Clinical Trials Register

Summary
EudraCT Number:	2017-003622-33
Sponsor's Protocol Code Number:	2017/2608
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:	2018-01-16
Trial 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

2017-003622-33

A.3

Full title of the trial

Randomized Phase II Trial Assessing the Inhibitor of Programmed Cell Death Ligand 1 (PD-L1) Immune Checkpoint Atezolizumab in Locally Advanced Cervical Cancer

Etude de Phase II randomisée évaluant l’Atezolizumab, inhibiteur du ligand de mort cellulaire programmée de type 1, dans les cancers du col utérin localement évolués

A.3.1

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

Randomized Phase II Trial Assessing Atezolizumab in Locally Advanced Cervical Cancer

Etude de Phase II randomisée évaluant l'atezolizumab dans les cancers du col utérin localement évolués

A.3.2

Name or abbreviated title of the trial where available

AtezoLACC

A.4.1

Sponsor's protocol code number

2017/2608

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	Gustave Roussy
B.1.3.4	Country	France
B.3.1 and B.3.2	Status of the sponsor	Non-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	Gustave Roussy
B.5.2	Functional name of contact point	CRA
B.5.3	Address:
B.5.3.1	Street Address	114, rue Edouard Vaillant
B.5.3.2	Town/ city	Villejuif
B.5.3.3	Post code	94805
B.5.3.4	Country	France
B.5.4	Telephone number	+331421142113861
B.5.5	Fax number	+33142116290
B.5.6	E-mail	Cedric.PARLAVECCHIO@gustaveroussy.fr

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	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	ATEZOLIZUMAB
D.3.9.2	Current sponsor code	RO5541267/F03
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)	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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Locally Advanced Cervical Cancer

E.1.1.1

Medical condition in easily understood language

Cancers du col utérin localement évolués

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	LLT
E.1.2	Classification code	10008229
E.1.2	Term	Cervical cancer
E.1.2	System Organ Class	100000004864

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10048683
E.1.2	Term	Advanced cancer
E.1.2	System Organ Class	100000004864

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 clinical benefits of the addition of atezolizumab to standard chemoradiotherapy (CRT) (first given concurrently with CRT, then continued as adjuvant treatment), compared with CRT alone, on investigator-assessed progression-free survival (PFS), as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and clinical progression

E.2.2

Secondary objectives of the trial

1. To evaluate the efficacy of atezolizumab plus standard CRT compared with CRT alone as measured by objective response rates, locoregional control and overall survival (OS).
2. To evaluate the safety of atezolizumab in combination with CRT compared to CRT alone, including the incidence and severity of acute and delayed radiation-induced side effects in the two treatment arms.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Signed informed consent (after informing the patient).
2. Age between 18 and 70 years.
3. Histologically confirmed cancer of the uterine cervix: squamous cell carcinoma (SCC), adenocarcinoma, or adenosquamous carcinoma.
4. At least one evaluable lesion according to RECIST v1.1 criteria for the assessment of the principal judgment criteria.
5. International Federation of Gynecology and Obstetrics (FIGO) classification (confirmed by both clinical staging and imaging):
(i) stage IB2-IIA tumour with positive pelvic nodal status, as assessed by magnetic resonance imaging (MRI) and/or fluorine-18 fluorodeoxyglucose positron emission tomography (18-FDG PET)/computerised tomography (CT);
(ii) stage IIB-IVA tumour, regardless of pelvic lymph node involvement;
(iii) stage IVB tumours only if the metastases are limited to the para-aortic lymph nodes.
No evidence of metastatic disease outside the para-aortic area by primary staging (including clinical examination, pelvic MRI, 18-FDG PET, +/- laparoscopic para-aortic lymph node staging).
6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.
7. Adequate haematologic and end-organ function, defined by the following laboratory results obtained within 15 calendar days prior to the first study treatment:
a. Absolute neutrophil count (ANC) ≥1,500/mm3 (≥1.5 x 109/L) without granulocyte colony-stimulating factor (G-CSF) support.
b. Polymorphonuclear neutrophils (PMN) >2,000/mm3 (>2.0 x 109/L).
c. Lymphocyte count ≥500/mm3 (≥ 0.5 x 109/L)
d. Platelet count ≥ 100,000/mm3 (≥ 100 x 109/L) without transfusion.
e. Haemoglobin ≥ 9.0 g/dL (90 g/L; patients may be transfused to meet this criterion).
f. International Normalized Ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 × upper limit of normal (ULN) for patients not receiving therapeutic anticoagulation. Patients receiving therapeutic anticoagulation should be on a stable dose.
g. Creatinine <1.5 ULN or calculated creatinine clearance (CrCL) ≥ 55 mL/min (calculated using the Cockcroft-Gault formula).
h. Aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase <2.5 x ULN.
i. Serum bilirubin <1.5 x ULN.
8. Proteinuria < 200 mg/dL (2 g/L).
9. Ability to comply with the study protocol.
10. Geographical, social and psychological ability to undergo the follow-up required by the study.
11. Women who are not postmenopausal (≥ 12 months of non-therapy-induced amenorrhoea) and not surgically sterile:
a. Must agree to either use an acceptable contraceptive method* or to remain abstinent** (refrain from heterosexual intercourse) during the treatment period and for at least 5 months after the last dose of atezolizumab in arm B and at least 6 months after the last cisplatine dose in arm A..
* Acceptable contraceptive methods include single or combined contraceptive methods that result in a failure rate of < 1% per year, such as: tubal ligation, male sterilization, hormonal implants, established, proper use of combined oral or injected hormonal contraceptives, and certain intrauterine devices. Alternatively, two methods (e.g., two barrier methods such as a condom and a cervical cap) may be combined to achieve a failure rate of < 1% per year. Barrier methods must always be supplemented with the use of a spermicide.
** Abstinence is acceptable only if it is in line with 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.
b. Must have a negative serum pregnancy test result within 7 days prior to initiation of study drug.
12. Patients must be affiliated to a social security system or beneficiary of the same, as per local regulatory requirements

E.4

Principal exclusion criteria

1. Histological types of cervical cancer other than those listed in the inclusion criteria, including:
a. Stage IB2 and IIA cervical cancer with no regional lymph node metastases (N0).
b. Stage IVB cervical cancer with presence of distant metastases other than para-aortic lymph node metastases.
2. Prior surgery for cervical cancer unless cone resection and paraaortic lymphadenectomy.
3. Prior pelvic radiotherapy, other radiotherapy, chemotherapy or immunotherapy.
4. Any malignancy other than the disease under study in the past 5 years excepting skin cancers such as BCC or SCC.
5. Pregnant or lactating women, or intending to become pregnant during the study.
6. Obesity (Body Mass Index [BMI] > 30).
7. History of clinically relevant cardiovascular disease, congestive heart failure (New York Heart Association [NYHA] Class II or greater), or a known left ventricular ejection fraction (LVEF) <50%, symptomatic coronary artery disease, poorly controlled cardiac arrhythmia, or myocardial infarction.
8. Active inflammatory bowel disease, lack of physical integrity of the upper gastrointestinal tract, malabsorption syndrome.
9. Serious infection requiring oral or IV antibiotics within 4 weeks prior to randomisation, including but not limited to hospitalization for complications of infection, bacteraemia, or severe pneumonia.
10. Treatment with another investigational therapy within 30 days prior to initiation of the study drug.
11. Major surgical procedure within 4 weeks prior to randomisation or anticipation of the need for a major surgical procedure during the study other than for diagnosis. The following are not considered a major surgical procedure and are therefore permitted: (i) placement of central venous access catheter(s) (e.g., port or similar); (ii) surgical lymph node staging with no perioperative complications; (iii) placement of ureteral catheters.
12. History of severe allergic anaphylactic reactions to chimeric, human or humanized antibodies, or fusion proteins.
13. Known hypersensitivity to Chinese hamster ovary (CHO) cell products or any component of the atezolizumab formulation.
14. Any contraindication to the use of Cisplatin
15. History of autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, meningoencephalitis, or glomerulonephritis (see Appendix 6 for a more comprehensive list of autoimmune diseases) with the following exceptions: patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone, patients with controlled Type 1 diabetes mellitus on a stable insulin regimen, and patients with mild autoimmune skin disorders (such as eczema or atopic dermatitis involving <10% of the skin) may be eligible for this study.
16. History of idiopathic pulmonary fibrosis (IPF, including pneumonitis), drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or active pneumonitis.
17. Pre-existing hearing impairment.
18. Peripheral neuropathy ≥grade 2
19. Positive test for human immunodeficiency virus (HIV).
20. Active hepatitis B (positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C (positive hepatitis C virus antibody [HCVAb] test at screening). Note: Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive hepatitis B core antibody [HBcAb] test) are eligible.
21. Known active tuberculosis.
22. Receipt of a live, attenuated vaccine within 4 weeks prior to randomisation or anticipation that such a live, attenuated vaccine will be required during the study. Note: Patients must agree not to receive live, attenuated influenza vaccine (e.g., FluMist®) within 28 days prior to randomisation, during treatment or within 5 months following the last dose of atezolizumab.
23. Prior treatment with CD137 agonists, anti-PD-1, or anti-PD-L1 therapeutic antibody or immune checkpoint targeting agents.
24. Treatment with systemic corticosteroids or other systemic immunosuppressive medications within 2 weeks prior to randomisation. The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) is allowed.
25. Treatment with systemic immunostimulatory agents (such as interferons or IL-2) within 6 weeks or five half-lives of the drug (whichever is shorter) prior to randomisation.
26. Illicit drug or alcohol abuse within 12 months prior to screening, in the investigator’s judgment.
27. Any other serious medical condition or abnormality in clinical laboratory tests that, in the investigator’s judgment, precludes the patient’s safe participation in and completion of the study.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is progression free survival (PFS), defined as the time from randomization to the first documented occurrence of disease progression, as determined by the investigator using RECIST v1.1, or death from any cause, whichever occurs first. Data for patients without disease progression or death will be censored at the date of the last follow-up.

E.5.1.1

Timepoint(s) of evaluation of this end point

The primary endpoint analysis will be performed when 54 primary endpoint events (progression or death) have occurred in the study.

E.5.2

Secondary end point(s)

- Overall survival (OS), defined as the time from randomisation to death due to any cause.
- Complete response rate at 8 weeks, defined as the percentage of patients with measurable disease at baseline, who have achieved complete response (CR) after treatment initiation, as determined by the investigator using RECIST v1.1 criteria.
- Locoregional control, defined as the cumulative rate of locoregional recurrence or progression with censoring of deaths without locoregional recurrence or progression.
- Distant tumour control: defined as the cumulative rate of (distant) metastatic events with censoring of deaths without metastatic progression. In case locoregional recurrence (or progression) and distant progression occur at the same time, the event will be counted as a distant event.
- Toxicity, defined as any adverse drug reaction (AE assessed at least possibly related to any study treatment) that occurs within 6 months following brachytherapy (acute toxicity) or more than 6 months following brachytherapy (late toxicity). Toxicities will be graded using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03 (NCI CTC-AE v4.03) at each visit.

E.5.2.1

Timepoint(s) of evaluation of this end point

see above

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

E.6.7

Pharmacodynamic

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

standard treatment of locally advanced cervical cancer

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

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

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

LVLS

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

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:

140

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

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

190

F.4.2

For a multinational trial

F.4.2.1

In the EEA

190

F.4.2.2

In the whole clinical trial

190

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)

None

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

2018-04-03

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-03-22

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

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