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, and the rate of radiation necrosis. The rate of radionecrosis will also be explored, as immune expression profiles.

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 Phase II Trial of Surgery and Stereotactic Radiosurgery With 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
NivolumabOpdivoNeoadjuvant Immunotherapy
IpilimumabYervoyNeoadjuvant Immunotherapy

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, and the rate of radiation necrosis. The rate of radionecrosis will also be explored, as immune expression profiles.

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 without known anaplastic lymphoma kinase (ALK), epidermal growth factor
      receptor (EGFR), and ROS mutation, renal cell carcinoma (RCC), melanoma, and triple negative
      breast cancer (TNBC) that is programmed death-ligand 1 positive (PD-L1 +). All participants
      will receive neoadjuvant immunotherapy and 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 will
      then receive SRS per standard of care guidelines. Patients will be followed for 18 months
      after initiating study treatment. Up to 20 participants will be recruited and treated. Blood
      will be collected periodically during the study for correlative assessments.
    

Trial Arms

NameTypeDescriptionInterventions
Neoadjuvant ImmunotherapyExperimentalPatients will receive a single dose of neoadjuvant nivolumab and ipilimumab 7 days (± 3 days) prior to surgical resection.
  • Nivolumab
  • Ipilimumab

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 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Proportion of patients that receive neoadjuvant ipilimumab and nivolumab prior to surgery and SRS
Time Frame:10 days
Safety Issue:
Description:Proportion of patients 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: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

July 23, 2021