Nivolumab with Ipilimumab or Relatlimab for the Treatment of Brain Metastasis in Patients with Melanoma Undergoing Surgery
This early phase I trial tests the safety and effectiveness of a single dose of nivolumab with ipilimumab or nivolumab with relatlimab (Opdualag) in treating patients undergoing surgery for melanoma that has spread to the brain from where it first started (metastatic). Melanoma that has spread to the brain is difficult to treat and tends to come back after treatment. Melanoma brain metastasis is a major cause of morbidity and mortality. The current standard of care is to do surgery to remove the cancer or undergo stereotactic radiosurgery which uses special equipment to position a patient and deliver radiation to cancers with high precision. This method may kill tumor cells with fewer doses over a shorter period and cause less damage to normal tissue. Immunotherapy with monoclonal antibodies, such as nivolumab, ipilimumab and relatlimab, 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 combined with ipilimumab or relatlimab before surgery may delay progression and improve survival.
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
- Resting baseline oxygen (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 Eastern Cooperative Oncology Group (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., fractionated stereotactic radiation therapy [fSRT]) to the brain is permitted
- A negative serum pregnancy test must be documented at the screening visit. Additionally, female subjects must exhibit a negative urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotroprin [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
- Female subjects of childbearing potential must be willing to use an adequate method of contraception. Contraception, for the duration of treatment and an additional 5 months after the last dose of the study drug. Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
- Male subjects of childbearing potential who are sexually active with women of child bearing potential do not require contraception
- Patients with a left ventricular ejection fraction (LVEF) >= 50% within the last 6 months prior to start of study treatment. If Patient’s LVEF < 50% they can be re-assessed. If an LVEF assessment has not been completed within the last 6 months it would require an LVEF assessment
- White blood cell (WBC) >= 2,000/mcL (performed within 21 days of treatment initiation)
- Absolute neutrophil count (ANC) >= 1,500/mcL (performed within 21 days of treatment initiation)
- Platelets >= 100,000/mcL (performed within 21 days of treatment initiation)
- Hemoglobin >= 9 g/dL (performed within 21 days of treatment initiation) * Must be stable without active bleeding or hemolysis, AND * Without transfusion or erythropoietin dependency for 14 days prior to initiation of trial therapy
- Serum creatinine OR measured or calculated* creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrC l]): Calculated creatinine clearance >= 40 mL/min (using the Cockcroft-Gault formula) (performed within 21 days of treatment initiation) * Creatinine clearance should be calculated per institutional standard
- Serum total bilirubin =< 1.5 X upper limit of normal (ULN) (performed within 21 days of treatment initiation) * Except subjects with Gilbert syndrome who must have a total bilirubin level of < 3.0 X ULN or < 2.5 mg/dL OR * Direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 1.5 X ULN (performed within 21 days of treatment initiation)
- International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants (performed within 21 days of treatment initiation)
- Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants (performed within 21 days of treatment initiation)
- Left ventricular ejection fraction (LVEF) assessment with documented LVEF 50% or higher CT within 6 months prior to start of study treatment.
Exclusion Criteria
- Age < 18 years old
- 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 < 10 mm in longest diameter. Note, subjects with multiple metastatic brain lesions that include non-targetable lesions of < 10 mm are allowed to enroll in the study as long as they have at least 1 lesion that is >= 10 mm in size of longest diameter
- Has ECOG PS 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 TB (bacillus tuberculosis)
- Hypersensitivity to either Nivo, Ipi, or Rela 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 adverse events (AEs) due to a previously administered agent * Note: Subjects with =< grade 2 neuropathy are an exception to this criterion and may qualify for the study * Note: If subject 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. Subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Subjects 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 Rela 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
- Has documented LVEF < 50% within 6 months prior to start of study treatment and unable to be re-assessed with an LVEF >= 50%
- Has an active infection requiring systemic therapy
- Had major surgical procedure, open biopsy, or significant traumatic injury within 21 days prior to day 1 of treatment on study
- Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
- Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
- Is pregnant, breastfeeding, or expecting to conceive children within the projected duration of the trial, starting with the pre-screening or screening visit through 5 months after the last dose of study drug. Subjects must not have a positive pregnancy test at enrollment or prior to administration of study medication. Male subjects of childbearing potential who are sexually active with women of child bearing potential do not require contraception
- Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-LAG-3 agent within 6 months prior to day 1 of treatment on study
- Patients with prior focal (SRS or fSRT) radiation to the lesion planned for resection will be excluded from the study, as distinguishing radiation necrosis from progression cannot be definitely performed until after surgery
- Has a known history of a positive test for human immunodeficiency virus (HIV) (HIV 1/2 antibodies), or known acquired immunodeficiency syndrome (AIDS). NOTE: Testing for HIV must be performed at sites where mandated locally
- Has known active hepatitis B (e.g., hepatitis B virus HBsAg surface protein antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected). Subjects must not have any positive test result for hepatitis B virus or hepatitis C virus indicating presence of virus, eg, hepatitis B surface antigen (HBsAg, Australia antigen) positive, or hepatitis C antibody (anti-HCV) positive (except if HCV-RNA negative)
- Has received a live/attenuated vaccine within 30 days of first treatment. Inactivated vaccines are permitted
- Has received treatment with botanical preparations (e.g., herbal supplements or traditional Chinese medicines) intended for general health support or to treat the disease under study within 2 weeks prior to treatment
- Participants must not be prisoners or involuntarily incarcerated
- Participants must not be compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT05704933.
PRIMARY OBJECTIVES:
I. To establish the safety and feasibility of doing surgical resection in patients with melanoma brain metastases (MBM) in 7-10 days after initial treatment with a single dose of nivolumab (Nivo)+ipilimumab (Ipi) or Opdualag (Nivo+relatlimab [Rela]).
II. To estimate the immune cell population differences among the treatment arms.
SECONDARY OBJECTIVES:
I. To characterize and compare the immune landscape in the MBM versus systemic disease, serum, and cerebral spinal fluid (CSF).
II. To evaluate the association between cellular compositions of the MBM tumor microenvironment (TME) and central nervous system (CNS) clinical response (defined based on Response Assessment in Neuro-Oncology Brain Metastases [RANO-BM] and immunotherapy [i]-RANO).
III. To evaluate the association between cellular compositions of the MBM TME and extracranial clinical benefit and global clinical benefit rate (defined based on Response Evaluation Criteria in Solid Tumors [RECIST] 1.1).
IV. To evaluate association between the immune landscape in the MBM and overall survival (OS), progression free survival (PFS), and adverse events (AE’s) from immune checkpoint inhibitors (ICI’s).
OUTLINE: Patients are randomized into 1 of 3 arms.
ARM I: Patients receive nivolumab intravenously (IV) and ipilimumab IV pre-surgery and undergo standard of care surgical resection on study. Patients receive either stereotactic radiosurgery (SRS) or fractionated stereotactic radiosurgery (fSRS) post-surgery then receive nivolumab IV and ipiliumab IV post radiation therapy. Patients also undergo lumbar puncture and blood sample collection during screening and on study, as well as standard of care brain magnetic resonance imaging (MRI) and computed tomography (CT) throughout study. Patients may also undergo biopsy of systemic disease at time of surgical resection.
ARM II: Patients receive Opdualag IV pre-surgery and undergo standard of care surgical resection on study. Patients receive either SRS or fSRS post-surgery then receive nivolumab IV and ipiliumab IV post radiation therapy. Patients also undergo lumbar puncture and blood sample collection during screening and on study, as well as standard of care brain MRI and CT throughout study. Patients may also undergo biopsy of systemic disease at time of surgical resection.
ARM III: Patients undergo standard of care surgical resection on study. Patients receive either SRS or fSRS post-surgery then receive nivolumab IV and ipiliumab IV post radiation therapy. Patients also undergo lumbar puncture and blood sample collection during screening and on study, as well as standard of care brain MRI and CT throughout study. Patients may also undergo biopsy of systemic disease at time of surgical resection.
Trial PhasePhase O
Trial Typetreatment
Lead OrganizationMoffitt Cancer Center
Principal InvestigatorPeter A.J. Forsyth
- Primary IDMCC-21273
- Secondary IDsNCI-2023-00993
- ClinicalTrials.gov IDNCT05704933