I. To determine the safety and tolerability of atezolizumab and idasanutlin in patients with
estrogen receptor positive (ER+) metastatic breast cancer (mBC) (Phase I).
II. To determine the anti-tumor effect of atezolizumab and cobimetinib or idasanutlin in
patients with ER+ mBC (Phase II).
I. To determine the anti-tumor duration of effect of atezolizumab and cobimetinib or
idasanutlin in patients with ER+ mBC (Phase II).
II. To determine the safety and tolerability of atezolizumab and cobimetinib or idasanutlin
in patients with ER+ mBC (Phase II).
I. To evaluate if CD8+ T cells are enhanced in the tumor with either MEK or MDM2 inhibition
II. To evaluate if MHC-I/II and/or PD-L1 expression is enhanced with MEK inhibition (Phase
III. To evaluate if T cell chemotractants (CCL5, CXCL9,10,11,13) are upregulated upon MDM2
antagonism (Phase II).
IV. To determine if baseline or changes in PDL1 expression, MHC expression, presence of tumor
infiltrating lymphocytes, neoantigen expression/ mutation burden (using ribonucleic acid
[RNA]-and whole exome sequencing), CCL5, CXCL9, CXCL10, CXCL11, and CXCL13 correlate with
clinical outcome (Phase II).
V. To determine if immunological activity of MEK inhibition can be tracked noninvasively
using Zr^89-atezolizumab (Phase II).
OUTLINE: This is a phase 1, dose-escalation study of idasanutlin followed by a phase II
study. Participants are assigned to 1 of 2 arms.
ARM I: Participants with TP53 gene mutation receive atezolizumab intravenously (IV) over 60
minutes starting with day 15 of course 1 and then on days 1 and 15 of subsequent courses, and
cobimetinib orally (PO) daily on days 1-21. Courses repeat every 28 days in the absence of
disease progression or unacceptable toxicity.
ARM II: Participants without TP53 gene mutation receive atezolizumab IV over 60 minutes
starting with day 15 of course 1 and then on days 1 and 15 of subsequent courses, and
idasanutlin PO daily on days 1-5. Courses repeat every 28 days in the absence of disease
progression or unacceptable toxicity.
After completion of study treatment, participants are followed for 28 days.
- Signed and dated written informed consent.
- Subjects ≥ 18 years of age.
- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
- Clinical stage IV invasive mammary carcinoma or unresectable locoregional recurrence
of invasive mammary carcinoma that is:
- ER/PR-positive (> 1% cells) by IHC and HER2 negative per ASCO guidelines (by IHC
- Previously exposed to an aromatase inhibitor (AI) or a selective
estrogen-receptor modulator/ downregulator (SERM; SERD) + a CDK4/6 inhibitor
- Appropriate candidates for chemotherapy
- Amenable to biopsy at the time of study entry
- Adequate organ function including:
- Absolute neutrophil count (ANC) ≥ 1.5 × 109/L
- Platelets ≥ 100 × 109/L
- Hemoglobin ≥ 9/g/dL (may have been transfused)
- Total serum bilirubin ≤ 1.5 times upper limit of normal (ULN)
- Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) ≤
2.5 × ULN (or ≤ 5 × ULN if liver metastases are present)
- Serum creatinine ≤ 1.5 x ULN or estimated creatinine clearance ≥ 50 mL/min as
calculated using the Cockcroft-Gault (CG) equation
- Thyroid Stimulating Hormone (TSH) ≤ 1 x ULN
- Amylase ≤ 1 x ULN
- Lipase ≤ 1 x ULN
- CPK ≤ 1.5 x ULN
- LVEF (echo) ≥ LLN (Cobi arm only)
- Female patients of childbearing potential must agree to use at least two methods of
acceptable contraception with a failure rate of < 1% per year from 15 days prior to
first trial treatment administration until at least 5 months after study participant's
final dose of study drugs. See appendix C for details.
Note: Females of childbearing potential are defined as those who are not surgically sterile
or post-menopausal (i.e. patient has not had a bilateral tubal ligation, a bilateral
oophorectomy, or a complete hysterectomy; or has not been amenorrheic for 12 months without
an alternative medical cause). Post-menopausal status in females under 55 years of age
should be confirmed with a serum follicle-stimulating hormone (FSH) level within laboratory
reference range for postmenopausal women.
- Patients unable to read/write in English are eligible to participate in the overall
study but will not participate in the Patient-Reported Outcome questionnaires
throughout the trial
- Re-enrollment of a subject that has discontinued the study as a pre-treatment screen
failure (i.e. a consented patient who did not receive study drugs) is permitted. If
re-enrolled, the subject must be re-consented. Only the screening procedures performed
outside of protocol-specified timing must be repeated.
- Prior therapy with anti-PD-L1 and anti-PD1 antibodies, MEK inhibitors or MDM2
- No more than 3 lines of chemotherapy in the metastatic setting
- No concurrent anticancer therapy. Required washout from prior therapy:
- Endocrine therapy: no required wash-out
- Chemotherapy: 14 days
- Major surgery: 14 days (provided wound healing is adequate)
- Radiation: 7 days
- Investigational/Biologic Therapy (half -life ≤ 40 hours): 14 days
- Investigational/Biologic Therapy (half -life > 40 hours): 28 days
- Use of corticosteroids or immunosuppressive medication is exclusionary, except
the following in the absence of active autoimmune disease:
- Subjects are permitted the use of corticosteroids with minimal systemic
absorption (e.g. topical, ocular, intra-articular, intranasal, and inhaled);
- Systemic corticosteroids at physiologic doses ≤10 mg/day of prednisone or
equivalent are permitted;
- Adrenal replacement steroid doses including doses > 10 mg daily prednisone
- A brief (less than 3 weeks) course of corticosteroids for prophylaxis (e.g.
CT scan premedication against contrast dye allergy) or for treatment of
non-autoimmune conditions (e.g. delayed-type hypersensitivity reaction
caused by a contact allergen) is permitted.
- Previous malignant disease other than breast cancer within the last 5 years, with the
exception of basal or squamous cell carcinoma of the skin, cervical carcinoma in situ,
or low-risk cancers considered curatively treated (i.e. complete remission achieved at
least 2 years prior to first dose of study drugs AND additional therapy not required
while receiving study treatment).
- All subjects with brain metastases, except those meeting the following criteria:
- Brain metastases that have been treated locally and are clinically stable for at
least 2 weeks prior to enrollment
- No history of intracranial or spinal cord hemorrhage
- No evidence of interim CNS disease progression
- Metastasis to the midbrain, pons, and medulla
- No ongoing neurological symptoms that are related to the brain localization of
the disease (sequelae that are a consequence of the treatment of the brain
metastases are acceptable.
- Subjects must be either off steroids or on a stable or decreasing dose of ≤ 10 mg
daily prednisone (or equivalent)
- Receipt of any organ transplantation including allogeneic stem-cell transplantation.
- Significant acute or chronic infections including, among others:
- Known history of testing positive for human immunodeficiency virus (HIV), or
acquired immunodeficiency syndrome (AIDS).
- Active tuberculosis
- Positive test for hepatitis B virus (HBV) surface antigen (and/or core antibody)
and/or confirmatory hepatitis C virus (HCV) RNA (if anti-HCV antibody tested
- Active autoimmune disease with reasonable possibility of clinically significant
deterioration when receiving an immunostimulatory agent:
- Subjects with Type 1 diabetes mellitus, vitiligo, psoriasis, hypo- or
hyperthyroid disease not requiring immunosuppressive treatment are eligible.
- Subjects requiring hormone replacement with corticosteroids are eligible if the
steroids are administered only for the purpose of hormonal replacement and at
doses ≤ 10 mg or 10 mg equivalent prednisone per day.
- Administration of steroids through a route known to result in a minimal systemic
exposure (topical, intranasal, intro-ocular, or inhalation) are acceptable.
- Interstitial lung disease that is symptomatic or which may interfere with the
detection or management of suspected drug-related pulmonary toxicity.
- Uncontrolled asthma [defined as having 3 or more of the following features of
partially controlled asthma within 28 days prior to starting study treatment: Daytime
symptoms more than twice per week, any limitation of activities, any nocturnal
symptoms/awaking, need for reliever/rescue inhaler more than twice per week, or known
lung function (PEF or FEV1) without administration of a bronchodilator that is < 80%
predicted or personal best (if known)].
- Current symptomatic congestive heart failure (New York Heart Association > class II),
unstable cardiac arrhythmia requiring therapy (e.g. medication or pacemaker), unstable
angina (e.g. new, worsening or persistent chest discomfort), or uncontrolled
hypertension (systolic > 160 mmHg or diastolic > 100mmHg). Or any of the following
occurring within 6 months (180 days) prior to first dose of study drugs: Myocardial
infarction, coronary/peripheral artery bypass graft, cerebrovascular accident or
transient ischemic attack. (Use of antihypertensive medication to control blood
pressure is allowed.)
- Concurrent treatment with a non-permitted drug (refer to prohibited medication list)
as well as foods or supplements that are strong or moderate CYP3A4 enzyme inducers or
inhibitors. Any of the above has to be discontinued at least 7 days prior to Cycle 1/
Day 1 of study treatment.
- Requirement of anticoagulant therapy with oral vitamin K antagonists such as Coumadin
(warfarin). Low-dose anticoagulants for the maintenance of patency in a central venous
access device or the prevention of deep vein thrombosis or pulmonary embolism is
allowed. Therapeutic use of low molecular weight heparin is allowed provided patients
are safely able to interrupt it prior to biopsy procedures.
- Persisting toxicity related to prior therapy that has not reduced to Grade 1 [National
Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) version 5.0];
however, alopecia and sensory neuropathy Grade ≤ 2 are acceptable and Grade ≤ 2
non-hematological toxicities well controlled with medical management are allowed (for
example: hypomagnesemia well controlled on magnesium replacement).
- Known severe (Grade ≥ 3 NCI-CTCAE) hypersensitivity reactions to monoclonal
antibodies, or history of anaphylaxis.
- Vaccination within 28 days of the first dose of study drugs and while on trial is
prohibited, except for administration of inactivated vaccines (for example,
inactivated influenza vaccine).
- Pregnant or breastfeeding females.
- Known current alcohol or drug abuse
- Prisoners or subjects who are involuntarily incarcerated.
- Known psychiatric condition, social circumstance, or other medical condition
reasonably judged by the patient's study physician to unacceptably increase the risk
of study participation; or to prohibit the understanding or rendering of informed
consent or anticipated compliance with scheduled visits, treatment schedule,
laboratory tests and other study requirements.
- Known risk factors for ocular toxicity, consisting of any of the following (Cobi arm
- presence of serous retinopathy within 6 months of protocol enrollment
- presence of retinal vein occlusion (RVO) within 6 months of protocol enrollment