| 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 [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 | 20.0 |
| 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 |
- To demonstrate that lenvatinib in combination with pembrolizumab is superior to Treatment of Physician’s Choice (TPC) in improving progression-free survival (PFS).
- To demonstrate that lenvatinib in combination with pembrolizumab is superior to TPC in improving overall survival (OS). |
|
| E.2.2 | Secondary objectives of the trial |
- To compare the objective response rate (ORR) of participants treated with lenvatinib in combination with pembrolizumab versus TPC by BICR.
- To evaluate the impact of treatment on Health-Related Quality of Life (HRQoL) as assessed by using the global score of the European Organisation for the Research and Treatment of Cancer (EORTC) QLQ-C30 for participants treated with lenvatinib in combination with pembrolizumab versus TPC.
- To assess safety and tolerability of treatment with lenvatinib in combination with pembrolizumab versus TPC in pMMR participants and in all-comer participants.
- To characterize the population pharmacokinetics (PK) of lenvatinib when co-administered with pembrolizumab in pMMR participants and in all-comer participants.
- To assess the exposure/response relationship between exposure to lenvatinib and efficacy/safety, if possible, using a mechanistic model-based approach in pMMR participants and in all-comer participants. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Histologically confirmed diagnosis of endometrial carcinoma.
2. Documented evidence of advanced, recurrent or metastatic EC.
3. Radiographic evidence of disease progression after 1 prior systemic, platinum-based chemotherapy regimen for recurrent, metastatic or primary unresectable disease.
- Participants who progress <1 year after completion of prior adjuvant or neoadjuvant platinum-based chemotherapy are eligible without further systemic treatment.
- Participants who progress ≥1 year after completion of prior adjuvant or neoadjuvant platinum-based chemotherapy must receive 1 additional cytotoxic systemic treatment prior to enrollment in this study.
4. Available historical or fresh tumor biopsy specimen for determination of MMR status.
5. At least 1 measurable target lesion according to RECIST 1.1 and confirmed by BICR, including the following criteria:
- Non-nodal lesion that measures ≥1.0 cm in the longest diameter
- Lymph node (LN) lesion that measures as ≥1.5 cm in the short axis
- The lesion is suitable for repeat measurement using computed tomography/magnetic resonance imaging (CT/MRI). Lesions that have had external beam radiotherapy (EBRT) or locoregional therapy must show radiographic evidence of subsequent growth.
6. ECOG performance status of 0 or 1 within 3 days of starting study treatment.
7. Female participants age ≥18 years and considered an adult per local regulations at the time of informed consent.
8. A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
a.) Not a WOCBP
OR
b.) A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 120 days after the last dose of study treatment.
9. The participant provides written informed consent for the study.
10. Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP ≤150/90 mm Hg at Screening and no change in antihypertensive medications within 1 week before C1D1.
11. Have adequate organ function. Specimens must be collected within 3 days prior to the start of study treatment. |
|
| E.4 | Principal exclusion criteria |
1. Carcinosarcoma (malignant mixed Műllerian tumor), endometrial leiomyosarcoma and endometrial stromal sarcomas.
2. Participants with 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 brain metastases must be stable for at least 4 weeks before starting study treatment.
3. Active malignancy (except for endometrial cancer, definitively treated in-situ carcinomas, or basal or squamous cell carcinoma of the skin) within the past 24 months.
4. Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of lenvatinib.
5. 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.
6. Clinically significant hemoptysis or tumor bleeding within 2 weeks prior to the first dose of study drug.
7. Significant cardiovascular impairment within 12 months of the first dose of study drug: such as history of congestive heart failure greater than NYHA Class II, unstable angina, myocardial infarction or cerebrovascular accident stroke, or cardiac arrhythmia associated with hemodynamic instability.
8. Active infection (any infection requiring systemic treatment).
9. Participants who have not recovered adequately from any toxicity and/or complications from major surgery prior to starting therapy.
10. Participants known to be positive for Human Immunodeficiency Virus (HIV). No HIV testing is required unless mandated by local heath authority.
11. Known active Hepatitis B or Hepatitis C. No testing for hepatitis B or C is required unless mandated by local health authority.
12. Has a history of (non-infectious) pneumonitis that required treatment with steroids, or has current pneumonitis.
13. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the participant's participation for the full duration of the trial, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.
14. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
15. 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 to the first dose of study drug.
16. 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.
17. Females who are breastfeeding or pregnant at Screening or Baseline. A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug.
18. Greater than 1 prior systemic anticancer regimen (other than adjuvant or neoadjuvant) for advanced, recurrent, or metastatic endometrial cancer.
19. Prior anticancer treatment within 28 days (or 5 times the half-life time, whichever is shorter). All acute toxicities related to prior treatments must be resolved to Grade ≤1, except for alopecia and Grade ≤2 peripheral neuropathy.
20. Prior treatment with any treatment targeting VEGF-directed angiogenesis, any anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
21. Participants who received prior treatment with an agent directed to a stimulatory or co-inhibitory T-cell receptor other than an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent, and who discontinued from that treatment due to a Grade 3 or higher immune-related adverse event.
22. Prior radiation therapy within 21 days prior to start of study treatment with the exception of palliative radiotherapy to bone lesions, which is allowed if completed 2 weeks prior to study treatment start.
23. Received a live vaccine within 30 days of planned start of study treatment.
24. Known intolerance to study treatment (or any of the excipients).
25. 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 the first dose of study treatment.
26. Participants with proteinuria >1+ on urine dipstick testing will undergo 24-h urine collection for quantitative assessment of proteinuria. Participants with urine protein ≥1 g/24 h will be ineligible.
27. Prolongation of QTc interval to >480 ms.
28. Left ventricular ejection fraction below the institutional normal range as determined by multigated acquisition scan or echocardiogram. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Progression-free survival: defined as the time from the date of randomization to the date of the first documentation of disease progression, as determined by blinded BICR of objective radiographic disease progression per RECIST 1.1 or death due to any cause(whichever occurs first).
Overall Survival: defined as the time from the date of randomization to the date of death due to any cause. Participants who are lost to follow-up and those who are alive at the date of data cut-off will be censored at the date the participant was last known alive, or date of data cut-off, whichever occurs first.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
An interim analysis for superiority of OS is planned for the study. The interim analysis will be conducted when there are approximately 363 death events observed in the pMMR participants, which is estimated to occur approximately 27 months after the first participant is randomized for the pMMR participants. The final PFS analysis is to occur at the time of the OS interim analysis.
The final PFS analysis will have a data cut off at 24 months to allow 3 months for BICR data to become available. By the data cut off at 24 months, it is estimated that there will be approximately 524 PFS events for the pMMR participants. The final analyses of the study are planned to occur when the total target of 518 death events for the pMMR participants are observed. |
|
| E.5.2 | Secondary end point(s) |
- Objective response rate (ORR) by BICR using RECIST 1.1.
- Health-Related Quality of Life using the EORTC QLQ-C30.
- Safety and tolerability of the two treatment groups.
- Plasma concentration of lenvatinib versus time.
- Model-predicted clearance and AUC for lenvatinib.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The secondary endpoints will be evaluated at the final analysis and as required during the interim analysis. |
|
| 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 | Yes |
| 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 | No |
| 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 | 11 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 49 |
| 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 |
| Brazil |
| Canada |
| Colombia |
| France |
| Germany |
| Ireland |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Mexico |
| New Zealand |
| Poland |
| Russian Federation |
| Spain |
| Taiwan |
| 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 telephone-call or visit, withdraws from the study or is lost to follow-up (ie, the participant is unable to be contacted by the investigator). |
|
| 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 | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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