| Eligibility |
Inclusion Criteria:
1. Signed Informed Consent Form
2. Women or men aged =18 years
3. Histologically or cytologically confirmed adenocarcinoma of the breast with metastatic
disease
4. Hormone receptor-negative (ER and PgR < 10%) and HER2-negative (IHC 0,1+ or 2+ ISH not
amplified) breast cancer, based on the status of the primary tumor and/or the biopsy
of metastatic disease before starting first-line therapy and assessed by local
laboratory.
5. Patients ER and PgR < 1% eligible to receive atezolizumab in combination with
nab-paclitaxel as standard of care treatment for metastatic triple-negative breast
cancer (TNBC), regardless of study participation.
6. PD-L1 positive defined as expression on tumor-infiltrating immune cells =1% (SP142
PD-L1 immunohistochemical assay, Ventana Medical Systems), based on the status of the
primary tumor and/or the biopsy of metastatic disease before starting first-line
therapy and assessed by local laboratory
7. Availability of a representative tumor specimen for translational research
8. Eligible for first-line taxane and carboplatin chemotherapy
9. No prior chemotherapy or targeted systemic therapy (including endocrine therapy) for
inoperable locally advanced or metastatic TNBC. Prior radiation therapy for metastatic
disease is permitted. There is no required minimum washout period for radiation
therapy; however, patients should have recovered from the effects of radiation before
enrollment
10. Previous chemotherapy with taxanes and/or carboplatin for early breast cancer
(neoadjuvant or adjuvant setting) is permitted if completed =12 months before study
entry
11. Previous therapy with immune checkpoint inhibitors for early breast cancer
(neoadjuvant or adjuvant setting) is permitted if completed =12 months before study
entry
12. ECOG performance status of 0 or 1
13. Life expectancy = 12 weeks
14. Measurable or evaluable disease as defined by RECIST v1.1.
15. Adequate hematologic and end-organ function, defined by laboratory results obtained
within 2 weeks prior to the first study treatment (Cycle 1, Day 1)
16. Negative human immunodeficiency virus (HIV) test at screening
17. Negative hepatitis B surface antigen (HBsAg) test at screening
18. Negative total hepatitis B core antibody (HBcAb) test at screening, or positive HBcAb
test followed by a negative hepatitis B virus (HBV) DNA test at screening. The HBV DNA
test will be performed only for patients who have a positive HBcAb test
19. Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody
test followed by a negative HCV RNA test at screening. The HCV RNA test will be
performed only for patients who have a positive HCV antibody test
20. Women of child bearing potential must agree to either use a contraceptive method with
a failure rate of = 1% per year or to remain abstinent (refrain from heterosexual
intercourse) during the treatment period and for at least 5 months after the last dose
of atezolizumab, or for at least 6 months after the last dose of paclitaxel. 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, hormonal
contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and
copper intrauterine devices. The reliability of sexual abstinence should be evaluated
in relation to the duration of the clinical trial and the preferred and usual
lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation,
symptothermal, or post-ovulation methods) and withdrawal are not acceptable methods of
contraception
21. Women of child bearing potential must have a negative serum pregnancy test result
within 7 days prior to initiation of study drug
22. For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use
contraceptive measures and agreement to refrain from donating sperm
Exclusion Criteria:
1. 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 at least 2 weeks prior to enrollment.
2. Known central nervous system (CNS) disease, except for treated asymptomatic CNS
metastases, provided all of the following criteria are met:
1. No ongoing requirement for corticosteroids as therapy for CNS disease
(anticonvulsants at a stable dose are allowed)
2. No stereotactic radiation within 7 days or whole-brain radiation within 14 days
prior to enrollment
3. No evidence of progression or hemorrhage after completion of CNS directed therapy
Note: Patients with new asymptomatic CNS metastases detected at the screening
scan must receive radiation therapy and/or surgery for CNS metastases. Following
treatment, these patients may then be eligible, if all other criteria above are
met.
3. Uncontrolled pleural effusion, pericardial effusion, or ascites (Note: patients with
indwelling catheters, such as PleurX® are allowed)
4. Uncontrolled tumor-related pain
1. Patients requiring narcotic pain medication must be on a stable regimen at study
entry.
2. Symptomatic lesions (e.g., bone metastases or metastases causing nerve
impingement) amenable to palliative radiotherapy should be treated prior to
enrollment. Patients should be recovered from the effects of radiation. There is
no required minimum recovery period.
3. 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 enrollment.
5. Uncontrolled hypercalcemia (>1.5 mmol/L [>6 mg/dL] ionized calcium or serum calcium
[uncorrected for albumin] >3 mmol/L [>12 mg/dL] or corrected serum calcium >ULN) or
clinically significant (symptomatic) hypercalcemia
a) Patients who are receiving bisphosphonate therapy or denosumab specifically to
prevent skeletal events and who do not have a history of clinically significant
(symptomatic) hypercalcemia are eligible.
6. Malignancies other than TNBC within 5 years prior to enrollment, 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, non-melanoma skin
carcinoma, or Stage I uterine cancer)
7. Pregnant or lactating women, or intending to become pregnant during the study
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 first
dose, unstable arrhythmias, or unstable angina
1. Patients with a known left ventricular ejection fraction (LVEF) < 40% will be
excluded
2. 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. Presence of an abnormal electrocardiogram (ECG) that is clinically significant in the
investigator's opinion, including complete left bundle branch block, second- or third
degree heart block, evidence of prior myocardial infarction, or QT interval corrected
using Fridericia's formula (QTcF) >470 ms demonstrated by at least two consecutive
ECGs
11. Serious infection requiring antibiotics within 2 weeks prior to enrollment, including
but not limited to infections requiring hospitalisation or IV antibiotics, such as
bacteremia, or severe pneumonia
12. Major surgical procedure within 4 weeks prior to enrollment or anticipation of the
need for a major surgical procedure during the study other than for diagnosis Note:
Placement of central venous access catheter(s) (e.g., port or similar) is not
considered a major surgical procedure and is therefore permitted
13. Treatment with investigational therapy within 30 days prior to initiation of study
treatment
14. 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 (CHO) cells or any component of the atezolizumab formulation
16. History of autoimmune disease, including but not limited to myasthenia gravis,
myositis, autoimmune hepatitis, systemic lupus erythematosus (SLE), rheumatoid
arthritis (RA), inflammatory bowel disease, vascular thrombosis associated with
antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome,
Guillain-Barré syndrome, multiple sclerosis (MS), vasculitis, or glomerulonephritis
(Note: Patients with a history of autoimmune-related hypothyroidism on a stable dose
of thyroid replacement hormone and patients with controlled Type 1 diabetes mellitus
on a stable insulin regimen may be eligible for this study)
17. Prior allogeneic stem cell or solid organ transplantation
18. History of idiopathic pulmonary fibrosis (IPF, including pneumonitis), drug-induced
pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic
organizing pneumonia), or evidence of active pneumonitis on screening chest CT scan.
(Note: History of radiation pneumonitis in the radiation field [fibrosis] is
permitted)
19. Positive test for human immunodeficiency virus (HIV)
20. Active hepatitis B (positive hepatitis B surface antigen [HBsAg] test or hepatitis B
virus [HBV] DNA polymerase chain reaction [PCR] test at screening) or hepatitis C
(positive hepatitis C virus antibody test at screening). Note:
- Patients with past HBV infection or resolved HBV infection (defined as having
negative HBsAg and HBV DNA test but a positive hepatitis B core antibody [HBcAb]
test) are eligible
- Patients positive for hepatitis C virus (HCV) antibody are eligible only if PCR
is negative for HCV ribonucleic acid (RNA)
21. Current treatment with anti-viral therapy for HBV
22. Active tuberculosis
23. Receipt of a live, attenuated vaccine within 4 weeks prior to enrollment or
anticipation that such a live, attenuated vaccine will be required during the study
Note: Patients must agree not to receive live, attenuated influenza vaccine (e.g.,
FluMist®) within 28 days prior to enrollment, during treatment or within 5 months
following the last dose of atezolizumab
24. Treatment with systemic immunostimulatory agents (including but not limited to
interferons or interleukin [IL]-2) within 4 weeks or five half-lives of the drug
(whichever is longer) prior to enrollment
25. Treatment with systemic immunosuppressive medications (including but not limited to
corticosteroids, cyclophosphamide, azathioprine, cyclosporine, methotrexate,
thalidomide, and antitumour necrosis factor [TNF] agents) within 2 weeks prior to
enrollment, or anticipated requirement for systemic immunosuppressive medications
during the trial
1. Patients who have received acute, low-dose (= 10 mg oral prednisone or
equivalent), systemic immunosuppressant medications may be enrolled in the study
2. Patients with a history of allergic reaction to IV contrast requiring steroid
pretreatment should have baseline and subsequent tumor assessments performed
using MRI
3. The use of corticosteroids (= 10 mg oral prednisone or equivalent) for chronic
obstructive pulmonary disease, mineralocorticoids (e.g., fludrocortisone) for
patients with orthostatic hypotension, and low dose supplemental corticosteroids
for adrenocortical insufficiency are allowed
26. Poor peripheral venous access
27. Illicit drug or alcohol abuse within 12 months prior to screening, in the
investigator's judgment
28. Any other serious medical condition or abnormality in clinical laboratory tests that,
in the investigator's judgment, precludes the patient's safe participation in and
completion of the study
29. History of hypersensitivity reactions to paclitaxel or other drugs formulated in the
same solvent as nab-paclitaxel
30. History of hypersensitivity reactions to carboplatin
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