| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| First-line treatment of participants with dMMR advanced or recurrent EC |
|
| E.1.1.1 | Medical condition in easily understood language |
| Stage III or IV or recurrent endometrial carcinoma (EC), centrally confirmed as dMMR, with no prior systemic therapy for advanced EC, except radiosensitizing chemotherapy or hormonal therapy. |
|
| 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 | 10014747 |
| E.1.2 | Term | Endometrial carcinoma recurrent |
| 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 pembrolizumab to chemotherapy with respect to PFS per RECIST 1.1 as assessed by BICR
2. To compare pembrolizumab to chemotherapy with respect to OS
|
|
| E.2.2 | Secondary objectives of the trial |
1. To compare pembrolizumab to chemotherapy with respect to ORR per RECIST 1.1 by BICR in participants with measurable disease at study entry
2. To compare pembrolizumab to chemotherapy with respect to DCR per RECIST 1.1 by BICR in participants with measurable disease at study entry
3. To compare pembrolizumab to chemotherapy with respect to DOR per RECIST 1.1 by BICR in participants with measurable disease at study entry
4. To compare pembrolizumab to chemotherapy with respect to PFS per RECIST 1.1 as assessed by the investigator
5. To compare pembrolizumab to chemotherapy with respect to PFS2 per RECIST 1.1 as assessed by the investigator
6. To compare the safety and tolerability of pembrolizumab to chemotherapy
7. To compare pembrolizumab to chemotherapy with respect to change from baseline score in the EORTC QLQ-C30 GHS/QoL
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Has a histologically confirmed diagnosis of inoperable, Stage III/IV, persistent or recurrent EC or carcinosarcoma (mixed Mullerian tumor) that is centrally confirmed as dMMR.
2.Has radiographically evaluable disease, either measurable or nonmeasurable per RECIST 1.1, as assessed by the investigator.
Prior Therapy
3.Has received no prior systemic therapy for EC.
4.Is female, at least 18 years of age at the time of providing the informed consent (either Authorization for Release of Tumor Tissue or main study consent).
5.Has ECOG performance status of 0 or 1 within 7 days before randomization.
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 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:
- Pembrolizumab (120 days after last dose)
- Chemotherapy (180 days after last dose)
The investigator should evaluate the potential for contraceptive method failure 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 for urine or 72 hours for serum before the first dose of study intervention.
If a urine test cannot be confirmed as negative, 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 must adhere to protocol.
Abstains from breastfeeding during the study intervention period and for at least 120 days after the last dose of pembrolizumab, 30 days after the last dose of cytotoxic chemotherapy agents (paclitaxel, docetaxel, carboplatin, cisplatin), or as per local regulations.
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.
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.
7.The participant (or legally acceptable representative) has provided documented informed consent/assent for the study. The participant may also provide consent/assent for FBR. However, the participant may participate in the study without participating in FBR.
8.Provides an archival tumor tissue sample or newly obtained (core, incisional, or excisional) biopsy of a tumor lesion not previously irradiated for verification of dMMR status and histology.
9.If HBsAg positive is eligible if they have received HBV antiviral therapy for at least 4 weeks and has undetectable HBV viral load prior to randomization.
Hepatitis B screening tests are not required unless:
-Known history of HBV infection
-As mandated by local health authority
Refer to the protocol for country-specific requirements.
10.With history of HCV infection is eligible if HCV viral load is undetectable at screening.
Hepatitis C screening tests are not required unless:
-Known history of HCV infection
-As mandated by local health authority
Refer to the protocol for country-specific requirements.
11.Has adequate organ function. Specimens must be collected within 7 days before randomization. |
|
| E.4 | Principal exclusion criteria |
1.Has uterine mesenchymal tumor such as an endometrial stromal sarcoma, leiomyosarcoma, or other types of pure sarcomas. Adenosarcomas are also not allowed. Neuroendocrine tumors are also not allowed.
2.Has EC of any histology that is pMMR.
3.Is a candidate for curative-intent surgery or curative-intent radiotherapy.
4.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 coinhibitory T-cell receptor.
5.Has received prior systemic anticancer therapy including investigational agents for EC. This includes any chemotherapy given for EC other than as a radiosensitizer.
6.Has had a major operation and has not recovered adequately from the procedure and/or any complications from the operation before starting study intervention.
7.Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines are allowed.
8.Is currently participating in or has participated in a study of an investigational agent for EC; or has participated in a study of an investigational agent for non-EC within 4 weeks before the first dose of study intervention; or has used an investigational device within 4 weeks before the first dose of study intervention.
9.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 intervention.
10.Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.
11.Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, for at least 4 weeks by repeat imaging, clinically stable and without requirement of steroid treatment for at least 14 days before the first dose of study intervention.
12.Has a known intolerance to any study intervention and/or any of its excipients.
13.Has an active autoimmune disease that has required systemic treatment in past 2 years.
14.Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
15.Has an active infection, requiring systemic therapy.
16.Has a known history of HIV infection. No HIV testing is required unless mandated by local health authority.
Refer to the protocol for country-specific requirements.
17. Has a history or current evidence of any condition, therapy, laboratory abnormality, or other circumstance that might confound the results of the study or interfere with the participant's participation for the full duration of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator.
18.Has had an allogenic tissue/solid organ transplant. Refer to the protocol for country-specific requirements. |
|
| 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) as Assessed by Blinded Independent Central Review (BICR)
2. Overall survival (OS)
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 30 months
2. Up to approximately 49 months
|
|
| E.5.2 | Secondary end point(s) |
1. Objective Response Rate (ORR) per RECIST 1.1 as Assessed by BICR
2. Disease Control Rate (DCR) per RECIST 1.1 as Assessed by BICR
3. Duration of Response (DOR) per RECIST 1.1 as Assessed by BICR
4. PFS per RECIST 1.1 as Assessed by Investigator
5. Progression-Free Survival 2 (PFS2) per RECIST 1.1 as Assessed by Investigator
6. Number of Participants Who Experience at Least One Adverse Event (AE)
7. Number of Participants Who Discontinue Study Treatment Due to an AE
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 (GHS) (Item 29) And Quality of Life (QoL) (Item 30) Combined Score
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 30 months
2. Up to approximately 30 months
3. Up to approximately 30 months
4. Up to approximately 30 months
5. Up to approximately 30 months
6. Up to approximately 27 months
7. Up to approximately 24 months
8. Baseline and up to approximately 25 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 | No |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 126 |
| 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 |
| Colombia |
| New Zealand |
| Peru |
| Ukraine |
| Ireland |
| Taiwan |
| Australia |
| Belgium |
| Canada |
| China |
| Czechia |
| Denmark |
| Finland |
| Germany |
| Hungary |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Netherlands |
| Norway |
| Poland |
| Russian Federation |
| Spain |
| Sweden |
| Turkey |
| 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
|
| The overall study ends when the last participant completes the last study-related contact, withdraws consent, or is lost to follow-up (ie, the participant is unable to be contacted by the investigator). For purposes of analysis and reporting, the overall study ends when the Sponsor receives the last laboratory test result or at the time of final contact with the last participant, whichever comes last. |
|
| 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 | 50 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 50 |
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