| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic squamous cell carcinoma of the esophagus |
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| E.1.1.1 | Medical condition in easily understood language |
| Males and females with metastatic squamous cell carcinoma of the esophagus who are eligible for 1L treatment |
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| 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 | 27.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10041824 |
| E.1.2 | Term | Squamous cell carcinoma of esophagus |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| 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. Part 1 (FP and TP Safety Run-in): To evaluate the safety and tolerability of treatment with lenvatinib + pembrolizumab in combination with FP.
2. Part 2 (Main Study): To compare overall survival (OS) between treatment arms.
3. Part 2 (Main Study): To compare progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), as determined by blinded independent central review (BICR), between treatment arms.
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| E.2.2 | Secondary objectives of the trial |
1. Part 2 (Main Study): To compare objective response rate (ORR) per RECIST 1.1 by BICR between treatment arms.
2. Part 2 (Main Study): To evaluate duration of response (DOR) per RECIST 1.1 by BICR between treatment arms.
3. Part 2 (Main Study): To compare OS, PFS, ORR, DOR per RECIST 1.1 by BICR between treatment arms in participants with programmed cell death ligand 1 (PD-L1) combined positive score (CPS) ≥10.
4. Part 2 (Main Study): To evaluate the safety and tolerability of lenvatinib + pembrolizumab + chemotherapy versus pembrolizumab + chemotherapy.
5. Part 2 (Main Study): To compare lenvatinib + pembrolizumab + chemotherapy versus pembrolizumab + chemotherapy with respect to mean change from baseline, and time to deterioration (TTD) in health related quality of life (HRQoL) using European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) and Quality of Life Questionnaire Oesophageal module (QLQ-OES18).
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. The participant must have a histologically or cytologically confirmed diagnosis of metastatic squamous cell carcinoma of the esophagus.
2. The participant must have measurable disease per RECIST 1.1 as determined by the local site investigator/radiology assessment. A lesion(s) situated in a previously irradiated area can be considered a target lesion(s) if progression has been demonstrated and the lesion(s) is considered measurable per RECIST 1.1 criteria.
3. Participants are at least 18 years of age on the day of signing the informed consent.
4. Male participants are eligible to participate if they agree to the following during the intervention period and for at least 7 days after the last dose of lenvatinib or 90 days after the last dose of chemotherapy, whichever comes last:
• Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent
OR
• Must agree to use contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause) as detailed below:
- Agree to use a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a WOCBP who is not currently pregnant.
- Please note that 7 days after lenvatinib is stopped, if the participant is on pembrolizumab only and is greater than 90 days post chemotherapy, no male contraception measures are needed.
• Refrain from donating sperm during the chemotherapy treatment period and for at least 90 days after the last dose of chemotherapy.
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 after the last dose of pembrolizumab, 30 days after the last dose of lenvatinib, or 180 days after the last dose of chemotherapy, whichever occurs last, 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.
• A WOCBP must have a negative highly sensitive pregnancy test within 72 hours (serum) or 24 hours (urine) (as required by local regulations) before the starting 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.
6. The participant (or legally acceptable representative) has provided documented informed consent/assent for the study.
7. Has an ECOG performance score of 0 to 1 assessed 0 to 3 days before randomization.
8. Has submitted a tumor tissue sample that meet the acceptance criteria for PD-L1 analysis before randomization. In addition, the PD-L1 CPS result must be determined by the central laboratory before randomization. Newly obtained biopsies are preferred to archived tissue.
9. Has 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.
10. Has adequate organ function. Specimens must be collected within 7 days prior to the start of study intervention. |
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| E.4 | Principal exclusion criteria |
1. Has had previous therapy for locally advanced unresectable or metastatic esophageal cancer. Participants may have received prior neoadjuvant or adjuvant therapy under specific circumstances.
2. Has locally advanced esophageal carcinoma.
3. Has metastatic adenocarcinoma of the esophagus.
4. Has direct invasion into adjacent organs such as the aorta or trachea (T4b disease).
5. Has radiographic evidence of > 90 degree encasement of a major blood vessel, or of intratumoral cavitation.
6. Has perforation risks or significant GI bleeding.
7. Has active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior to the first dose of study drug or tumor bleeding within 2 weeks prior to the first dose of study intervention.
8. Has uncontrollable pleural effusion, pericardial effusion, or ascites requiring frequent drainage or medical intervention (clinically significant recurrence requiring an additional intervention within 2 weeks of randomization).
9. Has GI obstruction, poor oral intake, or difficulty in taking oral medication. Participants with existing esophageal stent are not eligible. Also, participants with known gastrointestinal malabsorption or any other condition that may affect the absorption of lenvatinib.
10. Has had major surgery, open biopsy, or significant traumatic injury within 3 weeks prior to the first dose of study interventions, or anticipation of the need for major surgery during the course of study intervention.
11. 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 receptor (eg, CTLA-4, OX-40, CD137) or has previously participated in a pembrolizumab clinical study.
12. Has received prior therapy with anti-VEGF TKI or anti-VEGF mAb.
13. Is currently receiving brivudine, sorivudine analogs, or other inhibitors of the enzyme dihydropyrimidine dehydrogenase.
14. Has received prior radiotherapy within 2 weeks of start of study intervention or have had a history of radiation pneumonitis.
15. Has received a live or live attenuated vaccine within 30 days prior to the first dose of study intervention.
16. 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 intervention.
17. Has urine protein ≥1 g/24 hours.
18. Has inadequate cardiac function assessed as: QTcF value >470 msec for males and >480 msec for females (mean of 3 measurements corrected for HR using Fridericia's formula).
19. Has an LVEF below the institutional (or local laboratory) normal range, as determined by MUGA or ECHO.
20. 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, or has a history of organ transplant, including allogeneic stem cell transplant.
21. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.
22. Has known active CNS metastases and/or carcinomatous meningitis.
23. Has severe hypersensitivity (≥Grade 3) to treatment with an mAb or known sensitivity or intolerance to any component of lenvatinib, pembrolizumab, study chemotherapy agents and/or to any excipients, murine proteins, or platinum containing products.
24. 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).
25. Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
26. Has an active infection requiring systemic therapy.
27. Has poorly controlled diarrhea.
28. Has clinically significant cardiovascular disease within 12 months from first dose of study intervention.
29. Has a history or current evidence of any condition (eg, but not limited to, known deficiency of the enzyme DPD), 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 investigator.
30. Has peripheral neuropathy ≥Grade 2.
31. Has a known history of HIV infection.
32. Has a known history of hepatitis B or known active hepatitis C virus infection.
33. Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study.
34. Has weight loss of >20% within the last 3 months.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Part 1 (5-Fluorouracil [5-FU] plus cisplatin [FP] and paclitaxel plus
cisplatin [TP] Safety Run-in): Number of Participants With Dose Limiting Toxicities (DLTs)
2. Part 1 (FP and TP Safety Run-in): Number of Participants With Adverse Events (AEs)
3. Part 1 (FP Safety Run-in): Number of Participants who Discontinued Study Treatment Due to an AE
4. Part 2 (Main Study): Overall Survival (OS) in all Participants
5. Part 2 (Main Study): 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) in all Participants
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Up to ~21 days
2. Up to ~55 months
3. Up to ~55 months
4. Up to ~49 months
5. Up to ~41 months
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| E.5.2 | Secondary end point(s) |
1. Part 2 (Main Study): Objective Response Rate (ORR) per RECIST 1.1 as Assessed by BICR in all Participants
2. Part 2 (Main Study): Duration of Response (DOR) per RECIST 1.1 as Assessed by BICR in all Participants
3. Part 2 (Main Study): OS in Participants With Programmed Cell Death-Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥10
4. Part 2 (Main Study): PFS per RECIST 1.1 as Assessed by BICR in Participants With PD-L1 CPS ≥10
5. Part 2 (Main Study): ORR per RECIST 1.1 as Assessed by BICR in Participants With PD-L1 CPS ≥10
6. Part 2 (Main Study): DOR per RECIST 1.1 as Assessed by BICR in Participants With PD-L1 CPS ≥10
7. Part 2 (Main Study): Number of Participants With AEs
8. Part 2 (Main Study): Number of Participants who Discontinued Study Treatment Due to an AE
9. Part 2 (Main Study): Change From Baseline in Health-related Quality of life (HRQoL) Score Using European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30)
10. Part 2 (Main Study): Change From Baseline in HRQoL Score Using EORTC Quality of Life Questionnaire-Oesophageal Module (QLQ-OES18)
11. Part 2 (Main Study): Time to Deterioration (TTD) in HRQoL Score Using EORTC QLQ-C30
12. Part 2 (Main Study): TTD in HRQoL Score Using EORTC QLQ-OES18
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to ~34 months
2. Up to ~34 months
3. Up to ~49 months
4. Up to ~41 months
5. Up to ~34 months
6. Up to ~34 months
7. Up to ~49 months
8. Up to ~48 months
9. Baseline and ~24 months
10. Baseline and ~24 months
11. Up to ~ 24 months
12. Up to ~ 24 months
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| 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 | No |
| 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 | No |
| 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 | 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 80 |
| 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 |
| Chile |
| Costa Rica |
| Guatemala |
| Ukraine |
| Hong Kong |
| Taiwan |
| Canada |
| China |
| Japan |
| Korea, Republic of |
| Russian Federation |
| United Kingdom |
| United States |
| Denmark |
| France |
| Germany |
| Hungary |
| Italy |
| Romania |
| Spain |
| Türkiye |
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| 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
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| 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 |
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