| Eligibility |
Inclusion Criteria:
1. Metastatic or incurable locally advanced, histologically documented TNBC (negative for
HER2, ER and PR ). HER2 negativity is defined as either of the following by local
laboratory assessment: In situ hybridization (ISH) non-amplified (ratio of HER2 to
CEP17 < 2.0 or single probe average HER2 gene copy number < 4 signals/cell), or IHC 0
or IHC 1+ (if more than one test result is available and not all results meet the
inclusion criterion definition, all results should be discussed with the PI to
establish eligibility of the patient). ER and PR negativity are defined as < 1% and
<10%, respectively, of cells expressing hormonal receptors via IHC analysis
2. Adequate newly obtained core or excisional biopsy of a tumor lesion not previously
irradiated. No anti-tumor treatment is allowed between the time point for biopsy and
study entry. If a patient has undergone chemotherapy in the metastatic setting, a new
biopsy must be obtained after this therapy
3. Measurable disease according to iRECIST
4. Signed Informed Consent Form
5. Women or men aged = 18 years
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
7. In patients that have received (neo)adjuvant treatment with anthracyclines or
cyclophosphamide, a minimum of 12 months from treatment with anthracyclines or
cyclophosphamide until relapse of disease is required
8. A maximum of one previous line with chemotherapy in the metastatic setting
9. Female subject of childbearing potential should have a negative urine or serum
pregnancy test 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
10. 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. A woman is considered to be of childbearing potential if
she is postmenarcheal, has not reached a postmenopausal state (= 12 continuous months
of amenorrhea with no identified cause other than menopause), and has not undergone
surgical sterilization (removal of ovaries and/or uterus). Examples of contraceptive
methods with a failure rate of < 1% per year include bilateral tubal ligation, male
sterilization, proper use of hormonal contraceptives that inhibit ovulation and
hormone-releasing intrauterine devices (IUDs). Periodic abstinence (e.g., calendar,
ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable
methods of contraception
11. Male subjects should agree to use an adequate method of contraception starting with
the first dose of study therapy through 3 months after the last dose of study therapy
12. Able to swallow orally administrated medication.
13. Adequate organ function as defined in Table 1 in the protocol.
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. Patients with known PD-L1 positive TNBC, as assessed by the Ventana SP142 assay (IC
=1%), and no previous chemotherapy in the metastatic setting, should be offered
standard therapy with nab-paclitaxel/atezolizumab outside of the trial, if they had a
disease free interval of >12 months after previous (neo)adjuvant chemotherapy, unless
the patient for other reasons should not receive nab-paclitaxel, according to own
preferences, drug availability or recommendations by the treating physician. A history
of progression on taxanes in the neoadjuvant setting, or severe side effects from
taxane therapy, may represent sufficient reason to offer the patient inclusion into
the the ALICE-trial, if the physician considers that the patient should receive
antracyclines rather than taxanes as 1st line therapy for metastatic disease. If more
than one TNBC biopsy has been evaluated for PD-L1 by the SP142 assay, and the results
differ, the patient's PD-L1 status determination will be based on best clinical
judgment.
3. 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 > 2 weeks prior to randomization
4. Known CNS disease, except for asymptomatic CNS metastases, provided all of the
following criteria are met:
1. Measurable disease outside the CNS
2. No metastases to mesencephalon, pons, medulla oblongata, or spinal cord
3. No ongoing requirement for dexamethasone as therapy for CNS disease
4. No radiation of brain lesions within 7 days prior to randomization
5. No leptomeningeal disease
6. Patients with symptomatic CNS metastases must receive radiation therapy and/or
surgery for CNS metastases. Following treatment, these patients may be eligible,
if all other criteria are met
5. Uncontrolled pleural effusion, pericardial effusion, or ascites. Patients with
indwelling catheters (e.g., PleurX®) are allowed
6. 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
7. Ionized calcium > 1.2 x UNL. The use of bisphosphonates is allowed
8. Pregnant or breastfeeding
9. 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)
10. 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
11. Severe infection within 14 days prior to randomization, requiring hospitalization
12. 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
13. Major surgical procedure within 14 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
14. A history of severe allergic, anaphylactic, or other hypersensitivity reactions to
chimeric or humanized antibodies or fusion proteins
15. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster
ovary cells or any component of the atezolizumab formulation
16. Known hypersensitivity to doxorubicin or cyclophosphamide or any of their excipients
17. 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)
18. Undergone allogeneic stem cell or solid organ transplantation
19. A history of idiopathic pulmonary fibrosis (including pneumonitis) drug-induced
pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic
organizing pneumonia), or evidence of active pneumonitis on screening chest CT scan.
History of radiation pneumonitis in the radiation field (fibrosis) is permitted
20. A positive test for HIV
21. 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
22. Active tuberculosis
23. 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
24. Received treatment with immune checkpoint modulators, including anti-CTLA-4,
anti-PD-1, or anti-PD-L1 therapeutic antibodies
25. 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
26. 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
27. Received anti-cancer therapy (medical agents or radiation) within 1 week prior to
study Cycle 1, Day 1.
28. 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
29. Known psychiatric or substance abuse disorders that would interfere with cooperation
and the requirements of the trial
30. Any reason why, in the opinion of the investigator, the patient should not
participate. This includes a careful evulation of whether standard therapy is
preferable to the study therapy, for the individual patient.
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