| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| non-squamous non-small cell lung cancer |
|
| 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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10079440 |
| E.1.2 | Term | Non-squamous non-small cell lung cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 the antitumor activity of pembrolizumab in combination with chemotherapy compared with saline placebo in combination with chemotherapy using PFS per RECIST 1.1 as assessed by BICR of imaging.
2. To evaluate the antitumor activity of pembrolizumab in combination with chemotherapy compared with saline placebo in combination with
chemotherapy using OS. |
|
| E.2.2 | Secondary objectives of the trial |
1. To evaluate the antitumor activity of pembrolizumab in combination with chemotherapy compared with saline placebo in combination with
chemotherapy using ORR per RECIST 1.1 as assessed by BICR.
2. To evaluate the antitumor activity of pembrolizumab in combination with chemotherapy compared with saline placebo in combination with
chemotherapy using DOR per RECIST 1.1 as assessed by BICR.
3. To evaluate the safety and tolerability profile of pembrolizumab in combination with pemetrexed/platinum 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 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 |
•Have a histologically-confirmed or cytologically-confirmed diagnosis of stage IV (M1a or M1b AJCC 7th edition) non-squamous NSCLC.
•Have confirmation that EGFR or ALK-directed therapy is not indicated.
•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.
•Have not received prior systemic treatment for their advanced/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.
•Have provided tumor 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.
•Be ≥18 years of age on day of signing informed consent.
•Have a life expectancy of at least 3 months.
•Have a ECOG performance status of 0 or 1
•Have adequate organ function as indicated by the laboratory values specified in the protocol
•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.
•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 or through 180
days after last dose of chemotherapeutic agents as specified in the protocol.
•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 or through 180 days after last dose of chemotherapeutic agents as specified in the protocol. Males with pregnant partners must agree to use a condom; no additional method of contraception is required for the pregnant partner.
•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 |
•Has predominantly squamous cell histology NSCLC. Mixed tumors will be categorized by the predominant cell type; if small cell elements are present, the subject is ineligible.
•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.
•Before the first dose of trial treatment:
a)Has received prior systemic cytotoxic chemotherapy for metastatic disease
b)Has received antineoplastic biological therapy (e.g., erlotinib, crizotinib, cetuximab) for metastatic disease
c)Had major surgery (<3 weeks prior to first dose)
•Received radiation therapy to the lung that is >30 Gy within 6 months of the first dose of trial treatment
•Completed palliative radiotherapy within 7 days of the first dose of trial treatment
•Is expected to require any other form of antineoplastic therapy while on study
•Has received a live-virus vaccination within 30 days of planned treatment start. Seasonal flu vaccines that do not contain live virus are permitted.
•Has clinically active diverticulitis, intra-abdominal abscess, GI obstruction, peritoneal carcinomatosis
•Has a known history of prior malignancy except if the patient has undergone potentially curative therapy with no evidence of that disease recurrence for 5 years since initiation of that therapy.
•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 known untreated, asymptomatic brain metastases may participate but will require regular imaging of the brain as a site of disease.
•Previously had a severe hypersensitivity reaction to treatment with another mAb.
•Has a known sensitivity to any component of cisplatin, carboplatin or pemetrexed
•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.
•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.
•Is unable to interrupt aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs), other than an aspirin dose ≤ 1.3 g per day, for a 5-day period (8-day period for long-acting agents, such as piroxicam).
•Is unable or unwilling to take folic acid or vitamin B12 supplementation.
•Had prior treatment with any other anti-PD-1, or PD-L1 or PD-L2 agent or an antibody targeting other immuno-regulatory receptors or mechanisms. Has participated in any other MK-3475 trial and has been treated with MK-3475.
Examples of such antibodies include (but are not limited to) antibodies against IDO, PD-L1, IL-2R, GITR
•Has an active infection requiring therapy
•Has known history of Human Immunodeficiency Virus (HIV) (known HIV 1/2 antibodies positive).
•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.
•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 subject to participate, in the opinion of the treating Investigator.
•Has known psychiatric or substance abuse disorder that would interfere
with cooperation with the requirements of the trial.
•Is, at the time of signing informed consent, a known regular user of any
illicit drugs or had a recent history (within the last year) of substance
abuse (including alcohol).
•Has symptomatic ascites or pleural effusion. A subject who is clinically stable following treatment for these conditions (including therapeutic thoraco- or paracentesis) is eligible.
•Has a history of (non-infectious) pneumonitis that required steroids or
current pneumonitis.
•Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- Progression Free Survival (PFS) per RECIST 1.1 as assessed by BICR
- Overall Survival (OS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Interim analysis 1 (IA1)
Timing: To be performed after target number of PFS events (~370) are
observed
Purpose: To demonstrate superiority of pembrolizumab in combination
with pemetrexed/platinum in PFS and OS.
ORR will be tested after superiority of pembrolizumab in combination with pemetrexed/platinum is demonstrated in
PFS and OS.
Interim analysis 2 (IA2)
Timing: To be performed after ~468 PFS events are observed
Purpose: To demonstrate superiority of pembrolizumab in combination with pemetrexed/platinum in PFS and OS.
Final analysis (FA)
Timing: To be performed after target number of deaths (~416) are observed
Purpose: To demonstrate superiority of pembrolizumab in combination with pemetrexed/platinum in OS. |
|
| E.5.2 | Secondary end point(s) |
| •ORR per RECIST 1.1 by central imaging vendor |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| 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 | 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 | 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 | Yes |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| After Amd 10, the study will be unblinded. |
|
| 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
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 105 |
| 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 |
| Israel |
| Japan |
| United States |
| Austria |
| Belgium |
| Denmark |
| Finland |
| France |
| Germany |
| Ireland |
| Italy |
| Netherlands |
| Spain |
| United Kingdom |
|
| 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
|
| The overall trial ends when the last subject completes the last study-related phone call or visit, discontinues from the trial or is lost to follow-up (i.e., the subject is unable to be contacted by the investigator). |
|
| 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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