| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non-Small Cell Lung Cancer |
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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.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of the study is to compare the progression-free survival (PFS) of cemiplimab versus standard-of-care platinum-based chemotherapies in the first-line treatment of patients with advanced or metastatic non-small cell lung cancer (NSCLC) whose tumors express programmed cell death ligand-1 (PD-L1) in ≥50% of tumor cells. |
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| E.2.2 | Secondary objectives of the trial |
The key secondary objectives of the study are to compare cemiplimab versus platinum based chemotherapies with respect to the following:
• Overall survival (OS)
• Objective response rates (ORR)
|
|
| 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 |
Optional Genomics Sub-study.
The purpose of the genomic analyses is to identify genomic associations with clinical or biomarker response, other clinical outcome measures, and possible AEs. |
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| E.3 | Principal inclusion criteria |
1.Men and women ≥18 years of age (≥20 years of age in Japan)
2.Patients with histologically or cytologically documented squamous or non squamous NSCLC with stage IIIB or stage IIIC disease who are not candidates for treatment with definitive concurrent chemoradiation or patients with stage IV disease who received no prior systemic treatment for recurrent or metastatic NSCLC
a.Patients who received adjuvant or neoadjuvant platinum-doublet chemotherapy (after surgery and/or radiation therapy) and developed recurrent or metastatic disease more than 6 months after completing therapy are eligible
3.Archival or newly obtained formalin-fixed tumor tissue from a metastatic/recurrent site, which has not previously been irradiated
a.Tissue may be obtained from the primary site if it is still in place and the other metastatic sites are either not accessible (ie, brain), cannot be used (ie, bone), or the biopsy would put the patient at undue risk.
b.If an archival biopsy is used, it must be less than 5 months old
4.Tumor cells expressing PD L1 in ≥50% of tumor cells by IHC performed by the central laboratory
5.At least 1 radiographically measureable lesion by computed tomography (CT) or magnetic resonance imaging (MRI) per RECIST 1.1 criteria (see Appendix 4). Target lesions may be located in a previously irradiated field if there is documented (radiographic) disease progression in that site.
6.ECOG performance status of ≤1
7.Anticipated life expectancy of at least 3 months
8.Adequate organ and bone marrow function as defined below:
a.Hemoglobin ≥9.0 g/dL
b.Absolute neutrophil count ≥1.5 × 109/L
c.Platelet count ≥100,000/mm3
d.Glomerular filtration rate (GFR) >30 mL/min/1.73m2
e.Total bilirubin ≤1.5 × upper limit of normal (ULN) (if liver metastases ≤3 × ULN), with the exception of patients diagnosed with clinically confirmed Gilbert’s syndrome
f.Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 × ULN or ≤5 × ULN, if liver metastases
g.Alkaline phosphatase ≤2.5 × ULN (or ≤5.0 × ULN, if liver or bone metastases)
h.Not meeting criteria for Hy’s law (ALT >3 × ULN and bilirubin >2 × ULN)
9.Willing and able to comply with clinic visits and study-related procedures
10.Provide signed informed consent
11.Able to understand and complete study-related questionnaires
|
|
| E.4 | Principal exclusion criteria |
1.Patients that have never smoked, defined as smoking ≤100 cigarettes in a lifetime
2.Active or untreated brain metastases or spinal cord compression. Patients are eligible if central nervous system (CNS) metastases are adequately treated and patients have neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment) for at least 2 weeks prior to randomization. Patients must be off (immunosuppressive doses of) corticosteroid therapy.
3.Patients with tumors tested positive for EGFR gene mutations, ALK gene translocations, or ROS1 fusions
4.Encephalitis, meningitis, or uncontrolled seizures in the year prior to randomization
5.History of interstitial lung disease (eg, idiopathic pulmonary fibrosis, organizing pneumonia) or active, noninfectious pneumonitis that required immune-suppressive doses of glucocorticoids to assist with management. A history of radiation pneumonitis in the radiation field is permitted as long as pneumonitis resolved ≥6 months prior to
randomization.
6.Patients with active, known, or suspected autoimmune disease that has required systemic therapy in the past 2 years. Patients with vitiligo, type I diabetes mellitus, and hypothyroidism (including hypothyroidism due to autoimmune thyroiditis) only requiring hormone replacement are permitted to be randomized.
7.Patients with a condition requiring corticosteroid therapy (>10 mg prednisone/day or equivalent) within 14 days of randomization. Physiologic replacement doses are allowed even if they are >10 mg of prednisone/day or equivalent, as long as they are not being administered for immunosuppressive intent. Inhaled or topical steroids are permitted, provided that they are not for treatment of an autoimmune disorder.
8.Another malignancy that is progressing or requires treatment, with the exception of nonmelanomatous skin cancer that has undergone potentially curative therapy, or in situ cervical carcinoma or any other tumor that has been treated, and the patient is deemed to be in complete remission for at least 2 years prior to randomization, and no additional therapy is required during the study period.
9.Uncontrolled infection with hepatitis B or hepatitis C or human immunodeficiency virus; or diagnosis of immunodeficiency
10. Exclusion criterion removed
11.Active infection requiring systemic therapy within 14 days prior to randomization
12.Prior therapy with anti-PD 1 or anti-PD L1. Prior exposure to other immunomodulatory or vaccine therapy such as anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibodies is permitted, but the last dose of such an antibody should have been at least 3 months prior to the first dose of study drug.
13.Treatment-related immune-mediated AEs from immune-modulatory agents (including but not limited to anti-PD1/PD-L1 mAbs, anti-CTLA4 mAbs, and phosphoinositol 3-kinase [PI3K]-δ inhibitors) that have not resolved to baseline at least 3 months prior to initiation of treatment with study therapy. Patients are excluded from treatment with cemiplimab if they experienced immune-mediated AEs related to prior treatment with a blocker of the PD-1/PD-L1 pathway that were grade 3 or 4 in severity and/or required discontinuation of the agent, regardless of time of occurrence.
14.Receipt of an investigational drug or device within 30 days of screening or within 5 half lives of the investigational drug (whichever is longer)
15.Receipt of a live vaccine within 30 days of planned start of study medication
16.Major surgery or significant traumatic injury within 4 weeks prior to first dose
17.Documented allergic or acute hypersensitivity reaction attributed to antibody treatments
18.Exclusion criteria removed.
19.Known psychiatric or substance abuse disorder that would interfere with participation with the requirements of the study, including current use of any illicit drugs
20. Pregnant or breastfeeding women.
21. Sexually active men or women of childbearing potential who are
unwilling to practice highly effective contraception prior to the initial
dose, during the study, and for at least 6 months after the last dose.
22. Patients who are committed to an institution by virtue of an order
issued either by the judicial or the administrative authorities will be
excluded from this study.
23. Prior treatment with idelalisib.
24. Member of the clinical site study team and/or his/her immediate
family, unless prior approval granted by the Sponsor.
25. Recipients of organ transplants.
26. Active or latent tuberculosis |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is PFS as assessed by a blinded IRC using RECIST 1.1 (Eisenhauer 2009; see Appendix 4). Progression-free survival will be defined as the time from randomization to the date of the first documented tumor progression, as determined by the IRC (using RECIST 1.1) or death due to any cause. Patients will be censored according to rules listed below:
1. Patients who do not have a documented tumor progression or death will be censored on the date of their last evaluable tumor assessment.
2. Patients who do not have a documented tumor progression or death before initiation of new anti-tumor therapy will be censored on the date of their last evaluable tumor assessment prior to or on the date of new anti-tumor therapy.
3. Patients who withdraw consent before taking any study treatment, and as a consequence have no post-baseline tumor assessment, will be censored at the date of randomization.
4. Patients who do not have any evaluable tumor assessments after randomization and do not die will be censored on the date of randomization.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Through 108 weeks of treatment |
|
| E.5.2 | Secondary end point(s) |
The key secondary endpoints in the study will be OS and ORR.
Overall survival will be defined as the time from randomization to the date of death. A patient who has not died will be censored at the last known date of contact.
Objective response rate will be defined as the number of patients with a best overall response (BOR) of confirmed CR or PR divided by the number of patients in the efficacy analysis set.
Best overall response will be defined as the best overall response, as determined by the IRC per RECIST 1.1, between the date of randomization and the date of the first objectively documented progression or the date of subsequent anti-cancer therapy, whichever comes first.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Through 108 weeks of treatment |
|
| 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 | Yes |
| 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 | 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 | 4 |
| 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 | 43 |
| 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 |
| Belarus |
| Brazil |
| Bulgaria |
| Chile |
| China |
| Colombia |
| Czech Republic |
| Georgia |
| Greece |
| Hong Kong |
| Hungary |
| Italy |
| Malaysia |
| Mexico |
| Peru |
| Philippines |
| Poland |
| Portugal |
| Romania |
| Russian Federation |
| Spain |
| Taiwan |
| Thailand |
| Turkey |
| Ukraine |
|
| 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 study will end when the survival analysis is complete. |
|
| 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 | 4 |
| 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 | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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