| Eligibility |
Inclusion Criteria:
1. Metastatic hormone receptor positive breast cancer (primary or recurrent), defined as
ER+ >1% in metastatic biopsy (archival material or study biopsy) or cytology and HER2
negative in the last biopsy or cytology evaluable for HER2. HER2-analysis is to be
perfomed according to national criteria.
2. Adequate core or excisional study biopsy of a tumor lesion. Lesions in previously
irradiated areas may only be used for the biopsy if the lesion has appared or
progressed after radiation. No anti-tumor treatment is allowed between the time point
for biopsy and study entry.
3. Measurable metastatic disease according to RECIST
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
5. Signed Informed Consent Form
6. Women or men aged = 18 years
7. A minimum of 12 months from adjuvant/neoadjuvant chemotherapy with antracyclins to
relapse disease
8. A maximum of one previous line with chemotherapy in the metastatic setting
9. Chemotherapy is considered as preferred treatment
10. Previous endocrine and targeted therapy is allowed
11. No use of systemic corticosteroids at study entry
12. Female subject of childbearing potential should have a negative urine or serum
pregnancy within 7 days prior to receiving the first dose of study medication. If the
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will
be required
13. Female subjects of childbearing potential should agree to remain abstinent (refrain
from heterosexual intercourse) or use contraceptive methods that result in a failure
rate of < 1% per year, during the treatment period and for at least 5 months after the
last dose of study therapy.
14. Male subjects should agree to use an adequate method of contraception starting with
the first dose of study therapy through 7 months after the last dose of study therapy
15. Able to swallow and retain orally administered medication
16. Adequate organ function as defined in Table 1
Exclusion Criteria:
1. Malignancies other than breast cancer within 5 years prior to randomization, with the
exception of those with a negligible risk of metastasis or death and treated with
expected curative outcome (such as adequately treated carcinoma in situ of the cervix
or basal or squamous cell skin cancer)
2. Spinal cord compression not definitively treated with surgery and/or radiation, or
previously diagnosed and treated spinal cord compression without evidence that disease
has been clinically stable for > 8 weeks prior to randomization
3. Known CNS disease, except for asymptomatic CNS metastases, provided all of the
following criteria are met:
1. Measurable disease outside the CNS
2. Asymptomatic for CNS disease > 4 weeks
3. No ongoing requirement for corticosteroids as therapy for CNS disease
4. No radiation of brain lesions within 2 weeks prior to randomization
5. No leptomeningeal disease
4. Uncontrolled pleural effusion, pericardial effusion, or ascites. Patients with
indwelling catheters (e.g., PleurX®) are allowed
5. Uncontrolled tumor-related pain. Patients requiring narcotic pain medication must be
on a stable regimen at study entry. Symptomatic lesions (e.g., bone metastases or
metastases causing nerve impingement) amenable to palliative radiotherapy should be
treated prior to randomization. Asymptomatic metastatic lesions whose further growth
would likely cause functional deficits or intractable pain (e.g., epidural metastasis
that is not presently associated with spinal cord compression) should be considered
for loco-regional therapy if appropriate prior to randomization
6. Ionized calcium > 1.2 x UNL. The use of bisphosphonates is allowed
7. Pregnant or breastfeeding
8. Evidence of significant uncontrolled concomitant disease that could affect compliance
with the protocol or interpretation of results, including significant liver disease
(such as cirrhosis, uncontrolled major seizure disorder, or superior vena cava
syndrome)
9. Significant cardiovascular disease, such as New York Heart Association (NYHA) cardiac
disease (Class II or greater), myocardial infarction within 3 months prior to
randomization, unstable arrhythmias, or unstable angina Patients with a known left
ventricular ejection fraction (LVEF) < 40% will be excluded. Patients with known
coronary artery disease, congestive heart failure not meeting the above criteria, or
LVEF < 50% must be on a stable medical regimen that is optimized in the opinion of the
treating physician, in consultation with a cardiologist if appropriate
10. Severe infection within 21 days prior to randomization, requiring hospitalization
11. Received oral or IV antibiotics within 1 week prior to Cycle 1, Day 1. Patients
receiving routine antibiotic prophylaxis (e.g., to prevent chronic obstructive
pulmonary disease exacerbation or for dental extraction) are eligible
12. Major surgical procedure within 21 days prior to randomization or anticipation of the
need for a major surgical procedure during the course of the study other than for
diagnosis. Placement of central venous access catheter(s) is not considered a major
surgical procedure and is therefore permitted
13. A history of severe allergic, anaphylactic, or other hypersensitivity reactions to
chimeric or humanized antibodies or fusion proteins
14. Known hypersensitivity to any of the components of the investigational products
15. A history of autoimmune disease that has required systemic treatment in the past 2
years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
drugs). Replacement therapy (e.g., thyroxin, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment. Patients with eczema, psoriasis, lichen simplex chronicus
or vitiligo with dermatologic manifestations only (e.g., no psoriatic arthritis) are
permitted provided that they meet all of the following conditions:
1. Rash must cover less than 10% of body surface area.
2. Disease is well controlled at baseline and only requiring low potency topical
steroids
3. No acute exacerbations of underlying condition within the last 12 months (not
requiring PUVA [psoralen plus ultraviolet A radiation], methotrexate, retinoids,
biologic agents, oral calcineurin inhibitors, high potency or oral steroids)
16. Undergone allogeneic stem cell or solid organ transplantation
17. A history of idiopathic pulmonary fibrosis pneumonitis, or evidence of active
pneumonitis on screening chest CT scan. History of radiation pneumonitis in the
radiation field (fibrosis) is permitted
18. A positive test for HIV
19. Active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg]
test at screening) or hepatitis C. Patients with past hepatitis B virus (HBV)
infection or resolved HBV infection (defined as having a negative HBsAg test and a
positive antibody to hepatitis B core antigen [anti-HBc] antibody test) are eligible.
Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase
chain reaction (PCR) is negative for HCV RNA
20. Active tuberculosis
21. Currently receiving study therapy or has participated in a study of an investigational
agent and received study therapy or used an investigational device within 4 weeks of
the first dose of treatment
22. Received treatment with immune checkpoint modulators, including anti-CTLA-4,
anti-PD-1, or anti-PD-L1 therapeutic antibodies
23. Received treatment with systemic immunostimulatory agents (including but not limited
to interferons or IL-2) within 4 weeks or five half-lives of the drug (whichever is
shorter) prior to randomization
24. Received treatment with systemic corticosteroids or other systemic immunosuppressive
medications (including but not limited to prednisone, dexamethasone, cyclophosphamide,
azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [TNF] agents)
within 2 weeks prior to randomization, or anticipated requirement for systemic
immunosuppressive medications during the trial
1. Patients who have received acute, low-dose, systemic immunosuppressant
medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled
in the study
2. Patients with a history of allergic reaction to IV contrast requiring steroid
pre-treatment should have baseline and subsequent tumor assessments performed
using MRI
3. The use of inhaled corticosteroids for chronic obstructive pulmonary disease,
mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic
hypotension, and low-dose supplemental corticosteroids for adrenocortical
insufficiency are allowed
25. Received anti-cancer therapy (medical agents or radiation) within 2 weeks prior to
study Cycle 1, Day 1. Palliative radiotherapy for bone lesions is allowed up to 7 days
before start of therapy.
26. A history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the subject's
participation for the full duration of the trial, or is not in the best interest of
the subject to participate, in the opinion of the treating Investigator
27. Known psychiatric or substance abuse disorders that would interfere with cooperation
and the requirements of the trial
28. Received a live vaccine within 30 days of planned start of study therapy, or is
expected to receive such a vaccine while on therapy
a. Seasonal influenza vaccines for injection are generally inactivated flu vaccines
and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live
attenuated vaccines, and are not allowed.
29. Any reason why, in the opinion of the investigator, the patient should not participate
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