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Stereotactic Radiation and Nivolumab in the Management of Metastatic Breast Cancer Brain Metastases

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03807765
Recruitment Status : Active, not recruiting
First Posted : January 17, 2019
Last Update Posted : February 21, 2023
Bristol-Myers Squibb
Information provided by (Responsible Party):
H. Lee Moffitt Cancer Center and Research Institute

Brief Summary:
This study is to find out if administration of stereotactic radiosurgery (SRS) given after Nivolumab will improve overall response rate/anti-tumor activity in patients with metastatic breast cancer with brain metastases.

Condition or disease Intervention/treatment Phase
Metastatic Breast Cancer Brain Metastases Drug: Nivolumab Radiation: Stereotactic Radiosurgery Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 14 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase Ib Study of Stereotactic Radiation and Nivolumab in the Management of Metastatic Breast Cancer Brain Metastases
Actual Study Start Date : January 30, 2019
Actual Primary Completion Date : September 8, 2020
Estimated Study Completion Date : January 14, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer
Drug Information available for: Nivolumab

Arm Intervention/treatment
Experimental: Nivolumab followed by stereotactic radiosurgery (SRS)
480 mg Nivolumab will be given intravenously every 4 weeks, followed by SRS the week after the initial dose of Nivolumab.
Drug: Nivolumab
480 mg intravenous Nivolumab administered every 4 weeks.
Other Name: Opdivo

Radiation: Stereotactic Radiosurgery

Patients will receive single session SRS to intact brain metastases and post-operative cavities.

A linear accelerator (LINAC)-based frameless delivery system will be used to deliver the stereotactic radiation. The lesion will be defined using gadolinium enhanced MRI with 1 mm slices for treatment planning purposes prior to the delivery of radiation. The MRI image will be co-registered and fused with CT imaging. Doses will be prescribed to ensure coverage of at least 95% of the planning target volume (PTV) with the prescription dose. Treatments will be delivered using dynamic conformal arcs or intensity modulated radiotherapy.

Primary Outcome Measures :
  1. Number of Participants who experience Dose Limiting Toxicities [ Time Frame: Up to 8 weeks ]

    Neurologic dose limiting toxicities will be defined as: Symptomatic radionecrosis, >/= Grade 3 headache, >/= Grade 3 memory impairment, New onset >/= grade 3 seizures.

    3 participants will be enrolled with an 8 week safety observation period. If no patients develop unacceptable neurologic toxicity attributable to SRS, the study will proceed. If 1 patient develops unacceptable neurologic toxicity among the first 3, an additional 3 patients will be enrolled to determine the rate of unacceptable toxicity with 6 patients. If no more patients develop unacceptable neurologic toxicities among the first 6 patients, the study will proceed with a dose expansion of 6 patients.

    If 2 or more patients develop unacceptable neurologic toxicity among the first 3 or 6 patients, the dose of radiation therapy will be adjusted. If excessive toxicities are noted with radiation dose level -1, treatment will proceed with nivolumab alone.

Secondary Outcome Measures :
  1. Evaluation of intracranial local brain tumor following treatment [ Time Frame: At 3, 6 and 12 months post treatment ]
    Intracranial local brain tumor control following SRS and Nivolumab will be determined from irradiated lesions according to Response Assessment in Neuro-Oncology (RANO) criteria.

  2. Evaluation of intracranial distant brain tumor following treatment [ Time Frame: At 3, 6 and 12 months post treatment ]
    Intracranial distant brain tumor control following SRS and Nivolumab will be determined by the development of new lesions outside of the irradiated area.

  3. Intracranial Progression Free Survival (PFS) [ Time Frame: Up to 12 months ]
    Time from the date of start of treatment to the investigator-determined date of progression (determined by RANO) or death due to any cause, whichever occurs first.

  4. Extracranial Progression Free Survival (PFS) [ Time Frame: Up to 12 months ]
    Time from the date of start of treatment to the investigator determined date of progression (determined by Immune-Related Response Evaluation Criteria in Solid Tumors [irRECIST]) or death due to any cause, whichever occurs first.

  5. Overall Survival [ Time Frame: Up to 24 months ]
    Overall Survival defined as time from the date of start of treatment to death.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Provides signed and dated informed consent
  • Stated willingness to comply with all study procedures and availability for the duration of the study
  • Age 18 or older
  • Breast cancer with brain metastases, as documented by extracranial tumor biopsy with MRI brain imaging or intracranial surgical pathology revealing brain metastases
  • 10 or less brain metastases eligible for SRS to brain metastases or to the post-operative bed
  • Maximum diameter of the largest intact brain metastases ≤ 4 cm
  • Eastern Cooperative Oncology Group performance status 0 to 2
  • Prior treatment with taxane based chemotherapy with anthracyclines (if appropriate)
  • A formalin-fixed, paraffin-embedded tumor tissue block or 10 unstained slides of intracranial/extracranial tumor sample (archival or recent) for biomarker evaluation should be made available and submitted to the central lab for correlative studies. If attempts to obtain archival tissue are unsuccessful the patient may be enrolled.
  • Individuals with prior SRS/fractioned stereotactic radiotherapy (FSRT) treatment will be allowed if active measurable disease has not previously been treated with radiation therapy
  • Continuing concurrent use of hormonal therapy or HER2-targeted therapy is allowed if the patient exhibits brain metastases progression during treatment
  • Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin) within 24 hours prior to the administration of each dose of study agent.
  • WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug(s), plus 5 half-lives of study drug (half-life up to 25 days), plus 30 days (duration of ovulatory cycle) for a total of 5 months after treatment completion.

Exclusion Criteria:

  • Presence of leptomeningeal disease
  • Prior whole brain radiation therapy
  • All toxicities attributed to prior anticancer therapy must have been resolved to Grade 1 (NCI CTCAE Version 5) or baseline before administration of study drug(s) . Some exceptions apply.
  • Women who are pregnant or breastfeeding
  • Active, known, or suspected autoimmune disease. Patients with an autoimmune paraneoplastic syndrome requiring concurrent immunosuppressive treatment are excluded. Some exceptions apply.
  • Prior therapy with antiPD-1, antiPD-L1, antiPD-L2, antiCD137, or antiCTLA-4 antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways)
  • Interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity
  • Any patient requiring supplemental oxygen therapy
  • Patients with prior history of non-breast cancer malignancies are excluded except in the case of adequately treated basal cell cancer, squamous cell skin cancer, chronic lymphocytic leukemia, or other indolent diseases not requiring therapy
  • Known medical condition that, in the investigator's opinion, would increase the risk associated with study participation or study drug(s) administration or that would interfere with the interpretation of safety results
  • Major surgery or significant traumatic injury that has not been recovered from by 14 days before the initiation of study drug
  • Current or prior participation in a study of an investigational agent or investigational device within 2 weeks of first dose of study treatment
  • Positive test for: a. Hepatitis B virus using Hepatitis B virus surface antigen (Hepatitis B virus surface antigen) test b. Hepatitis C virus (HCV) using HCV ribonucleic acid or HCV antibody test that indicates acute or chronic infection c. Exception: Individuals with a positive test for HCV antibody but no detection of HCV ribonucleic acid indicating no current infection are eligible
  • Medical history of testing positive for HIV or AIDS. No HIV testing is required, unless mandated by a local health authority.
  • Inadequate hematologic function
  • Inadequate hepatic function
  • Inadequate pancreatic function
  • History of allergy or hypersensitivity to any of the study drugs or study drug components
  • Individuals who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03807765

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United States, Florida
H. Lee Moffitt Cancer Center and Research Institute
Tampa, Florida, United States, 33612
Sponsors and Collaborators
H. Lee Moffitt Cancer Center and Research Institute
Bristol-Myers Squibb
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Principal Investigator: Kamran Ahmed, MD H. Lee Moffitt Cancer Center and Research Institute
Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: H. Lee Moffitt Cancer Center and Research Institute
ClinicalTrials.gov Identifier: NCT03807765    
Other Study ID Numbers: MCC-19765
CA209-8NK ( Other Identifier: Bristol-Myers Squibb )
First Posted: January 17, 2019    Key Record Dates
Last Update Posted: February 21, 2023
Last Verified: February 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by H. Lee Moffitt Cancer Center and Research Institute:
breast cancer
brain metastases
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasm Metastasis
Brain Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Neoplastic Processes
Pathologic Processes
Central Nervous System Neoplasms
Nervous System Neoplasms
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action