Clinical Trials /

Neoadjuvant Immunotherapy in Brain Metastases

NCT04434560

Description:

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, the rate of radiation necrosis, and differences in immune expression profiles between patient arms.

Related Conditions:
  • Breast Carcinoma
  • Malignant Solid Tumor
  • Melanoma
  • Non-Squamous Non-Small Cell Lung Carcinoma
  • Ovarian Carcinoma
  • Renal Cell Carcinoma
  • Squamous Cell Lung Carcinoma
  • Urothelial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Neoadjuvant Immunotherapy in Brain Metastases
  • Official Title: A Randomized Phase II Trial of Surgery and Stereotactic Radiosurgery With and Without Neoadjuvant Nivolumab and Ipilimumab in Patients With Surgically-resectable, Solid Tumor Brain Metastases

Clinical Trial IDs

  • ORG STUDY ID: Pro00103812
  • SECONDARY ID: CA184-583
  • NCT ID: NCT04434560

Conditions

  • Brain Metastases, Adult

Interventions

DrugSynonymsArms
NivolumabOpdivoArm with checkpoint
IpilimumabYervoyArm with checkpoint

Purpose

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, the rate of radiation necrosis, and differences in immune expression profiles between patient arms.

Detailed Description

      Forty patients planned for standard of care resection of at least one solid tumor brain
      metastasis will be enrolled onto the study after providing informed consent. Primary tumor
      histology types are restricted to those known to extracranially respond to immunotherapy, and
      will include, but not be limited to, squamous non-small cell lung cancer (NSCLC),
      non-squamous NSCLC that is anaplastic lymphoma kinase positive (ALK+), epidermal growth
      factor receptor positive (EGFR+), and ROS negative, renal cell carcinoma (RCC), melanoma that
      is v-raf murine sarcoma viral oncogene homolog B1 negative (BRAF -), and triple negative
      breast cancer (TNBC) that is programmed death-ligand 1 positive (PD-L1 +). Participants will
      be randomized 1:1 (20 participants per arm) to either the neoadjuvant immunotherapy (arm 1)
      or standard of care (no neoadjuvant immunotherapy; arm 2). Patients in arm 1 will receive a
      single infusion of nivolumab at a dose of 3 mg/kg and ipilimumab at a dose of 1 mg/kg 7 days
      (±3 days) prior to surgical resection of their metastases. Approximately three weeks after
      resection, patients in both arms will then receive SRS per standard of care guidelines. After
      SRS, patients will continue on a maintenance treatment with an immunotherapy regimen at the
      discretion of the treating physician. Patients will be followed for up to 18 months after
      initiating study treatment.
    

Trial Arms

NameTypeDescriptionInterventions
Arm with checkpointExperimentalArm 1 (arm with checkpoint) will receive a single dose of neoadjuvant nivolumab and ipilimumab 7 days (± 3 days) prior to surgical resection.
  • Nivolumab
  • Ipilimumab
Arm without checkpointNo InterventionArm 2 (control arm without checkpoint) will proceed straight to surgical resection with no nivolumab/ipilimumab given prior to surgery.

    Eligibility Criteria

            Inclusion Criteria:
    
              -  1. Patients must have 1 to 3 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 that is ALK, EGFR, and ROS negative
    
                   3. RCC
    
                   4. Urothelial carcinoma
    
                   5. Ovarian carcinoma
    
                   6. Melanoma that is BRAF negative
    
                   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
                      there are plans to proceed onto a maintenance regimen including a standard of
                      care regimen with immunotherapy
    
              -  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 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 on the equivalent of > 4 mg of dexamethasone ≤ 7 days before receiving
                 study treatment
    
              -  7. 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
    
              -  8. Patients with a known history of hypersensitivity to nivolumab, or any components
                 of nivolumab
    
              -  9. Patients with a known history of hypersensitivity to ipilimumab, or any components
                 of ipilimumab
    
              -  10. Patients with active autoimmune disease requiring systemic immunomodulatory
                 treatment within the past 3 months.
    
              -  11. History and/or confirmed pneumonitis, or extensive bilateral lung disease on high
                 resolution/spiral CT scan.
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Feasibility of of neoadjuvant ipilimumab and nivolumab prior to surgery and SRS
    Time Frame:10 days
    Safety Issue:
    Description:Proportion of patients within the neoadjuvant treatment arm (Arm 1) who have their surgery delayed by more than 4 days or surgery never occurs as a direct or indirect result of ipilimumab and nivolumab treatment.

    Details

    Phase:Phase 2
    Primary Purpose:Interventional
    Overall Status:Not yet recruiting
    Lead Sponsor:Sarah Sammons, MD

    Trial 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

    Last Updated

    June 12, 2020