A Clinical Trial: Adjuvant Low-dose Ipilimumab + Nivolumab After Resection of Melanoma Macrometastases
Nivolumab (OpdivoTM, BMS), a human IgG-4 anti-PD-1 monoclonal antibody has demonstrated anti-tumor activity in patients with advanced melanoma. The investigators postulate that patients with melanoma nivolumab have a comparable tumor response rate at a dose range of 0.1 to 10 mg/kg q2wks. Ipilimumab (YervoyTM, BMS), a human IgG-1 anti-CTLA-4 monoclonal antibody improves the survival of patients with advanced melanoma. Adjuvant therapy with ipilimumab improves the relapse-free survival after complete resection of high-risk stage III melanoma (EORTC 18071). Combined treatment with ipilimumab plus nivolumab improves the tumor response rate and overall survival of patients with advanced melanoma but is associated with a higher incidence of immune related adverse events (CheckMate 067).Nivolumab and ipilimumab have distinct immunological mechanisms that can be revealed by analyzing TCR usage in blood lymphocytes.
Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms
An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes.
An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes.
|Eligible Ages||18 Years and Over|
- - All subjects must be either Stage IIIb/c or Stage IV AJCC (7th edition) and have histologically confirmed melanoma that is completely surgically resected in order to be eligible.
- - If Stage III melanoma (whether Stage IIIb or IIIc) the subjects must have clinically detectable lymph nodes that are confirmed as malignant on the pathology report Clinically detectable lymph nodes are defined as: - A palpable node (confirmed as malignant by pathology) - A non-palpable but enlarged lymph node by CT (at least 15 mm in short axis) and confirmed as malignant by pathology - A PET positive lymph node of any size confirmed by pathology - Evidence of pathologically macrometastatic disease in one or more lymph nodes defined by one or more foci of melanoma at least 1cm in diameter - All melanomas, except ocular/uveal melanoma, regardless of primary site of disease will be allowed - Complete resection of Stage III disease that is documented on the surgical and pathology reports or complete resection of Stage IV disease with margins negative that is documented on the pathology report.
- - Complete resection must be performed within 16 weeks prior to recruitment - Subjects must not have received systemic medical anti-cancer treatment (postsurgical local/locoregional radiation therapy applied according to local standard practice is allowed) - All subjects must have disease-free status documented by a complete physical examination and total body PET/CT imaging within 4 weeks prior to recruitment.
- - ECOG performance status score of 0 or 1 (Appendix 2) - In order to be recruited, tumor tissue from the resected site of disease must be provided for biomarker analyses.
- - Prior treated central nervous system (CNS) metastases must be without MRI evidence of recurrence for at least 4 weeks after treatment, subjects must be off immunosuppressive doses of systemic steroids (> 10 mg/day or equivalent) for at least 14 days prior to study drug administration, and must have returned to neurologic baseline post-operatively.
- - In addition to neurosurgery to treat CNS metastases, adjuvant radiation after the resection of CNS metastasis is allowed.
- - Prior surgery that required general anesthesia must be completed at least 4 weeks before study drug administration.
- - All baseline laboratory requirements will be assessed and should be obtained within 14 days of recruitment.
- - Subjects with leptomeningeal metastases - History of ocular/uveal melanoma - Medical History and Concurrent Diseases - Subjects with previous non-melanoma malignancies are excluded unless a complete remission was achieved at least 3 years prior to study entry and no additional therapy is required or anticipated to be required during the study period (exceptions include but are not limited to, non-melanoma skin cancers; in situ bladder cancer, in situ gastric cancer, or in situ colon cancers; in situ cervical cancers/dysplasia; or breast carcinoma in situ) - Subjects with active, known, or suspected autoimmune disease.
- - Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of study drug administration.
- - Prior therapy for melanoma except surgery for the melanoma lesion(s) and except adjuvant RT after neurosurgical resection for CNS lesions.
- - Treatment directed against the resected melanoma (eg, chemotherapy, targeted agents, biotherapy, or limb perfusion) that is administered after the complete resection.
- - Any serious or uncontrolled medical disorder or active infection that, in the opinion of the investigator, may increase the risk associated with study participation, study drug administration, or would impair the ability of the subject to receive protocol therapy.
- - Physical and Laboratory Test Findings - Positive test for hepatitis B virus surface antigen (HBVsAg) or hepatitis C virus ribonucleic acid (HCV RNA) indicating acute or chronic infection.
- - Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.
Phase 0: Exploratory study involving very limited human exposure to the drug to determine whether a drug is modulating its target.
Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans.
Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data.
Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.
Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.
|Phase 1/Phase 2|
The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.
|Universitair Ziekenhuis Brussel|
Category of organization(s) involved as sponsor (and collaborator) supporting the trial.
The disease, disorder, syndrome, illness, or injury that is being studied.
|Stage IIIC Skin Melanoma, Stage IV Skin Melanoma|
Currently, there is no standard of care or no available treatment for subjects with AJCC Stage IIIb/c and Stage IV NED melanoma who are at high risk for recurrence following complete resection of their metastasis. Ipilimumab (10mg/kg), interferon, pegylated interferon therapy or observations alone are the typical options for the Stage III patients who achieve a complete resection and are Food and Drug Administration (FDA) approved. In the EU, high-dose interferon is the only approved drug for the adjuvant treatment of melanoma patients. Given the unexceptional benefit and high toxicity profile in a patient population that is free of disease, it is controversial whether ipilimumab and interferon can be considered standard of care for Stage III melanoma. Nivolumab, a PD1 blocking monoclonal antibody, has shown superior anti-tumor activity across a wide range of dose-levels (0,1 to 10 mg/kg every 2 weeks) in patients with advanced melanoma. Nivolumab (at a dose of 3 mg/kg every 3 weeks) demonstrated a survival benefit in treatment naive patients with BRAF Wild Type (WT), metastatic melanoma in a Phase 3, randomized clinical trial and a PFS benefit over ipilimumab as a first-line therapy for advanced melanoma. Combination therapy with ipilimumab and nivolumab results in a higher response rate and PFS as compared to the results obtained with monotherapy. Combination therapy however significantly increases the incidence of grade > 3 adverse events, to the extent that this regimen would probably be associated with unacceptable toxicity in the adjuvant setting. The toxicity seems to be driven by Ipilimumab. The adverse events seen on Ipilimumab are dose dependent. Unlike PD-1 blockade, CTLA-4 blockade diversifies the peripheral T-cell pool, representing a pharmacodynamic effect that can be measured by a DNA-sequencing technology referred to as ImmunoSeq. This phase IB study will investigate the effect of low-dose ipilimumab and low-dose nivolumab on the peripheral T-cell repertoire of patients who are free of disease following the resection of melanoma macrometastases. Treatment with low-dose ipilimumab in combination with low-dose nivolumab will be safe and modify the peripheral T-cell repertoire in subjects with completely resected Stage IIIb/c and Stage IV melanoma who are at high risk for recurrence. Ipilimumab (YervoyTM, BMS), a human IgG-1 anti-CTLA-4 monoclonal antibody improves the survival of patients with advanced melanoma .Adjuvant therapy with ipilimumab improves the relapse-free survival after complete resection of high-risk stage III melanoma . Combined treatment with ipilimumab plus nivolumab improves the tumor response rate and overall survival of patients with advanced melanoma but is associated with a higher incidence of immune related adverse events. Nivolumab and ipilimumab have distinct immunological mechanisms that can be revealed by analyzing TCR usage in blood lymphocytes.
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