E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Advanced or Metastatic 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.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10059515 |
E.1.2 | Term | Non-small cell lung cancer metastatic |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 |
The coprimary objectives are to compare Progression Free Survival rate at 6 months after randomization and PFS rate at 1 year after randomization, as measured by investigator-assessed response using Response Evaluation Criteria in Solid Tumor (RECIST) 1.1 criteria, of nivolumab 240 mg every 2 weeks (Arm 1) and nivolumab 480 mg every 4 weeks (Arm 2) in subjects with advanced/metastatic (Stage IIIb/IV) NSCLC (non-Sq and Sq). |
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E.2.2 | Secondary objectives of the trial |
- To compare PFS rate in Arms 1 and 2 at 1 year after randomization by tumor histology and by response criteria before randomization
- To compare PFS rate at 2 years after randomization in Arms 1 and 2
- To compare the overall survival rate at 1 year after randomization and up to 5 years after randomization in Arms 1 and 2, in all treated subjects, by tumor histology, and by response criteria before randomization
- To assess safety and tolerability of nivolumab, as measured by the incidence and severity of AEs and specific laboratory abnormalities, in all treated subjects, in Arms 1 and 2, by tumor histology, and response criteria before randomization |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Signed Written Informed Consent
a) Subjects must have signed and dated an IRB/IEC-approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol-related procedures that are not part of normal
subject care.
b) Subjects must be willing and able to comply with scheduled visits, treatment schedule,laboratory tests, and other requirements of the study.
2. Target Population
a) Subjects with histologically or cytologically documented Sq- or non-SqNSCLC who present with Stage IIIB/Stage IV disease (according to version 7 of the International Association for the Study of Lung Cancer Staging Manual in Thoracic Oncology), or with recurrent or progressive disease following multimodal therapy (radiation therapy, surgical resection, or definitive chemoradiotherapy for locally advanced disease).
b) Subjects must have received and tolerated nivolumab 3 mg/kg or 240 mg every 2 weeks for approximately 4 months (16 weeks ± 2 weeks). Subjects may continue to receive pre-study nivolumab treatment during screening assessments as noted in Table 5.1-2 of the protocol.
c) Subjects must have at least 2 tumor assessments after the start of nivolumab and must demonstrate CR, PR, or SD to the pre-study nivolumab treatment on the latest scan within 28 days prior to randomization.
d) Subjects must have had measurable disease by CT or MRI per RECIST 1.1 criteria at the time of starting first dose of pre-study nivolumab treatment.
e) As of Amendment 01, this criterion is no longer applicable.
f) ECOG PS 0-2
g) Subjects with stable CNS metastases if CNS metastases are treated and subjects are neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment) for at least 2 weeks prior to enrollment. In addition, subjects must be either off corticosteroids or on a stable or decreasing dose of < 10 mg daily prednisone (or equivalent).
h) All baseline laboratory requirements will be assessed and should be obtained within 14 days (unless otherwise specified in Table 5.1-1) of first dose of randomized nivolumab. Screening laboratory values must meet the following criteria:
i) WBCs ≥ 2000/μL
ii) Neutrophils ≥ 1500/μL
iii) Platelets ≥ 100 x 10³/μL
iv) Hemoglobin ≥ 9.0 g/dL
v) Serum creatinine of ≤ 1.5 X ULN or creatinine clearance > 40 mL/minute (using cockcroft/Gault formula)
vi) AST ≤ 3X ULN
vii) ALT ≤ 3X ULN
viii) Total bilirubin ≤ 1.5X ULN (except subjects with Gilbert Syndrome who must have total bilirubin < 3.0 mg/dL)
i) Palliative radiotherapy must be completed at least 2 weeks prior to enrollment.
j) Subject Re-enrollment: This study permits the re-enrollment of a subject that has discontinued the study as a pre-treatment failure (ie, subject has not been randomized/has not been treated). If re-enrolled, the subject must be re-consented.
3. Age and Reproductive Status
a) Males and Females, ≥ 18 years of age.
b) Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study drug.
c) Women must not be breastfeeding.
d) WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with nivolumab plus 5 half-lives of nivolumab (125 days) plus 30 days (duration of ovulatory cycle) for a total of 155 days or 23 weeks post-treatment completion.
e) Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with nivolumab plus 5 half-lives of nivolumab (125 days) plus 90 days (duration of sperm turnover) for a total of 31 weeks post-treatment completion. In addition, male subjects must be willing to refrain from sperm donation during this time.
f) Azoospermic males are exempt from contraceptive requirements. WOCBP who are continuously not heterosexually active are also exempt from contraceptive requirements, and still must undergo pregnancy testing as described in this section.
Investigators shall counsel WOCBP, and male subjects who are sexually active with WOCBP, on the importance of pregnancy prevention and the implications of an unexpected pregnancy. |
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E.4 | Principal exclusion criteria |
1. Target Disease Exceptions
a) Subjects with carcinomatous meningitis.
b) Subjects with untreated, symptomatic central nervous system (CNS) metastases are excluded.
2. Medical History and Concurrent Diseases
Subjects with interstitial lung disease (eg, sarcoidosis) that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity. Subjects with chronic obstructive pulmonary disease whose disease is controlled at study entry are allowed.
b) Subjects with an active, known or suspected autoimmune disease. Subjects with Type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
c) Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of first randomized dose of study drug with the exception of the subjects allowed to enroll with treated or active CNS metastases requiring steroids. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
d) Subjects who received prior therapy with an anti-CTLA-4, anti-PD-L1, or anti-PD-L2, anti-CT137 (or any other antibody or drug specifically targeting T-cell costimulation or checkpoint pathways, except pre-study nivolumab) or subject is expected to require any other form of systemic antineoplastic therapy while receiving nivolumab.
e) Any other serious or uncontrolled medical disorder, active infection, physical exam finding, laboratory finding, altered mental status, or psychiatric condition that, in the opinion of the investigator, would limit the subject’s ability to comply with the study requirements, substantially increase the risk to the subject, or impact the interpretability of study results.
f) Other active malignancy requiring concurrent intervention.
g) Subjects with previous malignancies (except non-melanoma skin cancers, and the following in situ cancers: bladder, gastric, colon, endometrial, cervical/dysplasia, melanoma, or breast) are excluded unless a complete remission was achieved at least 2 years prior to study entry AND no additional therapy is required during the study period with the exception of anti-estrogen/androgen therapy or bisphosphonates.
h) All toxicities attributed to prior anti-cancer therapy other than alopecia, fatigue, or peripheral neuropathy must have resolved to Grade 1 (NCI CTCAE version 4) or baseline before administration of study drug.
i) Subjects must have recovered from the effects of major surgery or significant traumatic injury at least 14 days before the first dose of study treatment.
j) As of Amendment 01, this criterion has been moved to 3b.
3. Physical and Laboratory Test Findings
a) Positive for Hepatitis B virus or Hepatitis C virus indicating acute or chronic infection.
b) Known history of positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). NOTE: Testing for HIV must be performed at sites where mandated by local regulation
4. Allergies and Adverse Drug Reaction
a) History of severe hypersensitivity reactions to other monoclonal antibodies.
5. Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated. (Note: under certain specific circumstances a person who has been imprisoned may be included or permitted to continue as a subject. Strict conditions apply, and Bristol-Myers Squibb approval is required.)
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness
Eligibility criteria for this study have been carefully considered to ensure the safety of the study subjects and that the results of the study can be used. It is imperative that subjects fully meet all eligibility criteria. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The coprimary objectives of this trial will be assessed by PFS rate at 6 months after randomization and PFS rate at 1 year after randomization. PFS is defined as the time from the date of randomization to the date of first documented tumor progression determined by the investigator or death, whichever is earlier. Subjects who did not progress or die will be censored on the date of their last evaluable tumor assessment. The PFS rate at 6 months is the rate from KM estimate 6 months after randomization; PFS rate at 1 year is the rate from KM estimate at 1 year after randomization.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
6 months and 1 year after randomization |
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E.5.2 | Secondary end point(s) |
Secondary objectives will be assessed by:
- PFS rate at 1 year after randomization by tumor histology and by response criteria
- PFS rate at 2 years after randomization
- OS rate at 1 year and OS up to 5 years by arm, histology, and response status at randomization.OS is defined as time from the date of randomization to the date of death. Subjects who did not die by the end of the study will be censored at the last known date alive. OS rate at 1 year is the rate from KM estimated at one year after randomization.
- Safety and tolerability of nivolumab, as measured by incidence and severity of AEs and specific laboratory abnormalities |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Tumor assessment - every 8 weeks (±1 week) for the first year of the study, then every 3 months for the second year of the study, followed by the local standard of care afterwards
OS assessment - once per cycle. For subjects receiving nivolumab 240 mg every 2 weeks, cycle= each 14-day dosing period. For subjects receiving nivolumab 480 mg every 4 weeks, cycle=each 28-day dosing period.
The collection of non serious AE information should begin at initiation of study drug. Nonserious AE information should also be collected from the start of a placebo lead-in period or other observational period intended to establish a baseline status for the subjects
Laboratory tests conducted at every cycle with the exception of thyroid and pregnancy tests (see protocol for details)
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
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) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | No |
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 | No |
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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 40 |
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 |
Canada |
France |
Germany |
Ireland |
Italy |
Spain |
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 | 5 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 5 |