| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| High-risk locally advanced cervical cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Locally 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 | 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 concurrent chemoradiotherapy plus pembrolizumab with concurrent chemoradiotherapy plus placebo with respect to progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by blinded independent central review or by histopathologic confirmation of suspected local disease progression (in the absence of radiographic disease progression per RECIST 1.1)
2. To compare concurrent chemoradiotherapy plus pembrolizumab with concurrent chemoradiotherapy plus placebo with respect to overall survival (OS) |
|
| E.2.2 | Secondary objectives of the trial |
1. To compare concurrent chemoradiotherapy plus pembrolizumab with concurrent chemoradiotherapy plus placebo with respect to:
- PFS at 2 years per RECIST 1.1
- OS at 3 years
- Complete response rate at 12 weeks per RECIST 1.1
- Objective response rate per RECIST 1.1
- OS and PFS per RECIST 1.1 by programmed cell death 1 ligand 1 (PD-L1) status
- PFS after next-line treatment (PFS 2) following discontinuation of study treatment administration
- Change from baseline score in global quality of life and physical function using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)
- Change from baseline score in cervical cancer symptom experience using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Symptom Score for Cervical Cancer (EORTC CX24)
2. To evaluate the safety and tolerability of pembrolizumab in combination with concurrent chemoradiotherapy |
|
| 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 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. Has high-risk LACC (a or b below):
a. FIGO 2014 Stage IB2-IIB (with node-positive disease) – must meet criteria below for positive pelvic lymph node OR para-aortic lymph node involvement
Pelvic lymph node involvement as assessed by one of the following criteria:
- Histopathologic, biopsy-proven pelvic node involvement, or
- 2 or more positive pelvic nodes by MRI or CT (≥1.5 cm shortest dimension), or
- 2 or more positive pelvic nodes by PET / CT with SUV ≥2.5
Para-aortic lymph node involvement as assessed by one of the following criteria:
- Histopathologic, biopsy-proven para-aortic node involvement, or
- 1 or more positive para-aortic nodes by MRI or CT (≥1.5 cm shortest dimension), or
- 1 or more positive para-aortic nodes by PET / CT with SUV ≥2.5
b. FIGO 2014 Stages III-IVA (either node-positive or node-negative disease)
2. Has histologically-confirmed squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the cervix.
3. Has not previously received any definitive surgical, radiation, or systemic therapy for cervical cancer and is immunotherapy-naïve.
4. Has an ECOG performance status of 0 or 1 within 7 days prior to the first dose of study intervention
5. Is female, at least 18 years of age at the time of signing the informed consent.
6. 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 using 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), during the intervention period and for at least 120 days after the last dose of pembrolizumab or placebo and 180 days following the end of chemoradiotherapy. The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention.
- A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 24 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
- The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy
7. The participant (or legally acceptable representative if applicable) provides written 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.
8. Has radiographically evaluable disease, either measurable or nonmeasurable per RECIST 1.1, as assessed by the local site investigator/radiology
9. Has provided a tissue sample from a core or excisional biopsy of a tumor lesion for confirmation of adequacy by the central vendor prior to randomization. Formalin-fixed, paraffin embedded tissue blocks are preferred to slides
10. Has adequate organ function. Specimens must be collected within 7 days prior to the start of study intervention |
|
| E.4 | Principal exclusion criteria |
1. Has histological subtypes other than those allowed per inclusion criterion 2 (eg, sarcoma, small cell carcinoma with neuroendocrine differentiation, non-epithelial cancer).
2. Has FIGO 2014 Stage IVB disease.
3. Has undergone a previous hysterectomy defined as removal of the entire uterus or will have a hysterectomy as part of their initial cervical cancer therapy.
4. Has bilateral hydronephrosis, unless at least one side has been stented or resolved by positioning of nephrostomy
5. Has anatomy or tumor geometry or any other reason or contraindication that cannot be treated with intracavitary brachytherapy or a combination of intracavitary and interstitial brachytherapy
6. Has received a live vaccine within 30 days prior to the first dose of study intervention. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, 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.
7. Has received treatment with systemic immunostimulatory agents such as bacterial or viral vaccines, colony stimulating factors, interferons, interleukins and vaccine combinations within 6 weeks or 5 half-lives of the drug, whichever is shorter, prior to Cycle 1, Day 1.
8. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell recepto (eg, CTLA-4, OX-40, CD137).
9. Has received prior systemic anticancer therapy including investigational agents within 4 weeks prior to randomization.
10. 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
11. Has any contraindication to the use of cisplatin.
12. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study medication.
13. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.
14. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
15. 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.
16. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
17. Has an active infection requiring systemic therapy.
18. Has a known history of HIV infection.
19. Has a known history of Hepatitis B (defined as HBsAg reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
20. Has a known history of active tuberculosis (TB; Bacillus tuberculosis).
21. Has a history or current evidence of any condition, therapy, lab abnormality, or other circumstance that may increase the risk associated with study participation or study intervention administration or may interfere with the interpretation of study results, and in the judgment of the investigator or Sponsor, would make the participant inappropriate for entry into this study.
22. Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study.
23. Is pregnant or breastfeeding or expecting to conceive children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of pembrolizumab or placebo and 180 days following the end of chemoradiotherapy.
24. Has had an allogenic tissue/solid organ transplant. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
2. Overall Survival (OS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 38 months
2. Up to approximately 46 months |
|
| E.5.2 | Secondary end point(s) |
1. Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) at Month 24
2. Overall Survival (OS) at Month 36
3. Complete Response (CR) Rate Per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) at Week 12
4. Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
5. Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) in Programmed Cell Death 1 Ligand 1 (PD-L1) Positive Participants
6. Overall Survival (OS) in Programmed Cell Death 1 Ligand 1 (PD-L1) Positive Participants
7. Progression-Free Survival (PFS) After Next-Line Treatment (PFS 2) Following Discontinuation of Study Treatment
8. Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Global Health Status Score
9. Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Physical Function Score
10. Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Symptom Specific Scale for Cervical Cancer (EORTC QLQ-CX24) Score
11. Number of Participants Who Experience One or More Adverse Events (AEs)
12. Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 38 months
2. Up to approximately 46 months
3. Up to approximately 38 months
4. Up to approximately 46 months
5. Up to approximately 38 months
6. Up to approximately 46 months
7. Up to approximately 46 months
8. Baseline and up to approximately 46 months
9. Baseline and up to approximately 46 months
10. Baseline and up to approximately 46 months
11. Up to approximately 46 months
12. Up to approximately 46 months |
|
| 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 | Yes |
| E.6.11 | Pharmacogenomic | No |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 63 |
| 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 |
| Australia |
| Austria |
| Belgium |
| Brazil |
| Canada |
| Chile |
| China |
| Colombia |
| Czech Republic |
| Denmark |
| France |
| Germany |
| Greece |
| Guatemala |
| Hungary |
| Ireland |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Norway |
| Peru |
| Russian Federation |
| Spain |
| Sweden |
| Taiwan |
| Thailand |
| Turkey |
| Ukraine |
| 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
|
|
| 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 | 63 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 63 |
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