| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic Non-squamous Non-small Cell Lung Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Lung cancer (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 | 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 compare PFS per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) based on blinded independent central review (BICR) of the combinations of pembrolizumab + chemotherapy versus saline placebo + chemotherapy
- To compare overall survival (OS) of the combinations of pembrolizumab + chemotherapy versus saline placebo + chemotherapy
|
|
| E.2.2 | Secondary objectives of the trial |
- To compare objective response rate (ORR) per RECIST 1.1 based on BICR of the combinations of pembrolizumab + chemotherapy versus saline placebo + chemotherapy
- To compare duration of response (DOR) of the combinations of pembrolizumab + chemotherapy versus saline placebo + chemotherapy
- To evaluate the patient reported outcomes (PROs) mean score changes from baseline to weeks 12 and 27 in global health status and quality of life scale between pembrolizumab + chemotherapy versus saline placebo + chemotherapy
- To evaluate the PROs time to true deterioration (TTD) in the composite endpoint of cough, chest pain or dyspnea between pembrolizumab + chemotherapy versus saline placebo + chemotherapy
- To evaluate the safety and tolerability of the combination of pembrolizumab + chemotherapy and saline placebo + chemotherapy |
|
| 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 (Blood, serum/plasma and tissue) 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 histologically or cytologically confirmed diagnosis of Stage IV (AJCC Version 8 or current version as applicable) non-squamous NSCLC
2. Have documentation of tumor activating EGFR mutation, specifically either DEL19 or L858R
3. Have investigator determined radiographic disease progression per RECIST 1.1 after treatment with an EGFR TKI therapy:
a) Participants previously treated with 1st or 2nd generation EGFR TKI (eg, erlotinib/afatinib/gefitinib) are required to have confirmed documented absence of EGFR T790M mutation
b) Participants with confirmed acquired T790M mutation after 1st or 2nd generation EGFR TKI (eg, erlotinib/afatinib/gefitinib) are required to have osimertinib TKI treatment failure prior to enrollment
c) Participants previously failed osimertinib TKI treatment as 1st line therapy are eligible regardless of their EGFR T790M mutation status
4. 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
5. Have provided archival tumor tissue sample or newly obtained (no anti-neoplastic therapy since biopsy) core or excisional biopsy of a tumor lesion not previously irradiated. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archival tissue
6. Be ≥18 years of age on the day of signing informed consent
7. Have a life expectancy of at least 3 months
8. Have an ECOG performance status of 0 or 1 within 7 days prior to the first dose of study treatment but before randomization
9. A male participant must agree to use contraception as detailed in protocol Section 10.3 during the treatment period and for at least 120 days after the last dose of pembrolizumab and up to 180 days after last dose of chemotherapeutic agents
10. A female participant is eligible to participate if she is not pregnant (see protocol Section 10.3), not breastfeeding, and at least one of the following conditions applies:
a. Not a woman of childbearing potential (WOCBP) as defined in protocol Appendix 3
OR
b. A WOCBP who agrees to follow the contraceptive guidance in protocol Section 10.3 during the treatment period and for at least 120 days after the last dose of pembrolizumab and up to 180 days after the last dose of chemotherapeutic agents
11. The participant provides written informed consent for the study
12. Have adequate organ function as defined in the protocol. Specimens must be collected within 10 days prior to the start of trial treatment |
|
| E.4 | Principal exclusion criteria |
1. Has predominantly squamous cell histology NSCLC. Mixed tumors will be categorized by the predominant cell type; if small cell elements are present, the participant is ineligible
2. Has symptomatic ascites or pleural effusion. A participant who is clinically stable following treatment for these conditions (including therapeutic thoraco- or paracentesis) is eligible
3. A WOCBP who has a positive urine pregnancy test within 72 hours prior to randomization (see protocol Section 10.3). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
4. 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)
5. Has received prior systemic cytotoxic chemotherapy or investigational agent(s), excluding EGFR TKIs, for metastatic NSCLC
6. Has received prior radiotherapy within 2 weeks of start of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-central nervous system (CNS) disease
7. Has received a live vaccine within 30 days prior to the first dose of study treatment. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, bacillus Calmette–Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed
8. 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
9. 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
10. Has a known additional malignancy that is progressing or has required active treatment within the past 5 years
11. Has known active untreated 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 (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment
12. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients
13. Has a known sensitivity to any component of cisplatin, carboplatin, or pemetrexed
14. 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 (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed
15. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
16. Has an active infection requiring systemic therapy
17. Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority
18. 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] is detected or HCV antibody reactive, if HCV-RNA is not the local SOC) infection
19. Has a known history of active tuberculosis (TB; Bacillus tuberculosis)
20. 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
21. Has known psychiatric or substance abuse disorder that would interfere with cooperating with the requirements of the study
22. 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 after the last dose of pembrolizumab and up to 180 days after the last dose of chemotherapeutic agents |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1) Progression-free Survival (PFS) per RECIST 1.1 assessed by BICR
2) Overall survival (OS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
- 34 weeks after the last participant has been randomized (estimated approximately 372 PFS events across two treatment groups have been observed)
- Final PFS analysis: when least 12 months after the last participant has been randomized AND at least 414 PFS events have been observed (estimated~32 months after the first participant randomized)
- Final OS analysis: To be performed every 8 to 9 months until at least 30 months after the last participant has been randomized AND at least ~360 deaths have occurred for the final OS analysis (estimated ~59 months after the first participant randomized) |
|
| E.5.2 | Secondary end point(s) |
| 1) Objective response rate (ORR) per RECIST 1.1 assessed by BICR |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 34 weeks after the first 270 participants have been randomized (estimated ~19 months after the first participant randomized) |
|
| 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 | No |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| Quality of life patient reported outcomes |
|
| 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 |
| Crossover phase to pembrolizumab monotherary |
|
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 51 |
| 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 |
| Brazil |
| Canada |
| China |
| France |
| Germany |
| Hong Kong |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Mexico |
| Spain |
| Sweden |
| Taiwan |
| 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 | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
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