| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| 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 of previously treated subjects with nonsmall cell lung cancer in the strongly positive PDL1 stratum treated with MK3475 compared to docetaxel.
2) To compare progression free survival (PFS) per RECIST 1.1 by independent radiologists' review of previously treated subjects with nonsmall cell lung cancer in the strongly positive PDL1 stratum treated with MK3475 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) Evaluate safety and tolerability profile of MK3475 in previously treated subjects with nonsmall cell lung cancer in the strongly positive PDL1 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 previouslytreated subjects with NSCLC in the strongly positive PDL1 stratum and in overall population whose tumors express PD-L1 treated with MK3475 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 nonsmall cell lung cancer (NSCLC) and have at least one measurable lesion as defined by RECIST 1.1 (Response Evaluation Criteria in Solid Tumours). The target lesion(s) shoud also have bi-dimensional measurability for ummune related response criteria 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 platinumcontaining doublet for stage IIIB/IV or recurrent disease. The site’s study team must have reviewed pretrial images that are of diagnostic quality from at least 2 dates to confirm that radiographic progression has occurred per RECIST 1.1 following initiation of the firstline platinumcontaining doublet. The central imaging vendor must have received these scans and have conrifmed that they are of acceptable diagnostic quality 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 platinumcontaining doublet as adjuvant therapy within one year of signing informed consent will satisfy the prior treatment requirement.
6) Have a performance status of 0 or 1 on the ECOG Performance Scale (Eastern Cooperative Oncology Group). This is a scale of how the disease effects daily activities. 0 or 1 is normal activity or symptoms but ambulatory.
7) Have adequate organ function as indicated in the protocol
8) Have provided tissue for biomarker analysis from a newly obtained formalin fixed tumor tissue sample 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. Although patients using tyrosine kinase inhibitors prior to treatment on this protocol may continue using these until it is time to begin the appropriate wash out period for these medications. For patients in whom obtaining a new tumorbiopsy will be medically inappropriate, the investigator may appeasl to the Sponsor's study clinical director, an if there is agreement, the investigator may submit an archival formalin-fixed. paraffin embedded rumor specimen for PD-L1 analysis. The Tissue sample must be received and evaluated by the central vendor prior to randomization. Fine needle aspirates are not acceptable. Needle or excisional biopsies, or resected tissue is required.
9) Have a PDL1 positive tumour as determined by a central laboratory
10) 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.
11) Female subject of childbearing potential has a negative urine or serum pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. The serum pregnancy test must be
negative for the subject to be eligible.
12) Female subjects may be enrolled in the trial if they are:
- of nonchildbearing potential a female who is status post hysterectomy, oophorectomy or tubal ligation.
- of childbearing potential who are willing to use either 2 adequate barrier methods or a barrier method plus a hormonal method of contraception to prevent pregnancy, or to abstain from heterosexual activity throughout the trial, starting with the screening visit (Visit 1) through 120 days after the last dose of MK3475 or 180 days after the last dose of docetaxel.
13) Male subjects with a female partner(s) of childbearing potential must agree to use a 2 adequate barrier methods or a barrier method plus a hormonal method of contraception to prevent pregnancy, or to abstain from heterosexual
activity throughout the trial starting with the screening visit (Visit 1) through 120 days after the last dose of MK3475 or 180 days after the last dose of docetaxel is received. If their partner is pregnant, males must agree to use a condom and no additional method of contraception is required for the pregnant partner. |
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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. The 30 day window should be applied to the last dose of an antineoplastic investigational agent or last use of an investigational device with antineoplastic intent.
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 ECIies or as a premedication
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).
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 ECIies or as a premedication 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, biological therapy (e.g., cetuximab), major surgery or received radiation therapy of > 30 Gy within 3 weeks of the first dose of trial treatment; received prior 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 antiPD1, antiPDL1, antiPDL2, antiCD137, or antiCytotxic Tlymphocyteassociated antigen4 (CTLA4) antibody including ipilimumab or any other antibody or drug specifically targeting Tcell costimulation or checkpoint pathways). Has participated in another MK3475
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.
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 had an allogenic tissue / solid organ transplant.
11) Has interstitial lung disease or history of pnuemonitis. that required oral or intravenous glucocorticoids to assist with management. Lymphangitic spread of the NSCLC is not exclusionary.
12) Has received a live vaccine wihtin 30days prior to first administration of study drug. Seasonal flu vaccines that do not contain live virus are permitted.
13) Has an active infection requiring intravenous systemic therapy.
14) Has known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
15) 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.
16) 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.
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17) Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements
of the trial.
18) 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).
19) Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit (Visit 1) through 90 days after the last dose of trial treatment.
20) Subjects that require treatment with a strong inhibitor of CYP3A4 will be excluded. |
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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 MK3475 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 PDL1 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 PDL1 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 | 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 |
| Study is open label in regards to if patients are receiving MK-3475 or comparator. However, dose of |
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| 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 | 3 |
| 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 |
| New Zealand |
| Portugal |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 25 |
| 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 | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 25 |
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