Triple-Negative First-Line Study: Neoadjuvant Trial of Nab-Paclitaxel and MPDL3280A, a Pdl-1 Inhibitor in Patients With Triple Negative Breast Cancer

Study Drug Administration:

Each study cycle is 21 days. You will receive the study drugs in 2 sets of 4 cycles (4 cycles before surgery and 4 cycles after surgery).

On Day 1 of Cycle 1, you will receive atezolizumab by vein over about 60 minutes.

On Day 1 of each later cycle before and after surgery, if you tolerated the first infusion, you will receive future infusions of atezolizumab by vein over 30 minutes.

You will receive nab-paclitaxel by vein over about 30 minutes on Days 1, 8, and 15 of Cycles 1-4 before surgery.

If you have side effects, the study doctor may decide to lower your dose of study drugs or have you stop taking the drugs. You may be able to restart the study drug later at the same or a lower dose. The study doctor will discuss this with you.

Study Visits:

On Day 1 of all cycles:

• You will have a physical exam.
• Blood (about 2 tablespoons) will be drawn for routine tests.
• During Cycle 3, you will have an ultrasound of your breast(s) before surgery. Additional imaging may be done as part of your routine care, if the doctor thinks it is needed.
• During Cycle 3, blood (about 1 tablespoon each time) will be drawn before surgery and at the time of surgery.

On Days 8 & 15 of Cycles 1-4, blood (about 2 tablespoons) will be drawn for routine testing.

Within 6 weeks after you have received 4 cycles of study drugs, you will have surgery as part of your standard of care and part of the tumor tissue that is removed during surgery will be collected for biomarker testing. You will be given a surgery consent form that describes the procedure and its risks.

On Day 21 of Cycle 8, blood (about 1 tablespoon) will be drawn for routine and biomarker testing.

Length of Treatment:

You may receive the study drugs for about 4 cycles before your surgery and about 4 cycles after your surgery (8 cycles total). You will no longer be able to take the study drug, if intolerable side effects occur, or if you are unable to follow study directions. You may be able to continue taking the study drugs if the disease gets worse if the doctor thinks it is in your best interest.

Your participation on the study will be over after follow-up.

Follow-Up:

Every 6 months for up to 3 years, you will either have a clinic visit or you will be called by a member of the study staff and asked how you are doing. If you are called, each call should last about 15-20 minutes.

This is an investigational study. Atezolizumab is not FDA approved or commercially available. It is currently being used for research purposes only. Nab-paclitaxel is FDA approved and commercially available for the treatment of metastatic (has spread) breast cancer. The study doctor can explain how the study drug combination is designed to work.

Up to 37 participants will be enrolled in this study. All will take part at MD Anderson.

• Drug: MPDL3280A

  1200 mg by vein every 3 weeks for 12 weeks before surgery.

  Within 4 weeks after surgery, participants start another 4 cycles of MPDL3280A.

  Other Name: Atezolizumab
• Drug: Nab-paclitaxel
  100 mg/m2 by vein weekly for 12 weeks before surgery.
  Other Names:

  • Paclitaxel
  • Abraxane
  • ABI-007

Inclusion Criteria:

1. Signed written informed consent
2. Histologically confirmed primary invasive adenocarcinoma of the breast with the size of the primary tumor being at least 1.5 cm, or at least 1 biopsy confirmed involved lymph node >1.5 cm, on imaging by either mammography, ultrasound or breast MRI.
3. ER and PR expression both <10% by immunohistochemistry (IHC) and HER2 negative or non-amplified as determined by the current ASCO-CAP criteria which are as follows: HER2 testing by IHC as 0 or 1+. If HER2 is 2+, ISH (in situ hybridization) must be performed. HER2 is positive for gene amplification if: IHC 3+ based on circumferential membrane staining that is complete, intense, ISH positive based on: Single-probe average HER2 copy number >/= 6.0 signals/cell. Dual-probe HER2/CEP17 ratio >/= 2.0;c,e with an average HER2 copy number >/=4.0 signals/cell Dual-probe HER2/CEP17 ratio >/= 2.0;c,e with an average HER2 copy number <4.0 signals/cell Dual-probe HER2/CEP17 ratio < 2.0;c,e with an average HER2 copy number >/= 6.0 signals/cell
4. No prior treatment for primary invasive adenocarcinoma of the breast such as irradiation, chemotherapy, hormonal therapy, immunotherapy, investigational therapy or surgery other than the anthracycline and cyclophosphamide chemotherapy with or without 5-fluorouracil given as part of participation in protocol 2014-0185. Treatment for ductal carcinoma in situ is allowed, such as surgery, hormonal therapy and radiotherapy
5. ECOG performance status of 0-1
6. Baseline MUGA or echocardiogram scans with LVEF of > 50%
7. Patient must have adequate organ function as determined by the following laboratory values: ANC >/= 1500 cells/uL, WBC counts > 2500/uL, Lymphocyte count >/= 300/uL, Platelet count >/=100,000/uL; Hemoglobin >/= 9.0 g/dL, Total bilirubin </= 1.5 x upper limit of normal (ULN) with the following exception: Patients with known Gilbert disease who have serum bilirubin level </= 3 x ULN may be enrolled. AST and ALT </= 3.0 x ULN, Alkaline phosphatase </= 2.5 x ULN
8. Continued from #7: Serum creatinine </= 1.5 x ULN or creatinine clearance >/= 50 mL/min on the basis of the Cockcroft-Gault glomerular filtration rate estimation: (140 - age) x (weight in kg) x (0.85 if female)/ 72 x (serum creatinine in mg/dL), INR and aPTT </= 1.5 x ULN. This applies only to patients who do not receive therapeutic anticoagulation; patients receiving therapeutic anticoagulation (such as low-molecular-weight heparin or warfarin) should be on a stable dose
9. Men or women 18 years of age or older
10. Women of childbearing potential must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 6 months after the last dose of investigational product in such a manner that the risk of pregnancy is minimized. Men on study and for at least 6 months after the last dose of nab-paclitaxel also must be using contraception. Women of childbearing potential (WOCBP) are women who have not been postmenopausal greater than 1 year or undergone a hysterectomy and/or bilateral oophorectomy.
11. Negative serum or urine pregnancy test for women within 72 hours of receiving the first dose of the study medication for women of childbearing potential
12. Participated on protocol 2014-0185 TNBC Neoadjuvant Triaging protocol and classified as having insufficient tumor shrinkage by imaging (<80% shrinkage after 4 cycles of anthracycline-based chemotherapy based upon diagnostic imaging).

Exclusion Criteria:

1. Women who are pregnant or breast-feeding
2. Known metastatic disease
3. Disease free of prior malignancy for < 5 years with the exception of curatively treated basal cell carcinoma of the skin, carcinoma in situ of the cervix, or transitional cell carcinoma.
4. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways)
5. Has had major surgery within 21 days before Cycle 1, Day 1
6. Uncontrolled inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis)
7. Myocardial infarction within 6 months before starting therapy, symptomatic congestive heart failure (New York Heart Association > class II), unstable angina, or unstable cardiac arrhythmia requiring medication
8. Serious intercurrent infections or non-malignant medical illness that are uncontrolled or the control of which may be jeopardized by this therapy
9. Psychiatric disorders or other conditions rendering the subject incapable of complying with the requirements of the protocols
10. History or risk of autoimmune disease, including but not limited to systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Bell's palsy, Guillain-Barré syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis. Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone may be eligible. Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen may be eligible
11. Continued from #9: Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis would be excluded) are permitted provided that they meet the following conditions: Patients with psoriasis must have a baseline ophthalmologic exam to rule out ocular manifestations Rash must cover less than 10% of body surface area (BSA) Disease is well controlled at baseline and only requiring low potency topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, fluocinolone 0.01%, desonide 0.05%, alclometasone dipropionate 0.05%) No acute exacerbations of underlying condition within the last 12 months (not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate, retinoids, biologic agents, oral calcineurin inhibitors; high potency or oral steroids)
12. Known to be human immunodeficiency virus positive
13. Patients with prior allogeneic stem cell or solid organ transplantation
14. 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
15. Patients with 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 is negative for HCV RNA
16. Active tuberculosis
17. Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1 or anticipation that such a live, attenuated vaccine will be required during the study. Influenza vaccination should be given during influenza season only (approximately October to March). Patients must not receive live, attenuated influenza vaccine (e.g., FluMist) within 4 weeks prior to Cycle 1, Day 1 or at any time during the study
18. 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
19. 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), or anticipated requirement for systemic immunosuppressive medications during the trial. Patients who have received acute, low dose, systemic immunosuppressant medications (e.g., dexamethasone prior to the anthracycline-based chemotherapy for nausea) may be enrolled in the study. The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) is allowed
20. Concurrent disease or condition that would interfere with study participation or safety, such as any of the following: Active, clinically significant infection either grade > 2 by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03 or requiring the use of parenteral anti-microbial agents within 14 days before Day 1 of study drug, Clinically significant bleeding diathesis or coagulopathy, including known platelet function disorders, Non-healing wound, ulcer, or bone fracture
21. Known hypersensitivity to any of the components of atezolizumab or nab-paclitaxel
22. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins