| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Esophageal Squamous Cell Carcinoma (ESCC) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advance esophageal carcinoma |
|
| 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 | 25.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10030186 |
| E.1.2 | Term | Oesophageal squamous cell carcinoma NOS |
| 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. Safety Lead-in Phase: To evaluate the safety and tolerability of combination treatments that have not been evaluated in a separate study.
2. To estimate the objective response rate (ORR) as assessed by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).
|
|
| E.2.2 | Secondary objectives of the trial |
1. Efficacy Phase: To evaluate progression-free survival (PFS) as assessed by BICR per RECIST 1.1.
2. Efficacy Phase: To evaluate the duration of response (DOR) as assessed by BICR per RECIST 1.1
3. Efficacy Phase: To evaluate overall survival (OS).
4. Efficacy Phase: To evaluate the safety and tolerability of investigational treatment combinations based on the proportion of participants with AEs
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Histologically or cytologically confirmed diagnosis of metastatic or locally advanced unresectable ESCC
2.Have a life expectancy of greater than 3 months
3.Measurable disease per RECIST 1.1 as determined by the local site investigator/radiology assessment and verified by BICR. 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
4.Experienced investigator documented radiographic or clinical disease progression on one prior line of standard therapy. This study will only include 2L participants who have progressed during or after receiving at least one dose of standard therapy given in a 1L setting
5.Submits an evaluable baseline tumor sample for analysis. Newly obtained biopsies are preferred to archived tissue
6.Performance status of 0 or 1 on the ECOG Performance Scale before first dose of study intervention
7.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 allocation/randomization
8.Participants with a feeding tube to maintain adequate nourishment and for the administration of medications are allowed
9.Adequate organ function. Specimens must be collected within 7 days before the start of study intervention
10.At least 18 years of age on the day of providing documented informed consent
11.If male, agrees to the following during the intervention period and for at least the time needed to eliminate each study intervention after the last dose.The length of time required to continue contraception for each study intervention is as follows:
-Chemotherapy: 90 days
-Lenvatinib: 7 days
-Pembrolizumab, MK-4280A, and MK-4830: no contraception requirements
•Refrains from donating sperm
PLUS either:
•Abstains from heterosexual intercourse as their preferred and usual lifestyle and agrees to remain abstinent
OR
•Uses contraception unless confirmed to be azoospermic as detailed below:
-Uses a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a WOCBP who is not currently pregnant
-Contraceptive use by men 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
12.A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
• Not a WOCBP
OR
• A WOCBP and:
-Uses 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 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:
-Chemotherapy: 180 days
-Lenvatinib: 30 days
-Pembrolizumab, MK-4280A, and MK-4830: 120 days
The investigator should evaluate the potential for contraceptive method failure 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
-Has 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, 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 are in the protocol
-Abstains from breastfeeding during the study intervention period and for at least 120 days after study intervention
13.Has provided documented informed consent for the study. The participant may also provide consent/assent for FBR. However, the participant may participate in the study without participating in FBR.
14.Participants who have AEs due to previous anticancer therapies must have recovered to ≤Grade 1 or baseline. Participants with endocrine-related AEs who are adequately treated with hormone replacement or participants who have ≤Grade 2 neuropathy are eligible. |
|
| E.4 | Principal exclusion criteria |
1. Direct invasion into adjacent organs such as the aorta or trachea (T4b disease)
2. Experienced weight loss >10% over approximately 2 months prior to first dose of study therapy
3. Clinically apparent ascites or pleural effusion by physical examination
4. Received prior therapy with
-An anti–PD-1, anti–PD-L1, or anti–PD-L2 agent
-VEGF TKI (including lenvatinib) or anti-VEGF mAb
-Any agent directed to another stimulatory or coinhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137)
-An anti-LAG-3 antibody
-An agent targeting ILT4 or HLA-G
5.Received prior systemic anticancer therapy within 2 weeks before allocation/randomization
6. Received prior radiotherapy within 2 weeks of start of study intervention or has radiation-related toxicities requiring corticosteroids.
7. Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines are allowed
8. Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration
9. 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 medication
10. Known additional malignancy that is progressing or has required active treatment within the past 3 years
11. Known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, (ie, without evidence of progression) for at least 4 weeks as confirmed by repeat imaging performed during study screening, are clinically stable and have not required steroid treatment for at least 14 days before the first dose of study intervention
12. Severe hypersensitivity (Grade ≥3) to any study intervention and/or any of its excipients
13. 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
14. History of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
15. Active infection requiring systemic therapy
16. History of HIV infection. HIV testing is not required unless mandated by local health authority
17. History of Hepatitis B (defined as HBsAg reactive) or known active Hepatitis C virus (defined as detectable HCV RNA [qualitative]) infection
18. History or current evidence of any condition, therapy, laboratory abnormality, or other circumstance that might confound the results of the study, interfere with the individual’s ability to cooperate with the requirements of the study, or interfere with the individual's participation for the full duration of the study, such that it is not in the best interest of the individual to participate, in the opinion of the treating investigator.
19. History of allogenic tissue/solid organ transplant
20. Had major surgery within 3 weeks prior to first dose of study interventions
21. Pre-existing active Grade ≥3 GI fistula
22. Urine protein ≥1 g/24 hours
23. A LVEF below the institutional (or local laboratory) normal range, as determined by MUGA or ECHO
24. Radiographic evidence of >90 degree encasement or invasion of a major blood vessel, or of intratumoral cavitation
25. Prolongation of QTcF interval to >480 ms
26. Clinically significant cardiovascular disease within 12 months from first dose of study intervention, including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction, cerebral vascular accident, or cardiac arrhythmia associated with hemodynamic instability
27. Participants with known GI malabsorption or any other condition that may affect the absorption of lenvatinib
28. Active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior to the first dose of study drug
29. Has risk for significant GI bleeding, such as:
• Has had a serious nonhealing wound, peptic ulcer, or bone fracture within 28 days prior to allocation/randomization.
• Has significant bleeding disorders, vasculitis, or has had a significant bleeding episode from the GI tract within 12 weeks prior to allocation/randomization. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Number of Participants Experiencing a Dose-limiting Toxicity (DLT) During Safety Lead-in Phase
2. Number of Participants Experiencing an Adverse Event (AE) During Safety Lead-in Phase
3. Number of Participants Who Discontinue Study Treatment Due to an AE During Safety Lead-in Phase
4. Objective Response Rate (ORR)
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Up to ~ 3 weeks
2. Up to ~ 3 weeks
3. Up to ~ 3 weeks
4. Up to ~ 80 weeks
|
|
| E.5.2 | Secondary end point(s) |
1. Progression-Free Survival (PFS)
2. Duration of Response (DOR)
3. Overall Survival (OS)
4. Number of Participants Experiencing at Least One Adverse Event (AE) During the Efficacy Phase
5. Number of Participants Who Discontinue Study Treatment Due to An AE During the Efficacy Phase |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to ~ 180 weeks
2. Up to ~ 180 weeks
3. Up to ~ 180 weeks
4. Up to ~ 180 weeks
5. Up to ~ 104 weeks
|
|
| 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 | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| 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) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| First administration of the investigational agents combination in the specified population |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| 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 | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| umbrella platform, adaptive design |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 9 |
| 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 |
| Chile |
| Singapore |
| Switzerland |
| Hong Kong |
| Taiwan |
| Brazil |
| Japan |
| Korea, Republic of |
| Thailand |
| France |
| Italy |
| Norway |
| Türkiye |
|
| 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. 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. |
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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 | 4 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
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