A Randomized, Pilot Study to Evaluate the Molecular and Cellular Response to Treatment with Nivolumab with either Adjuvant Ipilimumab or Relatlimab in Adult Patients with Surgically Resectable Melanoma Brain Metastases
The purpose of this pilot study is to determine the safety and feasibility of giving a single dose of Nivolumab with Ipilimumab or Relatlimab in participants with brain metastases from melanoma who can undergo surgery for removal of their brain metastases 7- 10 days after receiving the study drug.
Primary Objectives: To establish the safety and feasibility of doing surgical resection in patients with MBM in 7-10 days after initial treatment with a single dose of Nivo+Ipi or Nivo+Rela. To estimate the immune cell population differences among the treatment arms. Secondary Objectives: To characterize and compare the immune landscape in the MBM versus systemic disease, serum, and CSF. To evaluate the association between cellular compositions of the MBM TME and CNS clinical response (defined based on RANO-BM and i-RANO). To evaluate the association between cellular compositions of the MBM TME and extracranial clinical benefit and global clinical benefit rate (defined based on RECIST 1.1). To evaluate association between the immune landscape in the MBM and overall survival (OS), progression free survival (PFS), and adverse events (AE s) from ICI s.
Immunotherapy; Radiotherapy; Surgery
BMS-936558 (Nivolumab); BMS-986016 (Relatlimab); Ipilimumab (); Nivolumab (Opdivo); Radiotherapy (); Relatlimab (); Yervoy (Ipilimumab)
- Inclusion Criteria:
- Age 18 years old or older on day of signing the informed consent.
- Histological confirmation of systemic cancer from melanoma.
- Surgery for metastatic brain lesions (i.e., MBM) is needed but not imminent. Imminent defined as requiring emergent intervention. A multidisciplinary team, including at least a neurosurgeon, radiation-oncologist, and neuro-oncologist, will determine the appropriateness for resection via craniotomy and level of urgency for surgery of the MBM.
- Resectable metastatic brain lesions (i.e., MBM) in whom surgical resection is a reasonable therapeutic option. A resectable metastatic brain lesion is defined as a lesion that is ≥10 mm in size of longest diameter and in a location outside of the brainstem. (Other target lesions, i.e. those that are not resected but are followed for response, can be ≥5 mm). A multidisciplinary team, including at least a neurosurgeon, radiation-oncologist, and neuro-oncologist, will determine the appropriateness for resection via craniotomy and level of urgency for surgery of the MBM.
- Patient is on ≤3 mg/day dexamethasone or equivalent/day over pre-op period.
- Patient did not receive treatment with immunotherapy within 6 months prior to day 1 of treatment on study.
- No treatment with dabrafenib and/or trametinib (BRAF MEKi) for 1 month.
- MRI with enhancing metastatic brain lesions (i.e., MBM) amenable to resection of contrast-enhancing tumor (determined by neurosurgeon). A multidisciplinary team, including at least a neurosurgeon, radiation-oncologist, and neuro-oncologist, will determine the appropriateness for resection via craniotomy and level of urgency for surgery of the MBM.
- Patient willing to undergo craniotomy and resection.
- Patient eligible for surgery in the 7-10 days after initial treatment.
- Patients who had prior surgical resection of MBM are eligible to enroll.
- Usual acceptable lab parameters, demonstrating adequate organ function as defined in protocol. All screening labs should be performed within 21 days of treatment initiation.
- Resting baseline O2 saturation by pulse oximetry of 92% or higher at rest.
- Be willing and able to provide written informed consent for the trial.
- Willing to provide tissue and blood samples for correlative research purposes.
- Has ECOG Performance Status (PS) of 0, 1 or 2.
- Adequate seizure prophylaxis in the pre- and perioperative period.
- Prior whole Brain radiation therapy (WBRT), single fraction radiation therapy (e.g., SRS), or multiple fraction radiation therapy (e.g., fSRT) to the brain is permitted.
- A negative serum pregnancy test must be documented at the screening visit. Additionally, female patients must exhibit a negative urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of study drug, therefore the screening pregnancy test may need to be repeated prior to the start of study drug dosing. A urine pregnancy test can be used for this. A pre-dosing urine pregnancy test must be performed prior to each dose during study phase. A urine pregnancy test will also be conducted at End of Treatment Visit.
- Other inclusion criteria apply
- Exclusion Criteria:
- Patient is on > 3 mg of dexamethasone/day or equivalent/day
- Has a metastatic brain lesion (or all brain lesions) that is (are) unresectable. Unresectable defined as located in the brainstem or measuring > Has ECOG Performance Status of >2.
- Has clear evidence of leptomeningeal disease.
- Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment, or has not recovered (i.e., ≤ Grade 1 or at baseline) from AEs due to a previously administered agent.
- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. Physiologic doses of steroid therapy (≤ 3 mg/day dexamethasone equivalents) by the time of first dose of treatment are allowed.
- Has a known history of active Bacillus Tuberculosis.
- Hypersensitivity to either Nivolumab, Ipilimumab, or Relatlimab or any of its excipients.
- Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events (AEs) due to agents administered more than 4 weeks earlier.
- Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from AEs due to a previously administered agent. Note: Patients with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study. Note: If patient received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
- Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
- Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with the use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Patients with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Patients that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Patients with hypothyroidism stable on hormone replacement or Sjogren's syndrome will not be excluded from the study.
- Has a prior history of life-threatening toxicity related to prior immune therapy (i.e., anti-CTLA-4 or anti- PD-1/PD-L1 treatment or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways) except those that are unlikely to re-occur with standard countermeasures (i.e., hormone replacement after adrenal crisis).
- Has prior treatment with Relatlimab or any other LAG-3 targeted agent at least 6 months prior to signing informed consent.
- Other than the medications explicitly stated in the exclusion criteria or elsewhere in the protocol, other medications or prior treatments are allowed.
- Has known history of, or any evidence of active, interstitial lung disease or noninfectious pneumonitis requiring corticosteroid therapy.
- Has history of myocarditis
- Other exclusions apply
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