E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Advanced Endometrial Cancer |
|
E.1.1.1 | Medical condition in easily understood language |
Advanced Endometrial Cancer is the cancer of the lining of the uterus (or womb). |
|
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 | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10014733 |
E.1.2 | Term | Endometrial cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
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 version 1.1 (RECIST 1.1) by blinded independent central review (BICR), modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ for the combination of pembrolizumab (MK-3475) plus lenvatinib (MK-7902) versus chemotherapy 2. To compare Overall Survival (OS) for the combination of pembrolizumab plus lenvatinib versus chemotherapy
|
|
E.2.2 | Secondary objectives of the trial |
1. To compare objective response rate (ORR) per RECIST 1.1 by BICR in mismatch repair proficient (pMMR) participants and in all-comer participants who have measurable disease at study entry 2. To evaluate the impact of treatment on Health-Related Quality-of-Life (HRQoL) as assessed by using the global score of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core-30 (QLQ C30) in pMMR and in all-comer participants 3. To compare the safety and tolerability of pembrolizumab plus lenvatinib versus chemotherapy in all-comer participants
|
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Have Stage III, Stage IV, or recurrent, histologically-confirmed endometrial carcinoma with disease that is either measurable or non-measurable per RECIST 1.1 but radiographically apparent, as assessed by BICR. 2. Have provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion that was not previously irradiated, for determination of MMR status. 3. Have an ECOG performance status of 0 or 1, as assessed within 7 days prior to the first dose of study intervention. 4. Be female and at least 18 years of age on the day of signing consent. 5. 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 post pembrolizumab or 30 days post lenvatinib, whichever occurs last, and 196 days after the last dose of chemotherapy. 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. 6. The participant (or legally acceptable representative if applicable) provides written informed consent for the study. 7. Have adequately controlled BP with or without antihypertensive medications, defined as BP ≤150/90 mm Hg with no change in antihypertensive medications within 1 week prior to randomization. 8. Have adequate organ function within 7 days prior to the first dose of study intervention. |
|
E.4 | Principal exclusion criteria |
1. Has carcinosarcoma (malignant mixed Műllerian tumor), endometrial leiomyosarcoma or other high grade sarcomas, or endometrial stromal sarcomas. 2. Participants with central nervous system (CNS) metastases are not eligible, unless they have completed local therapy and have discontinued the use of corticosteroids for this indication for at least 4 weeks before starting treatment in this study. Any signs or symptoms of CNS metastases must be stable for at least 4 weeks before starting study treatment. 3. Has a known additional malignancy (other than endometrial carcinoma) that is progressing or has required active treatment in the last 3 years. 4. Has gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of lenvatinib. 5. Has a pre-existing Grade ≥3 gastrointestinal or non-gastrointestinal fistula. 6. Has radiographic evidence of major blood vessel invasion/infiltration. The degree of tumor invasion/infiltration of major blood vessels should be considered because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis following lenvatinib therapy. 7. Has clinically significant hemoptysis or tumor bleeding within 2 weeks prior to randomization. 8. Has significant cardiovascular impairment within 12 months of the first dose of study intervention such as history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction or cerebrovascular accident (CVA) stroke, or cardiac arrhythmia associated with hemodynamic instability. 9. Has an active infection (any infection requiring systemic treatment). 10. Has had major surgery within 3 weeks prior to first dose of study interventions. 11. Has not recovered adequately from any toxicity and/or complications from major surgery prior to randomization. 12. Has a known history of human immunodeficiency virus (HIV) infection. 13. Has a known history of Hepatitis B or known active Hepatitis C virus infection. 14. Has a history of (non-infectious) pneumonitis that required treatment with steroids, or has current pneumonitis. 15. Has a known history of active tuberculosis. 16. 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. 17. Has a known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the study. 18. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to randomization. 19. Has an active autoimmune disease (with the exception of psoriasis) that has required systemic treatment in the past 2 years. Replacement therapy is not considered a form of systemic treatment. 20. 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 30 days post lenvatinib, whichever occurs last, and 196 days after the last dose of chemotherapy. 21. Has received prior systemic chemotherapy in any setting for the treatment of endometrial carcinoma. 22. Has received prior radiotherapy within 4 weeks prior to randomization. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 2-week washout is permitted for palliative radiation to non-CNS disease and vaginal brachytherapy. 23. Has received prior hormonal therapy for the treatment of endometrial carcinoma within 1 week of randomization. 24. Has received prior therapy with any treatment targeting VEGF-directed angiogenesis, 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 receptor (eg, CTLA-4, OX 40, CD137). 25. Has received a live vaccine within 30 days prior to the first dose of study intervention. 26. Has known intolerance to study intervention (or any of the excipients). 27. Has had an allogenic tissue/solid organ transplant. 28. 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. 29. Participants with proteinuria >1+ on urine dipstick testing will undergo 24-hr urinecollection for quantitative assessment of proteinuria. Participants with urine protein ≥1 g/24 hr will be ineligible. 30. Has prolongation of QTc interval to >480 ms (corrected by Fridericia Formula). 31. Has left ventricular ejection fraction (LVEF) below the institutional normal range as determined by multigated acquisition (MUGA) or echocardiogram (ECHO). |
|
E.5 End points |
E.5.1 | Primary end point(s) |
1. Progression-free survival (PFS) based on Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as assessed by blinded independent central review (BICR), modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ 2. Overall Survival (OS)
|
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. From the time of randomization to the first documented disease progression per RECIST 1.1 assessed by BICR (up to 24 months) 2. From the time of randomization up to death due to any cause (up to 24 months)
|
|
E.5.2 | Secondary end point(s) |
1. Objective response rate (ORR; either confirmed complete response [CR] or partial response [PR]) based on Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as assessed by blinded independent review (BICR) in mismatch repair proficient (pMMR) participants and in all-comer participants who have measurable disease at study entry 2. Change from baseline in Health-Related Quality-of-Life (HRQoL) global score of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core-30 (QLQ C30) in pMMR and in all-comer participants 3. A) Percentage of participants experiencing an adverse event (AE); B) Percentage of participants experiencing a serious AE (SAE); C) Percentage of participants experiencing an immune-related AE (irAE); and D) Percentage of participants discontinuing from study treatment due to an AE(s)
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to 24 months 2. Up to 27 months 3. A) Through 90 days after the last dose of study treatment (up to approximately 27 months); B) Through 120 days after the last dose of study treatment (up to approximately 28 months); C) Through 90 days after the last dose of study treatment (up to approximately 27 months); and D) Through the last dose of study treatment (up to approximately 24 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 | Yes |
E.6.12 | Pharmacoeconomic | Yes |
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 | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 55 |
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 |
Austria |
Belgium |
Brazil |
Canada |
China |
Germany |
Ireland |
Israel |
Italy |
Japan |
Korea, Republic of |
Mexico |
Poland |
Russian Federation |
Spain |
Taiwan |
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 | 3 |
E.8.9.1 | In the Member State concerned months | 5 |
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 |