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.
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.
