| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non-Small Cell Lung Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Stage IV 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 | 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 | 100000004864 |
|
| 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 if total baseline tumor mutation burden (TMB) in cfDNA is predictive of objective response per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) by the investigator by estimating the level of association. |
|
| E.2.2 | Secondary objectives of the trial |
1) To evaluate if total baseline TMB in cfDNA is predictive of progression-free survival (PFS) per RECIST 1.1 by investigator review or overall survival (OS) by estimating the level of association.
2) To evaluate the safety and tolerability of pembrolizumab + investigator choice 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, plasma,tissue and stool) 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-confirmed or cytologically confirmed diagnosis of stage IV (M1a, M1b, or M1c [AJCC 8th edition]) nonsquamous NSCLC
2. Have confirmation that EGFR-, B-RAF-, ROS1-, or ALK-directed therapy is not indicated (documentation of absence of tumor-activating EGFR or B-RAF mutations, AND absence of ALK or ROS1 gene rearrangements OR presence of a KRAS mutation)
3. Have measurable disease based on RECIST 1.1 as determined by the local site investigator/radiology assessment. Target lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions
4. Have not received prior systemic treatment for their advanced/metastatic NSCLC. Participants who received adjuvant or neoadjuvant therapy are eligible if the adjuvant/neoadjuvant therapy was completed at least 12 months prior to the development of metastatic disease
5. Have provided an evaluable archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion (that was not previously irradiated) for biomarker analysis (Fine Needle Aspiration [FNA] samples will not be accepted). Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue
6. Participant is ≥18 years of age inclusive, at the time of signing the informed consent
7. Have an ECOG performance status of 0 or 1 within 10 days prior to the first dose of study treatment
8. Male participants agree to use a contraception during the treatment period and for at least 120 days, corresponding to time needed to eliminate any study intervention(s) (pembrolizumab and/or any active comparator/combination) plus an additional 90 days (a spermatogenesis cycle) for study interventions where there is risk of clinically relevant genotoxicity after the last dose of study intervention and refrain from donating sperm during this period
9. Female participants not be pregnant or breastfeeding, and at least 1 of the following conditions applies:
a. Not be a woman of childbearing potential (WOCBP)
b. A WOCBP must agree to follow the contraceptive during the treatment period and for at least 120 days (corresponding to time needed to eliminate any study intervention(s) (pembrolizumab and or any active comparator/combination) after the last dose of pembrolizumab
10. The participant (or legally acceptable representative if applicable) provides written informed consent/assent for the study. The participant may also provide consent/assent for future biomedical research. However, the participant may participate in the main study without participating in future biomedical research
11. Have adequate organ function
|
|
| E.4 | Principal exclusion criteria |
1. Has predominantly squamous cell histology NSCLC. Mixed tumors will be categorized by the predominant cell type
2. Has small cell elements present in NSCLC tumor
3. Is a WOCBP who has a positive urine pregnancy test within 72 hours prior to treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
4. Has clinically active diverticulitis, intra-abdominal abscess, GI obstruction, peritoneal carcinomatosis
5. Has a known history of prior malignancy except if the participant has undergone potentially curative therapy with no evidence of that disease recurrence for 2 years since initiation of that therapy
6. Has symptomatic ascites or pleural effusion. A participant who is clinically stable following treatment for these conditions (including therapeutic thoraco- or paracentesis) is eligible
7. If participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study intervention
8. Has received prior radiotherapy within 2 weeks of start of study intervention. 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-CNS disease
9. Has received prior therapy with a PD-1/PD-L1 receptor inhibitor
10. Is expected to require any other form of antineoplastic therapy while on study (including maintenance therapy with another agent for NSCLC, radiation therapy, and/or surgical resection)
11. Has received a live vaccine within 30 days prior to treatment. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed
12. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients or to another monoclonal antibody
13. Has a known sensitivity to any component of cisplatin, carboplatin or pemetrexed
14. Has 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
15. Is on chronic systemic steroids. Participants with asthma that require intermittent use of bronchodilators, inhaled steroids, or local steroid injections would not be excluded from the study
16. Is unable or unwilling to take folic acid or vitamin B12 supplementation
17. 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 intervention
18. 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 drug
19. Has a known additional malignancy that is progressing or has required active treatment within the past 2 years
20. Has known active 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 , clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study intervention
21. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
22. Has an active infection requiring systemic therapy
23. Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority
24. 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
25. 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
26. Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study
27. 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 study intervention
28. Has had an allogenic tissue/solid organ transplant |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Objective response (OR): Complete response (CR) or partial response (PR) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Baseline (C1D1 pretreatment), complete response, partial response |
|
| E.5.2 | Secondary end point(s) |
1) PFS is defined as the time from the start of treatment to the first documented progressive disease (PD) or death due to any cause, whichever occurs first.
2) OS is defined as the time from the start of treatment to death due to any cause. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Baseline (C1D1 pretreatment), progressive disease, death |
|
| 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 | No |
| 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 | Yes |
| 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.8.2 | 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.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
| 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 | 8 |
| 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 |
| Canada |
| Hungary |
| Israel |
| Spain |
| 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 | 3 |
| 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 | 3 |
| 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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