| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Women with persistent, recurrent, or metastatic 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 | 10008229 |
| E.1.2 | Term | Cervical cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
1. To compare progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST 1.1) as assessed by investigator
2. To compare overall survival (OS) |
|
| E.2.2 | Secondary objectives of the trial |
1. To evaluate the objective response rate (ORR), duration of response (DOR), and 12-month PFS rate per RECIST 1.1 as assessed by Investigator
2. To evaluate Progression Free Survival (PFS) per RECIST 1.1 as assessed by BICR
2. To compare the safety and tolerability by the proportion of adverse events (AEs)
3. To evaluate changes in Health- Related Quality of Life (HRQoL) assessments using the global score of the European Organisation for the Research and Treatment of Cancer (EORTC) QLQ-C30 |
|
| 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 |
Merck will conduct Future Biomedical Research on DNA (Blood and tissue) specimens collected during this clinical trial. Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose
of the correct drug at the correct time |
|
| E.3 | Principal inclusion criteria |
1. Female participants who are at least 18 years of age on the day of
providing informed consent
2. Have persistent, recurrent, or metastatic squamous cell carcinoma,
adenosquamous carcinoma, or adenocarcinoma of the cervix which has
not been treated with systemic chemotherapy and is not amenable to
curative treatment (such as with surgery and/or radiation)
3. A female participant is eligible to participate if she is not pregnant
or breastfeeding, and at least one of the following conditions applies:
• Is not a WOCBP
OR
• Is a WOCBP and:
- Uses a contraceptive method that is highly effective (with a failure
rate of <1% per year), with low user dependency, or be abstinent from
heterosexual intercourse as their preferred and usual lifestyle (abstinent
on a long-term and persistent basis), as described in Appendix 5 during the intervention period and for at least the time needed to eliminate
each study intervention after the last dose of study intervention and
agrees not to donate eggs (ova, oocytes) to others or freeze/store for
her own use for the purpose of reproduction during this period. The
length of time required to continue contraception for each study
intervention is as follows:
o Pembrolizumab/placebo 120 days
o Chemotherapy 210 days
o Bevacizumab 210 days
The investigator should evaluate the potential for contraceptive method
failure (ie, noncompliance, recently initiated) in relationship to the first
dose of study intervention.
- Has a negative highly sensitive pregnancy test (urine or serum as
required by local regulations) within 72 hours before the first dose of
study intervention. If a urine test cannot be confirmed as negative (eg,
an ambiguous result), a serum pregnancy test is required. In such cases,
the participant must be excluded from participation if the serum
pregnancy result is positive. Additional requirements for pregnancy
testing during and after study intervention are in Section 8.3.4.2.
- Has had her medical history, menstrual history, and recent sexual
activity reviewed by the investigator to decrease the risk for inclusion of
a woman with an early undetected pregnancy.
4. The participant (or legally acceptable representative if applicable)
provides documented informed consent for the study. The participant
may also provide consent for future biomedical research. However, the
participant may participate in the main study without participating in
future biomedical research
5. Have measurable disease per RECIST 1.1 as assessed by the local site
investigator/radiology. Lesions situated in a previously irradiated area
are considered measurable only if progression has been demonstrated in
such lesions
6. Have provided archival tumor tissue sample or newly obtained core or
excisional biopsy of a tumor lesion not previously irradiated for
prospective determination of PD-L1 status prior to randomization
7. Have an Eastern Cooperative Oncology Group (ECOG) performance
status of 0 to 1 within 14 days prior to randomization
8. Have adequate organ function |
|
| E.4 | Principal exclusion criteria |
1. A WOCBP who has a positive urine pregnancy test within 72 hours prior to randomization. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
2. Has known active CNS metastases and/or carcinomatous meningitis. Participants with known brain metastases may participate provided that the brain metastases have been previously treated (except with chemotherapy) and are radiographically stable. To demonstrate radiographic stability of previously treated brain metastases, a minimum of 2 post-treatment brain imaging assessments are required: 1) The first brain imaging must be acquired after treatment of brain metastases has been completed 2) The second brain imaging must be obtained during screening (i.e. within 28 days prior to randomization) and >4 weeks after the previous post-treatment brain imaging
3. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years
4. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in doses exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to randomization
5. Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed
6. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
7. Has an active infection requiring systemic therapy
8. Has a known history of human immunodeficiency virus (HIV) infection
9. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection
10. Has a known history of active tuberculosis (TB; Bacillus tuberculosis)
11. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PDL2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137)
12. Has received prior systemic chemotherapy for treatment of cervical cancer (chemotherapy used as a radiosensitizing agent and completed at least 2 weeks prior to randomization is permitted)
13. Has not recovered adequately from toxicity and/or complications from surgery prior to randomization
14. Has received prior radiotherapy within 2 weeks prior to randomization. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease
15. Has received a live vaccine within 30 days prior to randomization. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed
16. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients
17. Has a contraindication or hypersensitivity to any component of cisplatin, carboplatin, paclitaxel, or bevacizumab
18. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to randomization
19. Is pregnant or breastfeeding or expecting to conceive within the
projected duration of the study, starting with the screening visit through
120 days following last dose of pembrolizumab/placebo and 210 days
following last dose of chemotherapy or bevacizumab (if applicable).
20. Has had an allogeneic tissue/solid organ transplant
21. Has a known psychiatric or substance abuse disorder that would interfere with cooperating with the requirements of the study
22. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- Progression-free survival (PFS) based on RECIST 1.1 as assessed by investigator
- Overall survival (OS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The first interim analysis (interim analysis for PFS and OS) will be conducted when approximately 370 PFS events have been observed for CPS ≥1 group. The second interim analysis (final PFS analysis and
interim OS analysis) may be conducted when at least 435 PFS events for CPS ≥1 group have been observed. It is estimated that approximately 508 PFS events for all-comers and approximately 247 PFS events for CPS ≥10 group will be observed by then. The final analysis (final OS analysis) may be conducted when at least 378 OS events for CPS ≥1 group have been observed. It is estimated that approximately 445 OS events for allcomers and approximately 196 OS events for CPS ≥10 group will be
observed by then. |
|
| E.5.2 | Secondary end point(s) |
- Objective response rate (ORR) by investigator using RECIST 1.1
- Duration of response (DOR) by investigator using RECIST1.1
- PFS rate at 12 months by investigator using RECIST 1.1
- PFS by BICR using RECIST 1.1
- Patient reported quality of life by EORTC QLQ-C30 global score
- Safety and tolerability of the two treatment arms |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| 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 |
| Argentina |
| Australia |
| Canada |
| Chile |
| Colombia |
| Israel |
| Japan |
| Korea, Republic of |
| Mexico |
| Peru |
| Taiwan |
| United States |
| Russian Federation |
| Turkey |
| Ukraine |
| France |
| Germany |
| Italy |
| Poland |
| Spain |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| 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 | 4 |
| 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 |
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