Nivolumab in Combination with Relatlimab in Treating Patients with Active Melanoma Brain Metastases
This phase II trial studies how well nivolumab/relatlimab-rmbw (nivolumab in combination with relatlimab) works in treating patients with melanoma that has spread from where it first started (primary site) to the brain (brain metastases). Nivolumab/relatlimab-rmbw is a fixed-dose formulation of two drugs, nivolumab and relatlimab-rmbw. Nivolumab is a monoclonal antibody directed against a receptor expressed on certain cancer cells called PD-1. Nivolumab binds to and blocks activation of PD-1, preventing the inhibition of the immune system and interfering with the ability of tumor cells to grow and spread. Immunotherapy with monoclonal antibodies, such as relatlimab-rmbw, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving nivolumab and relatlimab-rmbw together in a fixed-dose formulation may work to re-activate the immune system and reduce tumor growth in patients with melanoma brain metastases.
Inclusion Criteria
- Age >= 18 years old
- Life expectancy > 12 weeks
- Subjects must have signed and dated an institutional review board (IRB)/ independent ethics committees (IEC) approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol related procedures that are not part of normal subject care. * Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study
- Histologically confirmed malignant melanoma with measurable metastases in the brain (>= 0.5 cm)
- At least one measurable intracranial target lesion, which previously was not treated with local therapy (no prior stereotactic radiosurgery [SRS] to this lesion) * Largest diameter of >= 0.5cm, but =< 3cm as determined by contrast-enhanced MRI
- Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin blocks (blocks are preferred) OR at least 4 unstained slides, with an associated pathology report, for testing of tumor PD-L1 expression: * Tumor tissue should be of good quality based on total and viable tumor content * Patients who do not have tissue specimens may undergo a biopsy during the screening period. Acceptable samples include core-needle biopsies for deep tumor tissue or excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or mucosal lesions. Fine needle aspirations (FNA) will not be considered acceptable for tissue procurement * Tumor tissue from bone metastases is not evaluable for PD-L1 expression and is therefore not acceptable * However, if repeat biopsy is not feasible, and no archival tissue available patient still may be enrolled
- Prior SRT and prior excision of up to 5 MBM is permitted if there has been complete recovery, with no neurologic sequelae, and measurable non irradiated lesions remain
- Growth or change in a lesion previously irradiated will not be considered measurable. Regrowth in cavity of previously excised lesion will not be considered measurable * Any prior SRT to brain lesions or prior excision must have occurred >= 1 weeks before the start of dosing for this study
- Radiation to non-central nervous system (CNS) lesions. Prior radiation to non-CNS is allowed and does not require a washout period for treatment initiation
- Subjects must be free of neurologic signs and symptoms related to metastatic brain lesions and must not have required or received systemic corticosteroid therapy in the 5 days prior to beginning protocol therapy
- Eastern Cooperative Oncology Group (ECOG) performance status =< 1
- Absolute neutrophil count (ANC) >= 1.5 X 109/L
- Platelets >= 100 X 109/L (>= 60 for hepatocellular carcinoma [HCC])
- Hemoglobin >= 8.0 g/dL
- Creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 40 mL/min for participant with creatinine levels > 1.5 x institutional ULN
- Total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for participants with total bilirubin levels > 1.5 x ULN
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x ULN (=< 5 x ULN for participants with liver metastases)
- International normalized ratio (INR) OR prothrombin time (PTT) =< 1.5 x ULN unless participant is receiving anticoagulant therapy as long as prothrombin time (PT) or activated partial thromboplastin time (aPTT) is within therapeutic range of intended use of anticoagulants
- Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants
- Women of child-bearing potential (WOCBP) must not be breastfeeding and must have a negative pregnancy test within 3 days prior to initiation of dosing. She must agree to use an acceptable method of birth control from the time of the negative pregnancy test, through the duration of treatment with the study combination plus 5 half lives of study treatment for a total of 5 months post -treatment completion. WOCBP must agree to adhere to the contraceptive guidance. * NOTE: A female participant is eligible to participate if she is not a woman of childbearing potential
- All associated toxicity from previous or concurrent cancer therapy must be resolved (to =< grade 1 or baseline) prior to study treatment administration. This excludes non-serious toxicities. However, stable endocrinopathies requiring replacement therapy will be allowed
- Steroids for physiological replacement are allowed
Exclusion Criteria
- History of known leptomeningeal involvement (lumbar puncture not required)
- Previous stereotactic or highly conformal radiotherapy within 1 weeks before the start of dosing for this study * NOTE: The stereotactic radiotherapy field must not have included the brain index lesion(s)
- Subjects previously treated with SRT > 5 lesions in the brain. Prior whole brain radiation is not allowed
- Brain lesion size > 3 cm
- Prior checkpoint inhibitor therapy in the metastatic setting * Patients who received ipilimumab and/or anti-PD1 as adjuvant or neoadjuvant therapy must have a 6-month washout before receiving any dosing on this study
- Subjects with an active, known or suspected autoimmune disease. Subjects with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll
- Subjects with major medical, neurologic or psychiatric condition who are judged as unable to fully comply with study therapy or assessments should not be enrolled
- Subject has a history of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years. Note: The time requirement does not apply to participants who underwent successful treatment of superficial bladder cancer, in situ cervical cancer, or other in-situ cancers. Subjects with a completely treated prior malignancy and no evidence of disease for >= 2 years are eligible * Skin cancer exclusion: Please note that basal cell carcinoma and squamous cell carcinoma is exempt from needing resection prior to treatment. (Resection can be completed after the start of treatment)
- Has a known history of or is positive for hepatitis B (hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected) * NOTE: Without known history, testing needs to be performed to determine eligibility. Hepatitis C antibody (Ab) testing is allowed for screening purposes in countries where HCV RNA is not part of standard of care
- Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority
- The use of corticosteroids is not allowed for 10 days prior to initiation of therapy (based upon 5 times the expected half-life of dexamethasone) except patients who are taking steroids for physiological replacement. If alternative corticosteroid therapy has been used, consultation with the principal investigator (PI) is required to determine the washout period prior to initiating study treatment
- Subjects with a condition requiring systemic treatment with either corticosteroids (=< 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of study initiation. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease
- Major surgical procedure, open biopsy (excluding skin cancer resection), or significant traumatic injury within 14 days of initiating study drug (unless the wound has healed) or anticipation of the need for major surgery during the study
- Non-healing wound, ulcer, or bone fracture
- Women who are breast-feeding or pregnant
- Uncontrolled intercurrent illness (i.e., active infection >= grade 2) or concurrent condition that, in the opinion of the investigator, would interfere with the study endpoints or the subject's ability to participate
- History of clinically significant cardiac disease or congestive heart failure > New York Heart Association (NYHA) class 2. Subjects must not have unstable angina (anginal symptoms at rest) or new-onset angina within the last 3 months or myocardial infarction within the past 6 months or a history of myocarditis
- Troponin T (TnT) or I (TnI) > 2 x institutional ULN. Participants with TnT or TnI levels between > 1 to 2 x ULN will be permitted if repeat levels within 24 hours are =< 1 ULN. If TnT or TnI levels are between > 1 to 2 x ULN within 24 hours, the participant may undergo a cardiac consultation and be considered for treatment, following cardiologist recommendation. When repeat levels within 24 hours are not available, a repeat test should be conducted as soon as possible. If TnT or TnI repeat levels beyond 24 hours are < 2 x ULN, the participant may undergo a cardiac consultation and be considered for treatment, following cardiologist recommendation. Notification of the decision to enroll the participant following cardiologist recommendation has to be made to the principal investigator
- Investigational drug use within 14 days (or 5 half-lives, whichever is longer) of the first dose of nivolumab and relatlimab
- With a history of non-infectious pneumonitis that required steroids or current pneumonitis
Additional locations may be listed on ClinicalTrials.gov for NCT05704647.
Locations matching your search criteria
United States
Texas
Houston
PRIMARY OBJECTIVE:
I. To assess the intracranial objective response rate (iORR), defined as intracranial complete response (CR) + partial response (PR) per modified-Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria, of nivolumab/relatlimab-rmbw (nivolumab + relatlimab) (nivo+rela) in subjects with melanoma brain metastases (MBM) who are treatment naive to anti-PD-1 agents in the metastatic setting.
SECONDARY OBJECTIVES:
I. To determine the safety of the combination of nivo+rela.
II. To assess the clinical benefit rate (CBR), defined as CR + PR + stable disease (SD) > 6 months, of the combination.
III. To determine overall response rates (intracranial + extracranial), duration of response (DoR), progression free survival (PFS), and using a modified version of Immunotherapy Response Assessment for Neuro-Oncology (iRANO) and compared to modified RECIST version (v)1.1 and Response Assessment in Neuro-oncology – Brain Metastases (RANO-BM) for patients treated with nivo+rela.
IV. To determine the 1-year intracranial progression-free survival rate for the combination of nivo+rela.
V. To determine overall survival.
VI. Advanced magnetic resonance imaging (MRI) imaging to assess for edema, tumor response, and predictors of response and radiation necrosis.
VII. To evaluate the brain-specific safety and tolerability of the combination regimen in subjects with or without stereotactic radiation therapy (SRT) received prior to study entry, or on study.
VIII. To evaluate changes in neurocognitive function and health-related quality of life.
IX. To assess available tumor tissue – intracranial and/or extra cranial – in specimens obtained at baseline (archival and/or fresh tissue), on treatment, and at time of progression.
X. To assess immune cell subsets by flow cytometry, T-cell receptors (TCR) next-generation sequencing (NGS) for diversity and clonality, cytokine expression, cell-free deoxyribonucleic acid (cfDNA) from peripheral blood.
EXPLORATORY OBJECTIVES:
I. Radiotherapy-assisted progression-free survival (PFS) defined as time from study treatment initiation to the first occurrence of disease progression or death from any cause, whichever occurs first, as determined by the investigator according to RECIST v1.1 modified by excluding =< 5 lesions that can be treated by SRT from the sum of largest diameters from baseline onwards.
II. To explore the association between baseline and on-treatment gut microbiome features with response and toxicity.
III. To understand the association between habitual diet and gut microbiome features in this study population.
IV. To explore predictors of biological response through the change in metabolic parameters.
OUTLINE:
Patients receive nivolumab/relatlimab-rmbw intravenously (IV) for 25 cycles on study. Patients undergo MRI, computed tomography (CT) and/or positron emission tomography (PET)-CT throughout the study. Patients also undergo blood and stool sample collection and may undergo tissue biopsy throughout the study.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationM D Anderson Cancer Center
Principal InvestigatorHussein Abdul-Hassan Tawbi
- Primary ID2021-1203
- Secondary IDsNCI-2023-00571
- ClinicalTrials.gov IDNCT05704647