| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic nonsmall cell lung cancer (NSCLC) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Metastatic nonsmall 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 | 10059515 |
| E.1.2 | Term | Non-small cell lung cancer metastatic |
| 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 compare Progression-free Survival (PFS) as assessed by blinded independent central review according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), adjusted to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, for the combinations of pembrolizumab (MK-3475) + lenvatinib (MK-7902) versus pembrolizumab + matching placebo
2. To compare Overall Survival (OS) for the combinations of pembrolizumab + lenvatinib versus pembrolizumab + matching placebo
NOTE: As of Amendment 007-06, lenvatinib and matching placebo have been removed from the study. All participants remaining on study will continue on open-label pembrolizumab monotherapy. No further analyses of efficacy endpoints will be performed. Exploratory objectives may not be pursued. |
|
| E.2.2 | Secondary objectives of the trial |
1. To compare Objective Response Rate (ORR) as assessed by blinded independent central review using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, for the combinations of pembrolizumab + lenvatinib versus pembrolizumab + matching placebo
2. To evaluate the safety and tolerability for the combinations of pembrolizumab + lenvatinib versus pembrolizumab + matching placebo
3. To compare the mean change from Baseline in the global health status/quality of life, cough, chest pain, dyspnea, and physical functioning for the combinations of pembrolizumab + lenvatinib versus pembrolizumab + matching placebo
4. To compare the Time to True Deterioration in global health status/quality of life, cough, chest pain, dyspnea, and physical functioning for the combinations of pembrolizumab + lenvatinib versus pembrolizumab + matching placebo
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Have a histologically or cytologically confirmed diagnosis of NSCLC.
2. Have Stage IV NSCLC (American Joint Committee on Cancer [AJCC], version 8).
3. Have confirmation that EGFR-, ALK-, or ROS1-directed therapy is not indicated as primary therapy (documentation of the absence of tumor-activating EGFR mutations [eg,
DEL19 or L858R], AND absence of ALK and ROS1 gene rearrangements OR presence of a Kirsten rat sarcoma [K-ras] mutation).
4. Have measurable disease based on RECIST 1.1, as determined by the local site.
5. Tumor tissue that demonstrates PD-L1 expression in ≥1% of tumor cells (TPS ≥1%) as assessed by IHC 22C3 pharmDx at a central laboratory.
6. Be 18 years of age, inclusive, at the time of signing the ICF.
7. Have a life expectancy of at least 3 months.
8. Have an ECOG performance status of 0 or 1 within 7 days before the first dose of study intervention but before randomization.
CONTRACEPTIVE USE:
Contraceptive use by men and 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.
Male Participants
9. 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/matching placebo:
- 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 [Appendix 5]) as detailed below:
− Agree to use a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a woman of childbearing potential (WOCBP) who is not currently pregnant.
- Please note that 7 days after lenvatinib/matching placebo is stopped, if the participant is on pembrolizumab only, no male contraception
measures are needed.
Female Participants
10. 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), as described in Appendix 5 during the intervention period and for at least 120 days post pembrolizumab or 30 days post lenvatinib/matching placebo, whichever occurs last. 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 (urine or serum as required by local regulations) within 24 hours before the first dose of 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.
- Additional requirements for pregnancy testing during and after study intervention are located in Appendix 2.
- 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.
11. The participant (or legally acceptable representative if applicable) has provided documented informed consent/assent for the study.
12. Have adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP ≤150/90 mm Hg and no change in antihypertensive medications within 1 week prior to randomization.
13. Have adequate organ function. Specimens must be collected within 10 days before the start of study intervention. |
|
| E.4 | Principal exclusion criteria |
1. Has known untreated central nervous system 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 by repeat imaging, clinically stable, and without requirement of steroid treatment for at least 14 days before first dose of study intervention.
2. Has clinically significant hemoptysis or tumor bleeding within 2 weeks before the first dose of study intervention.
3. Has radiographic evidence of encasement or invasion of a major blood vessel, or of intratumoral cavitation. 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 after lenvatinib therapy.
4. Has a known history of an additional malignancy, except if the participant has undergone potentially curative therapy with no evidence of that disease recurrence for at least 3 years since initiation of that therapy.
5. Has an active autoimmune disease that has required systemic treatment in the past 2 years. Replacement therapy is not considered a form of systemic treatment and is allowed.
6. Has had an allogeneic tissue/solid organ transplant.
7. Has a known history of human immunodeficiency virus (HIV) infection; HIV testing is not required unless mandated by the local health authority.
8. Has a history of (noninfectious) pneumonitis that required systemic steroids or current pneumonitis/interstitial lung disease.
9. Has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive or hepatitis B virus [HBV]-DNA detected) or known active hepatitis C virus (HCV, defined as HCV-RNA [qualitative] detected or HCV antibody reactive, if HCV-RNA is not the local SOC) infection.
10. Has a history of a gastrointestinal condition or procedure that in the opinion of the investigator may affect oral study drug absorption.
11. Has significant cardiovascular impairment within 12 months of the first dose of study intervention, such as a history of congestive heart failure greater than New York Heart Association Class II, unstable angina, myocardial infarction, cerebrovascular accident (CVA)/stroke, or cardiac arrhythmia associated with hemodynamic instability.
12. Has not recovered adequately from any toxicity and/or complications from major surgery before starting therapy.
13. Has a known history of active tuberculosis (TB).
14. Has an active infection requiring systemic therapy.
15. Has a known psychiatric or substance abuse disorder that would interfere with the participant’s cooperation for the requirements of the study.
16. Previously had a severe hypersensitivity reaction to treatment with an mAb or has a known sensitivity or intolerance to any component of lenvatinib or pembrolizumab.
17. WOCBP who has a positive urine pregnancy test within 24 hours before the first dose of study intervention.
18. Has received prior systemic chemotherapy or other targeted or biological antineoplastic therapy for their metastatic NSCLC.
19. 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 received lenvatinib as monotherapy or in combination with anti-PD-1 agents.
20. Has received radiotherapy within 14 days before the first dose of study intervention or received lung radiation therapy of >30 Gy within 6 months before the first dose of study intervention.
21. Has a diagnosis of immunodeficiency or is receiving any form of immunosuppressive therapy within 7 days before the first dose of study intervention.
22. Is receiving systemic steroid therapy (doses exceeding 10 mg daily of prednisone equivalent) within 7 days before the first dose of study intervention.
23. Has received a live or attenuated vaccine within 30 days before the first dose of study intervention.
24. Participants with proteinuria >1+ on urine dipstick testing/urinalysis will undergo 24-hour urine collection for quantitative assessment of proteinuria. Participants withurine protein ≥1 g/24 hours will be ineligible.
25. Prolongation of QTc interval to >480ms and/or left ventricular ejection fraction (LVEF) below the institutional normal range as determined by a multigated acquisition scan (MUGA) or echocardiogram (ECHO).
26. Has a history or current evidence of any condition, therapy, or
laboratory abnormality that might confound the results of the study or interfere with the participant's ability to participate for the full duration of the study, or it is not in the best interest of the participant to participate, in the opinion of the treating investigator.
27. Has had major surgery within 3 weeks prior to first dose of study intervention.
28. Has pre-existing =Grade 3 gastrointestinal or non-gastrointestinal fistula.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Progression-free Survival (PFS) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
2. Overall Survival (OS)
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 24 months
2. Up to approximately 60 months
|
|
| E.5.2 | Secondary end point(s) |
1. Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
2. Number of participants who experience an adverse event (AE)
3. Number of participants who discontinue study treatment due to an AE
4. Change from Baseline in Global Health Status (GHS)(European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 [EORTC QLQ-C30] Item 29) Score
5. Change from Baseline in Quality of Life (QoL)(EORTC QLQ-C30 Item 30) Score
6. Change from Baseline in Cough (EORTC Quality of Life Questionnaire- LungCancer Module 13 [QLQ-LC13] Item 31) Score
7. Change from Baseline in Chest Pain (EORTC QLQ-LC13 Item 40) Score
8. Change from Baseline in Dyspnea (EORTC QLQ-C30 Item 8) Score
9. Change from Baseline in Physical Functioning (EORTC QLQ-C30 Items 1-5) Score
10. Time to True Deterioration (TTD) Based on Change from Baseline in Global Health Status (GHS)(EORTC QLQ-C30 Item 29) Score
11. Time to True Deterioration (TTD) Based on Change from Baseline in Quality of Life (QoL)(EORTC QLQ-C30 Item 30) Score
12. Time to True Deterioration (TTD) Based on Change from Baseline in the Composite Endpoint of Cough (EORTC QLQ-LC13 Item 31), Chest Pain (EORTC QLQ-LC13 Item40), or Dyspnea (EORTC QLQ-C30 Item 8)
13. Time to True Deterioration (TTD) Based on Change from Baseline in EORTC QLQ-C30 Physical Functioning (Items 1-5) Score |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 24 months
2. Through 90 days post last dose of study treatment (Up to approximately 27 months)
3. Through last dose of study treatment (Up to approximately 24 months)
4. - 13. Baseline (Cycle 1 Day 1: Predose) and at designated timepoints (Predose) up to 30 days post last dose. Each cycle is 21 days. (Up to approximately 25 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 | 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) | 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| As of Amendment 007-06, lenvatinib and matching placebo have been removed from the study. |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| As of Amendment 007-06, lenvatinib and matching placebo have been removed from the study. |
|
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 76 |
| 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 |
| Canada |
| China |
| Colombia |
| Israel |
| Japan |
| Korea, Republic of |
| Malaysia |
| Mexico |
| Taiwan |
| United States |
| Estonia |
| France |
| Poland |
| Germany |
| Italy |
| Hungary |
| Russian Federation |
| Turkey |
| Ukraine |
|
| 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
|
|
| 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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