NSABP B-59/GBG 96-GeparDouze is a prospective, randomized, double-blind, Phase III clinical
trial. This is a collaborative study being conducted by NSABP Foundation, Inc. in partnership
with the German Breast Group (GBG), and supported by funding by Genentech, a Member of the
Roche Group, and F. Hoffmann-La Roche, Ltd.
In this clinical trial of neoadjuvant and adjuvant administration of atezolizumab/placebo in
patients with high risk triple-negative breast cancer, the potential incremental efficacy and
safety of neoadjuvant administration of atezolizumab/placebo with a sequential regimen of
weekly paclitaxel with every-3-week carboplatin followed immediately by neoadjuvant
administration of atezolizumab/placebo with AC/EC will be evaluated. Patients will then
undergo surgery. Following recovery from surgery, patients will initiate approximately 6
months of adjuvant therapy with atezolizumab/placebo and receive the same investigational
agent they received pre-operatively. Administration of radiation therapy will be based on
local standards at the discretion of patients and investigators, but if administered,
atezolizumab/placebo will be administered concurrently.
The primary aims of the study are 1) to determine value of atezolizumab in improving
pathologic complete response in the breast and post-therapy lymph nodes evaluated
histologically (pCR breast and nodes [(ypT0/Tis ypN0)]), and 2) to determine the value of
atezolizumab in improving event-free survival (EFS). Secondary aims include: pathologic
complete response in the breast (ypT0/Tis); pathologic complete response in the breast and
lymph nodes (ypT0 ypN0); positive nodal status conversion rate; overall survival;
recurrence-free interval: distant disease-free survival; brain metastases free survival; and
toxicity. The stratification factors for the study are: 1) clinical size of the primary tumor
(1.1-3.0 cm; > 3.0 cm); 2) nodal status as determined by protocol-specified criteria
(negative, positive); 3) AC/EC (every 2 weeks; every 3 weeks); and 4) Region (North America;
Europe).
For patient eligibility, local testing on the diagnostic core must have determined the
patient's tumor to be ER-negative, PgR-negative, and HER2-negative by current ASCO/CAP
guidelines. Material from either the diagnostic core biopsy or the research biopsy must be
sent for central testing for confirmation of ER, PgR, and HER2 to confirm eligibility. If
local testing has determined a tumor to be HER2 equivocal or to have a borderline ER/PgR
status (% IHC staining < 10% for both), material may be submitted for central testing to
determine eligibility.
In order to proactively identify and further assess any cardiac toxicity that may occur with
the combination of anthracyclines and atezolizumab, this study includes a cardiac safety
lead-in for the first 60 patients who initiate AC/EC. The safety lead-in will consist of
assessment of ECG and serum troponin-T obtained just prior to administration of the first
dose of AC/EC, following completion of the administration of the 1st and 3rd cycle of AC/EC
prior to initiation of the atezolizumab/placebo. An additional assessment of LVEF with
echocardiogram or MUGA scan will also be obtained prior to the 3rd dose of AC/EC. In order to
provide an early assessment of cardiac safety, results of the troponin-T assessments, ECGs,
LVEF assessment, and cardiac safety data will be evaluated by the Data Safety Monitoring
Board (DSMB) when the last of the initial 20 patients who initiate AC/EC undergo their
scheduled post-surgery LVEF assessment. When the last of the first 60 patients to initiate
AC/EC undergo their scheduled post-surgery LVEF assessment, results of the troponin
assessments, ECGs, LVEF assessments, and cardiac safety data from all 60 patients will be
evaluated by the DSMB.
Research core biopsies of breast primary at baseline and 1-4 days prior to the second dose of
atezolizumab/placebo are a study requirement for all patients. One to three representative
blocks of residual primary tumor containing the maximum amount of tumor and node with the
largest focus of metastasis is required from the definitive breast surgery if gross residual
disease is greater than or equal to 1.0 cm. If gross residual disease is less than 1.0 cm,
tissue should be submitted, if possible. Blood specimens will be collected on all patients at
baseline for exploratory biomarker analysis and to support future correlative studies.
Accrual for this study will be 1,520 randomized patients. It is expected that approximately
760 patients will be randomized by sites in North America and approximately 760 patients, by
sites in Europe.
Inclusion Criteria:
- The patient must have consented to participate and, prior to beginning specific study
procedures, must have signed and dated an appropriate IRB-approved consent form that
conforms to federal and institutional guidelines for study treatment and for
submission of tumor samples from a research biospy as required by NSABP B-59/GBG
96-GeparDouze for baseline correlative science studies.
- The diagnosis of invasive adenocarcinoma of the breast must have been made by core
needle biopsy.
- Local testing on the diagnostic core must have determined the tumor to be ER-negative,
PgR-negative, and HER2-negative by current ASCO/CAP guidelines. (If local testing has
determined a tumor to be HER2 equivocal or to have a borderline ER/PgR status (% IHC
staining < 10% for both) and other eligibility criteria are met, material may be
submitted for central testing to determine eligibility.)
- Central testing for ER, PgR, and HER2 will be performed, and the tumor must be
determined to be ER-negative, PgR-negative, and HER2-negative by current ASCO/CAP
Guidelines Recommendations.
- The tumor specimen used for central ER, PgR, and HER2 testing must also be used for
central testing of PD-L1 status using the Ventana PD-L1 testing result including PD-L1
indeterminate Patients will be classifies as positive, negative, or indeterminate for
stratification purposes.
- Patients must be ≥ 18 years old.
- Patient may be female or male.
- The ECOG performance status must be 0-1.
- The primary tumor can be clinical stage T2 or T3, if clinically node negative
according to AJCC 7th Edition. If the regional lymph nodes are cN1 and cytologically
or histologically positive or cN2-N3 with or without a biopsy, the primary breast
tumor can be clinically T1c, T2, or T3.
- Ipsilateral axillary lymph nodes must be evaluated by imaging (mammogram, ultrasound,
and/or MRI) within 84 days prior to study entry. If suspicious or abnormal, FNA or
core biopsy is recommended. Findings of these evaluations will be used to define the
nodal status prior to study entry according to the following criteria:
- Nodal status - negative (Imaging of the axilla is negative; Imaging is suspicious
or abnormal but the FNA or core biopsy of the questionable node[s] on imaging is
negative)
- Nodal status - positive (FNA or core biopsy of the node[s] is cytologically or
histologically suspicious or positive; Imaging is suspicious or abnormal but FNA
or core biopsy was not performed.)
- Patients with synchronous bilateral or multicentric HER2-negative breast cancer are
eligible as long as the highest risk tumor is ER-negative and PgR-negative and meets
stage eligibility criteria. All of the other invasive tumors must also be
HER2-negative by ASCO/CAP Guidelines based on local testing. Central testing to
confirm TNBC status is only required for the highest risk tumor.
- Blood counts performed within 28 days prior to randomization must meet the following
criteria:
- ANC must be ≥ 1500/mm3;
- platelet count must be ≥ 100,000/mm3; and
- hemoglobin must be ≥10 g/dL.
- The following criteria for evidence of adequate hepatic function performed within 28
days prior to randomization must be met:
- total bilirubin must be ≤ ULN for the lab unless the patient has a bilirubin
elevation > ULN to 1.5 x ULN due to Gilbert's disease or similar syndrome
involving slow conjugation of bilirubin; and
- alkaline phosphatase must be ≤ 2.5 x ULN for the lab; and
- AST and ALT must be ≤ 1.5 x ULN for the lab.
- Patients with AST or ALT or alkaline phosphatase > ULN are eligible for inclusion in
the study if liver imaging (CT, MRI, abdominal ultrasound, PET-CT, or PET scan)
performed within 28 days prior to randomization does not demonstrate metastatic
disease and the requirements in criterion (just above) are met.
- Patients with alkaline phosphatase that is > ULN but less than or equal to 2.5 x ULN
or with unexplained bone pain are eligible for inclusion in the study if bone imaging
(bone scan, PET-CT scan, or PET scan) supported by additional studies when indicated
(CT, x-ray, MRI) performed within 28 days prior to randomization does not demonstrate
metastatic disease.
- Patients with N2 or N3 nodal disease or T3 primary disease must undergo liver and bone
imaging (as described in 4.1.13 and 4.1.14) within 28 days prior to randomization,
irrespective of baseline lab results, and studies must not demonstrate metastatic
disease. Chest imaging with chest x-ray PA and Lateral, CT of the chest, or PET-CT
must also be performed.
- Creatinine clearance ≥ 50 mL/min (see Section 7.2.1 for instructions regarding
calculation of creatinine clearance) performed within 28 days prior to randomization.
- PT/INR ≤ ULN within 28 days of randomization. Patients receiving therapeutic
anti-coagulants are not eligible.
- A serum TSH and AM (morning) cortisol performed within 28 days prior to randomization
to obtain a baseline value. Patients with abnormal TSH or AM cortisol baseline levels
should be further evaluated and managed per institutional standards. Asymptomatic
patients who require initiation or adjustment of medication or are followed without
initiating treatment based on endocrinologist's recommendations are eligible.
- LVEF assessment must be performed within 42 days prior to randomization. (LVEF
assessment performed by echocardiogram is preferred; however, MUGA scan may be
substituted based on institutional preferences.) The LVEF must be ≥ 55% regardless of
the cardiac imaging facility's lower limit of normal.
- For women of childbearing potential: agreement 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 atezolizumab/placebo or 12 months after the last dose of chemotherapy.
- A woman is considered to be of childbearing potential if she is not
postmenopausal, 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 partner sterilization; hormonal contraceptives
that inhibit ovulation; hormone-releasing intrauterine devices; copper
intrauterine devices.
- The reliability of sexual abstinence should be evaluated in relation to the
duration of the clinical study and the preferred and usual lifestyle of the
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or
postovulation methods) and withdrawal are not acceptable methods of
contraception.
- Patient must be willing and able to comply with scheduled visits, treatment plans,
laboratory tests, and other study procedures.
Exclusion Criteria:
- Excisional biopsy or lumpectomy performed prior to study entry.
- FNA alone to diagnose the breast cancer.
- Surgical axillary staging procedure prior to randomization. Exception: FNA or core
biopsy of an axillary node is permitted for any patient. A pre-neoadjuvant therapy
sentinel lymph node biopsy for patients with clinically negative axillary nodes is
prohibited.
- Definitive clinical or radiologic evidence of metastatic disease.
- Previous history of contralateral invasive breast cancer. (Patients with synchronous
and/or previous contralateral DCIS or LCIS are eligible.)
- Previous history of ipsilateral invasive breast cancer or ipsilateral DCIS. (Patients
with synchronous or previous ipsilateral LCIS are eligible.)
- History of non-breast malignancies (except for in situ cancers treated only by local
excision and basal cell and squamous cell carcinomas of the skin) within 5 years prior
to study entry.
- Treatment including radiation therapy, chemotherapy, or targeted therapy, for the
currently diagnosed breast cancer prior to randomization.
- Previous therapy with anthracyclines or taxanes for any malignancy.
- Cardiac disease (history of and/or active disease) that would preclude the use of the
drugs included in the treatment regimens. This includes but is not confined to:
- Active cardiac disease: angina pectoris that requires the use of anti-anginal
medication; ventricular arrhythmias except for benign premature ventricular
contractions; supraventricular and nodal arrhythmias requiring a pacemaker or not
controlled with medication; conduction abnormality requiring a pacemaker;
valvular disease with documented compromise in cardiac function; or symptomatic
pericarditis.
- History of cardiac disease: myocardial infarction documented by elevated cardiac
enzymes or persistent regional wall abnormalities on assessment of left
ventricular function within 6 months prior to randomization; history of
documented CHF; or documented cardiomyopathy.
- Uncontrolled hypertension defined as sustained systolic BP > 150 mmHg or diastolic BP
> 90 mmHg. (Patients with initial BP elevations are eligible if initiation or
adjustment of BP medication lowers pressure to meet entry criteria.) Patients
requiring ≥ 3 BP medications are not eligible.
- History of severe allergic, anaphylactic, or other hypersensitivity reactions to
chimeric or humanized antibodies or fusion proteins.
- Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells.
- Known allergy or hypersensitivity to the components of the atezolizumab formulation.
- Known allergy or hypersensitivity to the components of the doxorubicin, epirubicin,
cyclophosphamide, carboplatin, or paclitaxel formulations.
- Known allergy or hypersensitivity to liposomal or pegylated G-CSF formulations.
- Active or history of autoimmune disease or immune deficiency, including but not
limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus
erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid
syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or
multiple sclerosis for a more comprehensive list of autoimmune diseases and immune
deficiencies) with the following exceptions:
- Patients with a history of autoimmune-related hypothyroidism on a stable dose of
thyroid replacement hormone may be eligible for this study.
- Patients with controlled Type 1 diabetes mellitus on a stable dose of insulin
regimen may be eligible for this study.
- Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with
dermatologic manifestations only (e.g., patients with psoriatic arthritis are
excluded) are permitted provided all of following conditions are met: Rash must
cover < 10% of body surface area; Disease is well controlled at baseline and
requires only low-potency topical corticosteroids; No occurrence of acute
exacerbations of the underlying condition requiring psoralen plus ultraviolet A
radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors,
or high-potency or oral corticosteroids within the previous 12 months.
- History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis
obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active
pneumonitis on screening chest CT scan.
- Patients known to be HIV positive.
- Active hepatitis B virus (HBV) infection, defined as having a positive hepatitis B
surface antigen (HBsAg) test at screening. Patients with a past or resolved HBV
infection, defined as having a negative HBsAg test and a positive total hepatitis B
core antibody (HBcAb) test at screening, are eligible for the study if active HBV
infection is ruled out on the basis of HBV DNA viral load per local guidelines.
- Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody
test at screening confirmed by a polymerase chain reaction (PCR) positive for HCV RNA.
- Patients with clinically active tuberculosis.
- Severe infection within 28 days prior to randomization, including but not limited to
hospitalization for complications of infection, bacteremia, or severe pneumonia.
- Prior allogeneic stem cell or solid organ transplantation.
- Administration of a live, attenuated vaccine within 28 days prior to randomization or
anticipation that such vaccine will be required during the study. Patients must agree
not to receive live, attenuated influenza vaccine (e.g., FluMist) within 28 days prior
to randomization, during treatment or within 5 months following the last dose of
atezolizumab/placebo.
- Any other disease, metabolic dysfunction, physical examination finding, or clinical
laboratory finding giving reasonable suspicion of a disease or condition that
contraindicates the use of an investigational drug or that may affect the
interpretation of the results or render the patient at high risk from treatment
complications.
- Prior treatment with CD137 agonists or immune checkpoint-blockade therapies, including
anti-CD40, anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies.
- Treatment with systemic immunosuppressive medications (including but not limited to
interferons, IL-2) within 28 days or 5 half-lives of the drug, whichever is longer,
prior to randomization.
- Treatment with systemic immunosuppressive medications (including but not limited to
prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor
necrosis [anti-TNF] factor agents) within 14 days prior to randomization or
anticipation of need for systemic immunosuppressive medications during the study.
- Nervous system disorder (paresthesias, peripheral motor neuropathy, or peripheral
sensory neuropathy) ≥ Grade 2, per the CTCAE v4.0.
- Symptomatic peripheral ischemia.
- Pregnancy or lactation at the time of randomization or intention to become pregnant
during the study. (Note: Negative serum pregnancy test must be obtained within 14 days
prior to randomization).
- Use of any investigational agent within 28 days prior to randomization.
