An Investigational Immuno-therapy Study to Evaluate Safety and Effectiveness in Patients With Melanoma That Has Spread to the Brain, Treated With Nivolumab in Combination With Ipilimumab, Followed by Nivolumab by Itself

Not Recruiting

Trial ID: NCT02320058


This is a study of Nivolumab combined with Ipilimumab followed by Nivolumab by itself for the treatment of patients with Melanoma that has spread to the brain. Patients with histologically confirmed Malignant Melanoma and asymptomatic brain metastases are eligible for the study.

Official 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

Stanford Investigator(s)

Reena Thomas, MD PhD
Reena Thomas, MD PhD

Clinical Associate Professor, Neurology & Neurological Sciences Clinical Associate Professor (By courtesy), Neurosurgery


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Inclusion Criteria:

1. Target Population

   1. Histologically confirmed malignant melanoma with measurable metastases in the brain.
   Both asymptomatic and symptomatic patients.

   2. Cohort A (asymptomatic patients): At least 1 measurable brain metastasis ≥ 0.5 cm in
   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

   Cohort B (symptomatic patients): Subjects with neurologic signs and symptoms related
   to metastatic brain lesions are eligibile. Subjects must have at least 1 measurable
   brain metastasis ≥ 0.5 cm in and ≤ 3 cm in longest diameter that has not been
   previously irradiated. No immediate requirement (within 3 weeks prior to first
   treatment) for local intervention (surgery, radiosurgery, corticosteroid therapy).
   Steroid use is permitted as defined in the protocol.

   3. Prior stereotactic radiotherapy (SRT) and prior excision of up to 3 melanoma brain
   metastases is permitted if there has been complete recovery, with no neurologic
   sequelae, and measurable 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. lesions or prior excision must have occurred
   ≥ 3 weeks before the start of dosing for this study

   4. Must have tumor tissue available for biomarker analysis. Biopsy should be excisional,
   incisional, punch, or core needle

   5. Cohort A (asymptomatic): Subjects must be free of neurologic signs and symptoms
   related to metastatic brain lesions and must not have required or received systemic
   corticosteroid therapy within 10 days prior to first treatment.

   Cohort B (symptomatic): Subjects with neurologic signs and symptoms related to
   metastatic brain lesions are eligible per Amendment 02. Subjects with neurologic signs
   and symptoms may be treated with a total daily dose of no more than 4 mg of
   dexamethasone that is stable or tapering for 10 days prior to first treatment.
   Subjects with neurologic signs and symptoms who are not being treated with steroids
   are eligible for Cohort B and should have no experience of seizure within 10 days
   prior to first treatment.

   6. Allowable prior therapy:

      1. Approved adjuvant therapies, which may include molecularly-targeted agents, IFN
      α, and ipilimumab. Patients who received ipilimumab as adjuvant therapy must have
      a 6 month washout before receiving any dosing on this study

      2. For advanced disease, interleukin-2 at any dose and/or IFN-α (any formulation, no
      washout required); MEK and BRAF inhibitors: washout for at least 4 weeks prior to
      the start of dosing in this study

      3. Steroids for physiological replacement are allowed.

   7. Cohort A (asymptomatic): ECOG performance status ≤1 Cohort B (symptomatic): ECOG
   performance status ≤2

Exclusion Criteria:

2. Target Disease Exceptions

   1. History of known leptomeningeal involvement (lumbar puncture not required)

   2. 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)

   3. Brain lesions >3 lesions which were previously treated with SRT

   4. Brain lesion size > 3cm 3. Medical History and Concurrent Diseases

a) History of whole brain irradiation b) Subjects with an active, known or suspected
autoimmune disease c) 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 d) 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 e)
Cohort A (asymptomatic): The use of corticosteroids is not allowed within 10 days prior to
first treatment (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 sponsor Medical Monitor is
required to determine the washout period prior to initiating study treatment Cohort B
(symptomatic): Subjects with neurologic sign and symptoms related to brain metastases who
are being treated with a total daily dose of higher than 4 mg dexamethasone or equivalent
within 10 prior to the start of treatment with study drug are excluded.

4. Physical and Laboratory Test Findings

   1. Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus
   ribonucleic acid (HCV antibody) indicating acute or chronic infection

   2. 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

   5. Allergies and Adverse Drug Reaction

a) History of allergy to study drug components b) History of severe hypersensitivity
reaction to any monoclonal antibody

6. Other Exclusion Criteria

   1. Prisoners or subjects who are involuntarily incarcerated

   2. Subjects who are compulsorily detained for treatment of either a psychiatric or
   physical (e.g., infectious disease) illness Eligibility criteria for this study have
   been carefully considered to ensure the safety of the study subjects and that the
   results of the study can be used. It is imperative that subjects fully meet all
   eligibility criteria

Other protocol defined inclusion/exclusion criteria could apply


drug: Ipilimumab

drug: Nivolumab

Not Recruiting

Contact Information

Stanford University
School of Medicine
300 Pasteur Drive
Stanford, CA 94305

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