Atezolizumab Plus CArboplatin Plus Nab-paclitaxel

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