| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| First-line treatment of extensive stage small cell lung cancer (ES-SCLC) in combination with standard of care (SOC) chemotherapy |
|
| E.1.1.1 | Medical condition in easily understood language |
| Extensive Stage Small Cell Lung Cancer |
|
| 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 | 10041068 |
| E.1.2 | Term | Small cell lung cancer extensive stage |
| 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 evaluate PFS as assessed by BICR per RECIST 1.1 modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.
2. To evaluate OS. |
|
| E.2.2 | Secondary objectives of the trial |
1.To evaluate ORR as assessed by BICR per RECIST 1.1 modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.
2.To evaluate DOR as assessed by BICR per RECIST 1.1 modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.
3.To evaluate the safety profile in each treatment arm using CTCAE 4.0.
4.To evaluate the following patient-reported outcomes (PROs):
a) Mean change from baseline at Weeks 18 in global health status/quality of life using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) global health status/quality of life scale.
b)Time to true deterioration (TTD) in the composite endpoint of cough, chest pain, and dyspnea using the EORTC QLQ-C30 and Lung Cancer Module 13 (QLQ-LC13). |
|
| 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 |
1.Have a documented new diagnosis of SCLC by histology or cytology from brushing, washing, or needle aspiration of a defined lesion. Subjects who do not have histology samples (defined as core or excisional biopsy, or resections) will need to undergo a new biopsy to provide a tissue sample.
2.Have extensive stage disease defined as Stage IV (T any, N any, M 1a/b) by the American Joint Committee on Cancer, Seventh Edition.
3. Have at least 1 lesion that meets the criteria for being measurable, as defined by RECIST 1.1, and is appropriate for selection as a target lesion, as determined by local site investigator/radiology review. Lesions that appear measurable, but have undergone palliative irradiation, cannot be target lesions.
4.Have provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. Formalin-fixed, paraffinembedded (FFPE) tissue blocks are preferred to slides.
5.Have ECOG Performance Status of 0 or 1.
6.Have a life expectancy of at least 3 months.
7.Have adequate organ function as described in the protocol
8.Be ≥18 years of age on day of signing informed consent.
9.If female subject 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 and of childbearing potential, be willing to use an adequate method of contraception as outlined in protocol Section 5.7.2 –Contraception, starting with the first dose of study medication through 120 days after the last dose of pembrolizumab or saline placebo or up to 180 days after last dose of chemotherapeutic agents, whichever is later.
11.If male and of childbearing potential, agree to use an adequate method of contraception as outlined in Protocol Section 5.7.2 -Contraception, starting with the first dose of study medication through 120 days after the last dose of pembrolizumab or saline placebo or up to 180 days after last dose of chemotherapeutic agents, whichever is later.
12.Have 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 |
1.Has received prior systemic therapy for the treatment of SCLC.
2.Is 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 treatment for another health-related problem.
3.Is expected to require any other form of antineoplastic therapy for SCLC, including radiation therapy, while on study.
4.Has known central nervous system (ie, brain and/or spinal cord) metastases and/or carcinomatous meningitis. Subjects with brain metastases may participate only if they satisfy all of the conditions described in the protocol.
5.Has had major surgery within 3 weeks prior to receiving the first dose of trial treatment or has not recovered adequately from toxicity and/or complications from an intervention prior to receiving the first dose of study treatment.
6.Has a history of non-infectious pneumonitis that required steroids or has current pneumonitis.
7.Has a known history of interstitial lung disease.
8.Has a known additional malignancy that is progressing or requires active treatment. Exceptions include early stage cancers (carcinoma in situ or Stage 1) treated with curative intent, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, in situ cervical cancer, or in situ breast cancer that has undergone potentially curative therapy.
9.Has active autoimmune disease that has required systemic treatment in the past 2 years (ie, with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment.
10.Has a known history of, or active, neurologic paraneoplastic syndrome.
11.Has clinically active diverticulitis, intra-abdominal abscess, gastrointestinal obstruction, and/or abdominal carcinomatosis.
12. Has a history of a severe hypersensitivity reaction to treatment with another monoclonal antibody.
13. Is taking chronic systemic steroids (in doses >10 mg daily of prednisone equivalent) within 7 days prior to the first dose of trial treatment.
14. Has a diagnosis of immunodeficiency or is receiving any form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
15.Has received a live vaccine within 30 days prior to the first dose of trial drug. 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 (eg, FluMist®) are live attenuated vaccines and are not allowed.
16.Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PDL2 agent or with an agent directed to another co-inhibitory T-cell receptor (ie, CTLA-4, OX-40, CD137) or has previously participated in a Merck pembrolizumab (MK 3475) clinical trial.
17.Has severe hypersensitivity (Grade ≥3) to pembrolizumab and/or any of its excipients.
18.Has an active infection requiring systemic therapy.
19.Has a known history of HIV infection. No HIV testing is required unless mandated by local health authority.
20.20.Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
21.Has a known history of active TB (Bacillus Tuberculosis).
22.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 for the full duration of the study, or is not in the best interest of the subjec t to participate, in the opinion of the treating investigator.
23.Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
24.Has symptomatic ascites or pleural effusion. A subject who is clinically stable following treatment for these conditions (including therapeutic thoraco - or paracentesis) is eligible.
25.Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study starting with the screening visit through 120 days after the last dose of pembrolizumab or saline placebo or up to 180 days after last dose of chemotherapeutic agents, whichever is later.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. PFS as assessed by BICR RECIST 1.1 modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ
2. OS
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Progression-free Survial: Tumor imaging to be performed every 6 weeks (42 [±7] days) for the first 48 weeks of treatment from the date of randomization, then every 9 weeks (63 [±7] days) subsequently until documented disease progression, or the start of new anti-cancer treatment. Imaging is to follow calendar days regardless of any delays in dosing.
Survival: Subjects to be followed until death, withdrawal of consent or loss to follow up during treatment, 30 days after last dose of study treatment, every 6 weeks (42 [±7] days) or every 9 weeks (63 [±7] days) per imaging schedule during PFS follow-up, and then 8 weeks (±7days) in survival follow-up. Updated survival status may be requested by the Sponsor at any time during the course of the study. |
|
| E.5.2 | Secondary end point(s) |
3) ORR as assessed by BICR per RECIST 1.1 modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ
4) DOR as assessed by BICR per RECIST 1.1 modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ
5) AEs
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Objective Response Rate/Duration of Response: Tumor imaging to be performed every 6 weeks (42 [±7] days) for the first 48 weeks of treatment from the date of randomization, then every 9 weeks (63 [±7] days) subsequently until documented disease progression, or the start of new anti-cancer treatment. Imaging is to follow calendar days regardless of any delays in dosing.
AEs will be monitored throughout the study |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| 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 | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Exploratory biomarkers, quality of life |
|
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Open label in the Second Course phase |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| 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
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 66 |
| 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 |
| Chile |
| France |
| Germany |
| Hungary |
| Ireland |
| Israel |
| Japan |
| Korea, Republic of |
| New Zealand |
| Poland |
| Russian Federation |
| Spain |
| Switzerland |
| Taiwan |
| Turkey |
| United Kingdom |
| 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 | 6 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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