Atezolizumab, Pertuzumab, and High-Dose Trastuzumab in Treating Patients with Her2-Positive Breast Cancer with Central Nervous System Metastases
- Histologically confirmed metastatic breast cancer
- Histologically confirmed HER-2 positive by American Society of Clinical Oncology (ASCO) College of American Pathologists (CAP) 2013 guidelines by local laboratory. Central confirmation of HER-2 status is not required. * Immunohistochemistry (IHC) 3+ based on circumferential membrane staining that is complete, intense -AND/OR- * Fluorescence in situ hybridization (FISH) positive based on one of the three following criteria: ** Single-probe average HER2 copy number >= 6.0 signals/cell; OR ** Dual-probe HER2/CEP17 ratio >= 2.0 OR ** Dual-probe HER2/CEP17 ratio < 2.0 with an average HER2 copy number >= 6.0 signals/cell
- At least one measurable CNS lesion, 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 stereotactic radiosurgery (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 whole- brain radiation therapy 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 prior to start of protocol)
- Stable dose of dexamethasone 2 mg 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
- Absolute neutrophil count >= 1,000/ul (within 8 days prior to initiating protocol therapy)
- Platelets >= 75,000/ul (within 8 days prior to initiating protocol therapy)
- Hemoglobin >= 9 g/dL (within 8 days prior to initiating protocol therapy)
- Total bilirubin =< 1.5 mg/dL x institutional upper limit of normal except subject with documented Gilbert's syndrome (=< 5 x upper limit of normal [ULN]) or liver metastasis, who must have a baseline total bilirubin =< 3.0 mg/dL (within 8 days prior to initiating protocol therapy)
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 x institutional ULN OR =< 5.0 x institutional ULN for patients with documented liver metastases (within 8 days prior to initiating protocol therapy)
- Albumin > 2.5 mg/dL (within 8 days prior to initiating protocol therapy)
- Serum creatinine =< 1.5 x ULN (or glomerular filtration rate >= 60 ml/min as determined by the Cockcroft-Gault equation) (within 8 days prior to initiating protocol therapy)
- Female subjects of childbearing potential must have a negative serum or urine pregnancy test within 8 days of initiating protocol therapy; childbearing potential is defined as pre-menopausal women with intact uterus and ovaries
- Women of child-bearing potential and men must agree to use adequate contraception (barrier method of birth control; abstinence) prior to study entry, for the duration of study participation and 4 months after completion of atezolizumab administration
- Ability to understand and the willingness to sign a written informed consent document
- 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 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 > 2 mg/day or bioequivalent within 7 days of treatment initiation
- Patients unable to undergo gadolinium contrast-enhanced magnetic resonance imaging (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 planned treatment start
- 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 planned treatment start
- Subjects with a history of hypersensitivity to compounds of similar biologic composition to atezolizumab or any constituent of the product
- 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, chronic liver or renal disease, or severe malnutrition
- Pregnant women or women who are lactating/breastfeeding due to the teratogenic potential of the study drugs
- Active, second potentially life-threatening cancer
- Major surgery within 21 days of planned treatment start
- Active infection requiring iv antibiotics at treatment initiation
- 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 (e.g., 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
- Known human immunodeficiency virus (HIV), hepatitis B surface antigen (HepBsAg), or hepatitis C (HCV) ribonucleic acid (RNA); HIV-positive participants on combination antiretroviral therapy are ineligible because of the unclear effects of immune checkpoint inhibitors in this setting
- Live vaccines within 28 days of first dose of trial therapy and during trial treatment
- Known intolerance to trastuzumab or pertuzumab or atezolizumab
I. To evaluate the efficacy of atezolizumab in combination with pertuzumab and high-dose trastuzumab for the treatment of central nervous system (CNS) metastases in patients with HER2-positive metastatic breast cancer (MBC), as measured by overall response rate (ORR) in the CNS according to response assessment in neuro-oncology-brain metastases (RANO-BM) criteria.
I. To evaluate the safety, and tolerability of the combination of atezolizumab, pertuzumab and high-dose trastuzumab.
II. To evaluate the duration of response (DOR) in the CNS.
III. To evaluate the efficacy of the study combination, as defined by bi-compartmental progression-free survival (PFS) according to RANO-BM criteria.
IV. To evaluate the CNS response rates according to response assessment in immunotherapy neuro oncology-brain metastases (iRANO-BM) criteria.
V. To evaluate the extracranial ORR according Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.
VI. To evaluate the extracranial ORR according to immune-related response criteria (irRC).
VII. To evaluate clinical benefit rate at 18 and 24 weeks, defined as the proportion of participants with stable or responsive disease in both CNS and non-CNS at 18 and 24 weeks per RANO-BM criteria.
VIII. To evaluate PFS according to the RECIST 1.1 single-compartmental model.
IX. To describe the site of first progression (CNS versus [vs] extracranial vs both).
X. To evaluate the overall survival (OS) among patients included in this trial.
XI. To evaluate the impact of the experimental treatment on patient-reported outcome (PROs), as measured by the M.D. Anderson Symptom Inventory-Brain Tumor (MDASI-BT) assessment.
XII. To evaluate the impact of the study treatment, for these same patients, on investigator-assessed neurological evaluation, as measured by the Neurological Assessment in Neuro-Oncology (NANO) scale.
XIII. To evaluate the impact of the study treatment, for these same patients, on general health status assessed by European Quality of Life Five Dimension (EQ-5D) questionnaire.
I. To explore whether the number and/or type of mutations identified using a next generation sequencing (NGS) panel is correlated with patient outcomes (PFS, CNS ORR, clinical benefit rate [CBR], and OS).
II. To collect blood to study cell-free deoxyribonucleic acid (DNA) for quantification of tumor DNA content and copy number variation, using ultra-low pass whole genome sequencing, and to explore whether cell-free DNA (cfDNA) load is associated with patient outcomes (PFS, CNS ORR, CBR, and OS).
III. To collect blood to study cell-free DNA for targeted sequencing and/or whole exome sequencing to compare mutations and copy number variation between cfDNA and tumor biopsies.
IV. To characterize a broad array of immune markers in metastatic HER-2 positive breast cancer (characterization will be based on histology, protein expression, and messenger ribonucleic acid [mRNA] expression), and their changes with immune checkpoint blockade.
V. To explore how different immunosuppressive and/or immune-stimulating immune marker profiles at baseline correlate with patient outcomes (PFS, CNS ORR, CBR and OS).
VI. To characterize changes in immune marker profiles on treatment and at time of progression.
VII. To characterize serial changes in immune marker profile in peripheral blood mononuclear cells (PBMCs) and in plasma over the course of the trial treatment.
VIII. To explore whether induction of changes in the immunosuppressive and/or immune-stimulating immune marker profile in PBMC correlates with clinical outcomes (PFS, CNS ORR, and OS).
IX. To collect cerebrospinal fluid (CSF) to study cell-free DNA for quantification of tumor DNA content and copy number variation, using ultra-low pass whole genome sequencing, and to compare patterns of cfDNA serially over time in CSF compared to plasma.
X. To explore whether cfDNA load in CSF is associated with clinical outcomes (PFS, CNS ORR, complete response rate [CRR], and OS).
XI. To collect CSF to study cell-free DNA for targeted sequencing and/or whole exome sequencing before, on and after immunotherapy. To compare mutations and copy number variation between cfDNA in plasma versus CSF.
Patients receive atezolizumab intravenously (IV) over 30-60 minutes on day 1, pertuzumab IV over 30-60 minutes on day 1, and trastuzumab IV over 30-90 minutes on days 1, 8, and 15 of cycles 1-8 and day 1 of subsequent cycles. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days and then every 6-12 weeks or 6 months thereafter.
Trial Phase Phase II
Trial Type Treatment
Dana-Farber Harvard Cancer Center
Nancy Uan-Tsin Lin
- Primary ID 17-546
- Secondary IDs NCI-2018-00401
- Clinicaltrials.gov ID NCT03417544