| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment-Naive Stage IV or recurrent Non-Small Cell Lung Cancer (NSCLC) |
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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 | 21.1 |
| 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.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10080083 |
| E.1.2 | Term | Advanced lung cancer |
| 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 |
For Part 1
- To evaluate baseline tumor mutational burden as a candidate biomarker of clinical efficacy of nivolumab and ipilimumab combination therapy.
- To investigate the potential association between candidate biomarkers
in peripheral blood and tumor tissue at baseline
For Part 2
- To evaluate the association between baseline tissue TMB/bTMB and clinical efficacy (ORR) for participants in Part 2 |
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| E.2.2 | Secondary objectives of the trial |
For Part 1
- To evaluate efficacy in patient subgroups defined by baseline discovery biomarkers.
For Part 2
- To investigate bacterially generated and human components enteric biomarkers and identify potential associations with clinical outcomes, including safety and efficacy for participants |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Signed Written Informed Consent
2) Type of Participant and Target Disease Characteristics
a) Subjects with histologically confirmed Stage IV or recurrent NSCLC, squamous or non-squamous histology, with no prior systemic anticancer therapy (including EGFR and ALK inhibitors) given as primary therapy for advanced or metastatic disease. Prior adjuvant or neoadjuvant chemotherapy is permitted as long as the last administration of the prior regimen occurred at least 6 months prior to enrollment. Prior chemoradiation for locally advanced disease is also permitted as long as the last administration of chemotherapy or radiotherapy (which ever was given last) occurred at least 6 months prior to enrollment.
b) Measurable disease by CT or MRI per RECIST 1.1 criteria. Tumor assessment performed within 28 days of start of study treatment.
c) All participants must have tissue submitted during screening. This may include either a formalin-fixed paraffin-embedded (FFPE) tissue block or a minimum of 15 unstained tumor tissue slides.
Part 1: For cohort assignment purposes (PD-L1 status determination), archival tissue samples ≤ 3 months old will be allowed to determine PD-L1 IHC results. Fresh pre-dose biopsy samples (5 cores: 3 in FFPE and 2 in HypoThermosol®) will still need to be submitted.
Part 2: a fresh biopsy (preferred) or archival sample (≤ 3 months old) is required for enrollment, but treatment may start before test results are received.
d) ECOG Performance Status 0 or 1.
3) Age and Reproductive Status
a) Males and Females, ages 18 years (or age of majority) and older.
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 treatment.
c) Women must not be breastfeeding.
d) Women of childbearing potential must agree to follow instructions for method(s) of contraception for the duration of treatment followed by a period of 30 days (duration of ovulatory cycle) plus the time required for the investigational drug to undergo five half-lives. WOCBP treated with nivo + ipi combination should use an adequate method to avoid pregnancy for 5 months (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug.
e) Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment followed by a period
of 90 days (duration of sperm turnover) plus the time required for the investigational drug to undergo five half-lives. Males treated with nivo + ipi combination who are sexually active with WOCBP must continue contraception for 7 months (90 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug. In addition, male participants 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. |
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| E.4 | Principal exclusion criteria |
1) Medical Conditions
a) Subjects with known EGFR mutations which are sensitive to available targeted inhibitor therapy (including, but not limited to, deletions in exon 19 and exon 21 [L858R] substitution mutations) are excluded. All subjects with non-squamous histology must have been tested for EGFR mutation status; use of an FDA-approved test is strongly encouraged. Non-squamous subjects with unknown or indeterminate EGFR status are excluded.
b) Subjects with known ALK translocations which are sensitive to available targeted inhibitor therapy are excluded. If tested, use of an FDA-approved test is strongly encouraged. Subjects with unknown or indeterminate ALK status may be enrolled.
c) Subjects with untreated CNS metastases are excluded.
d) Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.
e) 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.
f) Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of enrollment. Inhaled or topical steroids, and adrenal replacement steroid doses < 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
g) Subjects with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity.
h) Subjects with serious or uncontrolled medical disorders and any known medical condition that, in the investigator’s opinion, would increase the risk associated with study participation or study drug administration or interfere with the interpretation of safety results.
i) Subjects with a known history of a positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). NOTE: Testing for HIV must be performed at sites where mandated locally.
2) Prior/Concomitant Therapy
a) Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.
b) Treatment with botanical preparations (eg herbal supplements or traditional Chinese medicines) intended for general health support or to treat the disease under study within 2 weeks prior to treatment.
3) Physical and Laboratory Test Findings
Screening laboratory values that meet the following criteria (using CTCAE v4):
a) WBC < 2000/L
b) Neutrophils < 1500/L
c) Platelets < 100 x 103/L
d) Hemoglobin < 9.0 g/dL
e) Serum creatinine > 1.5 x ULN, unless creatinine clearance ≥ 40 mL/min (measured or
calculated using the Cockroft-Gault formula)
Female CrCl = (140- age in years) x weight in kg x 0.85
72 x serum creatinine in mg/ dL
Male CrCl = (140- age in years) x weight in kg x 1.00
72 x serum creatinine in mg/ dL
f) AST > 3.0 x ULN
g) ALT > 3.0 x ULN
h) Total Bilirubin > 1.5 x ULN (except subjects with Gilbert Syndrome who must have a total bilirubin level of < 3.0x ULN).
i) Any positive test for hepatitis B virus or hepatitis C virus indicating presence of virus, e.g. Hepatitis B surface antigen (HBsAg, Australia antigen) positive, or hepatitis C antibody (anti-HCV) positive (except if HCV-RNA negative)
4) Allergies and Adverse Drug Reaction
a) History of allergy or hypersensitivity to study drug components.
5) Other Exclusion Criteria
a) Prisoners or participants who are involuntarily incarcerated. (Note: under certain specific circumstances a person who has been imprisoned may be included or permitted to continue as a participant. Strict conditions apply and Bristol-Myers Squibb approval is required.
b) Participants who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
For Part 1
-The clinical efficacy will be measured by the analysis endpoint of objective response rate (ORR). The association of ORR with candidate biomarkers in peripheral blood and tumor tissue at baseline and ontreatment will be assessed. Candidate biomarkers may
include:
- Baseline tissue TMB and blood TMB
- Potential biomarkers/signatures (including PDL1 expression) both at baseline and on treatment
- Immunomodulatory and pharmacodynamics activity
For Part 2
- The clinical efficacy will be measured by the analysis endpoint of objective response rate
(ORR). The association of ORR with baseline |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary endpoint will be analyzed six months after the first treatment of the last patient.
|
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| E.5.2 | Secondary end point(s) |
For Part 1
- ORR, disease control rate (DCR)
- Duration of response (DOR) and time to response (TTR)
- Progression free survival (PFS)
- Overall survival (OS)
For Part 2
- ORR, PFS, OS
- Incidence of AES, SAEs, and select AEs |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| All secondary endpoints will be analyzed at the same time as the primary endpoint. Additional survival analysis may be conducted for up to 5 years beyond analysis of the primary endpoint. |
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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 | No |
| 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 | 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) | 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 | No |
| E.8.1.1 | Randomised | No |
| 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.8.2.4 | 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| 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 |
| United States |
| Belgium |
| France |
| Germany |
| Italy |
| Netherlands |
| Romania |
| Spain |
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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
|
|
| 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 | 11 |
| E.8.9.1 | In the Member State concerned days | 8 |
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 24 |
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