| 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) Compare overall survival (OS) of previously-treated subjects with NSCLC in strongly positive PD-L1 stratum treated with MK-3475 compared to docetaxel.
2) Compare progression-free survival (PFS) per RECIST 1.1 by independent radiologists’ review of previously-treated subjects with NSCLC in strongly positive PD-L1 stratum treated with MK-3475 compared to docetaxel.
3) Evaluate OS of previously-treated subjects with NSCLC whose tumors express PD-L1 and are treated with MK-3475 compared to docetaxel.
4) Evaluate ORR per RECIST 1.1 by independent radiologists’ review in previously-treated subjects with NSCLC in the strongly positive PD-L1 stratum treated with MK-3475 compared to docetaxel.
5) Evaluate safety and tolerability profile of MK-3475 in previously-treated subjects with NSCLC in the strongly positive PD-L1 stratum. |
|
| E.2.2 | Secondary objectives of the trial |
1) Evaluate overall response rate (ORR) per RECIST 1.1 by independent radiologists’ review of 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) 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. |
|
| 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 > or = 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.The target lesion(s) should also have bidimensional measurability for irRC evaluation on study.
5)Have experienced investigator determined radiographic progression per RECIST 1.1 of NSCLC after treatment with at least two cycles of a platinum-containing doublet for stage IIIB/IV or recurrent disease.
a. Subjects with an EGFR mutation must also be able to demonstrate progression of disease on the EGFR tyrosine kinase inhibitor (either erlotinib or gefitinib or afatinib)
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
6)Have a performance status of 0 or 1 on the ECOG Performance Scale.
7)Have provided tissue for PD-L1 biomarker analysis from a newly obtained formalinfixed tumor tissue from a recent biopsy of a tumor lesion not previously irradiated; no systemic antineoplastic therapy may be administered between the PD-L1 biopsy and initiating study medication.
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.
9)Have a PD-L1 positive (either strongly or weakly) tumor as determined by IHC at a central laboratory (either in the neoplastic cells themselves or in mononuclear inflammatory cells infiltrating the tumor).
Inclusion Criteria for Optional Crossover from docetaxel to MK-3475 2mg/kg
arm
In order to be eligible for participation in the crossover phase, the subject must:
1. Be willing and able to provide written informed consent/assent for the trial.
2. Have been randomized into the docetaxel arm of MK-3475 PN010 study and taken at least one dose of study medication
3. Have experienced disease progression (either clinical or radiographic, as assessed by the investigator) from docetaxel or other subsequent anti-cancer therapies.
4. Have a performance status of 0 or 1 on the ECOG Performance Scale.
5. Subjects with known and treated brain metastasis are eligible provided they are clinically stable, and brain metastases have been treated. Steroid use for symptom control is allowed but the total daily dose should be < or = 10 mg of prednisone or its equivalent.
6. Have baseline imaging scan done within 30 days of the first dose of MK-3475
7. Have adequately recovered from adverse events of previous anti-cancer therapy.
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| E.4 | Principal exclusion criteria |
1)Has received prior therapy with docetaxel for NSCLC.
2) Is currently participating or has participated in a study of an
investigational agent or using an investigational device within 30 days of
the first dose of trial treatment.
3) 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 ECIs or as a pre-medication for docetaxel is allowed).
4) 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).
5) Has received prior systemic cytotoxic chemotherapy, antineoplastic
biological therapy (e.g., cetuximab), 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; received prior
tyrosine kinase inhibitor therapy or completed palliative radiotherapy
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-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). Has participated in another MK-3475 clinical trial.
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.
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.
10) Has had an allogeneic tissue/solid organ transplant.
11)Has interstitial lung disease or a history of pneumonitis that required oral or intravenous glucocorticoids to assist with management. Lymphangitic spread of the NSCLC is not exclusionary.
Exclusion Criteria for Optional Crossover from docetaxel to MK-3475
2mg/kg arm
The subject must be excluded from participating in the trial if the subject:
1. Has withdrawn consent from study (MK-3475 PN010).
2. Have active pneumonitis of Grade 2 or greater or history of pneumonitis requiring systemic steroid therapy.
3. Has received thoracic radiation therapy of > 30 Gy within 6 months have active and untreated brain metastasis.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
There are two primary endpoints of this study: overall survival (OS) and progression-free survival (PFS) per RECIST 1.1.
-Overall survival (OS) 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.
- Progression-free survival is defined as the time from randomization to the first documented disease progression per RECIST 1.1 based on blinded independent radiologists’ review or
death due to any cause, whichever occurs first.
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 PD-L1 vs. docetaxel, images will be read by independent radiologists blinded to treatment assignment to minimize bias in the response assessments.
All main statistical analyses will be performed in the strongly positive PD-L1 stratum.
The trial scheme allows two interim analyses and a final analysis. PFS will be tested at the second interim analysis, and will be tested at the final analysis if MK-3475 is not superior to the control in PFS at the second interim analysis. Testing will be done for OS at both the second interim analysis and the final analysis.
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|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Imaging scans will be performed every 9 weeks. |
|
| 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 of ORR in those subjects whose tumors weakly express PD-L1 will be conducted at interim analysis 1 to determine if these subjects are likely to have some potential clinical benefit from the drug.
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 | No |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Trial only double blind for PD-L1 status. Crossover if recommended by DMC at IA2 or final analysis. |
|
| 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 | 6 |
| 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 |
|
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 15 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 15 |
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