Neoadjuvant Immunotherapy in Brain Metastases
Condition: Brain Metastases, Adult
MeSH terms: Neoplasm Metastasis; Brain Neoplasms
Intervention: Nivolumab; Ipilimumab
Intervention description: Nivolumab will be given at the FDA-approved dose of 3 mg/kg.; Ipilimumab will be given at the FDA-approved dose of 1 mg/kg.
Intervention MeSH terms: Nivolumab; Ipilimumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 1.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Pro00103812; Sammons; Non-small-cell lung carcinoma; Renal cell carcinoma; Urothelial carcinoma; Melanoma; Ovarian carcinoma; Triple negative breast cancer; Solid tumor; Brain metastases; Nivolumab; Ipilimumab; Opdivo; Yervoy

Summary:

      The purpose of this phase 2 study is to assess the feasibility and efficacy of neoadjuvant
      immunotherapy in patients with previously untreated, surgically-resectable, solid tumor brain
      metastases. The primary objectives of this study are to 1) assess the feasibility of
      neoadjuvant ipilimumab and nivolumab treatment before surgery and stereotactic radiosurgery
      (SRS) in patients with solid tumor brain metastases as measured by the proportion of patients
      who have their surgery delayed or surgery never occurs, and 2) demonstrate that neoadjuvant
      immunotherapy will increase proliferation of circulating T-cells compared to baseline
      measurements. Exploratory objectives include describing patient progression free survival and
      overall survival, time to local and distant intracranial progression, and the rate of
      radiation necrosis. The rate of radionecrosis will also be explored, as immune expression
      profiles.
    

Eligibility criteria:

        Inclusion Criteria:

          -  1. Patients must have at least 1 previously untreated, solid tumor brain metastases
             that are ≤4 cm in the largest direction. At least one of the metastases must be
             surgically resectable. All metastases must be planned for treatment with SRS. Primary
             tumor histology must be one of the following:

               1. Squamous NSCLC

               2. Non-squamous NSCLC without known ALK, EGFR, and ROS mutation

               3. RCC

               4. Urothelial carcinoma

               5. Ovarian carcinoma

               6. Melanoma

               7. Triple negative breast cancer that is PD-L1 positive

               8. Other solid tumor histologies may be eligible at the discretion of the PI if they
                  are known to respond to immunotherapy containing regimens.

          -  2. Patient must be asymptomatic or minimally symptomatic, requiring the equivalent of
             ≤ 4 mg dexamethasone daily for at least 7 days prior to enrollment

          -  3. Patient or partner(s) meets one of the following criteria:

               1. Non-childbearing potential (i.e. not sexually active, physiologically incapable
                  of becoming pregnant, including any female who is post-menopausal or surgically
                  sterile, or any male who has had a vasectomy). Surgically sterile females are
                  defined as those with a documented hysterectomy and/or bilateral oophorectomy or
                  tubal ligation. Postmenopausal for purposes of this study is defined as 1 year
                  without menses.; or

               2. Childbearing potential and agrees to use one of the following methods of birth
                  control: approved hormonal contraceptives (e.g. birth control pills, patches,
                  implants, or infusions), an intrauterine device, or a barrier method of
                  contraception (e.g. a condom or diaphragm) used with spermicide.

          -  4. Age ≥ 18 years of age at the time of entry into the study

          -  5. Karnofsky Performance Score (KPS) ≥ 70

          -  6. Prothrombin and Partial Thromboplastin Times ≤ 1.2 x normal prior to resection

          -  7. Neutrophil count ≥ 1000 prior to resection

          -  8. Hemoglobin ≥ 9 g/dl prior to resection

          -  9. Platelet count ≥ 100,000/µl unsupported is necessary for eligibility on the study;
             however, because of risks of intracranial hemorrhage during resection, platelet count
             ≥ 125,000/µl is required for the patient to undergo resection, which can be attained
             with the help of platelet transfusion

          -  10. Creatinine ≤ 1.5 x ULN (upper limit of normal) prior to resection

          -  11. A signed informed consent form approved by the Institutional Review Board (IRB)
             will be required for patient enrollment into the study. Patients must be able to read
             and understand the informed consent document and must sign the informed consent
             indicating that they are aware of the investigational nature of this study

          -  12. Ability to undergo MRI

        Exclusion Criteria:

          -  1. Females who are pregnant or breast-feeding

          -  2. Patients with an impending, life-threatening cerebral herniation syndrome, based on
             the assessment of the study neurosurgeons or their designate

          -  3. Patients with severe, active co-morbidity, defined as follow:

               1. Patients with an active infection requiring intravenous treatment or having an
                  unexplained febrile illness (Tmax > 99.5°F/37.5°C)

               2. Patients with known immunosuppressive disease or known uncontrolled human
                  immunodeficiency virus infection

               3. Patients with unstable or severe intercurrent medical conditions such as severe
                  heart disease (New York Heart Association Class 3 or 4)

          -  4. Patients who have not recovered from the toxic effects of prior chemo- and/or
             radiation therapy. Guidelines for this recovery period are dependent upon the specific
             therapeutic agent being used:

          -  5. Patients must not have received immunotherapy within 3 months prior to enrollment

          -  6. Patients with prior, unrelated malignancy requiring current active treatment in the
             last 3 years with the exception of cervical carcinoma in situ and adequately treated
             basal cell or squamous cell carcinoma of the skin

          -  7. Patients with a known history of hypersensitivity to nivolumab, or any components
             of nivolumab

          -  8. Patients with a known history of hypersensitivity to ipilimumab, or any components
             of ipilimumab

          -  9. Patients with active autoimmune disease requiring systemic immunomodulatory
             treatment within the past 3 months.

          -  10. History and/or confirmed pneumonitis, or extensive bilateral lung disease on high
             resolution/spiral CT scan.