirmed before first dose
- Grade 3 or 4 venous thromboembolic event (VTE) that is considered by the investigator to be life-threatening or that is symptomatic and not adequately treated by anticoagulation therapy
- Evidence of active peptic ulcer disease, inflammatory bowel disease (eg, Crohn’s 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 of > 0.5 teaspoon (tsp) (2.5ml) of red blood, or other history of significant bleeding within 12 weeks
- Lesions invading or encasing any major blood vessels
- Any unresolved toxicity National Cancer Institute (NCI) CTCAE version (v)5.0 grade >= 2 from previous anticancer therapy
- Patients with clinically relevant ongoing complications from prior chemoradiation or radiation therapy are not eligible
- Receipt of the last dose of anticancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies) =< 28 days prior to the first dose of study drug
- Major surgery (eg, GI surgery, removal or biopsy of brain metastasis) within 8 weeks before first dose of study treatment. Complete wound healing from major surgery must have occurred 1 month before first dose and from minor surgery (eg, simple excision, tooth extraction) at least 10 days before first dose. Patients with clinically relevant ongoing complications from prior surgery are not eligible
- Current or prior use of immunosuppressive medication within 14 days before the first dose of nivolumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid
- History of allogenic organ transplantation
- Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc])
- History of active primary immunodeficiency
- Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis [TB] testing in line with local practice), hepatitis B (positive hepatitis B virus [HBV] surface antigen [HBsA]) result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (hepatitis C virus [HCV]) antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA)
- Receipt of live attenuated vaccine within 30 days prior to the first dose of study drug. Note: Patients, if enrolled, should not receive live vaccine whilst receiving investigational product (IP) and up to 30 days after the last 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 (Fridericia's correction formula [QTcF]) > 470 ms
- Brain metastases or spinal cord compression. Patients with suspected brain metastases at screening should have an magnetic resonance imaging (MRI) (preferred) or computed tomography (CT) each preferably with IV contrast of the brain prior to study entry. Patients whose brain metastases have been treated may participate provided they show radiographic stability (defined as 2 brain images, both of which are obtained after treatment to the brain metastases. These imaging scans should both be obtained at least four weeks apart and show no evidence of intracranial progression). In addition, any neurologic symptoms that developed either as a result of the brain metastases or their treatment must have resolved or be stable either, without the use of steroids, or are stable on a steroid dose of =< 10 mg/day of prednisone or its equivalent for at least 14 days prior to the start of treatment
- Has untreated central nervous system (CNS) metastases and/or carcinomatous meningitis identified either on the baseline brain imaging or identified prior to signing the informed consent form (ICF)
- 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 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. There is a potential for congenital abnormalities and for this regimen to harm breast feeding infants
I. To determine the recommended phase 2 dose (RP2D) for the combination of rucaparib plus ramucirumab and nivolumab. (Phase I)
II. To determine the overall response rate (ORR) in the 2 treatment cohorts. (Phase II)
I. To determine the safety of the study drug combination in the 2 treatment cohorts, defined as proportion of participants with adverse events (AEs) in each cohort.
II. To determine the ORR in homologous recombination deficiency (HRD) positive and HRD negative participants in the 2 treatment cohorts.
III. To determine the overall benefit rate (OBR) in the 2 treatment cohorts, defined as the proportion of participants with overall benefit to therapy.
IV. To determine the progression free survival (PFS) in the 2 treatment cohorts, 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.
V. To determine the overall survival (OS) in the 2 treatment cohorts, defined as the time from the start of treatment until death due to any cause.
I. To explore the genomic alterations correlating with treatment response to the study drug combination in the 2 treatment cohorts.
II. To explore mechanisms of resistance to the drug combination in the 2 treatment cohorts.
PHASE I: Patients receive rucaparib orally (PO) twice daily (BID) on days 1-28, ramucirumab intravenously (IV) over 60 minutes on days 1 and 15, and nivolumab IV over 30 minutes on day 1. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
PHASE II: Patients are assigned to 1 of 2 cohorts.
COHORT A: Patients receive rucaparib, ramucirumab and nivolumab as in Phase I. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
COHORT B: Patients receive rucaparib PO BID on days 1-28 and ramucirumab IV over 60 minutes on days 1 and 15. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30, 60, and 100 days and then at 6 months for females and 7 months for males.
Trial Phase Phase I/II
Trial Type Treatment
University of Kansas Hospital-Westwood Cancer Center
- Primary ID IIT-2018-RucaRamNivo
- Secondary IDs NCI-2020-01661
- Clinicaltrials.gov ID NCT03995017