A Study to Compare Atezolizumab (Anti-PD-L1 Antibody) in Combination With Adjuvant Anthracycline/Taxane based Chemotherapy Versus Chemotherapy Alone in Patients With Operable Triple-Negative Breast Cancer

• Register: EUCTR
• Last refreshed on: 11 June 2018
• Main ID: EUCTR2016-003695-47-ES
• Date of registration: 09/04/2018
• Prospective Registration: Yes
• Primary sponsor: F. Hoffman-La Roche Ltd.
• Public title: A Study to Compare Atezolizumab (Anti-PD-L1 Antibody) in Combination With Adjuvant Anthracycline/Taxane based Chemotherapy Versus Chemotherapy Alone in Patients With Operable Triple-Negative Breast Cancer
• Scientific title: A PHASE III, MULTICENTER, RANDOMIZED, OPEN-LABEL STUDY COMPARING ATEZOLIZUMAB (ANTI-PD-L1 ANTIBODY) IN COMBINATION WITH ADJUVANT ANTHRACYCLINE/TAXANEBASED CHEMOTHERAPY VERSUS CHEMOTHERAPY ALONE IN PATIENTS WITH OPERABLE TRIPLE-NEGATIVE BREAST CANCER
• Date of first enrolment: 09/04/2018
• Target sample size: 2300
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-003695-47
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: yes; Single blind: no; Double blind: no; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: no; Other: yes; Other specify the comparator: Paclitaxel, Doxorubicin/Epirubicin, Cyclophosphamide; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Australia, Austria, Belgium, Brazil, China, Costa Rica, Czech Republic, Denmark, France, Germany, Guatemala, Hong Kong, Hungary, Ireland, Israel, Italy, Japan, Korea, Republic of, Mexico, Poland, Romania, Russian Federation, Singapore, Spain, Switzerland, Taiwan, Thailand, Ukraine, United Kingdom, United States

Contacts

• Name: Trial Information Support Line-TISL
• Affiliation: F.Hoffmann-La Roche Ltd.

• Name: Trial Information Support Line-TISL
• Affiliation: F.Hoffmann-La Roche Ltd.

Key inclusion & exclusion criteria

Inclusion criteria:
- Age >= 18 years
- Eastern Cooperative Oncology Group Performance Status of 0 or 1
- Non-metastatic operable Stage II-III breast cancer; patients with node-negative disease must have a pathologic tumor size > 2cm
- Histologically documented TNBC that is centrally confirmed
- Confirmed tumor Programmed death-ligand 1 (PD-L1) evaluation (centrally conducted)
- Adequately excised: Patients must have undergone either breast-conserving surgery or mastectomy/nipple- or skin-sparing mastectomy
- Pathological tumor-node-metastasis staging: Patient must have had sentinel lymph node biopsy and/or axillary lymph node dissection for evaluation of pathologic nodal status
- Patients with synchronous bilateral invasive disease are eligible only if all bilateral invasive lesions are histologically confirmed as triple negative by central lab and have completed adequate pathological tumor-node metastasis staging bilaterally as described
- No more than 8 weeks (56 days) may elapse between definitive breast surgery and randomization
- Baseline left ventricular ejection fraction >= 53% measured by echocardiogram or multiple-gated acquisition scans
- Adequate hematologic and end-organ function
- Representative formalin-fixed, paraffin embedded tumor specimen from surgical resection in paraffin blocks or at least 25 unstained slides, with an associated pathology report documenting locally assessed ER, PgR, and HER2 negativity
- For women of childbearing potential: agreement to remain abstinent 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, or 6 months after the last dose of paclitaxel or doxorubicin, or 12 months after the last dose of cyclophosphamide
- For men: agreement to remain abstinent or use contraceptive measures and agreement to refrain from donating sperm during the treatment period and 6 months after the last dose of paclitaxel, cyclophosphamide, or doxorubicin/epirubicin
- Women who are not postmenopausal or have not undergone a sterilization procedure must have a negative serum pregnancy test result within 14 days prior to initiation of study drug
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 1150
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 1150

Exclusion criteria:
- Prior history of invasive breast cancer
- Any T4 clinical tumor
- For the currently diagnosed breast cancer, any previous systemic anti-cancer treatment planned in the context of this study
- Previous therapy with anthracyclines or taxanes for any malignancy
- History of ductal carcinoma in situ and/or lobular carcinoma in situ that was treated with any form of systemic, hormonal therapy, or radiotherapy (RT) to the ipsilateral breast where invasive cancer subsequently developed
- Contraindication to RT when adjuvant RT is clinically indicated
- Cardiopulmonary dysfunction
- Prior malignancies within 5 years prior to randomization
- 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 any component of the atezolizumab, paclitaxel, cyclophosphamide, or doxorubicin/epirubicin formulations and filgrastim or pegfilgrastim or granulocyte-macrophage colony-stimulating factor formulations
- Active or history of autoimmune disease or immune deficiency
- History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography scan
- Positive HIV test at screening
- Active hepatitis B, C virus infection and tuberculosis
- Urinary outflow obstruction
- Severe infections within 4 weeks prior to initiation of study treatment
- Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment
- Major surgical procedure other than for diagnosis within 4 weeks prior to initiation of study treatment or anticipation of need for a major surgical procedure during the course of the study
- Prior allogeneic stem cell or solid organ transplant
- Administration of a live attenuated vaccine within 4 weeks prior to initiation of study treatment or anticipation of need for such a vaccine during the study or within 5 months after the last dose of atezolizumab
- Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications
- Prior treatment with CD137 agonists or immune checkpoint-blockade therapies
- Treatment with systemic immunosuppressive medications within 2 weeks prior to initiation of study treatment or anticipation of need for systemic immunosuppressive medication during the study
- Pregnant or lactating, or intending to become pregnant during the study


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Triple-negative breast cancer (TNBC)
MedDRA version: 20.0 Level: PT Classification code 10006187 Term: Breast cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Therapeutic area: Diseases [C] - Cancer [C04]

Intervention(s)

Product Name: Atezolizumab
Product Code: RO5541267/F03
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: ATEZOLIZUMAB
CAS Number: 1380723-44-3
Current Sponsor code: RO5541267
Other descriptive name: MPDL3280A, Tecentriq
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 60-

Trade Name: Paclitaxel
Product Name: paclitaxel
Product Code: RO024-7506
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: PACLITAXEL
CAS Number: 33069-62-4
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: range
Concentration number: 0.3-1.2

Trade Name: Doxorubicin
Product Name: Doxorubicin
Product Code: Ro 020-3296
Pharmaceutical Form: Solution for injection
INN or Proposed INN: DOXORUBICIN HYDROCHLORIDE
CAS Number: 23214-92-8
Other descriptive name: DOXORUBICIN
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 2-

Trade Name: Cyclophosphamide
Product Name: cyclophosphamide
Product Code: Ro 004-2106
Pharmaceutical Form: Lyophilisate for solution for injection
INN or Proposed INN: CYCLOPHOSPHAMIDE
CAS Number: 50-18-0
Other descriptive name: Endoxan
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 20-

Trade Name: Epirubicin
Product Name: Epirubicin
Product Code: Ro 018-7742
Pharmaceutical Form: Solution for injection
INN or Proposed INN: epirubicin
CAS Number: 56390-09-1
Other descriptive name: EPIRUBICIN HYDROCHLORIDE
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 2-

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: Up to 7 years

Main Objective: • To evaluate the efficacy of adjuvant atezolizumab + paclitaxel, dose-dense doxorubicin/epirubicin, and cyclophosphamide (T-AC/EC) compared with T-AC/EC alone in patients with TNBC based on invasive disease-free survival (iDFS)

Secondary Objective: • To evaluate the efficacy of adjuvant atezolizumab + T-AC/EC compared with T-AC/EC alone based on iDFS in the PD-L1 selected and in the node-positive disease subpopulations, overall survival (OS), recurrence-free interval (RFI), Distant RFI and disease-free survival (DFS)
• To evaluate patient-reported outcomes (PROs) of function and health-related quality of life (HRQoL) associated with atezolizumab + T-AC/EC compared with T-AC/EC alone, as measured by the validated patient reported outcome tools
• To evaluate the safety and tolerability of atezolizumab + T-AC/EC compared with T-AC/EC alone
• To characterize the serum pharmacokinetics of atezolizumab when administered in combination with T-AC/ EC chemotherapy
• To evaluate the immune response to atezolizumab

Primary end point(s): 1. iDFS

Secondary Outcome(s)

Secondary end point(s): 1. iDFS in the subpopulation with PD-L1-selected tumor status (IC1/2/3) and node-positive disease
2. OS
3. iDFS including second primary non-breast invasive cancer as an event
4. RFI
5. Distant RFI
6. DFS
7. Occurrence and severity of adverse events as defined by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
8. Mean and mean changes from baseline score in function (role, physical) and global health status (GHS)/HRQoL by assessment timepoint, and between treatment arms as assessed by the functional and GHS/HRQoL scales of the EORTC QLQ-C30
9. Serum concentration of atezolizumab at specified timepoints
10. Incidence of anti-drug antibodies (ADAs) during the study relative to the prevalence of ADAs at baseline

Timepoint(s) of evaluation of this end point: 1-8. Up to 7 years
9-10. Day 1 of Cycle 1-4, 6, 10, and 15 and at treatment discontinuation visit (<= 30 days after last dose) and at 120 days after last dose of atezolizumab

Secondary ID(s)

WO39391

Source(s) of Monetary Support

F. Hoffmann-La Roche Ltd.