| 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 investigator or by histopathologic confirmation of suspected local disease progression (in the absence of radiographic disease progression per RECIST 1.1) assessed by investigator.
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) Compare concurrent chemoradiotherapy+pembrolizumab with concurrent chemoradiotherapy+placebo with respect to:
•PFS per RECIST 1.1 assessed by blinded independent central review (BICR)
•PFS at 2 yrs per RECIST 1.1 assessed by investigator&BICR
•OS at 3 yrs
•Complete response rate at 12 weeks per RECIST 1.1 assessed by investigator&BICR
•Objective response rate per RECIST 1.1 assessed by investigator&BICR
•OS and PFS per RECIST 1.1 by programmed cell death 1 ligand 1 (PD-L1) status assessed by investigator&BICR
•PFS after next-line treatment(PFS 2)
•Change from baseline(CFB) in global quality of life and physical function using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (EORTC QLQ-C30)
•CFB in cervical cancer symptom experience using EORTC Quality of Life Questionnaire-Symptom Score for Cervical Cancer (EORTC CX24)
2) Evaluate safety and tolerability of pembrolizumab in combination with concurrent chemoradiotherapy |
|
| E.2.3 | Trial contains a sub-study | No |
| 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 up to the L1 cephalad body level.
Pelvic lymph node involvement as assessed by one of the following criteria:
- Histopathologic, biopsy-proven pelvic node involvement, (high-risk LACC patient with locally evaluable disease is eligible if removal of positive lymph node[s] is documented), 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 (max) ≥2.5
Para-aortic lymph node involvement as assessed by one of the following criteria:
- Histopathologic, biopsy-proven para-aortic node involvement (high risk LACC patient with locally evaluable disease is eligible if removal of positive lymph node[s] is documented), 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 (max) ≥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, including investigational agents, 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 documented 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 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 investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention. Contraceptive use by
women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions is more stringent than the requirements above, the local label requirements are to be followed.
- A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 72 hours (serum) or 24 hours (urine) 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
-Abstains from breastfeeding during the study 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 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 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.
8. Has radiographically evaluable disease, either measurable or nonmeasurable per RECIST 1.1, as assessed by the local site investigator/radiology.
• As per inclusion criterion #1, for stage IB2-IIB (FIGO 2014) disease, if nodal involvement is assessed by CT or MRI, the participant must have measurable disease (≥1.5 cm in shortest dimension) per RECIST 1.1.
• High risk LACC patient with radiographically locally evaluable disease is eligible if removal of positive lymph node(s) is documented.
9. Has provided a tissue sample from a core, incisional, or excisional biopsy of a tumor to 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, nonepithelial cancer).
2. Has FIGO 2014 Stage IVB disease. Evidence of metastatic disease per RECIST 1.1 including lymph nodes above the L1 cephalad body or in the inguinal region. Participants with inguinal lymph node involvement should be discussed with Sponsor and may potentially be eligible after confirmation of the Sponsor with participant’s disease details.
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 or considered mild and not clinically significant in the opinion of the investigator.
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, 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 (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
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 history or current evidence of any condition, therapy, laboratory 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.
21. Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study.
22. Has had an allogenic tissue/solid organ transplant.
23. Evidence of metastatic disease per RECIST 1.1 including lymph nodes above the L1 cephalad body, in the inguinal region. Participants with inguinal lymph node involvement should be discussed with Sponsor and may potentially be eligible after confirmation of the Sponsor with participant’s disease details. |
|
| 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) .1) as Assessed by the Investigator
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) as Assessed by Blinded Independent Central Review (BICR)
2. Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) at Month 24 as Assessed by the Investigator
3. Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) at Month 24 as Assessed by BICR
4. Overall Survival (OS) at Month 36
5. Complete Response (CR) Rate Per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) at Week 12 as Assessed by the Investigator
6. Complete Response (CR) Rate Per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) at Week 12 as Assessed by BICR
7. Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by the Investigator
8. Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by BICR
9. 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 as Assessed by the Investigator
10. 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 as Assessed by BICR
11. Overall Survival (OS) in Programmed Cell Death 1 Ligand 1 (PD-L1) Positive Participants as Assessed by the Investigator
12. Overall Survival (OS) in Programmed Cell Death 1 Ligand 1 (PD-L1) Positive Participants as Assessed by BICR
13. Progression-Free Survival (PFS) After Next-Line Treatment (PFS 2) Following Discontinuation of Study Treatment
14. 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
15. Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Physical Function Score
16. 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
17. Number of Participants Who Experience One or More Adverse Events (AEs)
18. 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 38 months
3. Up to approximately 38 months
4. Up to approximately 46 months
5. Up to approximately 38 months
6. Up to approximately 38 months
7. Up to approximately 46 months
8. Up to approximately 46 months
9. Up to approximately 38 months
10. Up to approximately 38 months
11. Up to approximately 46 months
12. Up to approximately 46 months
13. Up to approximately 46 months
14. Baseline and up to approximately 46 months
15. Baseline and up to approximately 46 months
16. Baseline and up to approximately 46 months
17. Up to approximately 46 months
18. 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 | 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 | 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 | 2 |
| 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 |
| Brazil |
| Canada |
| Chile |
| China |
| Colombia |
| Guatemala |
| Israel |
| Japan |
| Korea, Republic of |
| Peru |
| Taiwan |
| Thailand |
| United States |
| Austria |
| France |
| Sweden |
| Spain |
| Czechia |
| Germany |
| Greece |
| Italy |
| Belgium |
| Denmark |
| Hungary |
| Ireland |
| Norway |
| Russian Federation |
| Turkey |
| Ukraine |
| United Kingdom |
|
| 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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