A Randomized, Double-Blind, Phase III Clinical Trial of Neoadjuvant Chemotherapy with Atezolizumab or Placebo in Patients with Triple-Negative Breast Cancer Followed by Adjuvant Continuation of Atezolizumab or Placebo "GeparDouze"

Overview

Sponsor-declared trial summary

Key facts

Sponsor

NSABP Foundation Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

13 Jun 2018 → 19 Nov 2025

Decision date (initial)

2023-12-12

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Roche Genentech

External identifiers

EU CT number

2023-508472-11-00

EudraCT number

2017-002771-25

ClinicalTrials.gov

NCT03281954

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy

To determine whether the addition of atezolizumab to chemotherapy
(weekly paclitaxel plus carboplatin followed by AC or EC) followed by
adjuvant atezolizumab improves event-free survival (EFS) in patients with
triple-negative breast cancer.

Secondary objectives 6

1. To determine whether the addition of atezolizumab to chemotherapy (weekly paclitaxel plus carboplatin followed by AC or EC) followed by adjuvant atezolizumab improves overall survival (OS) in patients with triple-negative breast cancer.
2. To determine whether the addition of atezolizumab to chemotherapy (weekly paclitaxel plus carboplatin followed by AC or EC) improves pathologic complete response in the breast and post-therapy lymph nodes evaluated histologically (pCR breast and nodes) in patients with triplenegative breast cancer.
3. To determine whether the addition of atezolizumab to chemotherapy (weekly paclitaxel plus carboplatin followed by AC or EC) followed by adjuvant atezolizumab improves disease-free survival (DFS) in patients with triple-negative breast cancer.
4. To determine whether the addition of atezolizumab to chemotherapy (weekly paclitaxel plus carboplatin followed by AC or EC) followed by adjuvant atezolizumab improves distant disease-free survival (DDFS) in patients with triple-negative breast cancer.
5. To evaluate toxicity associated with study therapy added to chemotherapy and radiation therapy. To evaluate immune-adverse events of special interest
6. To assess for potential augmentation of anthracycline-related cardiac toxicity with co-administration of study therapy.

Conditions and MedDRA coding

Patients with early breast cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 22

1. 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.
2. The diagnosis of invasive adenocarcinoma of the breast must have been made by core needle biopsy.
3. 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.)
4. 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.
5. 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.
6. Patients must be ≥ 18 years old.
7. Patient may be female or male.
8. The ECOG performance status must be 0-1
9. 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.
10. 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.
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
16. 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.
17. Creatinine clearance ≥ 50 mL/min (see Section 7.2.1 for instructions regarding calculation of creatinine clearance) performed within 28 days prior to randomization.
18. 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.
19. 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.
20. 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.
21. 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.
22. Patient must be willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.

Exclusion criteria 33

1. Excisional biopsy or lumpectomy performed prior to study entry.
2. FNA alone to diagnose the breast cancer.
3. 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.
4. Definitive clinical or radiologic evidence of metastatic disease.
5. Previous history of contralateral invasive breast cancer. (Patients with synchronous and/or previous contralateral DCIS or LCIS are eligible.)
6. Previous history of ipsilateral invasive breast cancer or ipsilateral DCIS. (Patients with synchronous or previous ipsilateral LCIS are eligible.)
7. 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.
8. Treatment including radiation therapy, chemotherapy, or targeted therapy, for the currently diagnosed breast cancer prior to randomization.
9. Previous therapy with anthracyclines or taxanes for any malignancy.
10. 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.
11. 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.
12. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins.
13. Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells.
14. Known allergy or hypersensitivity to the components of the atezolizumab formulation.
15. Known allergy or hypersensitivity to the components of the doxorubicin, epirubicin, cyclophosphamide, carboplatin, or paclitaxel formulations.
16. Known allergy or hypersensitivity to liposomal or pegylated G-CSF formulations.
17. 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.
18. 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.
19. Positive test for HIV.
20. 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.
21. 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.
22. Patients with clinically active tuberculosis.
23. Severe infection within 28 days prior to randomization, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia.
24. Prior allogeneic stem cell or solid organ transplantation.
25. 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.
26. 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.
27. 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.
28. 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.
29. 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.
30. Nervous system disorder (paresthesias, peripheral motor neuropathy, or peripheral sensory neuropathy) ≥ Grade 2, per the CTCAE v4.0.
31. Symptomatic peripheral ischemia.
32. 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).
33. Use of any investigational agent within 28 days prior to randomization.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. EFS is defined as time from randomization until event: EFS events are progression on protocol therapy resulting in administration of 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 6

1. Defined as time from randomization until death from any cause.
2. Defined as the absence of any invasive component in the resected breast specimen and all resected lymph nodes following completion of neoadjuvant therapy (ypT0/Tis ypN0).
3. Defined as time from the first breast surgical procedure to the first occurrence of disease recurrence or death from any cause. Events defining DFS are ipsilateral invasive breast tumor recurrence, ipsilateral local-regional invasive breast cancer recurrence, distant recurrence, contralateral invasive breast cancer, ipsilateral or contralateral DCIS, second primary non-breast invasive cancer and death attributable to any cause including breast cancer, non-breast cancer, or unknown cause.
4. Defined as time from randomization until distant recurrence, death from breast cancer, death from other causes, and second primary invasive cancer (non-breast).
5. Frequency and severity of adverse events graded according to the NCI Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0).
6. Troponin-T levels 1) prior to initial dose of AC/EC following completion of carboplatin/paclitaxel co-administered with atezolizumab/placebo and after administration of the 1st and 3rd cycles of AC/EC prior to administration of atezolizumab/placebo. LVEF levels at 1) baseline prior to initiation of carboplatin/paclitaxel and atezolizumab/placebo, 2) before 3rd cycle of AC/EC, and 3) after surgery.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Auxiliary 11

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

NSABP Foundation Inc.

Sponsor organisation

NSABP Foundation Inc.

Address

2 Allegheny Center

City

Pittsburgh

Postcode

15212-5402

Country

United States

Scientific contact point

Organisation

NSABP Foundation Inc.

Contact name

Judy Langer

Public contact point

Organisation

NSABP Foundation Inc.

Contact name

Judy Langer

Third parties 7

Locations

2 EU/EEA countries · 136 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 18 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications