| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment of advanced NSCLC |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced 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 | 10029522 |
| E.1.2 | Term | Non-small cell lung cancer stage IV |
| 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 |
| To evaluate the clinical activity (as assessed by objective response rate [ORR]) of specific pembrolizumab-based combinations |
|
| E.2.2 | Secondary objectives of the trial |
1) To evaluate the clinical activity (as assessed by progression-free survival [PFS] and overall survival [OS]) of specific pembrolizumab-based combinations. PFS and OS to different specific pembrolizumab-based combinations will be assessed independently in each biomarker-defined group
2) To determine the safety and tolerability of pembrolizumab in combination with MK-1308, MK-4280, or lenvatinib. Safety and tolerability to different specific pembrolizumab-based combinations will be assessed independently in each biomarker-defined group |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Merck will conduct Future Biomedical Research on DNA, RNA and tumour specimens collected during this clinical trial. Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time |
|
| E.3 | Principal inclusion criteria |
1. Have a histologically or cytologically confirmed diagnosis of Stage IV (American Joint Committee on Cancer [AJCC] v. 8) NSCLC and study participants should not have had prior systemic therapy for advanced disease.
2. Have confirmation that epidermal growth factor receptor– (EGFR-), anaplastic lymphoma kinase– (ALK-), c-ros oncogene 1 (ROS1), or B isoform of rapidly accelerated fibrosarcoma (B-Raf) directed therapy is not indicated as primary therapy. Documentation of absence of tumor activating EGFR mutations, B-Raf mutations, ALK gene rearrangements, and ROS1 gene rearrangements. If participant’s tumor is known to have a predominantly squamous histology, molecular testing for EGFR mutation and ALK and ROS1 translocations will not be required, as this is not part of current diagnostic guidelines.
3. Have measurable disease per RECIST 1.1 as assessed by the local site investigator/radiology. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
4. Male/female participants who are at least 18 years of age on the day of signing the informed consent.
5. A male participant must agree to use a contraceptive as detailed in the
protocol during the treatment period and for at least 120 days after the last dose of study treatment and refrain from donating sperm during this period.
6. A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
a.) Not a woman of childbearing potential (WOCBP)
OR
b.) A WOCBP who agrees to follow the contraceptive guidance in the protocol during the treatment period and for at least 120 days after the last dose of study treatment.
7. The participant (or legally acceptable representative if applicable) provides written informed consent for the study. The participant may also provide consent for Future Biomedical Research. However, the participant may participate in the main study without participating in Future Biomedical Research.
8. Have provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. Newly obtained biopsies are preferred to archival tissue. Repeat samples may be required if adequate tissue is not provided.
9. Participants must have adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP ≤150/90 mm Hg with no change in antihypertensive medications within 1 week prior to randomization.
10. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
11. Have adequate organ function as defined in the protocol. Specimens must be collected within 10 days prior to the start of study treatment.
|
|
| E.4 | Principal exclusion criteria |
1. Has significant cardiovascular impairment within 12 months of the first dose of study drug: such as history of congestive heart failure greater than NYHA Class II, unstable angina, myocardial infarction or cerebrovascular accident (CVA) stroke, cardiac arrhythmia associated with hemodynamic instability, or a left ventricular ejection fraction (LVEF) below the institutional normal range as determined by multigated acquisition scan (MUGA) or echocardiogram.
2. Prolongation of QTc interval to >480 ms.
3. Has symptomatic ascites or pleural effusion. A participant who is clinically stable following treatment for these conditions is eligible.
4. Has had an allogenic tissue/solid organ transplant.
5. A WOCBP who has a positive urine pregnancy test within 24 hours before the first dose of study treatment.
6. Participants with proteinuria >1+ on urine dipstick testing will undergo 24-hour urine collection for quantitative assessment of proteinuria. Participants with urine protein ≥1 g/24 h will be ineligible.
7. Participants who have not recovered adequately from any toxicity and/or complications from major surgery prior to starting therapy. Participants who have had major surgery within 3 weeks prior to first dose of study intervention.
8. Has preexisting ≥Grade 3 gastrointestinal or non-gastrointestinal fistula, gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of lenvatinib.
9. Radiographic evidence of major blood vessel invasion/infiltration.
10. Clinically significant hemoptysis or tumor bleeding within 2 weeks prior to the first dose of study drug.
11. Has received prior systemic chemotherapy treatment for metastatic/recurrent NSCLC.
12. Has current NSCLC disease that can be treated with curative intent with surgical resection, localized radiotherapy, or chemoradiation.
13. Is expected to require any other form of systemic or localized antineoplastic therapy while on study.
14. 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).
15. Has received previous treatment with another agent targeting the LAG-3 receptor.
16. Has received previous treatment with another agent targeting VEGF or the VEGF receptor.
17. Has received prior anticancer therapy including investigational agents within 4 weeks prior to randomization.
18. Has received prior radiotherapy within 2 weeks of start of study treatment or received lung radiation therapy of >30 Gy within 6 months prior to the first dose of study intervention.
19. Has received a live vaccine within 30 days prior to the first dose of study treatment.
20. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment.
21. 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 treatment.
22. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.
23. Has known active CNS metastases and/or carcinomatous meningitis.
24. Has severe hypersensitivity (≥Grade 3) to pembrolizumab, MK-1308, MK-4280, or lenvatinib and/or any of its excipients.
25. Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy is not considered a form of systemic treatment and is allowed.
26. Has a history of (noninfectious) pneumonitis that required steroids or has current pneumonitis.
27. Has an active infection requiring systemic therapy.
28. Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority.
29. Has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
30. Has a known history of active tuberculosis
31. 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.
32. Has known psychiatric or substance abuse disorders that would interfere with cooperating with the requirements of the study.
33. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days for females and 120 days for males after th |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| objective response rate (ORR) based on RECIST 1.1 as assessed by local site review |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| ORR will be used at interim analysis and first database lock |
|
| E.5.2 | Secondary end point(s) |
1. PFS based on RECIST 1.1 as assessed by local site review
2. OS
3. Safety as assessed by the number of participants experiencing AEs and the number of participants discontinuing study drug due to AEs. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Secondary endpoints will be analysed at final database lock |
|
| 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 | Yes |
| 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) | 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 | No |
| E.8.1.2 | Open | No |
| 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 | No |
| E.8.1.7.1 | Other trial design description |
| Adaptive randomization design |
|
| 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 | 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 43 |
| 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 |
| Hong Kong |
| Ireland |
| Italy |
| Japan |
| Korea, Republic of |
| Poland |
| Russian Federation |
| Singapore |
| South Africa |
| Spain |
| Switzerland |
| Taiwan |
| United Kingdom |
| United States |
|
| 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 | 4 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| 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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