| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Extensive-Stage Small Cell Lung Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Extensive-Stage Small Cell Lung Cancer |
|
| 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) |
|
| 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 evaluate the safety and tolerability of investigational treatment combinations based on the proportion of participants with adverse events
2. To estimate the objective response rate as assessed by blinded independent central review per RECIST 1.1 |
|
| E.2.2 | Secondary objectives of the trial |
1. To evaluate progression-free survival as assessed by blinded independent central review according to RECIST 1.1
2. To evaluate duration of response as assessed by blinded independent central review according to RECIST 1.1 |
|
| 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 second-line therapy
2. Participants must have progressed on or after treatment with an anti-PD-1/L1 mAb administered as part of first-line platinum-based systemic therapy for ES-SCLC. PD-1/L1 checkpoint inhibitor treatment progression is defined by meeting ALL of the following criteria:
a. Has received at least 2 doses of an anti-PD-1/L1 mAb
b. Has demonstrated radiographic disease progression during or after an anti-PD-1/L1 mAb as defined by investigator
c. Disease progression has been documented within 12 weeks from the last dose of an anti-PD-1/L1 mAb
3. Has extensive-stage SCLC defined as Stage IV by the American Joint Committee on Cancer, Eighth Edition
4. Has received 1 prior line of systemic therapy for SCLC. Study intervention will treat second-line ES-SCLC
5. Is male or female, at least 18 years of age at the time of providing documented informed consent
6. 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
- Pembrolizumab, MK-1308A, MK-4830, MK-4280A – no contraception measures required
• Be abstinent from heterosexual intercourse as their preferred and usual lifestyle and agree to remain abstinent
OR
• Must agree to use contraception unless confirmed to be azoospermic 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
7. 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 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. The length of time required to continue contraception for each study intervention is as follows:
- Lenvatinib – 30 days
- Pembrolizumab, MK-1308A, MK-4830, MK-4280A – 120 days
The investigator should evaluate the potential for contraceptive method failure in relationship to the first dose of study intervention
- A WOCBP must have a negative highly sensitive pregnancy test within 24 hours 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
- 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
- Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies
8. The participant (or legally acceptable representative) has provided documented informed consent for the study
9. 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
10. Submits an archival tumor tissue sample or newly obtained core, incisional, or excisional biopsy of a tumor lesion not previously irradiated, where such sample exists. The sample may be submitted after enrollment but must be submitted within 4 weeks after allocation/randomization
11. Has an ECOG performance status of 0 to 1 assessed within 7 days before allocation/randomization
12. Has adequate organ function as defined in the protocol. Specimens must be collected within 7 days before the start of study intervention
13. Participants who are HBsAg positive are eligible if they have received HBV antiviral therapy for at least 4 weeks and have undetectable HBV viral load before randomization
14. Participants with history of HCV infection are eligible if HCV viral load is undetectable at Screening
15. 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 before allocation/randomization
16. Has a predicted life expectancy of >3 months |
|
| 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 the start of study intervention
10. Has any major hemorrhage or venous thromboembolic events within 3 months before the start of study intervention. Participants with venous thrombosis diagnosed more than 3 months before the start 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 start of study intervention
13. Has a known history of, or active, neurologic paraneoplastic syndrome
14. Is considered a poor medical risk due to a serious, uncontrolled medical disorder or nonmalignant systemic disease
15. Has received prior therapy with an RTK inhibitor or anti-CTLA-4, anti-ILT-4, or anti- LAG-3 agents
16. Has received prior therapy with an anti-PD-1/L1 agent and was permanently discontinued from that treatment due to a treatment-related AE
17. Has received prior systemic anticancer therapy including investigational agents within 4 weeks before start of study intervention
18. Has received prior radiotherapy within 2 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease
19. Has received lung radiation therapy >30 Gy within 6 months before the first dose of study intervention
20. Has received a live or live attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines are allowed
21. 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
22. Has radiographic evidence of encasement or invasion of a major blood vessel, or of intratumoral cavitation
23. Has symptomatic ascites, pleural effusion, or pericardial effusion. A participant who is clinically stable following treatment for these conditions (including therapeutic thoracoor paracentesis) is eligible
24. 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
25. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years
26. Has known active CNS metastases and/or carcinomatous meningitis
27. Has a history of severe hypersensitivity reaction (≥Grade 3) to any study intervention and/or any of its excipients
28. Has an active autoimmune disease that has required systemic treatment in past 2 years. Replacement therapy is not considered a form of systemic treatment and is allowed
29. Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
30. Has an active infection requiring systemic therapy
31. Has a known history of HIV infection. No HIV testing is required unless mandated by local health authority
32. Has concurrent active Hepatitis B and Hepatitis C virus infection
33. 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
34. Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study
35. Has progressive disease as initial response to first-line systemic chemotherapy in combination with PD-1/L1 inhibitor for ES-SCLC
36. Has had an allogenic tissue/solid organ transplant |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Number of Participants Experiencing Dose-Limiting Toxicities (DLTs)
2. Number of Participants Who Experience at Least One Adverse Event (AE)
3. Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE)
4. Objective Response Rate (ORR) per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Up to 21 days in Cycle 1 (Cycle 1 = 21 days)
2. Up to approximately 60 months
3. Up to approximately 60 months
4. Up to approximately 60 months |
|
| E.5.2 | Secondary end point(s) |
1. Progression-free Survival (PFS) per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1)
2. Duration of Response (DOR) Per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 60 months
2. Up to approximately 60 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 | 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) | 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 |
|
| 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 |
|
| 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 | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| 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 |
| Russian Federation |
| United States |
| Austria |
| Germany |
| Hungary |
| Italy |
| Poland |
| Spain |
| Switzerland |
|
| 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
|
|
| 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 |
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