Clinical Trials Register

Summary
EudraCT Number:	2019-000623-40
Sponsor's Protocol Code Number:	BCD-100-5/FERMATA
National Competent Authority:	Czechia - SUKL
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2020-04-03
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

Czechia - SUKL

A.2

EudraCT number

2019-000623-40

A.3

Full title of the trial

An International Randomized Double-blind Clinical Trial of BCD-100 Plus Platinum-based Chemotherapy with and without Bevacizumab versus Placebo Plus Platinum-based Chemotherapy with and without Bevacizumab as First-Line Treatment of Subjects with Advanced Cervical Cancer

Mezinárodní randomizované, dvojitě zaslepené klinické hodnocení přípravku BCD-100 v kombinaci s chemoterapií na bázi platiny s bevacizumabem nebo bez něho v porovnání s placebem v kombinaci s chemoterapií na bázi platiny s bevacizumabem nebo bez něho v léčbě první linie u pacientek s pokročilým karcinomem děložního čípku

A.3.1

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

A Clinical Trial of BCD-100 or placebo, plus Platinum-based chemotherapy with or without bevacizumab, in subjects with advanced cervical cancer

A.3.2

Name or abbreviated title of the trial where available

FERMATA

A.4.1

Sponsor's protocol code number

BCD-100-5/FERMATA

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	JSC BIOCAD
B.1.3.4	Country	Russian Federation
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	JSC BIOCAD
B.4.2	Country	Russian Federation
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	JSC BIOCAD
B.5.2	Functional name of contact point	Clinical Trials Department
B.5.3	Address:
B.5.3.1	Street Address	Svyazi str., 34-A, Strelna
B.5.3.2	Town/ city	St. Petersburg
B.5.3.3	Post code	198515
B.5.3.4	Country	Russian Federation
B.5.4	Telephone number	+7812380 49 33 617
B.5.5	Fax number	+781249 34
B.5.6	E-mail	biocad@biocad.ru

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	BCD-100
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	PROLGOLIMAB
D.3.9.1	CAS number	2093956-19-3
D.3.9.2	Current sponsor code	BCD-100
D.3.9.4	EV Substance Code	SUB198018
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	20
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	Concentrate for 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

Advanced Cervical Cancer

E.1.1.1

Medical condition in easily understood language

Advanced Cervical Cancer

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	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10008236
E.1.2	Term	Cervical cancer stage IV
E.1.2	System Organ Class	100000004864

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10008231
E.1.2	Term	Cervical cancer recurrent
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 efficacy (OS, PFS, ORR and others) of combination of BCD-100 and standard front-line therapy of advanced squamous cervical cancer consisting of platinum-based chemotherapy with or without bevacizumab at Investigator’s discretion (Test Regimen) in comparison with the same established standard regimen combined with placebo (Comparator Regimen).

E.2.2

Secondary objectives of the trial

• To evaluate efficacy (OS, PFS, ORR and others) of Test Regimen versus Comparator Regimen according to PD-L1 status.
• To evaluate safety of Test Regimen versus Comparator Regimen.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Additional sub-study of pharmacokinetics after first BCD-100 infusion will be performed in all randomized subjects from selected countries (Russia, Romania and China).
Blood samples for this type of PK analysis will be taken predose, postdose (<30 minutes after infusion), then 6 (±2), 24 (±2), 48 (±2) hours after the end of the first BCD-100/Placebo infusion, on days 8 and 15 of cycle 1, then prior to second BCD-100/Placebo infusion (<30 minutes before infusion). Population for this type of PK analysis will include all subjects who took participation in PK sub-study, received at least one BCD-100 infusion and have not more than 2 missed/lost/spoilt post-dose samples.

E.3

Principal inclusion criteria

Subjects must satisfy all of the following criteria to be eligible for randomization:
1. Signing an IRB/EC-approved informed consent
2. Females ≥ 18 years of age on day of signing informed consent
3. Histologically confirmed squamous carcinoma of the cervix
4. Progressing thru or recurrent disease treated for curative intent or primary metastatic cervical cancer stage FIGO IVB
5. Agreement to newly obtained core or excisional biopsy of a tumor lesion not previously irradiated for determination of PD-L1 status prior to randomization (using archival biopsy material is only acceptable in subjects in whom obtaining a new sample is contraindicated)
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
7. For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or to use a contraceptive method with a failure rate of < 1% per year from the moment of signing informed consent, during the treatment period and at least 6 months after administration of the last dose of study drug. A woman is considered to be of childbearing potential if she is postmenarcheal, 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, fallopian tubes, and/or uterus). Examples of contraceptive methods with a failure rate of < 1% per year include but are not limited to bilateral tubal ligation and/or occlusion, male sterilization, and 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 subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) is not acceptable method of contraception.

E.4

Principal exclusion criteria

Subjects who meet any of the following criteria must not be randomized:
1. Indications for potentially curative treatment (surgery or radiation therapy)
2. Prior systemic treatment for recurrent, secondarily progressive or initially metastatic disease
3. Previous use of chemotherapy other than initial treatment for curative intent (e.g. chemotherapy used concurrently with radiation therapy, neoadjuvant or consolidation chemotherapy cycles before radiotherapy or 2 chemotherapy cycles after completion of chemoradiotherapy are allowed)
4. Contraindications to cisplatin, carboplatin, paclitaxel, or bevacizumab
5. Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with known brain metastases may participate provided that the brain metastases have been previously treated with radiotherapy or surgery only and are radiographically stable
6. Concomitant diseases or conditions which pose a risk of AE development during study treatment:
a. uncontrolled hypertension, defined as systolic > 150 mm Hg or diastolic > 90 mm Hg;
b. stable angina functional class III-IV;
c. unstable angina or myocardial infarction less than 6 months prior to randomization;
d. NYHA Grade III–IV congestive heart failure;
e. serious cardiac arrhythmia requiring medication (subjects with asymptomatic atrial fibrillation can be enrolled if controlled ventricular rate);
f. atopic asthma, Stage III–IV COPD, angioedema;
g. severe respiratory failure;
h.inadequate coagulation status: prothrombin time such that INR > 1.5 x ULN (participants receiving anticoagulant therapy are allowed as long as PT or aPTT is within therapeutic range of intended use of anticoagulants);
i.evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation) or tumor involving large vessels;
j.clinically significant peripheral vascular disease (e.g., aortic aneurism requiring surgical repair or peripheral arterial thrombosis) within 6 months prior to randomization;
k.history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to randomization;
l.history of haemoptysis (≥ 1/2 teaspoon of bright red blood per episode) or other serious haemorrhage or at risk of bleeding (gastrointestinal history of bleeds, gastrointestinal ulcers etc.) within 1 months priortorandomization;
m.evidence of abdominal free air;
n. any other diseases which pose unacceptable risk of AE development during study treatment in Investigator’s opinion.
7. Active or known or suspected autoimmune disease (subjects with Type 1 diabetes mellitus, hypothyroidism only requiring hormone replacement, or skin disorders (vitiligo, psoriasis, or alopecia) not requiring systemic treatment are permitted to enroll).
8. Condition requiring systemic treatment with either corticosteroids or other immunosuppressive medications within 14 days prior to randomization.
9. History of (non-infectious) pneumonitis that required corticosteroids or current pneumonitis
10. Neutrophils <1500/mcl or platelets <100 000/mcl or hemoglobin <90 g/l.
11. Creatinine ≥ 1.5 x UNL.
12. Bilirubin ≥ 1.5 x UNL (excluding Gilbert’s syndrome if bilirubin < 50 μmol/l) or AST/ALT ≥ 3 x UNL (excluding subjects with liver metastases if AST/ALT < 5 x UNL) or alkaline phosphatase ≥ 2.5 x UNL.
13. Chemotherapy or radiation therapy less than 28 days prior to randomization.
14. Major surgery procedure less than 28 days prior to randomization.
15. Previous use of PD-1/PD-L1/PD-L2 agent or another agent directed to stimulatory or co-inhibitory T-cell receptor (e.g. CTLA-4, OX 40, CD137).
16. Previous use of VEGF/VEGFR inhibitors, including bevacizumab, ramucirumab, aflibercept and tyrosine kinase inhibitors.
17. Prior invasive malignancy with any evidence of disease within the last 3 years. Subjects with non-melanoma skin cancer or carcinoma in situ (e.g. breast cancer) who have undergone potentially curative therapy are not excluded.
18. Pre-existing clinically significant (≥ grade 2) peripheral neuropathy or hearing impairment
19. Any conditions or circumstances that limit subject’s ability to comply with protocol requirements
20. Active hepatitis B, active hepatitis С or positive HIV1 or HIV2 test
21. Active infection requiring therapy or systemic antibiotics use less than 14 days prior to randomization. Severe infections within 28 days prior to first study drug administration.
22. Administration of a live vaccine within 28 days prior to randomization.
23. Current using of another investigational device or drug study, or less than 30 days since ending of using of another investigational device or drug study
24. Life expectancy less than 12 weeks
25. Significant adverse events (AE) of previous therapy excluding chronic and/or irreversible events which cannot affect study drug safety evaluation (e.g. alopecia)

E.5 End points

E.5.1

Primary end point(s)

overall survival (OS) — the time from the date of randomization until death

E.5.1.1

Timepoint(s) of evaluation of this end point

continuously throughout the trial

E.5.2

Secondary end point(s)

Progression-free survival (PFS) per RECIST 1.1 — the time from the date of randomization until progression of disease according to RECIST 1.1 criteria or death
PFS per iRECIST — the time from the date of randomization until progression of disease according to iRECIST criteria or death
Overall response rate (ORR) per RECIST 1.1
ORR per iRECIST
Disease control rate (DCR)
Time to response (TTR)
Duration of response (DOR)

E.5.2.1

Timepoint(s) of evaluation of this end point

continuously throughout the trial

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

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

Yes

E.6.13.1

Other scope of the trial description

Immunogenicity

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

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

Austria

Belgium

China

Czech Republic

Denmark

Finland

Georgia

Germany

Hungary

Poland

Romania

Russian Federation

Slovakia

Turkey

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

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

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

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:

224

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

F.4.2

For a multinational trial

F.4.2.1

In the EEA

150

F.4.2.2

In the whole clinical trial

316

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 - Patients to receive standard of care

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	AGO RESEARCH GmbH
G.4.3.4	Network Country	Germany

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2020-04-03

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-12-09

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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