Clinical Trials /

Atezolizumab + Pertuzumab + Trastuzumab In CNS Mets In BC

NCT03417544

Description:

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

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • 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

Clinical Trial IDs

  • ORG STUDY ID: 17-546
  • NCT ID: NCT03417544

Conditions

  • HER2-positive Metastatic Breast Cancer
  • Central Nervous System Metastases

Interventions

DrugSynonymsArms
ATEZOLIZUMABTecentriqATEZOLIZUMAB, PERTUZUMAB, TRASTUZUMAB
PERTUZUMABPerjetaATEZOLIZUMAB, PERTUZUMAB, TRASTUZUMAB
TRASTUZUMABHerceptinATEZOLIZUMAB, PERTUZUMAB, TRASTUZUMAB

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
ATEZOLIZUMAB, PERTUZUMAB, TRASTUZUMABExperimentalPatients 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).
  • ATEZOLIZUMAB
  • PERTUZUMAB
  • TRASTUZUMAB

Eligibility 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Response Rate in CNS
Time Frame:24 Weeks
Safety Issue:
Description:Assessed using RANO-BM criteria

Secondary Outcome Measures

Measure:Progression Free Survival
Time Frame:24 Weeks
Safety Issue:
Description:Assessed using RANO-BM criteria
Measure:Objective non-CNS response rates
Time Frame:24 weeks
Safety Issue:
Description:According to RECIST 1.1 and irRC criteria
Measure:Duration Response Rate
Time Frame:5 Years
Safety Issue:
Description:RANO-BM criteria and descriptive statistics will be used to summarize DOR intervals
Measure:Clinical Benefit Rate
Time Frame:18 and 24 weeks
Safety Issue:
Description:Incidence of SD, PR, or CR in non-CNS by RECIST 1.1 and in CNS by RANO-BM
Measure:Overall Survival
Time Frame:2 years
Safety Issue:
Description:Estimate the efficacy as measured by overall survival (OS) of Atezolizumab in combination with High-dose Trastuzumab and Pertuzumab
Measure:Dose Limiting Toxicity
Time Frame:baseline within 21 days of C1D1 treatment
Safety Issue:
Description: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
Measure:Patient Reported Outcomes by MDASI-BT
Time Frame:2 years
Safety Issue:
Description:Evaluated by M.D. Anderson Symptom Inventory Brain Tumor (MDASI-BT)
Measure:Patient Reported Outcomes by EQ-5D
Time Frame:2 years
Safety Issue:
Description:Evaluated by EQ-5D evaluations assessments
Measure:Investigator-Assessed Neurological Evaluation
Time Frame:2 years
Safety Issue:
Description:Evaluated by physician assessed Neurological Assessment in Neuro-Oncology (NANO) scale

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Nancy Lin, MD

Trial Keywords

  • HER2-positive metastatic Breast Cancer
  • Central Nervous System Metastases

Last Updated

February 21, 2018