| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non-Small Cell Lung Carcinoma |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 the progression free survival per RECIST 1.1 as assessed by blinded independent central radiologists’ review in subjects with PD-L1 strong, 1L metastatic NSCLC treated with MK-3475 compared to standard of care chemotherapies. |
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| E.2.2 | Secondary objectives of the trial |
1. Evaluate the safety and tolerability profile of MK-3475 in subjects with 1L metastatic PD-L1 strong NSCLC.
2. Evaluate the overall survival in subjects with 1L metastatic PD-L1 strong NSCLC treated with MK-3475 compared to standard of care chemotherapies.
3. Evaluate the overall response rate as assessed by RECIST 1.1 by blinded independent central radiology review in subjects with 1L metastatic PD-L1 strong NSCLC treated with MK-3475 compared to standard of care chemotherapies. |
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| 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) 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. |
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| E.3 | Principal inclusion criteria |
1. Have a histologically or cytologically confirmed diagnosis of stage IV, EGFR wt and EML4/ALK fusion negative NCSLC and have received no prior systemic chemotherapy treatment for their metastatic NSCLC. Completion of treatment with chemotherapy as part of neoadjuvant/adjuvant therapy is allowed as long as therapy was completed at least 6 months prior to the diagnosis of metastatic disease.
2. Subject must have at least one radiographically measurable lesion per RECIST 1.1 as determined by blinded independent central radiology review; eligibility will be determined by central review of the screening CT images.
3. Be ≥18 years of age on day of signing informed consent.
4. Have a life expectancy of at least 3 months
5. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Status
6. Have adequate organ function
7. Subject has no history of prior malignancy, with the exception of basal cell carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the skin, or in situ cervical cancer, or has undergone potentially curative therapy with no evidence of that disease recurrence for 5 years since initiation of that therapy.
8. Have provided newly obtained formalin fixed tumor tissue from a biopsy of a tumor lesion AFTER the diagnosis of metastatic disease has been made AND from a site not previously irradiated. Biopsies obtained PRIOR to the administration of any systemic therapy administered for the treatment of a subject’s tumor (such as neoadjuvant/adjuvant therapy) will not permitted for analysis. The tissue sample must be received by the central vendor prior to randomization. Fine needle aspirates are not acceptable. Needle or excisional biopsies, or resected tissue is required.
- Investigators must be able to produce the source documentation of the EGFR, ALK or KRAS mutation status in all subjects with non-squamous histologies AND for subjects in whom testing is clinically recommended. If any of the three (KRAS, EGFR or ALK) are documented as mutated or rearranged, additional information regarding the mutation status of the other molecules is not required as these mutations/rearrangements are mutually exclusive. If unable to test for these molecular changes, formalin fixed paraffin embedded tumor tissue of any age should be submitted to a central laboratory designated by the Sponsor for such testing. Subjects with non-squamous histologies will not be randomized until EGFR mutation, ALK translocation status and/or KRAS mutation status is available in source documentation at the site.
9. Have a PD-L1 strong tumor as determined by IHC at a central laboratory; only PD-L1 strong subjects will be randomized.
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| E.4 | Principal exclusion criteria |
1. Has an EGFR sensitizing mutation and/or an EML4/ALK translocation.
2. Is currently participating or has participated in a study of an investigational agent or using an investigational device within 30 days of the first dose of trial treatment.
3. Tumor specimen is not evaluable for PD-L1 expression by the central laboratory. If an additional tumor specimen is submitted AND evaluable for PD-L1 expression, the subject will be eligible to participate if PD-L1 expression is assessed as “strong” by the central laboratory.
4. Is receiving systemic steroid therapy > 3 days prior to the first dose of trial treatment or receiving any other form of immunosuppressive medication (corticosteroid use on study for management of ECIs is allowed or as a pre-medication for the control chemotherapies is allowed). Subjects who are receiving daily steroid replacement therapy serve as an exception to this rule. Daily prednisone at doses of 5-7.5 mg is an example of replacement therapy. Equivalent hydrocortisone doses are also permitted if administered as a replacement therapy.
5. Is expected to require any other form of systemic or localized antineoplastic therapy while on trial (including maintenance therapy with another agent for NSCLC, radiation therapy, and/or surgical resection).
6. Has received prior systemic cytotoxic chemotherapy, biological therapy, major surgery within 3 weeks of the first dose of trial treatment; received radiation therapy of > 30 Gy within 6 months of the first dose of trial treatment; received palliative radiotherapy of 30Gy or less within 7 days of the first dose of trial treatment.
7. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
8. Has known symptomatic central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by MRI for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are using no steroids for at least three days prior to study medication. Subjects with brain metastases for whom complete surgical resection would be clinically appropriate are excluded from the study.
9. Has an active autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Subjects that require inhaled corticosteroids would not be excluded from the study. Subjects with a history of autoimmune disease who have not required systemic steroids or immunosuppressive agents for 2 years prior to signing informed consent would not be excluded from this study, however subjects with any history of autoimmune induced thyroid dysfunction WILL be excluded from this study. Subjects with vitiligo or resolved childhood asthma/atopy would not be excluded from the study. Subjects that require local steroid injections would not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement would not be excluded from the study.
10. Has had an allogeneic tissue/solid organ transplant.
11. Has had a history of pneumonitis that has required oral or IV steroids. Subjects whose pneumonitis was solely a result of radiation therapy for their NSCLC would not be excluded from the study unless they received oral/IV steroids to manage the pneumonitis.
12. Has received or will receive a live vaccine within 30 days prior to the first administration of study medication.
13. Has an active infection requiring intravenous systemic therapy.
14. Has known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
15. Has known active Hepatitis B or C. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Progression-free-survival (PFS) is defined as the time from randomization to the first documented disease progression per RECIST 1.1 based on blinded central radiologists’ review or death due to any cause, whichever occurs first.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The planned PFS analysis will take place when approximately 175 PFS events have been observed between the MK arm and the control arm, which is expected to occur about 20 months after study start. If there are less than 110 OS events between two arms at the time, the analysis may be delayed for up to 2 months or until when the target OS number is reached, whichever occurs first. |
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| E.5.2 | Secondary end point(s) |
Overall Survival is defined as the time from randomization to death due to any cause. Subjects without documented death at the time of the final analysis will be censored at the date of the last follow-up.
Overall response rate is defined as the proportion of the subjects in the analysis population who have a complete response or partial response. Responses are based upon blinded central radiologists’ review per RECIST 1.1. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| overall survival and overall response rate will be evaluated twice, 1) after approximately 110 deaths have occurred which is expected to occur about 20 months after study start. 2) after approximately 170 deaths which is expected to be about 28 months after study start. |
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| 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 | No |
| 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 | Yes |
| 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 | 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| 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 |
| Austria |
| Belgium |
| Canada |
| France |
| Germany |
| Hong Kong |
| Hungary |
| Ireland |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Netherlands |
| New Zealand |
| Spain |
| United Kingdom |
| United States |
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| 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
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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