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Model-based clinical pharmacology profiling of ipilimumab in patients with advanced melanoma.

ABSTRACT: Ipilimumab is a fully human, monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4. The objective of the present study was to characterize the clinical pharmacology profile of ipilimumab using a population pharmacokinetic (PPK) approach.The PPK model was developed using 2095 ipilimumab serum concentration values from 499 patients with unresectable stage III or IV melanoma from four phase II studies, with ipilimumab doses ranging from 0.3 to 10?mg?kg(-1) . The structural PK model was determined by developing a base PPK model. The effect of covariates on model parameters was assessed by a full covariate model, which incorporated all pre-specified covariate-parameter relationships into the base model. The final model was developed by backward elimination, followed by exclusion of covariates determined not to be of clinical relevance to ipilimumab, and was rigorously validated against both internal and external datasets.Ipilimumab PK was linear and time-invariant, with dose-proportional exposures over the available dose range, yielding a terminal half-life of approximately 15 days. Clearance of ipilimumab increased with increasing body weight and baseline serum lactate dehydrogenase concentrations, but was not affected by age, gender, concomitant budesonide, Eastern Cooperative Oncology Group performance status or prior systemic anticancer therapy. Furthermore, ipilimumab exposure was not affected by moderate renal impairment or mild hepatic impairment.Ipilimumab concentration-time data were well described by a linear, two compartment, zero order i.v. infusion model. The model confirms that a body weight-normalized dosing regimen is appropriate for ipilimumab therapy in patients with advanced melanoma.

SUBMITTER: Feng Y

PROVIDER: S-EPMC4168385 | biostudies-other | 2014 Jul

REPOSITORIES: biostudies-other

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Model-based clinical pharmacology profiling of ipilimumab in patients with advanced melanoma.

Feng Yan Y Masson Eric E Dai David D Parker Susan M SM Berman David D Roy Amit A

British journal of clinical pharmacology 20140701 1

<h4>Aim</h4>Ipilimumab is a fully human, monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4. The objective of the present study was to characterize the clinical pharmacology profile of ipilimumab using a population pharmacokinetic (PPK) approach.<h4>Methods</h4>The PPK model was developed using 2095 ipilimumab serum concentration values from 499 patients with unresectable stage III or IV melanoma from four phase II studies, with ipilimumab doses ranging from 0.3 to 10 mg kg(-1) . T ...[more]

PMID: 24433434

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Project description:BackgroundIn patients with melanoma, ipilimumab (an antibody against cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4]) prolongs overall survival, and nivolumab (an antibody against the programmed death 1 [PD-1] receptor) produced durable tumor regression in a phase 1 trial. On the basis of their distinct immunologic mechanisms of action and supportive preclinical data, we conducted a phase 1 trial of nivolumab combined with ipilimumab in patients with advanced melanoma.MethodsWe administered intravenous doses of nivolumab and ipilimumab in patients every 3 weeks for 4 doses, followed by nivolumab alone every 3 weeks for 4 doses (concurrent regimen). The combined treatment was subsequently administered every 12 weeks for up to 8 doses. In a sequenced regimen, patients previously treated with ipilimumab received nivolumab every 2 weeks for up to 48 doses.ResultsA total of 53 patients received concurrent therapy with nivolumab and ipilimumab, and 33 received sequenced treatment. The objective-response rate (according to modified World Health Organization criteria) for all patients in the concurrent-regimen group was 40%. Evidence of clinical activity (conventional, unconfirmed, or immune-related response or stable disease for ≥24 weeks) was observed in 65% of patients. At the maximum doses that were associated with an acceptable level of adverse events (nivolumab at a dose of 1 mg per kilogram of body weight and ipilimumab at a dose of 3 mg per kilogram), 53% of patients had an objective response, all with tumor reduction of 80% or more. Grade 3 or 4 adverse events related to therapy occurred in 53% of patients in the concurrent-regimen group but were qualitatively similar to previous experience with monotherapy and were generally reversible. Among patients in the sequenced-regimen group, 18% had grade 3 or 4 adverse events related to therapy and the objective-response rate was 20%.ConclusionsConcurrent therapy with nivolumab and ipilimumab had a manageable safety profile and provided clinical activity that appears to be distinct from that in published data on monotherapy, with rapid and deep tumor regression in a substantial proportion of patients. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; ClinicalTrials.gov number, NCT01024231.).

Project description:High-dose ipilimumab (IPI) and high-dose interleukin-2 (IL-2) are approved agents for metastatic melanoma, but the efficacy and safety of the combination are unknown. The objective of this study was to evaluate the feasibility, safety, and efficacy of combination high-dose IPI and high-dose IL-2 in patients with histologically confirmed advanced unresectable stage III and IV melanoma. This Phase II, multicenter, open-label, single-arm trial was conducted in nine patients enrolled between 12/2014 and 12/2015. Subjects were treated with high-dose IPI 10 mg/kg intravenous (IV) every 3 weeks for four doses starting at week 1 and high-dose IL-2 (600,000 IU/kg IV bolus every 8 h for up to 14 doses) concurrently with IPI at weeks 4 and 7. After the first 12 weeks of combination therapy, maintenance IPI (10 mg/kg IV) monotherapy was administered every 12 weeks for up to 1 year. No patient had received prior PD-1 blockade, and only one received prior vemurafenib. Confirmed partial response was achieved in one (11%), stable disease in four (44%), and progressive disease in four (44%) of nine patients. Two patients achieved durable disease control of 44+ and 50+ months at the most recent follow-up without subsequent therapy. The median overall survival was not reached after a minimum 24 months of follow-up time. One-year and 2-year survival rates were 89 and 67%, respectively. Seven patients (78%) experienced grade 3 or 4 adverse events related to the study therapy, three of which were attributed to both agents. One patient discontinued the treatment due to liver and kidney toxicity. While toxicity was significant, all events were reversible, and there was no treatment-related mortality. In peripheral blood of patients with decreasing tumor burden, the ratio of the non-classical MHC-II proteins HLA-DM to HLA-DO increased 2-fold, raising the possibility of the ratio of HLA-DM:HLA-DO as a novel biomarker of response to treatment. Although the sample size was limited, combination therapy with high-dose IPI and high-dose IL-2 was feasible and associated with clinical benefit. IL-2-based compounds in combination with CTLA-4 blockade should be studied in advanced melanoma patients who fail to benefit from first-line PD-1 blockade. Clinical Trial Registration: ClinicalTrials.gov, NCT02203604. Registered 30 July 2014, https://clinicaltrials.gov/ct2/show/NCT02203604.

Dataset Information

Model-based clinical pharmacology profiling of ipilimumab in patients with advanced melanoma.

Publications

Model-based clinical pharmacology profiling of ipilimumab in patients with advanced melanoma.

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