A Study of Atezolizumab (Anti-PD-L1 Antibody) in Combination with Paclitaxel Compared with Placebo with Paclitaxel for Patients with Previously Untreated Inoperable Locally Advanced or Metastatic Triple Negative Breast Cancer

• Register: EUCTR
• Last refreshed on: 2 October 2017
• Main ID: EUCTR2016-004024-29-ES
• Date of registration: 15/09/2017
• Prospective Registration: No
• Primary sponsor: F. Hoffmann-La Roche Ltd
• Public title: A Study of Atezolizumab (Anti-PD-L1 Antibody) in Combination with Paclitaxel Compared with Placebo with Paclitaxel for Patients with Previously Untreated Inoperable Locally Advanced or Metastatic Triple Negative Breast Cancer
• Scientific title: A PHASE III, MULTICENTER, RANDOMISED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF ATEZOLIZUMAB (ANTI-PD-L1 ANTIBODY) IN COMBINATION WITH PACLITAXEL COMPARED WITH PLACEBO WITH PACLITAXEL FOR PATIENTS WITH PREVIOUSLY UNTREATED INOPERABLE LOCALLY ADVANCED OR METASTATIC TRIPLE NEGATIVE BREAST CANCER
• Date of first enrolment: 13/09/2017
• Target sample size: 540
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-004024-29
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no 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

Algeria, Argentina, Brazil, Canada, China, Croatia, Czech Republic, Egypt, France, Germany, Greece, India, Israel, Italy, Morocco, Romania, Russian Federation, Saudi Arabia, Slovakia, Spain, Turkey, United Kingdom, United States, Vietnam

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:
- Women or men aged >= 18 years
- Patients with locally advanced or metastatic, histologically documented TNBC by central testing (absence of human epidermal growth factor 2 [HER2], oestrogen receptor [ER], and progesterone receptor [PR] expression), not amenable to surgical therapy
a. HER2 negativity is defined as either of the following by central laboratory assessment: IHC 0, IHC 1+ or IHC2+/in situ hybridisation (ISH) as per American Society of Clinical Oncology (ASCO)-College of American Pathologists Guideline (CAP) guideline (ISH- is defined as a ratio of HER2 to CEP17 <2.0)
b. ER and PR negativity are defined as <1% of cells expressing hormonal receptors via IHC analysis as per ASCO-CAP guideline
- Eligible for taxane monotherapy
- No prior chemotherapy or targeted systemic therapy (including endocrine therapy) for inoperable locally advanced or metastatic TNBC. Prior radiation therapy for metastatic disease is permitted. Previous chemotherapy for early breast cancer is permitted if completed >=12 months before randomization
- Availability of formalin-fixed paraffin-embedded tumour block (preferred) or at least 25 unstained slides, collected <=3 months prior to randomisation, with an associated pathology report.
a. Patients with fewer than 25 unstained slides (but not fewer than 17) may be eligible upon discussion with the Medical Monitor
b. The tumor tissue should be of good quality based on total and viable tumor content and must be evaluable prospectively for HER2, ER, PR and PD-L1 expression via central testing. Tumor specimens not suitable for evaluation of PD-L1 expression include fine needle aspiration, brushing, cell pellet from pleural effusion, tumor tissue from bone metastases and lavage samples
- Eastern Cooperative Oncology Group performance status of 0 or 1
- Life expectancy >=12 weeks
- Measurable disease, as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
- Adequate haematologic and end-organ function test results within 2 weeks prior to the first study treatment
- Women of child bearing potential must agree to either use a contraceptive method with a failure rate of <=1% per year or to remain abstinent during the treatment period and for at least 5 months after the last dose of atezolizumab/placebo, or for at least 6 months after the last dose of paclitaxel
- Women of child bearing potential must have a negative serum pregnancy test result within 7 days prior to initiation of study drug
- For men: agreement to remain abstinent or use contraceptive measures, and agreement to refrain from donating sperm, as defined in the protocol
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 450
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 90

Exclusion criteria:
Cancer-Specific Exclusion Criteria:
- Spinal cord compression not definitively treated with surgery and/or radiation, or previously diagnosed and treated spinal cord compression without evidence that disease has been clinically stable for at least 2 weeks prior to randomization
- Known central nervous system (CNS) disease, except for treated asymptomatic CNS metastases, provided all of the following criteria are met:
a. Measurable disease outside the CNS
b. Metastases are limited solely to cerebellar and supratentorial lesions
c. No ongoing requirement for corticosteroids as therapy for CNS disease
d. No stereotactic radiation within 7 days or whole-brain radiation within 14 days prior to randomization
e. No evidence of progression or haemorrhage after completion of CNS directed therapy
Note: Patients with new asymptomatic CNS metastases detected at the screening scan must receive radiation therapy and/or surgery for CNS metastases. Following treatment, these patients may then be eligible if all other criteria above are met
- Leptomeningeal disease
- Uncontrolled pleural effusion, pericardial effusion, or ascites (Note: patients with indwelling catheters are allowed)
- Uncontrolled tumour-related pain
- Uncontrolled hypercalcemia or clinically significant (symptomatic) hypercalcemia
- Malignancies other than TNBC within 5 years prior to randomization, with the exception of those with a negligible risk of metastasis or death and treated with expected curative outcome

General Medical Exclusion Criteria:
- Pregnant or lactating women, or intending to become pregnant during the study
- Evidence of significant uncontrolled concomitant disease that could affect compliance with the protocol or interpretation of results, including significant liver disease
- Significant cardiovascular disease, such as New York Heart Association (NYHA) cardiac disease (Class II or greater), myocardial infarction within 3 months prior to randomization, unstable arrhythmias, or unstable angina
- Presence of an abnormal electrocardiogram (ECG) that is clinically significant
- Serious infection requiring antibiotics within 2 weeks prior to randomization, including but not limited to infections requiring hospitalization or IV antibiotics- Major surgical procedure within 4 weeks prior to randomization or anticipation of the need for a major surgical procedure during the course of the study other than for diagnosis
- Treatment with investigational therapy within 30 days prior to initiation of study treatment
- Inability to understand the local language(s) for which the Patient Reported Outcome (PRO) questionnaires are available
Exclusion Criteria Related to Study Treatment:
- History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
- Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary (CHO) cells or any component of the atezolizumab formulation
- History of hypersensitivity reactions to paclitaxel or other drugs formulated in the same solvent as paclitaxel (polyoxyethylated castor oil)
- History of autoimmune disease
- Prior allogeneic stem cell or solid organ transplantation
- History of idiopathic pulmonary fibrosis, drug-induced pneumonitis, organizing pneumonia, or evidence of active pneumonitis on screening chest computed tomography scan
- Positive test for human immunodeficiency virus
- Active hepatitis B or C
- Active tuberc

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 10075566 Term: Triple negative 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
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: ATEZOLIZUMAB
Current Sponsor code: RO5541267
Other descriptive name: MPDL3280A
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 60-
Pharmaceutical form of the placebo: Solution for infusion
Route of administration of the placebo: Intravenous use

Trade Name: Paclitaxel
Product Name: paclitaxel
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: equal
Concentration number: 6-

Trade Name: Paclitaxel
Product Name: paclitaxel
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: equal
Concentration number: 6-

Trade Name: Sindaxel (Paclitaxel)
Product Name: paclitaxel
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: equal
Concentration number: 6-

Trade Name: Sindaxel (Paclitaxel)
Product Name: paclitaxel
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: equal
Concentration number: 6-

Trade Name: Paclitaxel
Product Name: paclitaxel
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: equal
Concentration number: 6-

Trade Name: Paclitaxel
Product Name: paclitaxel
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: equal
Concentr

Primary Outcome(s)

Secondary Objective: -To evaluate the efficacy of atezolizumab plus paclitaxel compared with placebo plus paclitaxel as measured by overall survival (OS), 12-month and 18-month OS rates, health-related quality of life (HRQoL), 12-month PFS rate, objective response rate (ORR), duration of objective response (DoR), and clinical benefit rate(CBR)
-To characterize the pharmacokinetic(PK) of atezolizumab when administered concomitantly with paclitaxel
-To characterize the PK of paclitaxel when administered concomitantly with atezolizumab
-To evaluate the safety of atezolizumab plus paclitaxel compared with placebo plus paclitaxel
-To evaluate the immunogenicity of atezolizumab
-To assess the activity and safety of atezolizumab according to programmed death-ligand 1 (PD-L1) status
-To assess the efficacy of atezolizumab plus paclitaxel compared with placebo plus paclitaxel as measured by PFS in the subset of patients from mainland China and its consistency with the treatment effect in the Global population

Timepoint(s) of evaluation of this end point: 1. From randomisation to disease progression or death, whichever occurs first

Main Objective: - To evaluate the efficacy of atezolizumab plus paclitaxel compared with placebo plus paclitaxel as measured by progression-free survival (PFS)

Primary end point(s): 1. PFS, per RECIST v1.1 criteria

Secondary Outcome(s)

Secondary end point(s): 1. OS
2. 12-month and 18-month OS rates
3. Time to deterioration in Global Health Status/HRQoL
4. PFS rate at 12 months
5. ORR
6. DoR
7. CBR
8. Incidence of anti-therapeutic antibodies (ATAs) during the study relative to the prevalence of ATAs at baseline
9. Serum concentration (Cmin and Cmax) of atezolizumab at specified timepoints
10. Plasma concentration (Cmin and Cmax) of paclitaxel at specified timepoints
11. Incidence and severity of adverse events
12. Change from baseline in targeted vital signs and physical findings
13. Change from baseline in targeted clinical laboratory test results
14. Relationship between PD-L1 protein expression by immunohistochemistry in tumour tissues obtained within 3 months prior to patient randomization, and clinical outcomes

Timepoint(s) of evaluation of this end point: 1. From randomisation to death from any cause
2. 12 and 18 months after the first patient randomized
3. From the first day of treatment (Cycle 1, Day 1) until 1 year after treatment discontinuation
4. 12 months after the first patient randomized
5-7. Until the end of the study
8-9. Day 1 of Cycles 1, 2, 3, 4, 8, 12, 16; thereafter Day 1 of every eight cycles; at treatment discontinuation visit; and 120 days after last dose of atezolizumab
10. Day 1 of Cycles 1 and 3
11. From signing of the informed consent until the end of the study
12-13. From the first day of treatment (Cycle 1, Day 1) until the treatment discontinuation visit; or up to the end of the study if clinically indicated
14. Until the end of the study

Secondary ID(s)

2016-004024-29-SK

MO39196

Source(s) of Monetary Support

F. Hoffmann-La Roche Ltd