E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated | |
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 | LLT |
E.1.2 | Classification code | 10066490 |
E.1.2 | Term | Progression of non-small cell lung cancer |
E.1.2 | System Organ Class | 100000004864 |
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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) of previously-treated subjects with NSCLC in the strongly positive PD-L1 stratum treated with MK-3475 compared to docetaxel.
2) To compare progression-free survival (PFS) per RECIST 1.1 by independent radiologists’ review of previously-treated subjects with NSCLC in the strongly positive PD-L1 stratum treated with MK-3475 compared to docetaxel.
3) To evaluate OS of previously-treated subjects with NSCLC whose
tumors express PD-L1 and are treated with MK-3475 compared to docetaxel.
4) To evaluate PFS per RECIST 1.1 by independent radiologists’ review
of previously-treated subjects with NSCLC whose tumors express PD-L1 and are treated with MK-3475 compared to docetaxel.
5)Objective: Evaluate safety and tolerability profile of MK-3475 in previously-treated subjects with NSCLC in the strongly positive PD-L1 stratum. |
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E.2.2 | Secondary objectives of the trial |
1) To evaluate overall response rate (ORR) per RECIST 1.1 by
independent radiologists’ review in previously-treated subjects with NSCLC in the
strongly positive PD-L1 stratum and in overall study population whose tumors
express PD-L1 treated with MK-3475 compared to docetaxel.
2) To evaluate response duration per RECIST 1.1 by independent
radiologists’ review in previously-treated subjects with NSCLC in the strongly
positive PD-L1 stratum and in overall study population treated with MK-3475
compared to docetaxel. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) Be willing and able to provide written informed consent/assent for the trial.
2) Be ≥18 years of age on day of signing informed consent.
3) Have a life expectancy of at least 3 months.
4) Have a histologically or cytologically confirmed diagnosis of non-small cell lung cancer (NSCLC) and have at least one measurable lesion as defined by RECIST 1.1.
5) Have experienced investigator determined radiographic progression per RECIST 1.1 of NSCLC after treatment with a platinum-containing doublet for stage IIIB/IV or recurrent disease. The site’s study team must have reviewed pre-trial images that are of diagnostic quality from at least 2 dates to determine that radiographic progression has occurred per RECIST 1.1 following initiation of the first-line platinum-containing doublet. A platinum-containing doublet is defined as a platinum-based cytotoxic systemic agent administered in the same cycle as another cytotoxic systemic chemotherapeutic agent. The central imaging vendor must have received these scans prior to randomization in this trial for a possible retrospective analysis of this eligibility criterion. The central vendor will not be confirming eligibility prior to randomization. Completion of treatment with a platinum-containing doublet as adjuvant therapy within one year of signing informed consent will satisfy the prior treatment requirement.
a. Subjects with an EGFR sensitizing mutation must also be able to demonstrate progression of disease on the EGFR tyrosine kinase inhibitor (either erlotinib or gefitinib) in a similar manner to that above for the platinum-containing doublet. Radiographic images that demonstrate progression after initiation of the EGFR tyrosine kinase inhibitor therapy and after initiation of the platinum-containing doublet must also be submitted similarly for subjects with an EGFR sensitizing mutation prior to randomization. Subjects with an EGFR sensitizing mutation may have been treated previously with the tyrosine kinase inhibitor separately from the platinum-containing doublet; the order of treatment does not matter, but progression of disease as determined by RECIST 1.1 must be demonstrable for both regimens. An exception to this rule is the patient whose NSCLC tumor has an EGFR sensitizing mutation who receives four cycles of a platinum doublet, does not experience progression of disease, and begins therapy with an EGFR tyrosine kinase inhibitor as a maintenance therapy within 28 days of the last administration of the platinum doublet chemotherapy. For this patient, only one set of images demonstrating progression on the EGFR tyrosine kinase inhibitor is required for submission to the independent imaging vendor for the patient to be eligible.
b. Subjects with an ALK translocation must also be able to demonstrate progression of disease on crizotinib in a similar manner to that above for the platinum-containing doublet. Radiogaphic images that demonstrate progression after initiation of crizotinib and after initiation of the platinum-containing doublet must also be submitted similarly for subjects with an ALK translocation prior to randomization. Subjects with an ALK translocation may have been treated previously with the tyrosine kinase inhibitor separately from the platinum-containing doublet; the order of treatment does not matter, but progression of disease as determined by RECIST 1.1 must be demonstrable for both regimens.
6) Have a performance status of 0 or 1 on the ECOG Performance Scale.
7) Have provided tissue for biomarker analysis from a formalin fixed paraffin embedded tumor tissue sample or a newly obtained formalin fixed tumor tissue from a recent biopsy of a tumor lesion not previously irradiated; newly obtained formalin fixed specimens are encouraged. If new scientific data emerge that indicate that an existing biopsy or surgical specimen is suboptimal for identification of patients, then only new biopsies will be acceptable for determination of PD-L1 status. The tissue sample must be received by the central vendor prior to randomization. Fine needle aspirates are not acceptable. Needle or excisional biopsies, or resected tissue is required.
a. Investigators must be able to produce the source documentation of the EGFR mutation status or ALK translocation status. 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.
8) Have resolution of toxic effect(s) of the most recent prior chemotherapy to Grade 1 or less (except alopecia). If subject received major surgery or radiation therapy of > 30 Gy, they must have recovered from the toxicity and/or complications from the intervention.
Refer to Protocol for the complete list.
9) Have a PD-L1 positive (either strongly or weakly) tumor as determined by IHC at a central laboratory. |
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E.4 | Principal exclusion criteria |
1) Has received prior therapy with docetaxel for NSCLC.
2) Is receiving systemic steroid therapy within three days prior to the first dose of trial treatment or receiving any other form of immunosuppressive medication (corticosteroid use on study for management of ECI-ies or as a pre-medication for docetaxel is allowed).
3) Is expected to require any other form of systemic or localized antineoplastic therapy while on trial (including maintenance therapy with another agent for NSCLC or radiation therapy).
4) Has received maintenance chemotherapy (chemotherapy for subjects with a stable or better response to the prior line of treatment) with an additional agent other than that used in the first-line regimen ("switch maintenance"). The exception to this rule is the patient who has an EGFR sensitizing mutation in the tumor who is treated with four cycles of a platinum doublet chemotherapy followed by an EGFR tyrosine kinase inhibitor.
5) Has received prior systemic cytotoxic chemotherapy, biological therapy (e.g., cetuximab), major surgery within 3 weeks of the first dose of trial treatment; received radiation therapy of > 30 Gy within 6 months of the first dose of trial treatment; received prior tyrosine kinase inhibitor therapy or palliative radiotherapy of 30Gy or less within 7 days of the first dose of trial treatment.
6) Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotxic 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).
7) Has a known history of prior malignancy, with the exception of basal cell carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the skin, or in situ cervical cancer, and has undergone potentially curative therapy with no evidence of that disease recurrence for 5 years since initiation of that therapy.
- Note: The time requirement for no evidence of disease for 5 years does not apply to the tumor for which a subject is enrolled in the trial. The time requirement also does not apply to subjects who underwent successful definitive resection of basal cell carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the skin, or in situ cervical cancer.
8) Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by MRI for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are using no steroids for at least three days prior to study medication..
9) Has an active autoimmune disease, or a documented history of autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or resolved childhood asthma/atopy would be exception to this rule. Subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement will not be excluded from the study.
10) Has interstitial lung disease or a history of pneumonitis.
11) Has an active infection requiring intravenous systemic therapy.
12) Has known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
13) Has known active Hepatitis B or C.
14) Has received or will receive a live vaccine within 30 days prior to the first administration of study medication.
15) Has had an allogeneic tissue/solid organ transplant.
16) Subjects that require treatment with a strong inhibitor of CYP3A4 will be excluded. They may be included if there is an alternate treatment available (not a strong CYP3A4 inhibitor) and they are willing to switch prior to randomization. If a subject opts to change from a strong CYP 3A4 inhibitor to a weaker CYP 3A4 inhibitor, the subject must stop the strong CYP 3A4 inhibitor 7 days before study drug administration.
Include statement: Refer to protocol for complete list |
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E.5 End points |
E.5.1 | Primary end point(s) |
Overall Survival is the gold standard endpoint to demonstrate superiority of antineoplastic therapy. Progression free survival is an acceptable scientific endpoint for a randomized Phase III trial to demonstrate superiority of a new antineoplastic therapy, especially if it is believed that the median time to OS with the new therapy may be significantly longer than that seen with standard of care. RECIST 1.1 will be used to determine the dates of progression as this methodology is accepted by regulatory authorities. Because the treatment assignment is unblinded regarding MK-3475 vs. docetaxel, images will be read by independent radiologists blinded to treatment assignment to minimize bias in the response assessments. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Imaging scans will be performed every 9 weeks. |
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E.5.2 | Secondary end point(s) |
Importantly, PFS will also be assessed by irRC as determined by the investigators. ORR will be calculated by both methodologies, in addition to the duration of response. All main analyses will be performed in the strongly positive PD-L1 stratum.
An analysis that includes all patients will be conducted for primary and secondary endpoints if the study is positive for that endpoint in the strongly positive PD-L1 stratum. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Biomarker testing will be occur during the course of the study. Evaluation of PFS and duration of response will be ongoing throughout the study. |
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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 | 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 | Yes |
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) | Yes |
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 | 3 |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 90 |
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 |
Belgium |
Brazil |
Canada |
Chile |
Czech Republic |
Denmark |
France |
Germany |
Greece |
Hungary |
Italy |
Japan |
Korea, Republic of |
Lithuania |
Netherlands |
Portugal |
Russian Federation |
South Africa |
Spain |
Taiwan |
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 | 4 |
E.8.9.1 | In the Member State concerned days | 5 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 11 |