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History of Changes for Study: NCT03417544
Atezolizumab + Pertuzumab + Trastuzumab In CNS Mets In BC
Latest version (submitted March 14, 2022) on ClinicalTrials.gov
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Study Record Versions
Version A B Submitted Date Changes
1 January 24, 2018 None (earliest Version on record)
2 February 21, 2018 Recruitment Status, Study Status and Contacts/Locations
3 April 22, 2019 Study Status and Contacts/Locations
4 December 12, 2019 Study Status
5 June 30, 2020 Recruitment Status, Study Status, Contacts/Locations and Study Design
6 December 14, 2020 Study Status
7 April 27, 2021 Study Status
8 December 14, 2021 Study Status
9 March 14, 2022 Study Status
Comparison Format:

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Study NCT03417544
Submitted Date:  January 24, 2018 (v1)

Open or close this module Study Identification
Unique Protocol ID: 17-546
Brief Title: Atezolizumab + Pertuzumab + Trastuzumab In CNS Mets In BC
Official Title: A Phase II Study of Atezolizumab in Combination With Pertuzumab Plus High-dose Trastuzumab for the Treatment of Central Nervous System Metastases in Patients With Her2-positive Breast Cancer
Secondary IDs:
Open or close this module Study Status
Record Verification: January 2018
Overall Status: Not yet recruiting
Study Start: January 2018
Primary Completion: February 2020 [Anticipated]
Study Completion: February 2025 [Anticipated]
First Submitted: January 16, 2018
First Submitted that
Met QC Criteria:
January 24, 2018
First Posted: January 31, 2018 [Actual]
Last Update Submitted that
Met QC Criteria:
January 24, 2018
Last Update Posted: January 31, 2018 [Actual]
Open or close this module Sponsor/Collaborators
Sponsor: Nancy Lin, MD
Responsible Party: Sponsor-Investigator
Investigator: Nancy Lin, MD
Official Title: Sponsor Investigator
Affiliation: Dana-Farber Cancer Institute
Collaborators: Genentech, Inc.
Open or close this module Oversight
U.S. FDA-regulated Drug: Yes
U.S. FDA-regulated Device: No
Data Monitoring: Yes
Open or close this module Study Description
Brief Summary:

This research study is studying a drug called atezolizumab as a possible treatment HER2-positive metastatic breast cancer (MBC) that has spread to the brain.

The names of the study drugs involved in this study are:

  • Atezolizumab
  • Pertuzumab
  • Trastuzumab
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. It also means that the FDA (U.S. Food and Drug Administration) has not approved the combination of atezolizumab, trastuzumab, and pertuzumab for use in humans. The FDA 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 for some types of cancer the immune system does not work as it should and is prevented from attacking tumors. Atezolizumab works by blocking the PD-L1 pathway, which may help the immune system identify and catch tumor cells.
  • Pertuzumab and trastuzumab are targeted therapies approved by the FDA to be used alone or in combination with a chemotherapy drug to treat HER2-positive metastatic breast cancer that hasn't been treated with either trastuzumab or chemotherapy yet.
  • Pertuzumab and trastuzumab are called "targeted therapies" because they work by attaching themselves to specific receptors on the surface of breast cancer cells, known as HER2 receptors. When these targeted therapies attach to HER2 receptors, the signals that tell the cells to grow are blocked and the cancer cell may be marked for destruction by your immune system. This process allows pertuzumab and trastuzumab to help slow or stop the growth of the breast cancer. Pertuzumab and trastuzumab target different areas of the HER2 cell, so they are believed to work together more effectively.

In this research study, investigators are looking to see how well the cancer responds to the combination of atezolizumab in combination with pertuzumab and trastuzumab.

Open or close this module Conditions
Conditions: HER2-positive Metastatic Breast Cancer
Central Nervous System Metastases
Keywords: HER2-positive metastatic Breast Cancer
Central Nervous System Metastases
Open or close this module Study Design
Study Type: Interventional
Primary Purpose: Treatment
Study Phase: Phase 2
Interventional Study Model: Single Group Assignment
Number of Arms: 1
Masking: None (Open Label)
Allocation: N/A
Enrollment: 33 [Anticipated]
Open or close this module Arms and Interventions
Arms Assigned Interventions
Experimental: ATEZOLIZUMAB, PERTUZUMAB, TRASTUZUMAB

Patients will receive the following treatment:

  • Atezolizumab (IV) every 3 weeks (q3w)]
  • Pertuzumab (loading dose ), followed q3w thereafter by a predetermined dose in the protocol via IV)
  • High-dose Trastuzumab weekly for the first 24 weeks, and thereafter trastuzumab q3w).
Drug: ATEZOLIZUMAB
(IV) every 3 weeks
Other Names:
  • Tecentriq
Drug: PERTUZUMAB
Loading dose, followed every 3 weeks thereafter by a predetermined dose in the protocol via IV
Other Names:
  • Perjeta
Drug: TRASTUZUMAB
Predetermined dose per protocol via IV, weekly for 24 weeks and after every 3 weeks
Other Names:
  • Herceptin
Open or close this module Outcome Measures
Primary Outcome Measures:
1. Overall Response Rate in CNS
[ Time Frame: 24 Weeks ]

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

Assessed using RANO-BM criteria
2. Objective non-CNS response rates
[ Time Frame: 24 weeks ]

According to RECIST 1.1 and irRC criteria
3. Duration Response Rate
[ Time Frame: 5 Years ]

RANO-BM criteria and descriptive statistics will be used to summarize DOR intervals
4. Clinical Benefit Rate
[ Time Frame: 18 and 24 weeks ]

Incidence of SD, PR, or CR in non-CNS by RECIST 1.1 and in CNS by RANO-BM
5. Overall Survival
[ Time Frame: 2 years ]

Estimate the efficacy as measured by overall survival (OS) of Atezolizumab in combination with High-dose Trastuzumab and Pertuzumab
6. Dose Limiting Toxicity
[ Time Frame: baseline within 21 days of C1D1 treatment ]

Toxicity will be graded according to NCI CTCAE, Version 4.0. Toxicities will be summarized by maximum grade. Kaplan-Meier product-limit estimates and 90% confidence bands
7. Patient Reported Outcomes by MDASI-BT
[ Time Frame: 2 years ]

Evaluated by M.D. Anderson Symptom Inventory Brain Tumor (MDASI-BT)
8. Patient Reported Outcomes by EQ-5D
[ Time Frame: 2 years ]

Evaluated by EQ-5D evaluations assessments
9. Investigator-Assessed Neurological Evaluation
[ Time Frame: 2 years ]

Evaluated by physician assessed Neurological Assessment in Neuro-Oncology (NANO) scale
Open or close this module Eligibility
Minimum Age: 18 Years
Maximum Age:
Sex: All
Gender Based:
Accepts Healthy Volunteers: No
Criteria:

Inclusion Criteria:

- Eligibility will be assessed as part of the screening procedures for all patients.

  • Pathologically confirmed HER2-positive MBC by local laboratory with the following requirements: HER2 overexpressed or amplified (immunohistochemistry of 3+ or HER2 gene amplification by in situ hybridization with a ratio of HER2-gene signals to centromere 17 signals ≥ 2.0 or average HER2 copy number ≥ 6.0 signals/cells).
  • At least one measurable CNS metastasis, defined as ≥ 10 mm in at least one dimension
  • Unequivocal evidence of new and/or progressive brain metastases, and at least one of the following scenarios:
    • Treated with SRS or surgery with residual un-treated lesions remaining. Such participants are eligible for immediate enrollment on this study providing that at least one untreated lesion is measurable
    • Participants who have had prior WBRT and/or SRS and then whose lesions have subsequently progressed are also eligible. In this case, lesions which have been treated with SRS may be considered as target lesions if there is unequivocal evidence, in the opinion of the treating physician, of progression following SRS.
    • Participants who have not previously been treated with cranial radiation (e.g., WBRT or SRS) are eligible to enter the study, but such participants must be asymptomatic from their CNS metastases and not requiring corticosteroids for symptom control.
    • Both participants who present with systemic stable/absent or progressive disease are eligible to this trial, as long as they fulfill one of the above criteria.
  • Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
  • Left ventricular ejection fraction (LVEF) ≥ 50% by echocardiogram (echo) or multigated acquisition (MUGA) scan within 28 days before day 1 of study.
  • Stable dose of dexamethasone 2mg or less for at least 7 days prior to initiation of treatment
  • Concurrent administration of other anti-cancer therapy during the course of this study is not allowed. Note that concurrent use of supportive care medications (e.g. anti-resorptive agents, pain medications) is allowed.
  • The subject is 18 years old.
  • 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 (upper limit of normal) except subject with documented Gilbert's syndrome (≤5 x ULN) or liver metastasis, who must have a baseline total bilirubin ≤3.0 mg/dL;
    • AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional ULN ≤ 5.0 × institutional ULN for patients with documented liver metastases.
    • albumin >2.5mg/dL
    • serum creatinine ≤ 1.5 mg/dL (or glomerular filtration rate ≥ 60 ml/min as determined by the Cockcroft-Gault equation)
  • Female subjects of childbearing potential must have a negative serum or urine pregnancy test within 8 days of initiating protocol therapy.
  • 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:

  • Visceral crisis or impending visceral crisis at time of screening.
  • CNS complications for whom urgent neurosurgical intervention is indicated (e.g., resection, shunt placement).
  • Known leptomeningeal or brainstem metastases [Defined as positive CSF cytology and/or unequivocal radiological evidence of clinically significant leptomeningeal involvement. CSF sampling is not required in the absence of suggestive symptoms to exclude leptomeningeal involvement].
  • 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, hypersensitivity).
  • Chemotherapy or targeted therapy within 14 days prior to cycle 1 day 1 of protocol therapy.
  • Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
  • No washout is required for endocrine therapy. If a patient has been on endocrine therapy within 28 days of study entry, that same endocrine therapy is permitted to be continued during protocol therapy, at the investigator's discretion, as is continuation of ovarian suppression in premenopausal women. Starting a new endocrine therapy during protocol therapy is not permitted
  • Current use or history of receiving a non-approved, investigational treatment within 14 days prior to cycle 1 day 1 of protocol therapy
  • Subjects with a history of hypersensitivity to compounds of similar biologic composition to atezolizumab or any constituent of the product
  • The subject has an uncontrolled intercurrent illness, including, but not limited to, ongoing or active infection, 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, chronic liver or renal disease, or severe malnutrition.
  • The subject is pregnant or breast-feeding
  • No active, second potentially life-threatening cancer
  • Has had major surgery within 21 days before cycle 1, day 1
  • Active infection requiring iv antibiotics at day 1 of cycle 1
  • 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.
  • Symptomatic intrinsic lung disease or extensive tumor involvement of the lungs, resulting in dyspnea at rest
  • 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.
  • Has received a live vaccine within 28 days of planned start of study therapy.
  • Known intolerance to trastuzumab or pertuzumab or atezolizumab.
Open or close this module Contacts/Locations
Central Contact Person: Nancy Lin, MD
Telephone: 617-632-3800
Email: nlin@partners.org
Study Officials: Nancy Lin, MD
Principal Investigator
Dana-Farber Cancer Institute
Locations: United States, Massachusetts
Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02215
Contact:Contact: Nancy Lin, MD 617-632-3800 nlin@partners.org
Contact:Contact: Kelly Silvestri 617-632-2403 KellyM_Silvestri@DFCI.HARVARD.EDU
Contact:Principal Investigator: Nancy Lin, MD
Open or close this module IPDSharing
Plan to Share IPD: No
Open or close this module References
Citations:
Links:
Available IPD/Information:

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