Atezolizumab + Pertuzumab + Trastuzumab In CNS Mets In BC

• ClinicalTrials.gov Identifier: NCT03417544
• Recruitment Status: Active, not recruiting
• First Posted: January 31, 2018
• Results First Posted: May 7, 2024
• Last Update Posted: May 7, 2024
• Sponsor: Nancy Lin, MD
• Collaborator: Genentech, Inc.
• Information provided by (Responsible Party): Nancy Lin, MD, Dana-Farber Cancer Institute

Tracking Information

• First Submitted Date: January 16, 2018
• First Posted Date: January 31, 2018
• Results First Submitted Date: February 26, 2024
• Results First Posted Date: May 7, 2024
• Last Update Posted Date: May 7, 2024
• Actual Study Start Date: May 21, 2018
• Actual Primary Completion Date: May 20, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 10, 2024)

Confirmed Overall Response Rate in CNS [ Time Frame: Participants were evaluated for response every 6 weeks for the first 24 weeks and then every 9 weeks thereafter, through study completion, an average of 24 weeks ]

The proportion of patients who had confirmed complete response or confirmed partial response, assessed using neuro-oncology-brain metastases (RANO-BM) criteria. RANO-BM assess the response of brain metastases to treatment, using MRI scan. There are four categories as results: Complete Response (CR), Partial Response (PR), Stable Disease (SD), and Progressive Disease (PD), which is separately defined as disappearance of all target lesions, at least a 30% decrease in the sum of the diameters of target lesions, neither sufficient shrinkage to qualify as PR nor sufficient increase to qualify as progressive disease (PD) and at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (including the baseline sum if that is the smallest) or the appearance of one or more new lesions.

Original Primary Outcome Measures (submitted: January 24, 2018)

Overall Response Rate in CNS [ Time Frame: 24 Weeks ]

Assessed using RANO-BM criteria

Current Secondary Outcome Measures (submitted: April 10, 2024)

• Objective Non-CNS Response Rates [ Time Frame: Participants were evaluated for response every 6 weeks for the first 24 weeks and then every 9 weeks thereafter, through study completion, an average of 24 weeks ]
  The proportion of patients who had confirmed complete response or partial response, according to response Evaluation Criteria in Solid Tumors (RECIST 1.1) criteria. RECIST is used to assess the response of solid tumors to treatment. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions.
• Clinical Benefit Rate in CNS at 18 Weeks [ Time Frame: Participants were evaluated for response every 6 weeks for the first 24 weeks and then every 9 weeks thereafter, through study completion, an average of 24 weeks ]
  The proportion of patients who had stable disease, confirmed partial response or complete response, respectively, >=18 weeks, according to RANO-BM criteria
• Patient Reported Outcomes by MDASI-BT Stratified by CBR at 18 Weeks [ Time Frame: 24 weeks ]
  Evaluated by M.D. Anderson Symptom Inventory Brain Tumor (MDASI-BT). MDASI-BT assess 13 symptom items and 6 interference items from the core MDAST as well as 9 symptoms specific to brain tumors, and generate Symptom Severity Score (SSS) and Symptom Interference Score (SIS) separately. The scale of the scores are in a range of 0 to 10, where 0 represents "not present" or "not severe," and 10 represents "as bad as you can imagine" or "most severe." A higher score indicates a higher level of symptom severity. Mean of the scores are reported across groups with and without CBR at 18 weeks and in baseline, week 9 and week 24.
• Patient Reported Outcomes by EQ-5D Stratified by CBR at 18 Weeks [ Time Frame: 24 weeks ]
  Evaluated by EuroQol Five Dimension Questionnaire (EQ-5D) evaluations assessments to assess the general health status of patients enrolled in the study. EQ-5D scores are assessed with five dimensions with the range of 0 to 5, and a higher score indicates worse health. Mean of the scores are reported across groups with and without CBR at 18 weeks and in baseline, week 9 and week 24.
• Investigator-Assessed Neurological Evaluation (NANO) Stratified by CBR at 18 Weeks [ Time Frame: 24 weeks ]
  Evaluated by physician assessed Neurological Assessment in Neuro-Oncology (NANO) scale. The NANO scale is a quantifiable evaluation of 9 relevant neurologic domains based on direct observation and testing conducted during visits. The score defines overall response criteria and is with the range of 0 to 4. Higher score means worse response to the treatment. Mean of the scores are reported across groups with and without CBR at 18 weeks and in baseline, week 9 and week 24.
• Clinical Benefit Rate in CNS at 24 Weeks [ Time Frame: Participants were evaluated for response every 6 weeks for the first 24 weeks and then every 9 weeks thereafter, through study completion, an average of 24 weeks ]
  The proportion of patients who had stable disease, confirmed partial response or complete response, respectively, >=24 weeks, according to RANO-BM criteria

Original Secondary Outcome Measures (submitted: January 24, 2018)

• Progression Free Survival [ Time Frame: 24 Weeks ]
  Assessed using RANO-BM criteria
• Objective non-CNS response rates [ Time Frame: 24 weeks ]
  According to RECIST 1.1 and irRC criteria
• Duration Response Rate [ Time Frame: 5 Years ]
  RANO-BM criteria and descriptive statistics will be used to summarize DOR intervals
• 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
• 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
• 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
• Patient Reported Outcomes by MDASI-BT [ Time Frame: 2 years ]
  Evaluated by M.D. Anderson Symptom Inventory Brain Tumor (MDASI-BT)
• Patient Reported Outcomes by EQ-5D [ Time Frame: 2 years ]
  Evaluated by EQ-5D evaluations assessments
• Investigator-Assessed Neurological Evaluation [ Time Frame: 2 years ]
  Evaluated by physician assessed Neurological Assessment in Neuro-Oncology (NANO) scale

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• 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

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.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

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

Intervention

• Drug: ATEZOLIZUMAB
  (IV) every 3 weeks
  Other Name: Tecentriq
• Drug: PERTUZUMAB
  Loading dose, followed every 3 weeks thereafter by a predetermined dose in the protocol via IV
  Other Name: Perjeta
• Drug: TRASTUZUMAB
  Predetermined dose per protocol via IV, weekly for 24 weeks and after every 3 weeks
  Other Name: Herceptin

Study Arms

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).

Interventions:

• Drug: ATEZOLIZUMAB
• Drug: PERTUZUMAB
• Drug: TRASTUZUMAB

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: February 26, 2024): 19
• Original Estimated Enrollment (submitted: January 24, 2018): 33
• Estimated Study Completion Date: December 2025
• Actual Primary Completion Date: May 20, 2020 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03417544
• Other Study ID Numbers: 17-546
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Nancy Lin, MD, Dana-Farber Cancer Institute
• Original Responsible Party: Same as current
• Current Study Sponsor: Nancy Lin, MD
• Original Study Sponsor: Same as current
• Collaborators: Genentech, Inc.

Investigators

• Principal Investigator: Nancy Lin, MD; Dana-Farber Cancer Institute

• PRS Account: Dana-Farber Cancer Institute
• Verification Date: April 2024