FDA Expands Approval of Ipilimumab to Include Paediatric Patients 12 Years and Older with Unresectable or Metastatic Melanoma

Ipilimumab showed a consistent safety profile and comparable drug levels across paediatric and adult patients

On 24 July 2017, Bristol-Myers Squibb Company announced that the US Food and Drug Administration (FDA) has expanded the indication for ipilimumab (Yervoy ®) injection for intravenous use to now include the treatment of unresectable or metastatic melanoma in paediatric patients 12 years of age and older.

Ipilimumab was evaluated in two trials of paediatric patients: a dose-finding study in 33 patients aged two to 21 years with relapsed or refractory solid tumours and an open-label, single-arm trial in 12 adolescents (ages ranging from 12 to 16 years) with previously treated or untreated, unresectable stage III or IV melanoma.

The overall safety profile of ipilimumab in children and adolescents was consistent with the safety profile in adults, and similarities in disease between adult and paediatric patients 12 years and older allow for extrapolation of data. Based on a population pharmacokinetic analysis, exposure in adolescents 12 years and older is comparable to that in adults for the approved dose of 3 mg/kg, administered intravenously over 90 minutes every three weeks for a total of four doses.

Ipilimumabis associated with a Boxed Warning and can result in severe to fatal immune-mediated adverse reactions. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy.

“Metastatic melanoma is extremely rare in children and adolescents, which makes it particularly difficult to investigate in clinical trials. Though designing clinical trials in small pediatric populations can be challenging, this group of investigators committed to bringing a new therapy to those in need,” said Dr Lia Gore, University of Colorado School of Medicine and Children’s Hospital of Colorado in accompanied press release. “Ipilimumab’s approval represents the culmination of a long effort and gives physicians the ability to expand immuno-oncology – one of the most exciting areas of medicine – for the treatment of young adults with metastatic melanoma.”

The US FDA approval for ipilimumab in patients 12 years and older with metastatic melanoma marks Bristol-Myers Squibb’s first paediatric indication in onco-immunology. The expanded indication builds upon six years of experience with ipilimumab, which has been used to treat more than 38,000 adult patients with metastatic melanoma since its first approval.

About ipilimumab studies in paediatric patients

Ipilimumab has been evaluated in a total of 45 paediatric patients across two clinical trials. The safety and effectiveness of ipilimumab have been established in paediatric patients 12 years and older. The use of ipilimumab in this age group is supported by evidence from adequate and well-controlled studies of ipilimumab in adults and population pharmacokinetic data demonstrating that the exposure at a dose of 3 mg/kg in the paediatric and adult populations is comparable. In addition, the tumour biology and the course of advanced melanoma is sufficiently similar in adults and paediatric patients 12 years and older to allow extrapolation of data from adults to paediatric patients.

In a dose-finding trial, ipilimumab was evaluated in 33 paediatric patients with relapsed or refractory solid tumours. Patients enrolled in the study ranged from two to 21 years of age, with a median age of 13 years, and 20 of the patients were 12 years of age or older. Ipilimumab was administered at doses of 1, 3, 5 and 10 mg/kg intravenously over 90 minutes every three weeks for four doses and then every 12 weeks thereafter until progression or treatment discontinuation.

Ipilimumabwas also evaluated in an open-label, single-arm trial in 12 paediatric patients 12 years and older with previously treated or untreated, unresectable stage III or IV melanoma. Patients received ipilimumab 3 mg/kg (four patients) or 10 mg/kg (eight patients) intravenously over 90 minutes every three weeks for four doses.

Of the 17 patients 12 years of age and older with melanoma treated with ipilimumab across both studies, two patients experienced objective responses, including one partial response that was sustained for 16 months.

The approved dose for ipilimumabin paediatric patients with unresectable or metastatic melanoma is 3 mg/kg, administered intravenously over 90 minutes every three weeks for a total of four doses.

About the population pharmacokinetic analysis

Based on a population pharmacokinetic analysis using available pooled data from 565 patients from four phase II adult studies (n = 521) and two paediatric studies (n = 44), body weight normalised clearance of ipilimumab is comparable between adult and paediatric subjects.

The Bristol-Myers Squibb Company’s press release contains forward-looking statements.