Clinical Trial 18068

Cancer Type: Neurologic Oncology
Interventions:BMS-936558 (Nivolumab); Ipilimumab; Nivolumab; Yervoy (Ipilimumab)

Study Type: Treatment
Phase of Study: Phase II


    Study Title

    A Multi-Center Phase 2 Open-Label Study to Evaluate Safety and Efficacy in Subjects with Melanoma Metastatic to the Brain treated with Nivolumab in Combination with Ipilimumab followed by Nivolumab Monotherapy


    The purpose of this study is to give participants an opportunity to receive treatment with an investigational drug called nivolumab (also known as BMS-936558) in combination with ipilimumab (YERVOY) followed by nivolumab monotherapy.


    Primary Objective: * To assess the CNS clinical benefit rate (CBR, defined as complete response [CR] + partial response [PR] + stable disease [SD] > 6 months per protocol defined response criteria) in subjects with melanoma metastatic to the brain treated with nivolumab combined with ipilimumab followed by nivolumab monotherapy. Secondary Objectives: * To assess the extracranial clinical benefit rate defined as CR+PR+SD >6 months (per RECIST 1.1 criteria). * To assess the global clinical benefit rate (CBR), defined as CR+PR+SD >6 months CNS plus extracranial(per RECIST 1.1 with modifications). * To assess the CNS, extracranial, and global CBR per irRC (immune-related Response Criteria). * To assess overall survival (OS). * To evaluate the CNS-specific safety and tolerability of the combination regimen in patients with or without stereotactic radiotherapy (SRT) received prior to study entry, or on study. Exploratory Objectives: * To evaluate the overall safety and tolerability of the combination regimen in patients with or without stereotactic radiotherapy (SRT) received prior to study entry, or on study. * To evaluate association between baseline pathologic features of primary cutaneous melanoma (e.g., regression, ulceration, pattern and components of immune infiltrate) and CBR endpoints. * To explore potential biomarkers associated with clinical response to nivolumab combined with ipilimumab by analyzing tumor tissue specimens for proteins including, but not limited to, PD-1, PD-L1, and other markers related to immune cell populations involved in regulating immune responses in comparison to clinical outcomes. * To evaluate association between BRAF/NRAS mutation status and response endpoints. * To compare tissue biomarker profiles between paired tissues from extracranial and brain metastases from individual patients, where available; if possible this analysis will also be applied for sample sets that include a primary, an extracranial metastasis and a brain metastasis from the same patient. * To assess peripheral blood immune cell subpopulations (which may include but is not limited to CD4+ Tcell, CD8+ T-cell, Treg, NK, B-cell, MDSC, activated T-cells, memory/exhausted T-cells) and serum soluble factors with changes in post-treatment profiles as they relate to clinical endpoints and/or the occurrence of adverse events. * To assess the effects of natural genetic variation (SNPs) in select genes including, but not limited to, PD-1, PD-L1, PD-L2, and CTLA-4 on clinical endpoints and/or on the occurrence of adverse events. * To estimate the incidence of MRI-defined brain edema, hemorrhage and increase in tumor size before regression (pseudoprogression) in the brain metastases and to evaluate any association with the onset and/or clinical benefit rate (CR+ PR+SD >6 mo.) observed in the brain or non-CNS. * To compare computer-assisted tumor volume from three dimensional (3D) MRI to bi-dimensional measures with respect to absolute values and percent change from baseline.

    Inclusion Criteria

  • Histologically confirmed malignant melanoma with measurable metastases in both brain and extracranial compartments.
  • At least 1 measurable brain metastasis ≥ 0.5 cm in longest diameter and ≤ 3 cm in longest diameter that has not been previously irradiated. No clinical requirement for local intervention (surgery, radiosurgery, corticosteroid therapy) or other systemic therapy.
  • Prior therapy, if given, limited to stereotactic radiotherapy and prior excision of a single melanoma brain metastasis if there has been complete recovery and there are no neurologic sequelae. 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.
  • Must have tissue available from a prior biopsy of an extracranial metastasis for biomarker analysis. Biopsy should be excisional, incisional, (these are prioritized sample types), punch, or core needle. Fine needle aspirates or other cytology samples are not allowable. The prior biopsy material provided should be obtained after the most recent prior systemic therapy, when available, so that the biopsy is representative of the baseline state prior to entry into the present study.
  • 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 10 days prior to beginning protocol therapy.
  • Allowable prior therapy: Approved adjuvant regimen, which may include molecularly-targeted agent(s) and Interferon (IFN-α). For advanced disease, only prior cytokine therapy, defined as interleukin-2 at any dose and/or IFN-α (any formulation) within 6 months prior to study enrollment. Must have recovered fully from the sequelae of any prior therapy and be at least 3 weeks past the last exposure to any prior radiotherapy or allowable systemic therapy. Treatment with prior ipilimumab and any PD-1/pharmacodynamics (PD-L1) inhibitor is not allowed.
  • Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
  • Other protocol defined inclusion criteria could apply

  • Exclusion Criteria

  • History of known leptomeningeal involvement (lumbar puncture not required).
  • Previous stereotactic or highly conformal radiotherapy within 3 weeks before the start of dosing for this study. Note: the stereotactic radiotherapy field must not have included the brain index lesion/s.
  • Number of Central nervous system (CNS) lesions previously treated with stereotactic radiotherapy (SRT) is >3.
  • History of whole brain irradiation.
  • Autoimmune disease: potential participants with a documented history of inflammatory bowel disease, including ulcerative colitis and Crohn's disease are excluded from study treatment as are potential participants with a history of symptomatic disease (e.g., rheumatoid arthritis, systemic progressive sclerosis [scleroderma], Systemic Lupus Erythematosus, autoimmune vasculitis [e.g., Granulomatosis with polyangiitis (formerly Wegener's)], and sarcoidosis including interferon-induced sarcoidosis. Potential participants with motor neuropathy considered of autoimmune origin (e.g., Guillain-Barre Syndrome and Myasthenia Gravis) are excluded from study treatment.
  • Major medical, neurologic or psychiatric condition who are judged as unable to fully comply with study therapy or assessments.
  • Any concurrent malignancy other than non-melanoma skin cancer or carcinoma in situ of the cervix. For any prior invasive malignancy, at least 5 years must have elapsed since curative therapy and patients must have no residual sequelae of prior therapy.
  • 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). If alternative corticosteroid therapy has been used, consultation with the sponsor Medical Monitor is required to determine the washout period prior to initiating study treatment.
  • Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection.
  • Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) even if fully immunocompetent on ART - due to the unknown effects of HIV on the immune response to combined nivolumab plus ipilimumab or the unique toxicity spectrum of these drugs in patients with HIV.
  • History of allergy to study drug components.
  • History of severe hypersensitivity reaction to any monoclonal antibody.
  • Other protocol defined exclusion criteria could apply