| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic Nonsquamous Non-small Cell Lung Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Metastatic Nonsquamous 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 | 27.0 |
| 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.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10079440 |
| E.1.2 | Term | Non-squamous 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. Part 1: To evaluate the safety and tolerability of treatment with
lenvatinib (MK-7902) + platinum doublet chemotherapy +
pembrolizumab (MK-3475).
2. Part 2: To compare Progression-free Survival (PFS) as assessed by
blinded independent central review (BICR) according to 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 lenvatinib + platinum doublet chemotherapy +
pembrolizumab versus matching placebo + platinum doublet
chemotherapy + pembrolizumab.
3. Part 2: To compare Overall Survival (OS) for the combinations of
lenvatinib + platinum doublet chemotherapy + pembrolizumab versus
matching placebo + platinum doublet chemotherapy + pembrolizumab. |
|
| E.2.2 | Secondary objectives of the trial |
1. Part 2: To compare objective response rate (ORR) as assessed by
BICR according to RECIST 1.1, modified to follow a maximum of 10
target lesions and a maximum of 5 target lesions per organ.
2. Part 2: To evaluate duration of response (DOR) as assessed by BICR
according to RECIST 1.1, modified to follow a maximum of 10 target
lesions and a maximum of 5 target lesions per organ.
3. Part 2: To evaluate the safety and tolerability.
4. Part 2: To evaluate the mean change from baseline in global health
status/quality of life (QoL), cough, chest pain, dyspnea, and physical
functioning.
5. Part 2: To evaluate the time to true deterioration (TTD) in global
health status/QoL, cough, chest pain, dyspnea, and physical functioning. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Participant must:
1. Have a histologically or cytologically confirmed diagnosis of Stage IV
(American Joint Committee on Cancer [AJCC], version 8 or current
version) nonsquamous NSCLC.
2. Have confirmation that EGFR , ALK , or ROS1 directed therapy is not
indicated as primary treatment (documentation of absence of tumor
activating EGFR mutations AND absence of ALK and ROS1 gene
rearrangements OR presence of a KRAS mutation).
3. Have measurable disease per RECIST 1.1.
4. Have provided archival tumor tissue sample or newly obtained core or
excisional biopsy of a tumor lesion not previously irradiated. FFPE tissue
blocks are preferred to slides. Newly obtained biopsies are preferred to
archived tissue. Formalin fixed specimens after the participant has been
diagnosed with metastatic disease are preferred. Biopsies obtained prior
to receipt of adjuvant/neoadjuvant chemotherapy are permitted if
recent biopsy is not feasible.
5. Be male or female ≥18 years of age inclusive, at the time of signing
the informed consent form (ICF).
6. Have a life expectancy of at least 3 months.
7. Have an ECOG performance status of 0 or 1 within 7 days prior to the
first dose of study intervention but before randomization.
8. 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 and up to 180 days after the
last dose of chemotherapeutic agents:
• 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. Note: Men with a pregnant or
breastfeeding partner must agree to remain abstinent from penilevaginal
intercourse or use a male condom during each episode of penilevaginal
penetration.
9. 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), during the
intervention period and for at least 120 days post pembrolizumab and 30
days post-lenvatinib/matching placebo, and up to 180 days post last
dose of chemotherapeutic agents, 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.
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- 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.
10. The participant (or legally acceptable representative) has provided
documented informed consent for the study.
11. Have adequate organ function as indicated by the laboratory values.
Specimens must be collected and reviewed within 10 days prior to the
first dose of study intervention.
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. |
|
| E.4 | Principal exclusion criteria |
If participant:
1. Has known untreated central nervous system (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 by repeat
imaging [the repeat imaging must be performed during the screening
period]), clinically stable, and have not required steroids for at least 14
days prior to the first dose of study intervention.
2. Has a history of (noninfectious) pneumonitis that required systemic
steroids or current pneumonitis/interstitial lung disease.
3. Radiographic evidence of intratumoral caviations, encasement, or
invasion of a major blood vessel. Additionally, the degree of proximity to
major blood vessels should be considered for exclusion because of the
potential risk of severe hemorrhage associated with tumor
shrinkage/necrosis after lenvatinib therapy. (In the chest, major blood
vessels include the main pulmonary artery, the left and right pulmonary
arteries, the 4 major pulmonary veins, the superior or inferior vena cava,
and the aorta).
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 (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, etc.) is allowed.
6. Has a diagnosis of immunodeficiency or is receiving chronic systemic
steroid therapy (doses exceeding 10 mg daily of prednisone equivalent)
or any other form of immunosuppressive therapy within 7 days prior the
first dose of study intervention.
7. Has had an allogeneic tissue/solid organ transplant.
8. Has a known history of human immunodeficiency virus (HIV)
infection. HIV testing is not required unless mandated by the local health
authority.
9. Has a known history of Hepatitis B (defined as Hepatitis B surface
antigen [HBsAg] reactive or HBV DNA detected) or known active
Hepatitis C virus (defined as HCV RNA [qualitative] detected or HCV
antibody reactive, if HCV RNA is not the local SOC) infection. No testing
for Hepatitis B or Hepatitis C is required unless mandated by the local
health authority.
10. Has a history of a gastrointestinal condition or procedure that in the
opinion of the investigator may affect oral drug absorption.
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11. Has active hemoptysis (at least 0.5 tsp of bright red blood) within 2
weeks prior to the first dose of study intervention.
12. Has significant cardiovascular impairment within 12 months prior to
the first dose of study intervention, including history of congestive heart
failure greater than New York Heart Association (NYHA) Class II,
unstable angina, myocardial infarction, cerebrovascular accident
(CVA)/stroke, or cardiac arrhythmia associated with hemodynamic
instability.
13. Has a known history of active tuberculosis.
14. Has an active infection requiring systemic therapy.
15. Has had major surgery within 3 weeks prior to first dose of study
interventions.
16. Has known psychiatric or substance abuse disorders that would
interfere with the participant's cooperation to meet with the
requirements of the study.
17. Previously had a severe hypersensitivity reaction to treatment with a
monoclonal antibody or has a known sensitivity to any component of
lenvatinib or pembrolizumab, or as applicable, carboplatin, cisplatin, or
pemetrexed.
18. A WOCBP who has a positive urine pregnancy test within 24 hours
prior to randomization or treatment allocation. If the urine test is
positive or cannot be confirmed as negative, a serum pregnancy test will
be required.
19. Has preexisting ≥Grade 3 gastrointestinal or non-gastrointestinal
fistula.
20. Has received prior systemic chemotherapy or other targeted or
biological antineoplastic therapy for their metastatic NSCLC.
21. Has received prior treatment with pembrolizumab or any other anti
PD 1, anti PD L1, anti PD L2 agent, with lenvatinib or any other RTKi, or
with an agent directed to another stimulatory or co inhibitory T cell
receptor (eg, CTLA-4, OX-40, CD137, GITR).
22. Has received radiotherapy within 14 days prior to the first dose of
study intervention or received lung radiation therapy of >30 Gy within 6
months prior to the first dose of study intervention.
23. Has received systemic steroid therapy (in doses exceeding 10 mg
daily of prednisone equivalent) within 7 days prior to the first dose of
study intervention.
24. Has received a live or live attenuated vaccine within 30 days prior to
the first dose of study intervention. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Part 1: Number of Participants with a Dose-limiting Toxicity.
2. Part 1: Number of Participants with One or More Adverse Events.
3. Part 1: Number of Participants With Study Intervention
Discontinuations Due to Adverse Events.
4. Part 2: Progression-free Survival (PFS) as Assessed by BICR according
to RECIST 1.1, modified to follow a maximum of 10 target lesions and a
maximum of 5 target lesions per organ.
5. Part 2: Overall Survival (OS).
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Cycle 1; each cycle is 21 days (up to 21 days)
2. Through 90 days post last dose of study treatment (Up to
approximately 27 months)
3. Up to approximately 24 months
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4. Up to approximately 36 months
5. Up to approximately 47 months
|
|
| E.5.2 | Secondary end point(s) |
1. Part 2: Objective Response Rate (ORR) as Assessed by BICR according
to RECIST 1.1, modified to follow a maximum of 10 target lesions and a
maximum of 5 target lesions per organ.
2. Part 2; Duration of Response (DOR) as Assessed by BICR according to
RECIST 1.1, modified to follow a maximum of 10 target lesions and a
maximum of 5 target lesions per organ.
3. Part 2: Number of Participants with One or More Adverse Events.
4. Part 2: Number of Participants Who Discontinue Study Treatment Due
to an Adverse Event.
5. Part 2: Change from Baseline in Global Health Status/Quality of Life
(QoL); Cough; Chest Pain; Dyspnea; and Physical Functioning.
6. Part 2: Time to True Deterioration Defined as the Time from Baseline
to the First Onset of a ≥10-Point Deterioration from Baseline With
Confirmation in Global Health Status/QoL, Cough, Chest Pain, Dyspnea,
and Physical Functioning.
7. Time to True Deterioration in the Composite Endpoint (Combination of
Cough, Chest Pain, or Dyspnea Defined as the Time to First Onset of a ≥
10-Point Deterioration from Baseline in Any One of 3 Scale Items With
Confirmation. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 19 months
2. Up to approximately 19 months
3. Up to approximately 27 months
4. Up to approximately 24 months
5. Baseline (Cycle 1 Day 1) and at designated timepoints up to 30 days
post last dose. Each cycle is 21 days. (Up to approximately 25 months)
6. Baseline (Cycle 1 Day 1) and at designated timepoints up to 30 days
post last dose. Each cycle is 21 days. (Up to approximately 25 months)
7. Baseline (Cycle 1 Day 1) and at designated timepoints 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 | Yes |
| 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 | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| 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 | No |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 66 |
| 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 |
| Argentina |
| Chile |
| New Zealand |
| Australia |
| Canada |
| China |
| Israel |
| Japan |
| Korea, Republic of |
| Russian Federation |
| United Kingdom |
| United States |
| France |
| Germany |
| Poland |
| Spain |
| 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
|
|
| 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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