E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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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 |
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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 |
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E.1.3 | Condition being studied is a rare disease | No |
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). |
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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. |
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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. |
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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. |
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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. 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 history of positive HIV.
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)
26. Known hypersensitivity or allergy to paclitaxel, cisplatin, carboplatin, bevacizumab, BCD-100 or any of their excipients. Known hypersensitivity or allergy to drugs derived from Chinese hamster (CHO) ovary cells or history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins.
27. Pregnancy or breast-feeding |
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E.5 End points |
E.5.1 | Primary end point(s) |
overall survival (OS) — the time from the date of randomization until death |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
continuously throughout the trial |
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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) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
continuously throughout the trial |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 90 |
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 | No |
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 |
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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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |