| 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.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10059515 |
| E.1.2 | Term | Non-small cell lung cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| 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 objective 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 NSCLC, is stage IV, does not have an EGFR sensitizing (activating) mutation or ALK translocation, and has not received prior systemic chemotherapy treatment for their metastatic NSCLC.
2. Have measurable disease based on RECIST 1.1 as determined by the site.
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, 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 a formalin fixed tumor tissue sample from a biopsy of a tumor lesion either at the time of or after the diagnosis of 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 neoadjuvant/adjuvant therapy) will not be permitted for analysis. The tissue sample must be received by the central vendor prior to randomization. Fine needle aspirates, Endobronchial Ultrasound (EBUS) or cell blocks are not acceptable. Needle or excisional biopsies, or resected tissue is required.
9. The subject’s tumor does not harbor an EGFR sensitizing (activating) mutation or ALK translocation. EGFR sensitizing mutations are those mutations that are amenable to treatment with tyrosine kinase inhibitors including erlotinib, gefitinib, or afatanib. Investigators must be able to produce the source documentation of the EGFR mutation and ALK translocation status 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 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 nonsquamous histologies will not be randomized until the EGFR mutation status and/or ALK translocation status is available in source documentation at the site. For patients enrolled who are known to have a tumor of predominantly squamous histology, molecular testing for EGFR and ALK translocation will not be required as this is not standard of care and is not part of current diagnostic guidelines.
10. Have a PD-L1 strong tumor as determined by IHC at a central laboratory.
11. Female subjects must have a negative urine or serum pregnancy test at screening (within 72 hours of first dose of study medication) if of childbearing potential or be of non-child bearing potential.
12. If of childbearing potential, female subjects must be willing to use two adequate barrier methods throughout the study, starting with the screening visit through 120 days after the last dose of study therapy and up to 180 days after last dose of chemotherapeutic agents.
13. Male subjects with a female partner(s) of child-bearing potential must agree to use two adequate barrier methods throughout the trial starting with the screening visit through 120 days after the last dose of pembrolizumab is received. Such methods of contraception, or abstinence from heterosexual activity, are required from the screening visit (Visit 1) through 180 days after the last dose of chemotherapy. Males with pregnant partners must agree to use a condom; no additional method of contraception is required for the pregnant partner.
14. 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.
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| E.4 | Principal exclusion criteria |
1. Has an EGFR sensitizing mutation and/or an ALK translocation.
2. Has received systemic therapy for the treatment of their stage IV NSCLC. Completion of 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 metastatic disease.
3. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigation device within 4 weeks of the first dose of treatment.
4. 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.
5. 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, as pre-medication for the control chemotherapies, and/or a premedication for IV contrast allergies/reactions 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.
6. 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).
7. Has received prior systemic cytotoxic chemotherapy, biological therapy, OR major surgery within 3 weeks of the first dose of trial treatment; received thoracic radiation therapy of > 30 Gy within 6 months of the first dose of trial treatment.
8. 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).
9. Has untreated central nervous system (CNS) metastases and/or carcinomatous meningitis identified either on the baseline brain imaging obtained during the screening period OR identified prior to signing the ICF. Subjects whose brain metastases have been treated may participate provided they show radiographic stability (defined as 2 brain images, both of which are obtained after treatment to the brain metastases. These imaging scans should both be obtained at least four weeks apart and show no evidence of intracranial progression). In addition, any neurologic symptoms that developed either as a result of the brain metastases or their treatment must have returned to baseline or resolved. Any steroids administered as part of this therapy must be completed at least three days prior to study medication.
10. 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.
11. Has had an allogeneic tissue/solid organ transplant.
12. Has interstitial lung disease (ILD) OR has had a history of pneumonitis that has required oral or IV steroids.
13. Has received or will receive a live vaccine within 30 days prior to the first administration of study medication. Seasonal flu vaccines that do not contain a live virus are permitted.
14. Has an active infection requiring intravenous systemic therapy.
15. Has known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
16. Has known active Hepatitis B, Hepatitis C or tuberculosis. 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.
17. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating Investigator.
18. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
19. 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).
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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 independentcentral 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.
Objective 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 independent 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 objective 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.
Following Amendment 06, the final OS analysis is no longer required and will not be performed as described above. This is due to the study hypothesis for OS being supported at the interim analysis with database cutoff of May 9, 2016. |
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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 | 8 |
| 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 | 3 |
| E.8.9.1 | In the Member State concerned months | |
| 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 days | 0 |
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