Nivolumab and Relatlimab for the Treatment of Metastatic or Unresectable Solid Tumors with ARID1A Mutation
This phase II trial studies the effect of nivolumab in combination with relatlimab in treating patients with solid tumors that have spread to other places in the body (metastatic) or cannot be removed by surgery (unresectable) with ARID1A Mutation. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Relatlimab is a monoclonal antibody that may interfere with the ability of tumor cells to grow and spread. Giving nivolumab and relatlimab may help to control the disease.
Inclusion Criteria
- Documented inactivating ARID1A mutation based on Clinical Laboratory Improvements Amendment (CLIA)-certified next-generation sequencing (NGS) platform. Mutation status will be verified by MD Anderson’s Precision Oncology Decision Support (PODS) team
- Histological or cytological evidence of metastatic or surgically unresectable solid tumor other than bladder cancer
- All patients must have measurable disease by computed tomography (CT) or magnetic resonance imaging (MRI) per the Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1
- Evaluable tumor tissue (archived or new biopsy) must be provided for biomarker analysis as formalin-fixed paraffin-embedded (FFPE) tumor block or minimum of 10 slides. Archived tissue may be from prior biopsy of unresectable or metastatic disease or from prior surgical resection
- Eastern Cooperative Oncology Group (ECOG) performance status of =< 2
- Prior palliative radiotherapy must have been completed at least 2 weeks prior to the first dose of study treatment. Patients must have measurable disease outside the radiation field to be eligible. Patients with progression in a previously radiated field will also be eligible
- White blood cells (WBC) >= 2000/uL (obtained within 7 days prior the first dose of study treatment)
- Neutrophils >= 1500/uL (obtained within 7 days prior the first dose of study treatment)
- Platelets >= 100,000/uL (obtained within 7 days prior the first dose of study treatment)
- Hemoglobin >= 9.0 g/dL (obtained within 7 days prior the first dose of study treatment)
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x upper limit of normal (ULN; or =< 5 X ULN for participants with liver metastases) (obtained within 7 days prior the first dose of study treatment)
- Total bilirubin =< 1.5 x ULN (except patients with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL) (obtained within 7 days prior the first dose of study treatment)
- Serum creatinine =< 1.5 x ULN or creatinine clearance (CrCl) >= 30 mL/min (using the Cockcroft-Gault formula) (obtained within 7 days prior the first dose of study treatment)
- Re-enrollment: This study permits the re-enrollment of a patient who has discontinued the study as a pre-treatment failure (i.e., patient has not been treated). If re-enrolled, the patient must be re-consented and inclusion/exclusion criteria reassessed
- Patients are required to consent to participate in Protocol PA13-0291 for correlative studies. Patients will need to consent for mandatory biopsy and peripheral blood collections as required by the study
- Patients must be >= 18 years of age at enrollment
- Females of childbearing potential (FCBP) must agree to follow instructions for method(s) of contraception from the time of enrollment, for the duration of study treatment, and for 10 months after the last study dose of study treatment
- Males who are sexually active with FCBP must agree to follow instructions for method(s) of contraception for the duration of study treatment), and for 7 months after the last dose of study treatment. Male patients should refrain from donating sperm during the study
- FCBP must have a negative serum or urine pregnancy test within 24 hours prior to the start of study treatment
Exclusion Criteria
- Have a troponin T or I * > 2 × institutional ULN: patient is excluded. * Between > 1 to 2 × ULN enrollment will be permitted if a repeat assessment remains < 2 × ULN and patient undergoes a cardiac evaluation and is cleared by a cardiologist or cardio-oncologist
- History of myocarditis
- Prior treatment with an anti-PD-1, anti-PD-L1, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways
- Active brain metastases or leptomeningeal metastases. Patients with brain metastases are eligible if these have been treated and there is no MRI evidence of progression for at least 4 weeks after treatment is complete and within 28 days prior to first dose of study treatment. Where MRI is contraindicated CT scan is acceptable. Cases must be discussed with the medical monitor. Brain lesions are not considered measurable disease. There must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study treatment administration
- Any serious or uncontrolled medical disorder, that in the opinion of the investigator, may increase the risk associated with study participation or study treatment administration, impair the ability of the patient to receive protocol therapy, or interfere with the interpretation of study results
- Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, prostate cancer without evidence of prostate specific antigen progression or carcinoma in situ such as gastric, prostate, cervix, colon, melanoma, or breast
- Patients with active, known or suspected autoimmune disease. Patients with vitiligo, type I diabetes mellitus, or residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll
- Patients with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of first dose of study treatment. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease
- All toxicities attributed to prior anti-cancer therapy other than neuropathy, alopecia, and fatigue must have resolved to grade 1 (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] v5.0) or baseline before administration of first dose of study treatment. Patients with toxicities attributed to prior anti-cancer therapy that are not expected to resolve and result in long-lasting sequelae, such as neuropathy after platinum-based therapy, are permitted to enroll. Neuropathy must have resolved to grade 2 per the NCI CTCAE v5.0
- Treatment with any chemotherapy, radiation therapy, biological therapy, or investigational therapy within 28 days of first dose of study treatment
- Patients with active viral (any etiology) hepatitis are excluded. However, patients with serologic evidence of chronic hepatitis B virus (HBV) infection (positive hepatitis B surface antigen test and a positive hepatitis B core antibody test) who have a viral load below the limit quantification (HBV deoxyribonucleic acid [DNA] titer < 1000 cps/mL or 200 IU/mL) and are not currently on viral suppressive therapy will be eligible. The addition of HBV suppressive medication (i.e., entecavir) should be considered during the period of study treatment. Patients with a history of hepatitis C virus infection who have completed curative antiviral treatment and have a viral load below the limit of quantitation will be eligible
- Human immunodeficiency virus (HIV) infection with a current history of acquired immunodeficiency syndrome-defining illness or HIV infection with CD4+ T cell count < 350 cells/uL and HIV viral load more than 400 copies/uL
- Patients that are pregnant or lactating
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT04957615.
PRIMARY OBJECTIVES:
I. To estimate objective response rate (ORR) and overall survival (OS) in patients with ARID1A mutations receiving nivolumab and relatlimab combination therapy.
II. To estimate ORR and OS in patients with ARID1A mutations plus CXCL13-high expression and ARID1A mutations plus CXCL13-low expression receiving nivolumab and relatlimab combination therapy.
SECONDARY OBJECTIVES:
I. To estimate progression free survival (PFS) in patients harboring ARID1A mutations treated with nivolumab and relatlimab combination therapy.
II. To estimate PFS in patients with ARID1A mutations plus CXCL13-high expression and ARID1A mutations plus CXCL13-low expression treated with nivolumab and relatlimab combination therapy.
III. To determine predictors of response and resistance to nivolumab and relatlimab combination therapy in patients with ARID1A mutations, ARID1A mutations plus CXCL13-high expression, and ARID1A mutations plus CXCL13-low expression,, as assessed by peripheral and tumor-infiltrating immune cell subpopulations.
IV. To determine the expression pattern of CXCL13 in ARID1A mutant tumors.
OUTLINE:
Patients receive nivolumab and relatlimab intravenously (IV) over 30 minutes on day 1 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) or magnetic resonance imaging (MRI), tissue biopsy and blood sample collection during screening and on the trial.
After completion of study treatment, patients are followed up every 6 months.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationM D Anderson Cancer Center
Principal InvestigatorFunda Meric-Bernstam
- Primary ID2021-0207
- Secondary IDsNCI-2021-06371
- ClinicalTrials.gov IDNCT04957615