Neoadjuvant Immunotherapy in Brain Metastases

A Phase II Trial of Surgery and Stereotactic Radiosurgery With Neoadjuvant Nivolumab and Ipilimumab in Patients With Surgically-resectable, Solid Tumor Brain Metastases

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.

Study Overview

• Status: Terminated
• Conditions: Brain Metastases, Adult
• Intervention / Treatment: Drug: Nivolumab; Drug: Ipilimumab

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.

• Study Type: Interventional
• Enrollment (Actual): 1
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
NO_INTERVENTION: Standard of Care (no neoadjuvant immunotherapy); Patients will proceed to surgical resection with no nivolumab/ipilimumab given prior to surgery.
EXPERIMENTAL: Neoadjuvant Immunotherapy; Patients will receive a single dose of neoadjuvant nivolumab and ipilimumab 7 days (± 3 days) prior to surgical resection.	Drug: Nivolumab; Nivolumab will be given at the FDA-approved dose of 3 mg/kg.; Other Names: Opdivo; Drug: Ipilimumab; Ipilimumab will be given at the FDA-approved dose of 1 mg/kg.; Other Names: Yervoy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.		10 days
Proliferation of Circulating T-cells as Measured by Mean Fold-change Between Baseline and Day 1 in Ki67 Levels.	Ki-67 is a nuclear protein involved in cell proliferation regulation.	baseline to day 1

Collaborators and Investigators

• Sponsor: Sarah Sammons, MD
• Collaborators: Bristol-Myers Squibb; Duke University

Publications and helpful links

Helpful Links

• Duke Health
• The Preston Robert Tisch Brain Tumor Center

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 4, 2020
• Primary Completion (ACTUAL): June 17, 2021
• Study Completion (ACTUAL): June 17, 2021

Study Registration Dates

• First Submitted: June 12, 2020
• First Submitted That Met QC Criteria: June 12, 2020
• First Posted (ACTUAL): June 17, 2020

Study Record Updates

• Last Update Posted (ACTUAL): July 26, 2022
• Last Update Submitted That Met QC Criteria: July 22, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Keywords: Nivolumab; Melanoma; Ipilimumab; Solid tumor; Renal cell carcinoma; Opdivo; Urothelial carcinoma; Triple negative breast cancer; Brain metastases; Yervoy; Ovarian carcinoma; Non-small-cell lung carcinoma; Pro00103812; Sammons
• Additional Relevant MeSH Terms: Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms; Neoplasms by Site; Neoplastic Processes; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasm Metastasis; Brain Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Nivolumab; Ipilimumab
• Other Study ID Numbers: Pro00103812; CA184-583 (OTHER: Bristol Myers Squibb)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No