E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Metastatic programmed cell deathligand 1 (PD-L1) positive (TPS ≥50%) non-small cell lung cancer (NSCLC) |
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E.1.1.1 | Medical condition in easily understood language |
Non-small cell lung cancer |
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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 | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10029522 |
E.1.2 | Term | Non-small cell lung cancer stage IV |
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 overall survival (OS) in subjects treated with pembrolizumab plus ipilimumab versus pembrolizumab plus placebo. 2. To compare the progression-free survival (PFS) per RECIST 1.1 based on blinded independent central review (BICR) in subjects treated with pembrolizumab plus ipilimumab versus pembrolizumab plus placebo. |
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E.2.2 | Secondary objectives of the trial |
1. To compare the confirmed objective response rate (ORR) per RECIST 1.1 based on BICR in subjects treated with pembrolizumab plus ipilimumab versus pembrolizumab plus placebo. 2. To evaluate the duration of response (DOR) per RECIST 1.1 (based on BICR) in subjects treated with pembrolizumab plus ipilimumab and pembrolizumab plus placebo. 3. To evaluate the mean change from baseline in EORTC QLQ-C30 global health status/quality of life score in subjects treated with pembrolizumab plus ipilimumab compared to pembrolizumab plus placebo. 4. To evaluate TTD in the composite endpoint of cough (EORTC QLQ-LC13 Q1), pain in chest (EORTC QLQ LC13 Q10), and shortness of breath (EORTC QLQ-C30 Q8) in subjects treated with pembrolizumab plus ipilimumab and pembrolizumab plus placebo. 5. Objective: To evaluate the safety and tolerability profile of pembrolizumab plus ipilimumab in subjects treated with pembrolizumab plus ipilimumab. |
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E.2.3 | Trial contains a sub-study | No |
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, serum/plasma 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. |
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E.3 | Principal inclusion criteria |
1. Be willing and able to provide written informed consent for the trial. The subject may also provide consent/assent for future biomedical research (FBR); however, the subject may participate in the main trial without participating in FBR. 2. Be at least 18 years of age on the day of signing informed consent. 3. Have a histologically or cytologically confirmed diagnosis of Stage IV metastatic NSCLC (AJCC version 8). 4. Have measurable disease per RECIST 1.1 as assessed by the local site investigator/radiology. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesion. 5. Have a life expectancy of at least 3 months. 6. Have an ECOG Performance Status of 0 or 1. 7. Have adequate organ function as indicated in the protocol. Specimens must be collected within 10 days prior to the start of trial treatment. 8. Have provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. Tumor demonstrates PD-L1 expression in ≥50% of tumor cells (TPS ≥50%) as assessed by IHC as determined by an FDA-approved test (22C3 Pharm IHC PharmDx [Dako] assay) at a central laboratory. Formalin-fixed, paraffin-embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue. 9. Female subjects of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. 10. A female subject is eligible to participate if she is not pregnant (see Section 12.5), not breastfeeding, and at least one of the following conditions applies: (1) is not considered to be a woman of childbearing potential (WOCBP) as described in Section 12.5 or (2) is a WOCBP who agrees to follow the contraceptive guidance in Section 12.5 during the treatment period and for at least 120 days (corresponding to time needed to eliminate any study treatment(s) (MK and or any active comparator/combination). 11. A male subject must agree to use contraception as detailed in Section 12.5 of this protocol during the treatment period and for at least 120 days after the last dose of study treatment and refrain from donating sperm during this period |
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E.4 | Principal exclusion criteria |
1. Has received prior systemic chemotherapy/other targeted or biological antineoplastic therapy treatment for their Stage IV metastatic NSCLC. 2. Tumor harbors an EGFR-sensitizing (activating) mutation or an ALK translocation. 3. Is currently participating in or has participated in a trial of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of trial treatment. 4. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137). 5. Has received prior radiotherapy within 2 weeks of start of trial treatment or received lung radiation therapy of >30 Gy within 6 months of the first dose of trial treatment. Subjects 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. 6. The subject’s NSCLC can be treated with curative intent with surgical resection, localized radiotherapy, or chemoradiation. 7. Tumor specimen is not evaluable for PD-L1 expression. 8. Is receiving systemic steroid therapy ≤7 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 events of clinical interest (ECIs), as a premedication 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 to 7.5 mg (or hydrocortisone equivalent doses) is an example of replacement therapy. c) Subjects who use inhaled steroids for the control of asthma serve as an exception to this rule. 9. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. 10. Has known untreated-CNS metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are radiologically stable (i.e., without evidence of progression for at least 4 weeks by repeat imaging [note that the repeat imaging should be performed during study screening]), clinically stable, and without requirement of steroid treatment for at least 14 days prior to first dose of trial treatment. 11. Has an 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, physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment. 12. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (i.e., doses exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of trial drug. 13. Has a history of (non-infectious) pneumonitis that required systemic steroids or current pneumonitis/interstitial lung disease. 14. Has had an allogeneic tissue/solid organ transplant. 15. Has received a live vaccine within 30 days prior to the first dose of trial treatment. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid vaccine. 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. 16. Has an active infection requiring systemic therapy. 17. Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority. 18. Has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (defined as hepatitis c virus (HCV) RNA [qualitative] is detected) infection. 19. Has a known history of active tuberculosis (TB; Bacillus Tuberculosis). 20. 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. 21. Has known psychiatric or substance abuse disorders that would interfere with cooperating with the requirements of the trial. 22. 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).
Refer to protocol for the rest of exclusion criteria
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Overall survival (OS) 2. Progression-free survival (PFS) per RECIST 1.1 based on BICR |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
IA1 (~ 12 months after the last subject randomised); IA2 (~ 19 months after the last subject randomised); FA (~27 months after the last subject randomised) |
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E.5.2 | Secondary end point(s) |
- Objective response rate (ORR) per RECIST 1.1 based on BICR - Duration of response (DOR) - Safety and tolerability - Change from baseline in global health status/quality of life score from the EORTC QLQ-C30 (items 29 and 30) - Time to true deterioration (TTD) in PRO composite endpoint |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
IA1 (~ 12 months after the last subject randomised) |
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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 | 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 | Yes |
E.6.13.1 | Other scope of the trial description |
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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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
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 | Yes |
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
| Information not present in EudraCT |
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 | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 63 |
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 |
Argentina |
Australia |
Brazil |
Canada |
Chile |
Colombia |
France |
Germany |
Hungary |
Ireland |
Italy |
Korea, Republic of |
Latvia |
Mexico |
New Zealand |
Peru |
Poland |
South Africa |
Spain |
Taiwan |
Thailand |
Turkey |
Ukraine |
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 | 6 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | 27 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
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 |