| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| NSCLC with squamous or nonsquamous histology |
|
| E.1.1.1 | Medical condition in easily understood language |
| Non-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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061873 |
| E.1.2 | Term | Non-small cell lung cancer |
| 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 pembrolizumab (MK-3475) + lenvatinib (MK-7902) to docetaxel with respect to overall survival (OS) [Cohort 1]
2) To compare pembrolizumab + lenvatinib to docetaxel with respect to progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by blinded independent central review (BICR) [Cohort 1]
|
|
| E.2.2 | Secondary objectives of the trial |
1. To compare pembrolizumab + lenvatinib to docetaxel with respect to objective response rate (ORR) per RECIST 1.1 by BICR [Cohort 1]
2. To assess ORR with lenvatinib monotherapy per RECIST 1.1 by BICR [Cohort 2]
3. To assess duration of response (DOR) with pembrolizumab + lenvatinib and docetaxel per RECIST 1.1 by BICR [Cohort 1]
4. To assess the safety and tolerability of treatment with pembrolizumab + lenvatinib versus docetaxel [Cohort 1] and with lenvatinib monotherapy [Cohort 2]
5. To compare pembrolizumab + lenvatinib to docetaxel with respect to the mean change from baseline in global health status/quality of life (QoL), cough, chest pain, dyspnea, and physical functioning [Cohort 1]
6. To compare pembrolizumab + lenvatinib to docetaxel with respect to time to true deterioration (TTD) in global health status/QoL, cough, chest pain, dyspnea, and physical functioning scales [Cohort 1]
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Have a histologically or cytologically confirmed diagnosis of metastatic squamous or nonsquamous NSCLC
2. Have PD on treatment with an anti-PD-1/PD-L1 mAb administered either as monotherapy or in combination with other checkpoint inhibitors or other therapies. Anti- PD-1/PD-L1 treatment progression is defined by meeting ALL of the following criteria:
• Treatment with at least 2 doses of an anti-PD-1/PD-L1 mAb
• PD after an anti-PD-1/PD-L1 mAb as defined by RECIST v1.1. The initial evidence of PD is confirmed by a second assessment no less than 4 weeks from the date of the first documented PD, in the absence of rapid clinical progression
• PD documented within 12 weeks from the last dose of anti-PD-1/PD-L1 mAb
3. Have PD during/after platinum doublet chemotherapy
4. Have confirmation that EGFR-, ALK-, or ROS1-directed therapy is not indicated as primary therapy (documentation of absence of tumor-activating EGFR mutations [eg, DEL19 or L858R], and absence of ALK and ROS1 gene rearrangements OR presence of a K-ras mutation)
5. Have submitted prestudy imaging that confirmed evidence of PD based on investigator review of at least 2 images per RECIST 1.1, following initiation of an anti-PD-1/PD-L1 inhibitor
6. Have measurable disease based on RECIST 1.1 as determined by the local site assessment.
• Have at least 1 measurable lesion by CT or MRI per RECIST 1.1
7. Have provided tumor tissue for PD-L1 biomarker analysis from an archival sample (defined as: from initial diagnosis of NSCLC and prior to receiving immunotherapy [antiPD-1/PD-L1], from the primary lesion or a metastatic lesion)
8. Have provided prior to allocation tissue from a newly obtained formalin-fixed sample from a new biopsy (defined as: after completion of immunotherapy [anti-PD-1/PD-L1] and before receiving an allocation number), of a tumor lesion not previously irradiated
9. Be ≥18 years of age on the day of signing the ICF
10. Have ECOG performance status of 0 or 1 within 3 days before the first dose of study intervention but before allocation
11. Have a life expectancy of at least 3 months
12. Male participants receiving pembrolizumab ± lenvatinib or lenvatinib are eligible to participate if they agree to the following during the intervention period and for at least 120 days after the last dose of study intervention:
Male participants randomized to docetaxel are eligible to participate if they agree to the following during the intervention period and for at least 180 days after the last dose of docetaxel:
• 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)
• 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
13. A female participant is eligible to participate if she is not pregnant or breastfeeding and at least 1 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 is abstinent from heterosexual intercourse as her 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 study intervention , and agrees not to donate eggs (ova, oocytes) to others or freeze/store these for her own use for the purpose of reproduction during this period
• A WOCBP randomized to docetaxel is eligible to participate if she is using a contraceptive method that is highly effective with low user dependency or is abstinent from heterosexual intercourse as her preferred and usual lifestyle and agrees not to donate or freeze/store eggs during the intervention period and for at least 180 days after the last dose of docetaxel
• A WOCBP must have a negative highly sensitive pregnancy test ([urine or serum] as required by local regulations) within 72 hours before the first dose of study intervention
14. Provide (or legally acceptable representative must provide if applicable) written informed consent for the study
15. 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 before allocation
16. If participant received major surgery or radiation therapy of >30 Gy, they have recovered from the toxicity and/or complications from the intervention
17. Have adequate organ function
|
|
| E.4 | Principal exclusion criteria |
1. Has received docetaxel as monotherapy or in combination with other therapies
2. Has received lenvatinib as monotherapy or in combination with an anti-PD-1/PD-L1 inhibitor
3. Has received radiotherapy within 2 weeks before the first dose of study intervention or has received lung radiation therapy >30 Gy within 6 months before the first dose of study intervention
4. Has received a live vaccine within 30 days before the first dose of study intervention
5. Has clinically significant hemoptysis (at least 0.5 teaspoon of bright red blood) or tumor bleeding within 2 weeks before the first dose of study intervention
6. Has radiographic evidence of major blood vessel invasion/infiltration
7. Has clinically significant cardiovascular impairment within 12 months of the first dose of study intervention, such as history of congestive heart failure greater than New York Heart Association Class II, unstable angina, myocardial infarction or cerebrovascular accident/transient ischemic attack (TIA)/stroke, cardiac revascularization, or cardiac arrhythmia associated with hemodynamic instability
8. Has a history of a gastrointestinal condition or procedure that, in the opinion of the investigator, may affect oral study intervention absorption
9. Is a WOCBP who has a positive urine pregnancy test within 72 hours before allocation
10. Is currently participating in a clinical trial and receiving study therapy or participated in a study of an investigational agent within 4 weeks of the first dose of study intervention
11. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (exceeding 10 mg of prednisone or equivalent daily) or any other form of immunosuppressive therapy within 7 days before the first dose of study intervention
12. Has a known history of an additional malignancy, except if the participant has undergone potentially curative therapy with no evidence of disease recurrence for 3 years since initiation of that therapy
13. Has known active central nervous system metastases and/or carcinomatous meningitis
14. Has severe hypersensitivity (Grade ≥3) to pembrolizumab and/or any of its excipients
15. Has a sensitivity to any of the excipients contained in lenvatinib
16. Has a sensitivity to any of the excipients contained in docetaxel
17. Has an active autoimmune disease that has required systemic treatment in the past 2 years (ie, with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs)
18. Has a history of (noninfectious) pneumonitis that required systemic steroids or current pneumonitis/interstitial lung disease
19. Has an active infection requiring systemic therapy
20. Has a known history of human immunodeficiency virus (HIV) infection
21. Has a known history of hepatitis B (defined as hepatitis B surface antigen (HBsAg) reactive or known active hepatitis C virus (HCV) (defined as HCV RNA [qualitative] is detected) infection
22. Has a known history of active tuberculosis
23. 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 participation 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
24. Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study
25. Has a left ventricular ejection fraction (LVEF) below the institutional normal range, as determined by multigated acquisition (MUGA) or echocardiogram (ECHO)
26. Has QT interval corrected with Fridericia’s formula (QTcF) prolongation to >480 ms
27. Has urinary protein ≥1 g/24 hours after having >1+ proteinuria on urine dipstick testing
28. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through at least 120 days after the last dose of pembrolizumab or lenvatinib, or 180 days after the last dose of docetaxel
29. Has had an allogeneic tissue/solid organ transplant |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Cohort 1: Overall Survival (OS)
2. Cohort 1: Progression-free Survival (PFS) 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 ~52 months
2. Up to ~37 months
|
|
| E.5.2 | Secondary end point(s) |
1. Cohorts 1 and 2: Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
2. Cohort 1: Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
3. Cohorts 1 and 2: Number of Participants Experiencing an Adverse Event (AE)
4. Cohorts 1 and 2: Number of Participants Discontinuing Study Treatment Due to an Adverse Event (AE)
5. Cohort 1: Change from Baseline in European Organization for Research and Treatment (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status / Quality of Life (Items 29 & 30) Scale Score
6. Cohort 1: Change from Baseline in EORTC Quality of Life Questionnaire Lung Cancer Module 13 (QLQ-LC13) Cough (Item 31) Scale Score
7. Cohort 1: Change from Baseline in EORTC QLQ-LC13 Chest Pain (Item 40) Scale Score
8. Cohort 1: Change from Baseline in EORTC QLQ-C30 Dyspnea (Item 8) Scale Score
9. Cohort 1: Change from Baseline in EORTC QLQ-C30 Physical Functioning (Items 1 to 5) Scale Score
10. Cohort 1: Time to True Deterioration (TTD) in EORTC QLQ-C30 Global Health Status / Quality of Life (Items 29 & 30) Scale Score
11. Cohort 1: Time to True Deterioration (TTD) in EORTC QLQ-LC13 Cough (Item 31) Scale Score
12. Cohort 1: Time to True Deterioration (TTD) in EORTC QLQ-LC13 Chest Pain (Item 40) Scale Score
13. Cohort 1: Time to True Deterioration (TTD) in EORTC QLQ-C30 Dyspnea (Item 8) Scale Score
14. Cohort 1: Time to True Deterioration (TTD) in EORTC QLQ-C30 Physical Functioning (Items 1 to 5) Scale Score |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to ~5 years
2. Up to ~5 years
3. Up to ~5 years
4. Up to ~5 years
5. Baseline and Week 12
6. Baseline and Week 12
7. Baseline and Week 12
8. Baseline and Week 12
9. Baseline and Week 12
10. Up to ~5 years
11. Up to ~5 years
12. Up to ~5 years
13. Up to ~5 years
14. Up to ~5 years |
|
| 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 | 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 | 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 35 |
| 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 |
| Colombia |
| France |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Russian Federation |
| Spain |
| United Kingdom |
| United States |
|
| 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 |
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