| 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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10048683 |
| E.1.2 | Term | Advanced cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061873 |
| E.1.2 | Term | Non-small cell lung cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
| To characterize the safety of nivolumab administered as a flat dose in combination with weight-based ipilimumab dosing in Cohorts A and B. |
|
| E.2.2 | Secondary objectives of the trial |
To estimate the efficacy of nivolumab administered as a flat dose in combination with weight-based ipilimumab dosing in Cohorts A and B.
To assess participant reported outcomes (PROs) in Cohorts A and B. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Signed Written Informed Consent
2) Type of Participant/Target Disease Characteristics
a) Eastern Cooperative Oncology Group Performance Status of less or equal to 1.
b) Cohort A (1st-line NSCLC):
i) Participants 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.
(1)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.
(2)Prior definitive 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.
c) Cohort B (second-line NSCLC)
i) Subjects with histologically- or cytologically-documented squamous or non-squamous cell NSCLC who present with Stage IIIB/ Stage IV disease (per IASLC), or with recurrent or progressive disease following multimodal therapy (radiation therapy, surgical resection or definitive chemoradiation therapy for locally advanced disease).
ii) Subjects must have experienced disease recurrence or progression during or after one prior platinum doublet-based chemotherapy regimen for advanced or metastatic disease.
(1).Maintenance therapy following platinum doublet-based chemotherapy is not considered as a separate regimen of therapy
(2).Subjects who received platinum-containing adjuvant, neoadjuvant or definitive chemoradiation therapy given for locally advanced disease, and developed recurrent (local or metastatic) disease within 6 months of completing therapy are eligible.
(3).Subjects with recurrent disease > 6 months after platinumcontaining adjuvant, neoadjuvant or definitive chemoradiation therapy given for locally advanced disease, who also subsequently progressed during or after a platinum doublet-based regimen given to treat the recurrence, are eligible.
d) Evaluable disease by computed tomography (CT) or magnetic resonance imaging (MRI); radiographic tumor assessment performed within 28 days of start of study treatment.
e) Participants must have tissue submitted for PD-L1 immunohistochemical (IHC) testing prior to the treatment assignment. If PD-L1 IHC testing has already been conducted during screening for another BMS study, it does not need to be repeated for CA209817.
i) Either a formalin-fixed, paraffin-embedded (FFPE) tissue block or unstained tumor tissue sections, with an associated pathology report, must be submitted for biomarker evaluation prior to treatment assignment. The tumor tissue sample may be fresh or archival if obtained within 12 months prior to enrollment (6 months for slides).
ii) Tissue must be a core needle biopsy, excisional or incisional biopsy. Fine needle biopsies or drainage of pleural effusions with cytospins are not considered adequate for biomarker review. Biopsies of bone lesions that do not have a soft tissue component or decalcified bone tumor samples are also not acceptable.
(1).Samples collected via other procedures, including, but not limited to, endobronchial ultrasound (EBUS) guided biopsy, transbronchial lung biopsy (TBLB) may be approved by the BMS medical monitor (MM)/study director (SD) on a case by case basis.
f) Prior palliative radiotherapy to non-central nervous system (CNS) lesions must have been completed at least 2 weeks prior to the treatment assignment. Participants with symptomatic tumor lesions at baseline that may require palliative radiotherapy within 4 weeks of the treatment assignment are strongly encouraged to receive palliative
radiotherapy prior to starting study therapy.
3) Age and Reproductive Status
a) Males and Females, ages 18 (or age of majority) and older.
b) Women of childbearing potential must have a negative serum/urine pregnancy test 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 with study treatment(s) nivolumab and ipilimumab plus 5 half-lives of study
treatment plus 30 days (duration of ovulatory cycle) for a total of 5 months post-treatment completion
e) Males who are sexually active must agree to follow instructions for method(s) of contraception for the duration of treatment with study treatment(s) nivolumab and ipilimumab plus 5 half-lives of the study treatment plus 90 days (duration of sperm turnover) for a total of 7 months post-treatment completion. 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. |
|
| E.4 | Principal exclusion criteria |
1) Target Disease Exceptions
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.
Subjects with non-squamous histology and 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.
2) Medical Conditions
a) Participants with untreated CNS metastases are excluded.
i) Participants are eligible if CNS metastases are adequately treated and
participants are neurologically returned to baseline (except for residual
signs or symptoms related to the CNS treatment) for at least 2 weeks
prior to treatment assignment. In addition, participants must be either
off corticosteroids, or on a stable or decreasing dose of less or equal to
10 mg daily prednisone (or equivalent) for at least 2 weeks prior to
treatment assignment.
b) Participants with carcinomatous meningitis.
c) Participants must have recovered from the effects of major surgery or
significant traumatic
injury at least 14 days before treatment assignment.
d) Active malignancy requiring concurrent intervention.
e) Participants with an active, known or suspected autoimmune disease.
Participants 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) Participants with a condition requiring systemic treatment with either
corticosteroids (> 10 mg daily prednisone equivalent) or other
immunosuppressive medications within 14 days of treatment
assignment. Inhaled or topical steroids, and adrenal replacement steroid
> 10 mg daily prednisone equivalent, are permitted in the absence of
active
autoimmune disease.
g) Participants with interstitial lung disease that is symptomatic or may
interfere with the detection or management of suspected drug-related
pulmonary toxicity.
h) Known history of testing positive for human immunodeficiency virus
(HIV) or known acquired immunodeficiency syndrome (AIDS).
i) 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.
3) Prior/Concomitant Therapy
a) Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-
CD137, or anti-CTLA-4 antibody, or any other antibody or drug
specifically targeting T-cell co-stimulation or checkpoint pathways
4) Physical and Laboratory Test Findings
a) White blood cells (WBC) < 2000/μL
b) Neutrophils < 1500/μL
c) Platelets < 100*103/μL
d) Hemoglobin < 9.0 g/dL
e) Serum creatinine more than 1.5 x upper limit of normal (ULN) or
calculated creatinine clearance < 40 mL/min (using the Cockcroft-Gault
formula)
f) aspartate aminotransferase (AST)/ alanine aminotransferase (ALT): >
3.0 x ULN
g) Total bilirubin more than 1.5 x ULN (except participants with Gilbert
Syndrome who must have a
total bilirubin level of < 3.0x ULN)
h) Any positive test for hepatitis B virus or hepatitis C virus indicating
acute or chronic infection.
5) Allergies and Adverse Drug Reaction
a) History of allergy or hypersensitivity to study drug components.
6) Other Exclusion Criteria
a) Prisoners or participants who are involuntarily incarcerated. (Note:
under certain specificcircumstances a person who has been imprisoned
may be included or permitted to continueas 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(eg, infectious disease) illness |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary objective of the study will be assessed by summarizing the number and percentage of participants who experience high grade (Grade 3-4 and Grade 5) treatment-related select and immune-mediated adverse events (imAEs) in Cohorts A and B. The select AEs of interest are the following: pneumonitis, interstitial nephritis, diarrhea/colitis, hepatitis, rash, endocrinopathies, and hypersensitivity/infusion reaction events |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The analysis is scheduled to occur once all patients have initiated study therapy and have been followed for at least 3 months. |
|
| E.5.2 | Secondary end point(s) |
Progression-free survival (PFS) defined as the time from first dosing date to the date of the first documented tumor
progression, as determined by investigators (per Response Evaluation Criteria in Solid Tumors [RECIST] v1.1), ordeath due to any cause, whichever occurs first.
Objective Response Rate (ORR) defined as the number and percentage of participants with a best overall response
(BOR) of confirmed complete response (CR) or partial response (PR).
Best overall response (BOR) is defined as the best response designation, recorded between the date of first dose and the date of the initial objectively documented tumor progression per RECIST v1.1 or the date of subsequent therapy, whichever occurs first.
Overall survival (OS) defined as the time from first dosing date to the date of death. Duration of Response (DOR) defined as the time between the date of first confirmed response to the date of the first documented tumor progression (per RECIST 1.1), or death due to any cause, whichever occurs first.
Participant reported outcomes (PROs): assessment of changes in disease-related symptoms and function
dimensions of Health Related Quality of Life (HRQoL) using Functional Assessment of Cancer Therapy-Lung
(FACT-L) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The analysis is scheduled to occur once all patients have initiated study therapy and have been followed for at least 3 months |
|
| 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 | No |
| 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) | 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 | 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 | 2 |
| 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 | 49 |
| 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 |
| Belgium |
| Canada |
| Chile |
| France |
| Germany |
| Greece |
| Hungary |
| Italy |
| Mexico |
| Netherlands |
| Poland |
| Russian Federation |
| Spain |
| Switzerland |
| Turkey |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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 | 4 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 4 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
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