| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Untreated unresectable Pleural Mesothelioma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cancer of mesothelial tissue in the lungs |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To compare progression free survival (PFS) as determined by Blinded Independent Committee Review and overall survival (OS) of nivolumab combined with ipilimumab to pemetrexed plus cisplatin or carboplatin regimen as first line treatment in patients with unresectable pleural mesothelioma. |
|
| E.2.2 | Secondary objectives of the trial |
-) To compare the objective response rate (ORR) as determined by BICR, of nivolumab combined with ipilimumab to pemetrexed plus cisplatin or carboplatin as first line treatment in patients with unresectable pleural mesothelioma.
-) To compare the Disease Control Rate (DCR) as determined by BICR, of nivolumab combined with ipilimumab to pemetrexed plus cisplatin or carboplatin as first line treatment in patients with unresectable pleural mesothelioma.
-) To evaluate whether PD-L1 expression is a predictive biomarker for ORR, PFS, and OS. |
|
| 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 |
| This collection for additional research is intended to expand the translational R&D capability at Bristol-Myers Squibb, and will support as yet undefined research aims that will advance our understanding of disease and options for treatment. It may also be used to support health authority requests for analysis, and advancement of pharmacodiagnostic development to better target drugs to the right subjects. This may also include genetic/genomic exploration aimed at exploring disease pathways, progression and response to treatment etc. |
|
| E.3 | Principal inclusion criteria |
1. Signed Written Informed Consent
2. Target Population
a) Histologically proven diagnosis of malignant pleural Mesothelioma, thoracoscopy is highly recommended.
b) Must have advanced unresectable disease that is not amenable to therapy with curative intent (surgery with or without chemotherapy). Subjects that refuse potentially curative salvage surgery are ineligible.
c) Available (archival and/or fresh) pathological samples for centralized PD-L1 IHC testing during the screening period. Subjects cannot randomize until the tumor tissue has been received at the central laboratory that will confirm if the sample is appropriate for PD-L1 expression testing, and contains a minimum of 100 evaluable tumor cells. Testing result
is not required prior to randomization, and subjects can initiate therapy before the result of PD-L1 testing.
d) Prior palliative radiotherapy is acceptable, however at least 14 days must have passed prior to first treatment, and all signs of early toxicity must have remitted.
e) Eastern Cooperative Oncology Group (ECOG) Performans Status of 0-1.
f) Measurable disease, defined as tumor thickness perpendicular to the chest wall or mediastinum that could be measured in two positions at three separate levels on transverse cuts of CT scan, and that can be accurately measured at baseline by CT-Scan and is suitable for repeated assessment using modified Response Evaluation Criteria in Solid Tumors [m-RECIST] for pleural mesothelioma.
g) 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, ages over 18 years, inclusive
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 treatment start.
c) Women must not be breastfeeding.
d) Women of childbearing potential (WOCBP) must agree to follow instructions for method(s) of contraception from the time of enrollment for the duration of treatment with:
i) ARM A: for a period of 30 days (duration of ovulatory cycle) plus the time required for the investigational drug to undergo five half-lives. The terminal half-life of nivolumab is up to 25 days. WOCBP randomized to receive nivolumab plus ipilimumab should use an adequate method to avoid pregnancy for 23 weeks after the last dose of investigational drug.
ii) ARM B: chemotherapy plus 5-half-lives of chemotherapy plus 30 days (duration of ovulatory cycle) for a total of 30 days post treatment completion or a duration specified by the local labels of the chemotherapy drugs received, whichever is longer.
e) Men who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with:
i) ARM A: nivolumab plus 5 half-lives of nivolumab plus 90 days (duration of sperm turnover) for a total of 31 weeks post treatment completion.
ii) Arm B: chemotherapy plus 5 half-lives of chemotherapy plus 90 days (duration of sperm turnover) for a total of 90 days post treatment completion or a duration specified by the local labels of the chemotherapy drugs received, whichever is longer (for subjects treated in the control arm).
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) Primitive peritoneal, pericardial, testis or tunica vaginalis mesothelioma.
b) Brain metastasis, except if surgically resected or treated with stereotaxic radiotherapy with no evolution within the 3 months before inclusion, and asymptomatic subject. In addition, subjects 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 first treatment.
2. Medical History and Concurrent Diseases
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) Prior systemic therapy for Pleural Mesothelioma.
c) Prior intraoperative intracavitary chemotherapy for Pleural Mesothelioma.
d) Subjects with previous malignancies (except non-melanoma skin cancers, and in situ cancers such as the following: bladder, gastric, colon, cervical/dysplasia, melanoma, or breast) are excluded unless a complete remission was achieved at least 3 years prior to first treatment and no additional therapy is required or anticipated to be required during
the study period.
e) Other active malignancy requiring concurrent intervention.
f) Subjects with an active, known or suspected autoimmune disease.
g) Subjects with a condition requiring systemic treatment with either corticosteroids (> 10mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of first treatment. Inhaled or topical steroids, and adrenal replacement steroid < 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
h) Subjects with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity.
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.
j) Excluding subjects with serious or uncontrolled medical disorders
3. Physical and Laboratory Test Findings
a) Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
b) Any positive test result 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)
c) Inadequate hematologic, renal or hepatic function defined by any of the following screening laboratory values:
i) WBC < 2000/microL
ii) Neutrophils < 1500/microL
iii) Platelets < 100 x 103/microL
iv) Hemoglobin <9.0 g/dL
v) Serum creatinine >1.5 x ULN or creatinine clearance < 60 mL/min (using the Cockcroft Gault formula)
vi) AST/ALT >3.0 x ULN (> 5 x ULN if liver metastases)
vii)Total Bilirubin >1.5 x ULN (except subjects with Gilbert Syndrome who must have a total bilirubin level < 3.0 mg/dL)
4. Allergies and Adverse Drug Reaction
a) History of allergy or hypersensitivity to platinum-containing compounds or other study drug components
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 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| To compare the Progression free survival (PFS) and overall survival (OS) of nivolumab in combination with ipilimumab to platinum-doublet chemotherapy in subjects with malignant pleural Mesothelioma. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The study will end when analysis of overall survival is complete. The duration of study will be approximately 48 months. |
|
| E.5.2 | Secondary end point(s) |
- To compare the objective response rate (ORR) assessment of nivolumab in combination with ipilimumab to platinum-doublet chemotherapy in subjects with malignant pleural Mesothelioma.
- Disease related symptom improvement |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| PFS rates at 6, 12, 18, 24, 36, 48 months and 5 year will be estimated |
|
| 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 | Yes |
| 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 | 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 | 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 |
| Australia |
| Belgium |
| Brazil |
| Canada |
| Chile |
| Colombia |
| Finland |
| France |
| Germany |
| Greece |
| Italy |
| Japan |
| Mexico |
| Netherlands |
| Poland |
| Romania |
| Russian Federation |
| South Africa |
| Switzerland |
| Turkey |
| 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
|
| Last follow up visit of the last patient |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 21 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 28 |
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