| 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 | 21.1 |
| 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)
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) |
|
| 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
2. To compare pembrolizumab + lenvatinib to lenvatinib monotherapy
with respect to ORR per RECIST 1.1 by BICR
3. To assess duration of response (DOR) with pembrolizumab +
lenvatinib and docetaxel per RECIST 1.1 by BICR
4. To assess the safety and tolerability of treatment with pembrolizumab
+ lenvatinib versus docetaxel
5. To assess the safety and tolerability of treatment with lenvatinib
monotherapy
6. 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
7. 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 |
|
| 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 one prior 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. Evidence
of PD is defined as:
- imaging prior to anti-PD-1/PD-L1 treatment or image showing nadir
during anti-PD-1/PD-L1 treatment; AND
- imaging to determine that radiographic progression has occurred per
RECIST 1.1 within 12 weeks (84 days) from the last dose of an anti-PD-
1/PD-L1 mAb.
3. Have PD during/after platinum doublet chemotherapy for metastatic
disease.
4. Have confirmation that EGFR-, ALK-, or ROS1-directed therapy is not
indicated as primary therapy (documentation of absence of tumoractivating
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 mAb
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 randomization 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 a randomization
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 7 days before the
first dose of study intervention but before randomization
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 or 30 days after the last dose of lenvatinib:
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
pembrolizumab or 30 days after the last dose of lenvatinib,
whichever occurs last; 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 24 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
randomization
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. Specimens must be collected within 10
days before the start |
|
| 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 mAb
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 intratumoral cavitation, 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.
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. Has a pre-existing ≥Grade 3 gastrointestinal or non-gastrointestinal
fistula.
10. Is a WOCBP who has a positive urine pregnancy test within 24 hours
before randomization
11. 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
12. 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
13. 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
14. Has known active central nervous system metastases and/or
carcinomatous meningitis
15. Has severe hypersensitivity (Grade ≥3) to pembrolizumab and/or
any of its excipients
16. Has a sensitivity to any of the excipients contained in lenvatinib
17. Has a sensitivity to any of the excipients contained in docetaxel
18. 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)
19. Has a history of (noninfectious) pneumonitis that required systemic
steroids or current pneumonitis/interstitial lung disease
20. Has an active infection requiring systemic therapy
21. Has a known history of human immunodeficiency virus (HIV)
infection
22. 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
23. Has active tuberculosis
24. 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
25. Has a known psychiatric or substance abuse disorder that would
interfere with the participant's ability to cooperate with the
requirements of the study
26. Has a left ventricular ejection fraction (LVEF) below the institutional
normal range, as determined by multigated acquisition (MUGA) or
echocardiogram (ECHO)
27. Has QT interval corrected with Fridericia's formula (QTcF)
prolongation to >480 ms
28. Participants with proteinuria >1+ on urine dipstick testing/urinalysis
will undergo 24-hour urine collection for quantitative assessment of
proteinuria. Participants with urine protein ≥1 g/24 h will be ineligible.
29. 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
30. Has had an allogeneic tissue/solid organ transplant |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Overall Survival (OS)
2. 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 ~48 months
2. Up to ~36 months |
|
| E.5.2 | Secondary end point(s) |
1. Objective Response Rate (ORR) Per Response Evaluation Criteria in
Solid Tumors Version 1.1 (RECIST 1.1) - Pembrolizumab+Lenvatinib vs.
Docetaxel
2. Objective Response Rate (ORR) Per Response Evaluation Criteria in
Solid Tumors Version 1.1 (RECIST 1.1) - Pembrolizumab+Lenvatinib vs.
Lenvatinib Monotherapy
3. Duration of Response (DOR) Per Response Evaluation Criteria in Solid
Tumors Version 1.1 (RECIST 1.1)
4. Number of Participants Experiencing an Adverse Event (AE)
5. Number of Participants Discontinuing Study Treatment Due to an
Adverse Event (AE)
6. 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 Combined
Score
7. Change from Baseline in EORTC Quality of Life Questionnaire Lung
Cancer Module 13 (QLQ-LC13) Cough (Item 31) Scale Score
8. Change from Baseline in EORTC QLQ-LC13 Chest Pain (Item 40) Scale
Score
9. Change from Baseline in EORTC QLQ-C30 Dyspnea (Item 8) Scale
Score
10. Change from Baseline in EORTC QLQ-C30 Physical Functioning (Items
1 to 5) Scale Combined Score
11. Time to True Deterioration (TTD) in EORTC QLQ-C30 Global Health
Status / Quality of Life (Items 29 & 30) Scale Combined Score
12. Time to True Deterioration (TTD) in EORTC QLQ-LC13 Cough (Item
31) Scale Score
13. Time to True Deterioration (TTD) in EORTC QLQ-LC13 Chest Pain
(Item 40) Scale Score
14. Time to True Deterioration (TTD) in EORTC QLQ-C30 Dyspnea (Item
8) Scale Score
15. Time to True Deterioration (TTD) in EORTC QLQ-C30 Physical
Functioning (Items 1 to 5) Scale Combined Score |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to ~18 months
2. Up to ~36 months
3. Up to ~36 months
4. Up to ~48 months
5. Up to ~48 months
6. Baseline and Week 12
7. Baseline and Week 12
8. Baseline and Week 12
9. Baseline and Week 12
10. Baseline and Week 12
11. Up to ~48 months
12. Up to ~48 months
13. Up to ~48 months
14. Up to ~48 months
15. Up to ~48 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 | 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 65 |
| 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 |
| Australia |
| Canada |
| Colombia |
| France |
| Germany |
| Greece |
| Hungary |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Portugal |
| Puerto Rico |
| 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 |
| 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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