E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Extensive-Stage Small Cell Lung Cancer |
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E.1.1.1 | Medical condition in easily understood language |
Extensive-Stage Small Cell Lung Cancer |
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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 | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10041068 |
E.1.2 | Term | Small cell lung cancer extensive stage |
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. To estimate the objective response rate as assessed by blinded independent central review according to RECIST 1.1 2. To estimate 6-month progression free survival rate as assessed by blinded independent central review according to RECIST 1.1
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E.2.2 | Secondary objectives of the trial |
1. To evaluate duration of response based on RECIST 1.1 as assessed by blinded independent central review 2. To evaluate progression free survival based on RECIST 1.1 as assessed by blinded independent central review 3. To evaluate overall survival 4. To evaluate the best tumor size change as assessed by blinded independent central review 5. To evaluate the safety and tolerability of investigational treatment combinations based on proportion of adverse events 6. To evaluate changes in health-related quality of life assessments from baseline using the EORTC-QLQ-C30
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Has histologically or cytologically confirmed diagnosis of ES-SCLC in need of first-line therapy 2. Has extensive-stage SCLC defined as Stage IV (T any, N any, M1a/b/c) 3. Is male or female, at least 18 years of age at the time of providing documented informed consent 4. Male participants are eligible to participate if they agree to the following during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention. The length of time required to continue contraception for each study intervention is as follows: - Lenvatinib (7 days) - Etoposide, Cisplatin, or Carboplatin (180 days) - Pembrolizumab, MK-4830, or MK-5890 (no contraception measures) ● Refrain from donating sperm PLUS either: ● 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 ● 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 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 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: - Lenvatinib (30 days) - Etoposide, Cisplatin, or Carboplatin (180 days) - Pembrolizumab, MK-4830, or MK-5890 (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 e a negative highly sensitive pregnancy test within 24 hours (urine test) or 72 hours (serum test) 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 - Abstains from breastfeeding during the study intervention period and for at least 120 days after study intervention - Has had her medical history, menstrual history and recent sexual activity reviewed by the investigator to decrease the risk for inclusion of a woman with an early undetected pregnancy 6. The participant has provided documented informed consent for the study 7. Has measurable disease per RECIST 1.1 as assessed by local site investigator/radiology and verified by BICR. Lesions situated in a previously irradiated area are considered measurable if progression has been shown in such lesions. At least 1 lesion that meets the criteria for being measurable, must be appropriate for selection as a target lesion 8. Submits an archival tumor tissue sample or newly obtained core, incisional, or excisional biopsy of a tumor lesion not previously irradiated where such sample exist. The sample may be submitted after enrollment but must be submitted within 4 weeks after randomization 9. Has an ECOG performance status of 0 or 1 assessed within 7 days before randomization 10. Has adequate organ function as defined in the protocol. Specimens must be collected within 10 days before the first dose of study intervention 11. Has adequately controlled BP with or without antihypertensive medications, defined as BP ≤150/90 mm Hg with no changes in antihypertensive medications within 1 week before randomization 12. Has a predicted life expectancy of >3 months |
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E.4 | Principal exclusion criteria |
1. Has had major surgery within 3 weeks before first dose of study interventions 2. Has a preexisting ≥Grade 3 gastrointestinal or non-gastrointestinal fistula 3. Has urine protein ≥1 g/24 hours 4. Has a LVEF below the institutional (or local laboratory) normal range, as determined by MUGA or ECHO 5. Prolongation of QTcF interval to >480 ms 6. Has clinically significant cardiovascular disease or major arterial thromboembolic event within 12 months before 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 7. Has active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks before the first dose of study intervention 8. Has gastrointestinal malabsorption or any other condition that might affect oral study intervention absorption 9. Has serious nonhealing wound, ulcer, or bone fracture within 28 days before first dose of study intervention 10. Has any major hemorrhage or venous thromboembolic events within 3 months before the first dose of study intervention. Participants with venous thrombosis diagnosed more than 3 months before the first dose of study intervention must be on stable doses of anticoagulants 11. Has a history of inflammatory bowel disease 12. Has a history of a gastrointestinal perforation within 6 months before the first dose of study intervention 13. Is considered a poor medical risk due to a serious, uncontrolled medical disorder or nonmalignant systemic disease. Examples include, but are not limited to, uncontrolled major seizure disorder, unstable spinal cord compression, or superior vena cava syndrome 14. 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 (eg, anti-CTLA-4, anti-OX-40, anti-CD137, anti-CD27) 15. Has received prior treatment (chemotherapy, radiotherapy, or surgical resection) including investigational agents for SCLC 16. Is expected to require any other form of antineoplastic therapy for SCLC, including radiation therapy, while on study 17. Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines are allowed 18. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks before the first dose of study intervention 19. Has radiographic evidence of encasement or invasion of a major blood vessel, or of intratumoral cavitation 20. Has symptomatic ascites, pleural effusion, or pericardial effusion. A participant who is clinically stable following treatment for these conditions (including therapeutic thoraco-or paracentesis) is eligible 21. 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 22. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years 23. Has known active CNS metastases and/or carcinomatous meningitis 24. Has a history of severe hypersensitivity reaction (≥ Grade 3) to any study intervention and/or any of its excipients 25. 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). 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 26. Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease 27. Has a known history of, or active, neurologic paraneoplastic syndrome 28. Has an active infection requiring systemic therapy 29. Has a known history of HIV infection. No HIV testing is required unless mandated by local health authority 30. Has a known history of Hepatitis B (defined as HBsAg reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection 31. Has a history or current evidence of any condition, therapy, laboratory abnormality or other circumstances that might confound the results of the study, 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 32. Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study 33. Has had an allogenic tissue/solid organ transplant |
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E.5 End points |
E.5.1 | Primary end point(s) |
1. 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) 2. Six-Month Progression-Free Survival (PFS) as Assessed by BICR per RECIST 1.1
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 5 years 2. Up to approximately 6 months
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E.5.2 | Secondary end point(s) |
1. Duration of Response (DOR) as Assessed by BICR per RECIST 1.1 2. PFS as Assessed by BICR per RECIST 1.1 3. Overall Survival (OS) 4. Percent Change From Baseline in Tumor Size as Assessed by BICR 5. Number of Participants Who Experienced an Adverse Event (AE) 6. Number of Participants Who Discontinued Study Treatment Due to an AE 7. Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) Global Health Status/Quality of Life Scale (Items 29 and 30) at Week 19
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 5 years 2. Up to approximately 5 years 3. Up to approximately 5 years 4. Baseline, 5 years 5. Up to approximately 5 years 6. Up to approximately 5 years 7. Baseline, Week 19
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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 | 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 | 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) | 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 |
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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 | 3 |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 25 |
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 |
Australia |
Canada |
Israel |
Korea, Republic of |
United States |
Austria |
Poland |
Spain |
Switzerland |
Germany |
Italy |
Hungary |
Russian Federation |
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E.8.7 | Trial has a data monitoring committee | No |
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 | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 5 |