| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non-Small Cell Lung Carcinoma |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 the overall survival (OS) in subjects with TPS≥50%, 1L
advanced/metastatic NSCLC treated with pembrolizumab compared to standard of care
(SOC) chemotherapies.
2) To compare the OS in subjects with TPS≥20%, 1L advanced/metastatic
NSCLC treated with pembrolizumab compared to standard of care (SOC)
chemotherapies.
3) To compare the OS in subjects with TPS≥1%, 1L advanced/metastatic
NSCLC treated with pembrolizumab compared to SOC chemotherapies. |
|
| E.2.2 | Secondary objectives of the trial |
1) To compare the progression-free survival (PFS) by RECIST 1.1 as assessed by central independent radiologists’ review in subjects with TPS≥50%, 1L advanced / metastatic NSCLC treated with pembrolizumab compared to SOC
chemotherapy.
2) To compare the PFS by RECIST 1.1 as assessed by central independent
radiologists’ review in subjects with TPS≥20%, 1L advanced/metastatic NSCLC treated
with pembrolizumab compared to SOC chemotherapy.
3) To compare the PFS as assessed by RECIST 1.1 by central independent
radiologists’ review in subjects with TPS≥1%, 1L advanced/metastatic NSCLC treated
with pembrolizumab compared to SOC chemotherapy.
4) To evaluate the ORR by RECIST 1.1 by central independent radiologists’
review in subjects with TPS≥50%, 1L advanced/metastatic NSCLC treated with
pembrolizumab compared to SOC 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) 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 |
•Have measurable disease based on RECIST 1.1. as determined by the site.
•Be ≥18 years of age on the day of signing informed consent.
•Have a life expectancy of at least 3 months.
•Have not received prior systemic chemotherapy treatment for their advanced/metastatic NSCLC. Treatment with chemotherapy and/or radiation as part of neoadjuvant/adjuvant therapy is allowed as long as therapy was completed at least 6 months prior to the diagnosis of advanced or metastatic disease.
•Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Status
•Have adequate organ function.
•Have 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 have undergone potentially curative therapy with no evidence of that disease recurrence for 5 years since initiation of that therapy.
•Have provided formalin fixed tumor tissue sample from a biopsy of a tumor lesion either at the time of or after the diagnosis of advanced or metastatic disease has been made AND from a site not previously irradiated to assess for PD-L1 status. Biopsies obtained PRIOR to the administration of any systemic therapy administered for the treatment of a subject’s tumor (such as 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. Core needle or excisional biopsies, or resected tissue is required.
•Have a histologically or cytologically confirmed diagnosis of advanced or metastatic, NSCLC and not have an EGFR sensitizing (activating) mutation or an ALK translocation. EGFR sensitizing mutations are those mutations that are amenable to treatment with TKIs including erlotinib, gefitinib or afatanib. Investigators must be able to produce the source documentation of the EGFR mutation and ALK translocation in all subjects with non-squamous histologies AND for subjects in whom testing is clinically recommended. If either an EGFR sensitizing mutation or ALK translocation is detected, additional information regarding the mutation status of the other molecule is not required. If documentation is unavailable or the site is 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 status and/or ALK translocation status is available in source documentation at the site.
Have a PD-L1 positive tumor (TPS≥1%) as determined by IHC at a central laboratory; only PD-L1 positive (TPS≥1%)subjects will be randomized. If the tumor specimen is not evaluable for PD-L1 expression by the central laboratory, the subject is not eligible to participate in the study. |
|
| E.4 | Principal exclusion criteria |
Has an EGFR sensitizing mutation and/or ALK translocation. For patients enrolled who are known to have a tumor of predominantly squamous histology, molecular testing for EGFR mutation and ALK translocation will not be required as this is not standard of care and is not part of current diagnostic guidelines.
•Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of trial treatment.
•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 positive (TPS≥1%) by the central laboratory.
•Subjects with squamous histology who received carboplatin in combination with paclitaxel in the adjuvant setting.
•Is receiving systemic steroid therapy < 3 days prior to the first dose of trial treatment or receiving any other form of immunosuppressive medication.
a. Corticosteroid use on study after Cycle 1 for management of AEs, SAEs and ECIs, as a pre-medication for the control chemotherapies, as a pre-medication for IV contrast allergies/reactions or if considered necessary for a subject’s welfare is allowed.
b. Subjects who receive 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.
c. Equivalent hydrocortisone doses are also permitted if administered as a replacement therapy.
•The subject’s NSCLC can be treated with curative intent with either surgical resection and/or chemoradiation
•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).
•Has received any prior systemic cytotoxic chemotherapy, biological therapy OR had major surgery within 3 weeks of the first dose of trial treatment; received lung radiation therapy of > 30 Gy within 6 months of the first dose of trial treatment.
•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).
•Has known central nervous system metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are clinically stable (neurologically asymptomatic) and have no evidence of new or enlarging brain metastasis by imaging at least 4 weeks after treatment of the brain metastases (e.g. surgery, RT) and are off steroids for at least 3 days prior to the first dose of study medication.
•Has active autoimmune disease, that has required systemic treatment in past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (i.e., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Subjects that require inhaled corticosteroids would not be excluded from the 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.
•Has had an allogeneic tissue/solid organ transplant.
•Has interstitial lung disease OR has had a history of pneumonitis that has required oral or IV steroids.
•Has received or will receive a live vaccine within 30 days prior to the first administration of study medication.
•Has an active infection requiring intravenous systemic therapy.
•Has known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). HIV testing is required at screening.
•Has known active Hepatitis B or C. Hepatitis B and Hepatitis C testing is required at screening.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
- At interim analysis 1, when approximately 250 deaths have ocurred in both arms and at least 6 months after the last patient is enrolled
- At interim analysis 2, which will conducted approximately 38 months after enrollment completion (February 2018)
- final OS analysis will be conducted approximately 45 months (September 2018) after enrollment completion. |
|
| E.5.2 | Secondary end point(s) |
| Progression-Free Survival |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- At interim analysis 1, when approximately 250 deaths have ocurred in both arms and at least 6 months after the last patient is enrolled
- At interim analysis 2, which will conducted approximately 38 months after enrollment completion (February 2018)
- final OS analysis will be conducted approximately 45 months (September 2018) after enrollment completion. |
|
| 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 | No |
| 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 | 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) | 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 | 44 |
| 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 |
| Brazil |
| Canada |
| Chile |
| China |
| Colombia |
| Guatemala |
| Hong Kong |
| Japan |
| Korea, Republic of |
| Malaysia |
| Mexico |
| Peru |
| Philippines |
| Russian Federation |
| South Africa |
| Taiwan |
| Thailand |
| Turkey |
| Ukraine |
| Vietnam |
| Bulgaria |
| Estonia |
| Hungary |
| Latvia |
| Lithuania |
| Poland |
| Portugal |
| Romania |
| Sweden |
| Switzerland |
| Czechia |
| Argentina |
|
| 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 | 4 |
| 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 | 4 |
| 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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