Clinical Trials Register

Summary
EudraCT Number:	2016-003472-52
Sponsor's Protocol Code Number:	YO39523
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2017-09-08
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

France - ANSM

A.2

EudraCT number

2016-003472-52

A.3

Full title of the trial

A PHASE III, MULTICENTER, RANDOMIZED STUDY OF ATEZOLIZUMAB VERSUS PLACEBO ADMINISTERED IN COMBINATION WITH PACLITAXEL, CARBOPLATIN, AND BEVACIZUMAB TO PATIENTS WITH NEWLY-DIAGNOSED STAGE III OR STAGE IV OVARIAN, FALLOPIAN TUBE, OR PRIMARY PERITONEAL CANCER

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A Study of Atezolizumab Versus Placebo Given with Paclitaxel, Carboplatin, and Bevacizumab to Patients with Newly-Diagnosed Stage III/IV Ovarian, Fallopian Tube, Or Primary Peritoneal Cancer

A.4.1

Sponsor's protocol code number

YO39523

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	F. Hoffman-La Roche Ltd.
B.1.3.4	Country	Switzerland
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	F. Hoffmann-La Roche Ltd.
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	F.Hoffmann-La Roche Ltd.
B.5.2	Functional name of contact point	Trial Information Support Line-TISL
B.5.3	Address:
B.5.3.1	Street Address	Grenzacherstrasse 124
B.5.3.2	Town/ city	Basel
B.5.3.3	Post code	4070
B.5.3.4	Country	Switzerland
B.5.4	Telephone number	+41 61688 1111
B.5.5	Fax number	+41 61691 9319
B.5.6	E-mail	global.rochegenentechtrials@roche.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Atezolizumab
D.3.2	Product code	RO5541267/F03
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ATEZOLIZUMAB
D.3.9.1	CAS number	1380723-44-3
D.3.9.2	Current sponsor code	RO5541267
D.3.9.3	Other descriptive name	MPDL3280A, Tecentriq
D.3.9.4	EV Substance Code	SUB178312
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	60
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	Yes
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Avastin
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration Ltd.
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	bevacizumab
D.3.2	Product code	RO4876646/F02
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	BEVACIZUMAB
D.3.9.1	CAS number	216974-75-3
D.3.9.2	Current sponsor code	RO4876646
D.3.9.3	Other descriptive name	Avastin
D.3.9.4	EV Substance Code	SUB16402MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	25
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Ovarian cancer, fallopian tube cancer, primary peritoneal cancer

E.1.1.1

Medical condition in easily understood language

Ovarian cancer are diseases in which cells from either ovary, fallopian tube, or lining of the abdominal cavity grow abnormally into cancer cells and spread

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10033128
E.1.2	Term	Ovarian cancer
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

•To evaluate the efficacy of atezolizumab (Atezo) versus (vs) placebo (PL) in combination with paclitaxel (Pac)+ carboplatin (Carb)+ bevacizumab (Bev) in all OC, FTC, and PPC patients and in those with programmed death ligand-1 (PD-L1)−positive tumors

E.2.2

Secondary objectives of the trial

•To evaluate the efficacy and duration of efficacy of Atezo vs PL in combination with Pac + Carb +Bev among patients with measurable residual disease in the primary surgery group
•To determine the impact of Atezo vs PL in combination with Pac + Carb +Bev on patient-reported abdominal symptoms of OC, as measured by two items from the abdominal and gastrointestinal symptom scale of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Ovarian Cancer Module 28 (QLQ-OV28)
•To evaluate patient-reported outcomes of function and health-related quality of life( HRQoL) associated with Atezo vs PL in combination with Pac + Carb +Bev as measured by the functional and HRQoL scales of the EORTC QLQ Core 30 (QLQ-C30)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Age >= 18 years
- Receive a histologic diagnosis of epithelial OC, FTC, or PPC fulfilling the following criteria: epithelial tumors histologically of Mullerian origin
- Patients with Stage III or Stage IV who have gross residual disease after primary surgery or who will undergo neoadjuvant treatment and planned interval surgery after Cycle 3
- Eastern Cooperative Oncology Group performance status of 0, 1, or 2
- Life expectancy > 12 weeks
- Adequate hematologic and end-organ function test results
- On a stable anticoagulant regimen, if therapeutic anticoagulation is indicated
- For women of childbearing potential: agreement to remain abstinent or use contraceptive methods that have a failure rate of < 1% per year during the treatment period and for at least 5 months after the last dose of study drug and 6 months after the last dose of Bev, Pac, or Carb, whichever is later
- Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures, including all patient-reported outcomes questionnaires
- Availability of a representative formalin-fixed, paraffin-embedded tumor specimen in paraffin blocks or at least 20 unstained slides for detailed tissue requirements at screening

E.4

Principal exclusion criteria

- Received a current diagnosis of borderline epithelial ovarian tumor
- Recurrent invasive epithelial ovarian, fallopian tube, or primary peritoneal cancer that was treated only with surgery
- Non-epithelial ovarian tumors
- Received prior radiotherapy to any portion of the abdomen or pelvis
- Received prior chemotherapy for any abdominal or pelvic tumor, including neoadjuvant chemotherapy for ovarian, primary peritoneal or fallopian tube cancer
- Received any hormonal, biological, and/or targeted therapy for epithelial ovarian, fallopian tube or primary peritoneal cancer
- Synchronous primary endometrial cancer
- Prior history of primary endometrial cancer, except if all of the mentioned conditions are met: Stage IA cancer, superficial myometrial invasion without lymphovascular invasion, and Grade < 3 or poorly differentiated subtypes which includes papillary serous, clear cell or other International Federation of Gynecological Oncologists Grade 3 lesions
- With the exception of non-melanoma skin cancer and other specific malignancies as noted above, other invasive malignancies with any evidence of other cancers present within the last 5 years or previous cancer treatment that contraindicates this protocol therapy
- History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
- History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis based on a screening chest computed tomography scan
- Known hypersensitivity or allergy to biopharmaceutical agents produced in Chinese hamster ovary cells or any component of the Atezo and/or Bev formulations
- Active or history of autoimmune disease or immune deficiency that includes but is not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener’s granulomatosis, Sjogren’s syndrome, Guillain-Barré syndrome, or multiple sclerosis
- Active tuberculosis, hepatitis B and C virus infection, positive test for HIV
- Significant cardiovascular disease (e.g., New York Heart Association cardiac disease, myocardial infarction within 3 months before initiation of study treatment, unstable arrhythmias, or unstable angina)
- Inadequately-controlled hypertension
- Prior history of hypertensive crisis or hypertensive encephalopathy
- Administration of a live, attenuated vaccine within 4 weeks prior to initiation of study treatment
- Prior allogeneic bone marrow transplantation or solid organ transplant
- Prior treatment with CD137 agonists or immune checkpoint blockade therapies, anti−PD-1, anti−PD-L1, or anti-cytotoxic T-lymphocyte-associated protein 4 therapeutic antibodies
- Treatment with systemic immunostimulatory agents within 4 weeks or 5 half-lives of the drug, whichever is longer, prior to initiation of study treatment, systemic immunosuppressive medications within 2 weeks prior to initiation of study treatment
- History of hypertensive crisis or hypertensive encephalopathy, hemoptysis within 1 month prior to initiation of study treatment, abdominal fistula or gastrointestinal perforation within 6 months prior to initiation of study treatment
- Evidence of active bleeding, bleeding diathesis, coagulopathy, tumor that involves major vessels
- Current use of full-dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic purposes that has not been stable prior to initiation of study treatment
- Significant vascular disease within 6 months prior to initiation of study treatment
- Evidence of active bleeding, bleeding diathesis, coagulopathy, tumor that involves major vessels, abdominal free air not explained by paracentesis or recent surgical procedure
- Core biopsy or other minor surgical procedures that exclude the placement of a vascular access device, within 7 days prior to the first dose of bevacizumab
- Major surgical procedures within 28 days of randomization
- Clinical signs of gastrointestinal obstruction requiring routine parenteral hydration, parenteral nutrition, or tube feeding
- Grade >= 2 peripheral neuropathy as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0
- Known history of severe hypersensitivity reactions to products that contain Cremophor® and severe allergic reactions to platinum-containing compounds

E.5 End points

E.5.1

Primary end point(s)

1.Investigator-assessed progression-free survival
2.Overall survival

E.5.1.1

Timepoint(s) of evaluation of this end point

1,2. Up to 56 months

E.5.2

Secondary end point(s)

1.Objective response
2.Duration of response
3.Clinically-meaningful improvement in abdominal pain or bloating using scales of the EORTC QLQ-OV28 for patients in the neoadjuvant group
4.Clinically-meaningful improvement, remaining stable or deterioration in function and HRQoL using scales of the EORTC QLQ-C30 for patients in the neoadjuvant group and the primary surgery group

E.5.2.1

Timepoint(s) of evaluation of this end point

1-2. Up to 56 months
3-4. During the Concurrent treatment period:
For the neoadjuvant patient group: Cycle (C)1 Day(D) 1, post-C3/Pre-Interval Surgery visit, C4 D1, C 6 D1, For the primary surgery group: C 1D 1, and on D 1 of every other cycle thereafter until C 6;
During the Maintenance treatment period: C 8 D 1 and on D 1 of each cycle every 12 weeks thereafter until C 22;
After completing all protocol treatment: End of treatment/discontinuation visit within 30 days of last dose of study drug
During the Post-treatment follow-up period: every 3 months for first year of survival follow-up period, which starts 3 weeks (± 14 days) after last maintenance treatment; every 6 months for second year of survival follow-up period; and every year for 3 years of survival follow-up period

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

108

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Australia

Austria

Belgium

Brazil

China

Czech Republic

Denmark

Finland

France

Germany

Greece

Israel

Italy

Japan

Korea, Republic of

Norway

Poland

Russian Federation

Spain

Sweden

Turkey

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

When the approximate preplanned numbers of deaths among the PD-L1-positive patients and the intent-to-treat(ITT) population have been observed.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

715

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

585

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

400

F.4.2.2

In the whole clinical trial

1300

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Currently, the Sponsor does not have any plans to provide atezolizumab or any other study treatments or interventions to patients who have completed the study. The Sponsor may evaluate whether to continue to provide atezolizumab in accordance with the Roche Global Policy on Continued Access to Investigational Medicinal Product, available at the following Web site:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2017-08-18

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-07-04

P. End of Trial
P.	End of Trial Status	Ongoing

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