Phase III Randomized, Double-Blind Trial of Atezolizumab with Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer Patients
- Trial ID
- 2023-508472-11-00
- Protocol
- NSABP B-59/GBG 96
- Sponsor
- NSABP Foundation Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this randomized, double-blind, Phase III clinical trial is to evaluate whether the addition of **atezolizumab** to chemotherapy, specifically weekly paclitaxel plus carboplatin followed by AC or EC, and subsequent adjuvant atezolizumab, enhances event-free survival (EFS) in patients with triple-negative breast cancer. This is clinically significant as improving EFS could potentially lead to better long-term outcomes and reduced recurrence rates in this aggressive subtype of breast cancer.
Secondary objectives include:
- Determining if the addition of atezolizumab improves overall survival (OS) in these patients.
- Assessing whether it enhances pathologic complete response (pCR) in the breast and post-therapy lymph nodes.
- Evaluating improvements in disease-free survival (DFS) and distant disease-free survival (DDFS).
- Evaluating the toxicity associated with the study therapy when added to chemotherapy and radiation therapy, as well as immune-adverse events of special interest.
- Assessing potential augmentation of anthracycline-related cardiac toxicity with the co-administration of the study therapy.
Participants
The clinical trial involves a total of **572 participants** diagnosed with early **breast cancer**, specifically focusing on those with triple-negative breast cancer. The study population includes both male and female subjects aged 18 years and older, with an **ECOG performance status** of 0-1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants were selected based on specific inclusion criteria, such as having ER-negative, PgR-negative, and HER2-negative tumors, as determined by local and central testing. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The selection process ensures that participants have adequate hepatic and renal function, as well as appropriate blood counts, to safely undergo the study treatments. The trial includes a vulnerable population, reflecting the careful consideration of ethical standards in participant selection.
Plans and Procedures
The clinical trial is designed as a **randomized, double-blind, controlled** study to evaluate the efficacy of adding **atezolizumab** to a chemotherapy regimen in patients with **triple-negative breast cancer**. The trial aims to assess whether this combination improves event-free survival (EFS) compared to a placebo. The study involves the administration of **atezolizumab** or placebo alongside a chemotherapy regimen consisting of weekly **paclitaxel** and **carboplatin**, followed by **doxorubicin** or **epirubicin** and **cyclophosphamide**. The trial is expected to last until November 2027, with participant recruitment having started in January 2018.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, including imaging and laboratory tests. Following randomization, participants will attend regular follow-up visits to monitor treatment response and adverse events. These visits will include assessments such as blood counts, liver function tests, and imaging studies to ensure the absence of metastatic disease. The end-of-study visit will occur after the completion of the treatment regimen, where final evaluations will be conducted to assess the primary and secondary endpoints, including EFS and overall survival.
The expected length of participant involvement is up to 52 weeks, depending on the treatment arm and individual response. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, or withdrawal of consent. Participants are required to comply with scheduled visits, treatment plans, and study procedures to remain in the trial. The trial's design ensures that all participants receive either the investigational drug or a placebo, maintaining the integrity of the double-blind methodology.
Treatment
The clinical trial involves the administration of several experimental and non-experimental treatments. **Atezolizumab**, marketed as Tecentriq, is a **solution for infusion** administered intravenously. It is a protein-based therapeutic agent with a maximum daily dose of 1200 mg, administered over a treatment period of up to 52 weeks. The administration schedule and participant compliance are monitored to ensure adherence to the protocol.
**Cyclophosphamide monohydrate**, marketed under the name Endoxan, is provided in both **solution for injection** and **coated tablet** forms. The injectable solution is administered intravenously, with a maximum daily dose of 600 mg/m², while the oral form is also dosed at 600 mg/m². The treatment period for both forms is up to 12 weeks. Compliance is monitored through regular assessments and dosing records.
**Doxorubicin hydrochloride** is available as DOXO-cell in various concentrations (10 mg, 50 mg, and 150 mg) and is administered as a **solution for injection**. The maximum daily dose is 60 mg/m², with a treatment duration of up to 12 weeks. This anthracycline antibiotic is administered intravenously, and participant adherence is tracked through scheduled visits and dosing logs.
**Carboplatin**, marketed as Carboplatin onkovis, is provided as a **solution for infusion**. It is a platinum-based chemotherapeutic agent administered intravenously, with a maximum daily dose of 750 mg. The treatment period extends up to 12 weeks, with compliance monitored through infusion records and participant follow-up.
**Epirubicin hydrochloride**, marketed as FARMORUBICIN, is administered as a **solution for injection**. This anthracycline is given intravenously, with a maximum daily dose of 90 mg/m² over a 12-week period. Compliance is ensured through regular monitoring and documentation of dosing schedules.
**Paclitaxel**, marketed as Paclitaxel onkovis, is provided as a **solution for infusion**. It is a taxane-based chemotherapeutic agent administered intravenously, with a maximum daily dose of 80 mg/m². The treatment duration is up to 12 weeks, with adherence monitored through infusion records and participant assessments.
The trial also includes a **placebo** control, administered as a sterile concentrate for intravenous use. The placebo is used to maintain the double-blind nature of the study, ensuring unbiased results. Compliance with placebo administration is monitored similarly to active treatments.
Efficacy
Efficacy in this clinical trial will be assessed primarily through the measurement of **event-free survival (EFS)**. EFS is defined as the time from randomization until the occurrence of specific events, including progression on protocol therapy leading to non-protocol cancer therapy or inoperability, local invasive recurrence following mastectomy, local invasive recurrence in the ipsilateral breast following lumpectomy, regional recurrence, distant recurrence, contralateral invasive breast cancer, second non-breast primary cancer, or death from any cause prior to recurrence or second primary cancer.
Secondary endpoints include overall survival, defined as the time from randomization until death from any cause, and the absence of any invasive component in the resected breast specimen and all resected lymph nodes following completion of neoadjuvant therapy (ypT0/Tis ypN0). Disease-free survival (DFS) will also be evaluated, defined as the time from the first breast surgical procedure to the first occurrence of disease recurrence or death from any cause. Additional secondary endpoints include the time from randomization until distant recurrence, death from breast cancer, death from other causes, and second primary invasive cancer (non-breast).
The frequency and severity of adverse events will be graded according to the NCI Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0). Troponin-T levels will be measured at specific timepoints: prior to the initial dose of AC/EC following completion of carboplatin/paclitaxel co-administered with atezolizumab/placebo, and after the administration of the 1st and 3rd cycles of AC/EC prior to administration of atezolizumab/placebo. Left ventricular ejection fraction (LVEF) levels will be assessed at baseline prior to initiation of carboplatin/paclitaxel and atezolizumab/placebo, before the 3rd cycle of AC/EC, and after surgery.
Inclusion and Exclusion Criteria
Inclusion Criteria
- The patient must have consented to participate and, prior to beginning specific study procedures, must have signed and dated an appropriate IRBapproved consent form that conforms to federal and institutional guidelines for study treatment and for submission of tumor samples 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. Formalin-fixed, paraffin-embedded (FFPE) breast tissue from core biopsy has therefore to be sent to the GBG central pathology laboratory prior to randomization for central confirmation of TNBC status and for correlative science studies.
- 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 (SP142) assay kit. Patients will be eligible irrespective of PD-L1 testing result including PD-L1 indeterminate. Patients will be classified 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 (ultrasound, and/or MRI) within 42 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 13 are met.
- Patients with alkaline phosphatase that is > ULN but ≤ 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 42 days prior to randomization does not demonstrate metastatic disease.
- Patients with N2 or N3 nodal disease or T3 primary disease must undergo liver imaging within 28 days prior to randomization and bone imaging (as described in criteria 14 and 15) within 42 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 prior to randomization. For laboratories that do not report an ULN for the INR assay, use ≤ 1.2 as the value for the ULN. 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 and male patients with female partners 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; 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 (see Appendix B) 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 lowpotency 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.
- Positive test for HIV.
- 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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Not Recruiting | 01 Jan 2018 | 805 |
 Spain | Not Recruiting | 01 Jan 2018 | 173 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
FARMORUBICIN® 50 mg HL Pulver zur Herstellung einer Injektionslösung | Other | PULVER ZUR HERSTELLUNG EINER INJEKTIONSLÖSUNG | INJECTABLE SOLUTION | 90 | 12 | PRD4259237 |
DOXO-cell 150 mg Injektionslösung | Other | INJEKTIONSLÖSUNG | INJECTABLE SOLUTION | 60 | 12 | PRD1964700 |
DOXO-cell 10 mg Injektionslösung | Other | INJEKTIONSLÖSUNG | INJECTABLE SOLUTION | 60 | 12 | PRD1964698 |
Endoxan | Other | SOLUTION FOR INJECTION | INJECTABLE SOLUTION | 600 | 12 | PRD351416 |
Endoxan 100 mg | Other | SOLUTION FOR INJECTION | INJECTABLE SOLUTION | 600 | 12 | PRD351422 |
Endoxan | Other | SOLUTION FOR INJECTION | INJECTABLE SOLUTION | 600 | 12 | PRD351419 |
Paclitaxel onkovis, 6 mg/ml, Konzentrat zur Herstellung einer Infusionslösung | Other | KONZENTRAT ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INTRAVENOUS | 80 | 12 | PRD803002 |
DOXO-cell 50 mg Injektionslösung | Other | INJEKTIONSLÖSUNG | INJECTABLE SOLUTION | 60 | 12 | PRD1964693 |
Endoxan | Other | SOLUTION FOR INJECTION | INJECTABLE SOLUTION | 600 | 12 | PRD351417 |
Endoxan® | Other | COATED TABLET | ORAL USE | 600 | 12 | PRD351418 |