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

Sponsor

H. Lee Moffitt Cancer Center and Research Institute (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT03807765

Collaborator

Bristol-Myers Squibb (Industry)

Enrollment

Location

Arm

47.5

Anticipated Duration (Months)

0.3

Patients Per Site Per Month

Study Details

Study Description

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

Study Design

Study Type:

Interventional

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 :

Jan 30, 2019

Actual Primary Completion Date :

Sep 8, 2020

Anticipated Study Completion Date :

Jan 14, 2023

Arms and Interventions

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 Names: 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.

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 Names:

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.

Outcome Measures

Primary Outcome Measures

Number of Participants who experience Dose Limiting Toxicities [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

Evaluation of intracranial local brain tumor following treatment [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.
Evaluation of intracranial distant brain tumor following treatment [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.
Intracranial Progression Free Survival (PFS) [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.
Extracranial Progression Free Survival (PFS) [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.
Overall Survival [Up to 24 months]
Overall Survival defined as time from the date of start of treatment to death.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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