| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| metastatic squamous NSCLC |
|
| 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 | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10023775 |
| E.1.2 | Term | Large cell lung cancer recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10001245 |
| E.1.2 | Term | Adenosquamous cell lung cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10001247 |
| E.1.2 | Term | Adenosquamous cell lung cancer recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| 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.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10029515 |
| E.1.2 | Term | Non-small cell lung cancer recurrent |
| 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 |
In subjects with metastatic squamous non-small cell lung cancer (NSCLC) receiving investigator’s choice of standard of care chemotherapy (i.e. carboplatin and a taxane):
1. To evaluate progression free survival (PFS) per RECIST 1.1 as assessed by a central imaging vendor in subjects treated with Pembrolizumab compared to placebo.
2. To evaluate overall survival (OS) in subjects treated with Pembrolizumab
compared to placebo.
|
|
| E.2.2 | Secondary objectives of the trial |
In 1L subjects with metastatic squamous non-small cell lung cancer (NSCLC) receiving investigator’s choice of standard of care chemotherapy (i.e. carboplatin and a taxane):
1. To evaluate the objective response rate (ORR) and duration of response
(DOR) per RECIST 1.1 as assessed by a central imaging vendor in subjects treated
with Pembrolizumab compared to placebo.
2. To evaluate the safety and tolerability profile of Pembrolizumab. |
|
| 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 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 |
The subject must:
1. Have a histologically or cytologically confirmed diagnosis of stage IV (M1a or M1b-AJCC 7th edition) squamous NSCLC. Patients with mixed histology (example
adenosquamous) are allowed if there is squamous component in the specimen.
2. 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.
3. Have not received prior systemic treatment for their metastatic NSCLC. Subjects 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.
4. Have provided tumour tissue from locations not radiated prior to biopsy; formalin- fixed specimens after the subject has been diagnosed with metastatic disease will be preferred for determination of PD-L1 status prior to randomization. Biopsies obtained prior to receipt of adjuvant/neoadjuvant chemotherapy will be permitted if recent biopsy is not feasible.
5. Be ≥18 years of age on day of signing informed consent.
6. Have a life expectancy of at least 3 months.
7. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group
(ECOG) Performance Status.
8. Have adequate organ function as indicated by the, 'Adequate Organ Function Laboratory Values Algorithm' within the protocol
9. If female of childbearing potential , have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
10. If female of childbearing potential, be willing to use an adequate method of contraception as outlined in the protocol, for the course of the study through 120 days after the last dose of study medication
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
11. If male subject with a female partner(s) of child-bearing potential, must agree to use an adequate method of contraception as outlined in the protocol, starting with the first dose of study therapy through 120 days after the last dose of study therapy. Males with pregnant partners must agree to use a condom; no additional method of contraception is required for the pregnant partner.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
12. Subject has voluntarily agreed to participate by giving written informed
consent/assent for the trial. The subject may also provide consent/assent for Future Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical Research.
|
|
| E.4 | Principal exclusion criteria |
Subject must be excluded if subject:
1. Has non-squamous histology NSCLC. Mixed tumours will be categorized by the predominant cell type; if small cell elements are present, the subject is ineligible; for non-small cell histology if there is any squamous element is present (example adenosquamous), the subject is eligible; the squamous element does not have to be predominant.
2. 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 prior to administration of pembrolizumab.
3. Before the first dose of trial treatment: a) Has received prior systemic cytotoxic chemotherapy for metastatic disease b) Has received other targeted or biological antineoplastic therapy (e.g., erlotinib, crizotinib, cetuximab) for metastatic disease c) Had major surgery (<3 weeks prior to first dose)
4. Received radiation therapy to the lung that is > 30 Gy within 6 months of the first dose of trial treatment.
5. Completed palliative radiotherapy within 7 days of the first dose of trial treatment.
6. Is expected to require any other form of antineoplastic therapy while on study.
7. Has received a live-virus vaccination within 30 days of planned treatment start. Seasonal flu vaccines that do not contain live virus are permitted.
8. Has a known history of prior malignancy except if the subject has undergone potentially curative therapy with no evidence of that disease recurrence for 5 years since initiation of that therapy
9. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are clinically stable for at least 2 weeks and, have no evidence of new or enlarging brain metastases and also are off steroids 3 days prior to dosing with study medication. Stable brain metastases by this definition should be established prior to the first dose of study medication. Subjects with asymptomatic brain metastases (i.e., no neurological symptoms, no requirements for corticosteroids, and no lesion >1.5 cm) may participate but will require regular imaging of the brain as a site of disease.
10. Has pre-existing peripheral neuropathy that is ≥ Grade 2 by Common Terminology Criteria for Adverse Events (CTCAE) version 4 criteria.
11. Previously had a severe hypersensitivity reaction to treatment with another
monoclonal antibody.
12. Has a known sensitivity to any component of carboplatin or paclitaxel or nabpaclitaxel.
13. 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 (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
14. Is on chronic systemic steroids. Subjects with asthma that require intermittent use of bronchodilators, inhaled steroids, or local steroid injections would not be excluded from the study.
15. Had prior treatment with any other anti-PD-1, or PD-L1 or PD-L2 agent or an
antibody or a small molecule targeting other immuno-regulatory receptors or
mechanisms. Has participated in any other pembrolizumab trial and has been treated with pembrolizumab. Examples of such antibodies include (but are not limited to) antibodies against IDO, PD-L1, IL-2R, GITR.
16. Has an active infection requiring therapy.
17. Has known history of Human Immunodeficiency Virus (HIV) (known HIV 1/2
antibodies positive).
18. Has known active Hepatitis B or C. Active Hepatitis B is defined as a known positive HBsAg result. Active Hepatitis C is defined by a known positive Hep C Ab result and known quantitative HCV RNA results greater than the lower limits of detection of the assay.
19. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject’s participation in the study, or is not in the best interest of the subject to participate, in the opinion of the treating Investigator.
20. Has known psychiatric or substance abuse disorder that would interfere with
cooperation with the requirements of the trial.
21. Is, at the time of signing informed consent, a regular user (including “recreational use”) of any illicit drugs or had a recent history (within the last year) of substance abuse (including alcohol).
22. Has interstitial lung disease or a history of pneumonitis that required oral or
intravenous glucocorticoids to assist with management. Lymphangitic spread of the NSCLC is not exclusionary.
23. Is pregnant or breastfeeding, or expecting to conceive or father children while on study medication and for the required duration of contraception after the last dose of study medication. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1) Progression-free Survival (PFS) per RECIST 1.1 assessed by
a blinded independent central imaging vendor review
2) Overall survival (OS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Interim analysis (IA) 1
*Timing: To be performed after approximately 200 subjects have had approximately 28 weeks of follow-up
*Purpose: To demonstrate superiority of pembrolizumab in combination with carboplatin and a taxane in ORR
Interim analysis (IA) 2
*Timing: To be performed after a target number of PFS events (approximately 331) is observed
*Purpose: 1) To demonstrate superiority of pembrolizumab in combination with carboplatin and a taxane in PFS; 2) To demonstrate superiority of pembrolizumab in combination with carboplatin and a taxane in OS |
|
| E.5.2 | Secondary end point(s) |
1) ORR (Objective response rates) per RECIST 1.1 by blinded independent central imaging vendor review
2) DOR (Duration of Response) per RECIST 1.1 by blinded independent central imaging vendor review
3) Safety as assessed by a variety of parameters of AEs |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
All secondary efficacy endpoints will be evaluated as part of the trial's
final analyses.Safety endpoints will be evaluated at each of time points specified for the primary efficacy endpoints. |
|
| 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 | 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 | Yes |
| 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 | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.1.7.1 | Other trial design description |
| Cross over is only allowed at documented disease progression |
|
| 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 | Yes |
| 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 | 10 |
| 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 |
| France |
| Germany |
| Hungary |
| Italy |
| Japan |
| Korea, Democratic People's Republic of |
| Mexico |
| Netherlands |
| Poland |
| Russian Federation |
| Spain |
| Thailand |
| Turkey |
| 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 | 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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