Neoadjuvant Immunotherapy in Brain Metastases

NCT ID: NCT04434560

Last Updated: 2022-07-26

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 1 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-11-04
• Study Completion Date: 2021-06-17

Brief 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.

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.

Conditions

Brain Metastases, Adult

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Standard of Care (no neoadjuvant immunotherapy)

Patients will proceed to surgical resection with no nivolumab/ipilimumab given prior to surgery.

Group Type: NO_INTERVENTION

No interventions assigned to this group

Neoadjuvant Immunotherapy

Patients will receive a single dose of neoadjuvant nivolumab and ipilimumab 7 days (± 3 days) prior to surgical resection.

Group Type: EXPERIMENTAL

Nivolumab

Intervention Type: DRUG

Nivolumab will be given at the FDA-approved dose of 3 mg/kg.

Ipilimumab

Intervention Type: DRUG

Ipilimumab will be given at the FDA-approved dose of 1 mg/kg.

Interventions

Nivolumab

Nivolumab will be given at the FDA-approved dose of 3 mg/kg.

Intervention Type: DRUG

Ipilimumab

Ipilimumab will be given at the FDA-approved dose of 1 mg/kg.

Intervention Type: DRUG

Other Intervention Names

Opdivo; Yervoy

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Bristol-Myers Squibb

INDUSTRY

Sponsor Role: collaborator

Duke University

OTHER

Sponsor Role: collaborator

Sarah Sammons, MD

OTHER

Sponsor Role: lead

Responsible Party

Sarah Sammons, MD

Assistant Professor of Medicine

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Sarah Sammons, MD

Role: PRINCIPAL_INVESTIGATOR

Duke University

Locations

Duke University Medical Center

Durham, North Carolina, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Related Links

http://tischbraintumorcenter.duke.edu/

The Preston Robert Tisch Brain Tumor Center

http://www.dukehealth.org/clinical-trials

Duke Health

Other Identifiers

CA184-583

Identifier Type: OTHER

Identifier Source: secondary_id

Pro00103812

Identifier Type: -

Identifier Source: org_study_id