| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| 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 | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10025048 |
| E.1.2 | Term | Lung cancer non-small cell recurrent |
| 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 |
| The primary objective of the study is to compare the objective response rate (ORR) of high dose cemiplimab(“HDREGN2810”) and standard dose cemiplimab plus ipilimumab combination therapy (“SDREGN2810/ipi”) to the ORR of standard dose cemiplimab (“SDREGN2810”) in the second-line treatment of patients with advanced squamous or non-squamous non-small cell lung cancer (NSCLC), in patients whose tumors express programmed cell death ligand 1 (PD-L1) in <50% of tumor cells. |
|
| E.2.2 | Secondary objectives of the trial |
-To compare the ORR of HDREGN2810 and SDREGN2810/ipi to the ORR of
SDREGN2810 in the second-line treatment of patients with advanced squamous or
non-squamous NSCLC in all patients.
-To compare the OS of HDREGN2810, and SDREGN2810/ipi combination therapy
compared to the OS of SDREGN2810 in the second-line treatment of patients with
advanced squamous or non-squamous NSCLC in patients with PD-L1 in <50% of
tumor cells and in all patients.
-To compare the PFS of HDREGN2810 and SDREGN2810/ipi combination therapy to
the PFS of SDREGN2810 in the second-line treatment of patients with advanced
squamous or non-squamous NSCLC in patients with PD-L1 in <50% of tumor cells
and in all patients.
-To evaluate the safety and tolerability of HDREGN2810 and SDREGN2810/ipi
compared to those of SDREGN2810 therapy
|
|
| 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 |
Genomics Sub-study
-Patients who agree to participate in the genomics sub-study will be required to sign a separate genomics sub-study ICF before collection of the samples. Patients are not required to participate in the genomics sub-study in order to enroll in the primary study. Samples for DNA extraction should be collected on day 1/baseline (predose) but may be collected at any study visit.
-The purpose of the genomic analyses is to identify genomic associations with clinical or biomarker responses, other clinical outcome measures, and possible AEs. In addition, associations between genomic variants and prognosis or progression of other diseases may also be studied. |
|
| E.3 | Principal inclusion criteria |
1. Men and women ≥18 years of age
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 chemo-radiation or patients with stage IV disease. Patients must have PD after receiving one prior line of chemotherapy treatment for advanced NSCLC.
3. Availability of an archival or on-study obtained formalin-fixed, paraffin-embedded tumor tissue biopsy sample. Guidance on biopsy sites:
a. Archival or fresh biopsies are acceptable;
b. If an archival biopsy is used, it has to be less than 5 months old;
c. The biopsy should be from a metastatic or recurrent site which has not previously
been irradiated.
Exception: the primary tumor is still in place and the other metastatic sites are either not
accessible (brain) or cannot be used (bone) or the biopsy would put the patient at risk
4. Biopsy evaluable for expression of PD-L1 as determined by the PD-L1 IHC 22C3 pharmDx assay performed by the central laboratory
5. At least 1 radiographically measureable lesion by computed tomography (CT) per RECIST 1.1 criteria. 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. 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 ≥75,000/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. ALT < 3 ULN and bilirubin < 2 x ULN
8. Willing and able to comply with clinic visits and study-related procedures
9. Provide signed informed consent
10. Able to understand and complete study-related questionnaires
|
|
| E.4 | Principal exclusion criteria |
1. Patients who 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 (see exclusion criteria 7) for details on timing of discontinuation of steroids)
3. Patients with tumors tested positive for EGFR gene mutations, ALK gene translocations, or ROS1 fusions. All patients will have their tumor evaluated for EGFR mutations, ALK rearrangement, and ROS1 fusions by a central laboratory.
4. Encephalitis, meningitis, or uncontrolled seizures in the year prior to randomization
5. History of interstitial lung disease (eg, idiopathic pulmonary fibrosis or organizing pneumonia), or active, noninfectious pneumonitis that required immune-suppressive doses of glucocorticoids to assist with management, or of pneumonitis within the last 5 years. A history of radiation pneumonitis in the radiation field is permitted as long as pneumonitis resolved ≥6 months prior to randomization.
6. Ongoing or recent evidence of significant autoimmune disease that required treatment with systemic immunosuppressive treatments, which may suggest a risk of immune-related treatment emergent adverse events (irTEAEs). The following are not exclusionary: vitiligo, childhood asthma that has resolved, residual hypothyroidism that required only hormone replacement, or psoriasis that does not require systemic treatment
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. Previous treatment with idelalisib (ZYDELIG®) at any time
9. Prior treatment with an anti-CTLA-4 antibody or anti-PD-1/PD-L1 for lung cancer
10. Another malignancy that is progressing or requires treatment, with the exception of nonmelanomatous skin cancer that has undergone potentially curative therapy, in situ cervical carcinoma, or any other localized 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
11. Known active hepatitis B (known positive result) or hepatitis C (known positive result) and known quantitative HCV RNA results greater than the lower limits of detection of the assay). Uncontrolled infection with human immunodeficiency virus, (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV) infection; or diagnosis of immunodeficiency.
12. Active infection requiring systemic therapy within 14 days prior to randomization
13. Treatment-related immune-mediated AEs from immune-modulatory agents (including but not limited to anti-PD1/PD-L1 monoclonal antibodies, anti-CTLA4 monoclonal antibodies, and phosphatidylinositide 3-kinase 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 or therapy being studied (whichever is longer)
15. Receipt of a live vaccine within 30 days prior to randomization
16. Major surgery or significant traumatic injury within 4 weeks prior to randomization
17. Documented allergic or acute hypersensitivity reaction attributed to antibody treatments in general or to agents specifically used in the study
18. Known psychiatric or substance abuse disorder that would interfere with participation with the requirements of the study, including current use of any illicit drugs
19. Pregnant or breastfeeding women
20. Women of childbearing potential who are unwilling to practice highly effective contraception prior to the initial dose/start of the first treatment, during the study, and for at least 6 months after the last dose.
21. 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. Active or latent tuberculosis. Latency should be confirmed by purified protein derivative (PPD)/QuantiFERON testing according to local guidelines.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is objective response rate (ORR) defined as the proportion of patients achieving CR or PR as assessed by a blinded IRC based on RECIST 1.1 assessments, in patients whose tumors express
PD-L1 in <50% of tumor cells.
Objective response rate is 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 response recorded, 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.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary endpoint of ORR will be analyzed when all enrolled patients have an opportunity to
complete 7 months of study treatment and have had at least two on-treatment tumor assessments. |
|
| E.5.2 | Secondary end point(s) |
-Objective response rate in all patients
-Overall survival in patients whose tumors express PD-L1 in <50% of tumor cells and in all patients.
Overall survival is defined as the time from randomization to the date of death. A patient
who is lost to follow-up will be censored at the last date that the patient was known to be
alive.
-PFS in patients whose tumors express PD-L1 in <50% of tumor cells and in all patients.
Progression-free survival is defined as the time from randomization to the date of the first documented tumor progression, as determined by the IRC (based on RECIST 1.1 assessments, or death. Patients will be censored according to the rules listed below:
o Patients without a documented tumor progression or death will be censored on the
date of their last evaluable tumor assessment.
o Patients without any evaluable tumor assessments after randomization and did not die will be censored on the date of randomization.
-The incidences of TEAEs, serious adverse events (SAEs), deaths, and laboratory
abnormalities. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The secondary endpoint of OS will be analyzed 12 months after the analysis of ORR. The secondary endpoint of PFS will be analyzed at the same time as analysis of ORR. |
|
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | No |
| 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 | 7 |
| 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 |
| Australia |
| Austria |
| Belgium |
| Canada |
| France |
| Germany |
| Korea, Republic of |
| Netherlands |
| Poland |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
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