| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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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 | LLT |
| E.1.2 | Classification code | 10048683 |
| E.1.2 | Term | Advanced cancer |
| E.1.2 | System Organ Class | 100000004864 |
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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 main objective of this trial is to characterize the safety of nivolumab administered as a flat dose in combination with weight-based ipilimumab dosing. |
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| E.2.2 | Secondary objectives of the trial |
| The secondary objective of this trial is to estimate the efficacy of nivolumab administered as a flat dose in combination with weight-based ipilimumab dosing |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Signed Written Informed Consent
a) Participants 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 participant care.
2) Type of Participant and Target Disease Characteristics
a) ECOG Performance Status of less or equal to 1.
b) Cohort A (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) Evaluable disease by CT or MRI; radiographic tumor assessment performed within 28 days of start of study treatment.
d) Participants must have tissue submitted for PD-L1 IHC testing prior to the treatmentassignment. 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 guided biopsy, transbronchial lung biopsy may be approved by the BMS MM/SD on a case by case basis.
e) Prior palliative radiotherapy to non-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 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 with study treatment(s) nivolumab and ipilimumab plus 5 half-lives of study treatment (half-life up to 25 days)
plus 30 days (duration of ovulatory cycle) for a total of 5 months 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 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. |
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| E.4 | Principal exclusion criteria |
1) 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.
2) 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
3) Physical and Laboratory Test Findings
a) 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 ULN or calculated creatinine clearance < 40 mL/min (using the
Cockcroft-Gault formula)
f) AST/ALT: > 3.0 x ULN
g) Total bilirubin 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.
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 (eg, infectious disease) illness.
Eligibility criteria for this study have been carefully considered to ensure the safety of the study participants and that the results of the study can be used. It is imperative that participants fully meet all eligibility criteria |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint will be a summary of the number and percentage of participants who experience high grade (Grade 3-4 and Grade 5) treatment-related select and immune-mediated adverse events. The select adverse events of interest are the following: pneumonitis, interstitial nephritis, diarrhea/colitis, hepatitis, rash, endocrinopathies, and hypersensitivity/infusion reaction events. |
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| 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. |
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| E.5.2 | Secondary end point(s) |
Progression-free survival (PFS)
Objective Response Rate (ORR)
Overall survival (OS)
Duration of Response (DOR)
Participant reported outcomes (PROs) |
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| 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. |
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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 | 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 | 1 |
| 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 | 8 |
| 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 |
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| 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
|
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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 | 2 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 19 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 13 |
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