Advanced (unresectable or metastatic) melanoma
Conditions
Interventions
The medical interventions for this trial include both Nivolumab and Ipilimumab.
All compounds will be supplied by the Sponsor company.
One cycle of treatment is defined as six weeks. Subjects will b
Sponsors
Bristol-Myers Squibb
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
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 testing, and other requirements of the study 2. Target Population a) Histologically confirmed unresectable Stage III or Stage IV melanoma, as per AJCC staging system. b) Eastern Cooperative Oncology Group (ECOG) performance status of * 1 (Refer to Appendix 2) c) Treatment naïve subjects (ie, no prior systemic anticancer therapy for unresectable or metastatic melanoma). Note that prior adjuvant or neoadjuvant melanoma therapy is permitted if it was completed at least 6 weeks prior to randomization, and all related adverse events have either returned to baseline or stabilized. d) Measurable disease by CT or MRI per RECIST 1.1 criteria.5.4.3.1 e) Tumor tissue from an unresectable or metastatic site of disease must be provided for biomarker analyses. In order to be randomized, a subject must be classified as PD-L1 positive, PD-L1 negative, or PD-L1 indeterminate. If an insufficient amount of tumor tissue from an unresectable or metastatic site is available prior to the start of the screening phase, subjects must consent to allow the acquisition of additional tumor tissue for performance of biomarker analyses. f) Subjects must have known BRAF V600 mutation status or consent to BRAF V600 mutation testing per local institutional standards during the Screening Period g) Prior radiotherapy must have been completed at least 2 weeks prior to study drug administration. Screening laboratory values must meet the following criteria and should be obtained within 14 days prior to randomization: - WBC greater than or equal to 2000/µL - Neutrophils greater than or equal to 1500/µL - Platelets greater than or equal to 100 x103/µL - Hemoglobin > 9.0 g/dL - Serum creatinine less than or equal to 1.5 x ULN or creatinine clearance (CrCl) greater than or equal to 40 mL/min (using the Cockcroft-Gault formula): - AST/ALT less tha or equal to 3 x ULN - Total Bilirubin less than or equal to 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL). i) 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) after obtaining agreement from the medical monitor prior to re enrolling a subject. If re-enrolled, the subject must be re-consented. 3. Age and Reproductive Status a) Men and women, less than or equal to 18 years of age b) Women of childbearing potential (WOCBP) must use method(s) of contraception as indicated in Appendix 5. For a teratogenic study drug and/or when there is insufficient information to assess teratogenicity (preclinical studies have not been done), a highly effective method(s) of contraception (failure rate of less than 1% per year) is required. The individual methods of contraception and duration should be determined in consultation with the investigator. WOCBP must follow instruct
Exclusion criteria
Exclusion criteria: 1. Target Disease Exceptions a) Active brain metastases or leptomeningeal metastases. Subjects with brain metastases are eligible if these have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for at least 8 weeks after treatment is complete and within 28 days prior to first dose of study drug administration. There must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration. b) Ocular melanoma 2. Medical History and Concurrent Diseases a) Any participation in a Phase 3 ipilimumab trial b) Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results. c) 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. d) Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll. e) Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids, and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. f) 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 costimulation or immune checkpoint pathways. 3. Physical and Laboratory Test Findings a) Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection b) Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). 4. Allergies and Adverse Drug Reaction a) History of allergy to study drug components. b) History of severe hypersensitivity reaction to any monoclonal antibody. 5. Sex and Reproductive Status a) WOCBP who are pregnant or breastfeeding b) Women with a positive pregnancy test at enrollment or prior to administration of study medication. 6. Other Exclusion Criteria a) Prisoners or subjects who are involuntarily incarcerated b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| The primary objective will be measured by the co-primary endpoints of overall surival (OS) and Progression Free Survival (PFS) in all randomized subjects. OS is defined as the time between the date of randomization and the date of death due to any cause. OS will be censored on the last date a subject was known to be alive. OS data will be collected continuously while subjects are on study medication and every 3 months via in-person or phone contact after discontinuation of study medication. PFS is defined as the time between the date of randomization and the first date of documented progression, as determined by the investigator, or death due to any cause, whichever occurs first. Subjects who die without a reported progression will be considered to have progressed on the date of their death. Subjects who did not progress or die will be censored on the date of their last evaluable tumor assessment. Subjects who did not have any on study tumor assessments and did not die will be censored on their date of randomization. Subjects who started anti-cancer therapy without a prior reported progression will be censored on the date of their last evaluable tumor assessment prior to the initiation of subsequent anti-cancer therapy. Tumor assessments are scheduled to be performed at Week 12, every 6 Weeks up to Week 49 and then every 12 to 24 Weeks until disease progression. | — |
Secondary
| Measure | Time frame |
|---|---|
| The first secondary objective (to compare ORR between the experimental arms and the control group) will be measured by the endpoint of ORR. The ORR is defined as the number of subjects with a BOR of CR or PR divided by the number of randomized subjects for each treatment group. The BOR is defined as the best response designation, as determined by the investigator, recorded between the date of randomization and the date of objectively documented progression per RECIST 1.1 or the date of subsequent anti-cancer therapy, whichever occurs first. For subjects without documented progression or subsequent therapy, all available response designations will contribute to the BOR assessment. Tumor assessments are scheduled to be performed at Week 12, every 6 Weeks up to Week 49 and then every 12 to 24 Weeks until disease progression. The second secondary objective (to evaluate differences in OS, PFS, and ORR between the two experimental arms) and will be measured by the endpoints of OS, PFS, and ORR. The third secondary objective (to evaluate PD-L1 expression as a predictive biomarker) will be measured by the endpoint OS based on PD-L1 expression level. PD-L1 expression will be evaluated in tumor specimens collected prior to randomization. The forth secondary objective (to evaluate HRQoL) will be measured by mean changes from baseline in the EORTC-QLQ-C30 global health status/QoL composite scale and by mean changes from baseline in the remaining EORTC QLQ-C30 scales. HRQoL will be evaluated per Section 5.1 of the protocol. | — |
Countries
Netherlands
Outcome results
None listed