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Atezolizumab + Stereotactic Radiation in Triple-negative Breast Cancer and Brain Metastasis

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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03483012
Recruitment Status : Recruiting
First Posted : March 29, 2018
Last Update Posted : December 13, 2019
Sponsor:
Collaborator:
Genentech, Inc.
Information provided by (Responsible Party):
Nancy Lin, MD, Dana-Farber Cancer Institute

Brief Summary:

This research study is studying the combination of a drug called atezolizumab and a radiation procedure called stereotactic radiosurgery (SRS) as a possible treatment for triple-negative breast cancer that has spread to the brain.

The interventions involved in this study are:

  • Atezolizumab
  • Stereotactic radiosurgery (SRS)

Condition or disease Intervention/treatment Phase
Breast Cancer Drug: Atezolizumab Procedure: Stereotactic radiosurgery (SRS) Phase 2

Detailed Description:

This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease. "Investigational" means that the intervention is being studied.

The FDA (the U.S. Food and Drug Administration) has not approved atezolizumab for this specific disease but it has been approved for other uses.

Atezolizumab is a protein that affects the immune system by blocking the PD-L1 pathway. The PD-L1 pathway controls the body's natural immune response, but tumors can interrupt this pathway and partially resist or escape the immune system. By blocking the PD-L1 pathway, Atezolizumab may help the immune system identify and catch tumor cells.

Stereotactic radiosurgery (SRS) is a standard procedure used to treat patients with cancer in the brain. SRS uses many precisely focused radiation beams to treat tumors. It is not surgery in the traditional sense because there's no incision. Instead, SRS uses 3-D imaging to target high doses of radiation to the affected area with minimal impact on the surrounding healthy tissue. Like other forms of radiation, SRS works by damaging the DNA of the targeted (tumor) cells. The affected cells then lose the ability to reproduce, which causes tumors to shrink.

When given separately, atezolizumab and SRS, work in different ways to help stop cancer cells from growing and spreading. However, it is not known if giving atezolizumab and SRS at the same time will have a better effect than giving each treatment on its own. It is hoped that SRS treatment will damage cancer cells and make them more visible to the immune system.

The researchers conducting this study are testing to see whether giving SRS with atezolizumab may boost the body's immune response to cancer, and therefore improve upon the effects of either SRS or atezolizumab given alone.

In this research study, the investigators will measure the length of time that the participant receive this study intervention without the disease getting worse. The investigators will also look at how well the disease responds to atezolizumab and SRS as well as the safety of the combination.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 45 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study of Atezolizumab in Combination With Stereotactic Radiation for Patients With Triple-negative Breast Cancer and Brain Metastasis
Actual Study Start Date : May 1, 2018
Estimated Primary Completion Date : September 30, 2021
Estimated Study Completion Date : September 30, 2025

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Atezolizumab + Stereotactic radiosurgery (SRS)
  • Atezolizumab administered intravenously once every 3 weeks
  • Stereotactic radiosurgery (SRS) begin within 14 days after brain MRI obtained
Drug: Atezolizumab
Atezolizumab is a protein that affects your immune system by blocking the PD-L1 pathway
Other Name: Tecentriq

Procedure: Stereotactic radiosurgery (SRS)
Stereotactic radiosurgery (SRS) is a standard procedure used to treat patients with cancer in the brain. SRS uses many precisely focused radiation beams to treat tumors




Primary Outcome Measures :
  1. Progression Free Survival [ Time Frame: 24 weeks ]
    Assessed using RANO-BM criteria


Secondary Outcome Measures :
  1. Extracranial Objective Response Rate [ Time Frame: 24 weeks ]
    Assessed by RECIST 1.1

  2. Extracranial Objective Response Rate [ Time Frame: 24 weeks ]
    Assessed by immune-related response criteria (irRC)

  3. Progression free survival [ Time Frame: 24 weeks ]
    Assessed by RECIST 1.1

  4. Clinical Benefit Rate [ Time Frame: 16 and 24 weeks ]
    defined as CR, PR and stable disease

  5. Overall Survival [ Time Frame: 2 years ]
    evaluate the overall survival (OS) of atezolizumab in combination with SRS in patients with TNBC and brain metastasis

  6. Patient-Reported Outcome [ Time Frame: 2 years ]
    Evaluated by MDASI-BT assessment.

  7. Development of radiation necrosis [ Time Frame: 2 years ]
    Assessed by neuroradiology assessment or dual-phase PET-CT studies

  8. Investigator-Assessed Neurological Evaluation [ Time Frame: 2 years ]
    Evaluated by physician assessed Neurological Assessment in Neuro-Oncology (NANO) scale

  9. Dose Limiting Toxicity [ Time Frame: First dose of atezolizumab until Cycle 3 Day 1 ]
    NCI CTCAE, Version 4.0

  10. Abscopal response rate [ Time Frame: 2 years ]
    According to abscopal response definition



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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

Inclusion Criteria:

  • Participants must have histologically or cytologically confirmed Stage IV invasive breast cancer. Participants without pathologic or cytologic confirmation of metastatic disease should have unequivocal evidence of metastasis from physical examination or radiologic evaluation.
  • Either the primary tumor and/or metastatic tumor must be triple-negative as defined below:

    • Hormone receptor status: the invasive tumor must be ER- and PR-negative, or staining present in <1% by immunohistochemistry (IHC)
    • HER2 status: the invasive tumor must be Human Epidermal Growth Factor Receptor 2 Negative (HER2-negative) by the ASCO CAP guidelines
  • In cases where both primary tumor and metastatic sample(s) have been tested for ER, PR, and HER2, the triple-negative status of the most recent sample should be used.
  • Participants must have a diagnosis of brain metastases for which SRS is indicated, as determined by a radiation oncologist.
  • The contrast-enhancing intraparenchymal brain metastases(s) must be well circumscribed and must have a maximum diameter of ≤ 3.0 cm in any direction on the enhanced scan.
  • Participants must not have more than 5 new or progressive lesions in the brain requiring SRS treatment (greater than 5 total brain lesions are allowed as long as no more than 5 lesions require SRS treatment).
  • Participants must have measurable extracranial disease as defined by RECIST 1.1.
  • Participants must be willing to undergo a research biopsy at baseline and at Cycle 2 Day 1 if extracranial metastases are safely accessible. Participants for whom biopsies cannot be safely performed must be willing to submit an archival primary and/or metastatic specimen. The biopsies may be waived with prior PI approval for the first 6 participants enrolled to the safety run in phase.
  • Prior systemic therapy:

    • Participants must have discontinued systemic therapy at least 14 days prior to initiating protocol therapy.
    • There is no limit to the number of prior lines of systemic therapy. Participants who have not received any systemic therapy for metastatic disease are also eligible.
    • Participants may initiate or continue bisphosphonate therapy on study.
  • Prior local therapy:
  • Prior surgery, whole brain radiation or SRS is allowed as long as the most recent brain progression is amenable to SRS treatment.
  • Resolution of all chemotherapy-related or radiation-related toxicities to Grade 1 severity or lower, except for stable sensory neuropathy (≤ Grade 2 allowed) and alopecia (of any grade).
  • Participant is ≥18 years old.
  • ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A)
  • Stable dose of dexamethasone 2mg or less for at least 7 days prior to initiation of treatment
  • Participants must have normal organ and marrow function as defined below:

    • absolute neutrophil count ≥1,000/μl
    • platelets ≥75,000/μl
    • hemoglobin ≥9 g/dL
    • total bilirubin ≤1.5mg/dL (≤2.0 in patients with known Gilberts syndrome)
    • AST(SGOT)/ALT(SGPT) ≤2.5 × institutional ULN. ≤5.0 × institutional ULN for patients with documented liver metastases.
    • albumin >2.5mg/dL
    • serum creatinine ≤1.5mg/dL or calculated GFR ≥60 mL/min
  • Female subjects of childbearing potential must have a negative serum or urine pregnancy test within 8 days of initiating protocol therapy.
  • For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 90 days after the last dose of study treatment. A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, established, proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception. The effects of atezolizumab on the developing human fetus are unknown and radiotherapy has known teratogenic effects so women of child-bearing potential and men must agree to use adequate contraception (barrier method of birth control; abstinence) prior to study entry and for the duration of study participation and 4 months after completion of atezolizumab administration.
  • The subject is capable of understanding and complying with the protocol and has signed the informed consent document

Exclusion Criteria:

  • CNS complications for whom urgent neurosurgical intervention is indicated (e.g., resection, shunt placement).
  • Known leptomeningeal or brainstem metastases. The presence of leptomeningeal enhancement alone, without associated clinical manifestations and/or positive CSF cytology, will not be constituted as known leptomeningeal metastases.
  • Treatment with high dose systemic corticosteroids defined as dexamethasone >2mg/day or bioequivalent within 7 days of initiating therapy.
  • Patients unable to undergo gadolinium contrast-enhanced MRI or receive IV contrast for any reason (e.g., due to pacemaker, ferromagnetic implants, claustrophobia, extreme obesity, hypersensitity).
  • Participants who are receiving any other investigational agents.
  • Previous treatment with any anti-PD-1, PD-L1, or PD-L2 agent.
  • Subjects with a history of hypersensitivity to compounds of similar biologic composition to atezolizumab or any constituent of the product
  • The participant has an uncontrolled intercurrent illness, including, but not limited to uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, congestive heart failure-New York Heart Association Class III or IV, active ischemic heart disease, myocardial infarction within the previous six months, uncontrolled diabetes mellitus, gastric or duodenal ulceration diagnosed within the previous 6 months, severe malnutrition or psychiatric illness/social situations that would limit compliance with study requirements.
  • Participant has a medical condition that requires chronic systemic steroid therapy or on any other form of immunosuppressive medication. For example, patients with autoimmune disease that requires systemic steroids or immunosuppression agents should be excluded. Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
  • Has evidence of active, noninfectious pneumonitis that requires treatment with steroids.
  • Has a history of interstitial lung disease.
  • The participant is known to be positive for the human immunodeficiency virus (HIV), HepBsAg, or HCV RNA. HIV-positive participants on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with atezolizumab.
  • Individuals with a history of different malignancy are ineligible except for the following circumstances. Individuals with a history of other malignancies are eligible if they have been disease-free for at least 3 years or are deemed by the principal investigator to be at low risk for recurrence of that malignancy.
  • Has received a live vaccine within 28 days of planned start of study therapy.
  • The participant is pregnant or breast-feeding.

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): NCT03483012


Contacts
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Contact: Kelley Cassidy 617-632-3548 ckelley14@partners.org

Locations
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United States, Massachusetts
Dana-Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Kelley Cassidy    617-632-3548    ckelley14@partners.org   
Principal Investigator: Nancy U Lin, MD         
Sponsors and Collaborators
Dana-Farber Cancer Institute
Genentech, Inc.
Investigators
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Principal Investigator: Nancy U Lin, MD Dana-Farber Cancer Institute
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Responsible Party: Nancy Lin, MD, Principal Investigator, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier: NCT03483012    
Other Study ID Numbers: 17-519
First Posted: March 29, 2018    Key Record Dates
Last Update Posted: December 13, 2019
Last Verified: December 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Nancy Lin, MD, Dana-Farber Cancer Institute:
Breast Cancer
Additional relevant MeSH terms:
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Breast Neoplasms
Triple Negative Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Atezolizumab
Antineoplastic Agents