FDA Indication Sought for Ibrutinib in Pediatric Chronic GVHD

A supplemental new drug application has been submitted to the FDA seeking approval for ibrutinib (Imbruvica) for the treatment of pediatric and adolescent patients aged 1 year or older with chronic graft-versus-host disease (cGVHD) after failure of 1 or more lines of systemic therapy, according to an announcement by AbbVie.¹

The sNDA is supported with findings from the phase 1/2 IMAGINE clinical trial (NCT03790332), a dose-finding and safety study of ibrutinib in 59 patients with relapsed/refractory or new on-set moderate/severe cGVHD.

Thus far in the study, ibrutinib treatment has shown an overall response rate of 78% and a pharmacokinetic (PK) profile that is consistent with adult dosing. Data also demonstrate that after 20 weeks of treatment with ibrutinib, response rates were sustained in 70% of the treatment-naïve patient population and 58% of the relapsed/refractory group.

The safety profile of ibrutinib in IMAGINE appears to be consistent with the known profile of the agent. Based on data from the adult cGHVD population treated with ibrutinib, the most common grade ≥ 3 AEs include pyrexia (8.5%), neutropenia (6.8%), stomatitis (6.8%), hypoxia (6.8%), osteonecrosis (6.8%), alanine aminotransferase increased (5.1%), hypokalemia (5.1%), and pneumothorax (5.1%).

In the IMAGINE trial, patients with moderate to severe cGVHD aged 1-22 with a Karnofsky or Lansky performance score of ≥ 60 are treated with ibrutinib 120 mg/m2 once daily during phase 1, which is escalated to 240 mg/m2 after 14 days in patients without grade 3 toxicity to determine the recommended phase 2 dose of the agent. The coprimary end points of the study are PK, and safety/tolerability determined by the number of patients with AEs. As secondary end points, the study is investigating safety/tolerability, response rate at week 24, duration of response, overall survival, late effects surveillance, and laboratory parameters.²

Ibrutinib was granted FDA approval in 2017 as the first single agent for the treatment of adult patients with cGVHD following failure of prior systemic therapy. If granted approval for pediatric patients with cGVHD after failure of frontline systemic therapy, it would be the first FDA-approved Bruton’s tyrosine kinase inhibitor option for the patient population.¹

"We are committed to this work with Imbruvica in the hopes of providing the first FDA-approved BTKi treatment option for younger patients with cGVHD, including a new oral suspension formulation," said James Dean, MD, PhD, Imbruvica Global Development lead and executive medical director at AbbVie, in a press release "For young children, the availability of a liquid oral suspension versus an oral capsule or tablet can be significant to enable them to take the recommended dose and address challenges swallowing capsules or tablets."

_References:

_{1. AbbVie seeks new indication for imbruvica® (ibrutinib) in pediatric patients with chronic graft versus host disease (cGVHD). News release. February 28, 2022. Accessed February 28, 2022. https://bit.ly/3M7WnnX}

_{2. Phase 1/2 dose finding and safety study of ibrutinib in pediatric subjects with chronic graft versus host disease (cGVHD). Clinicaltrials.gov. Accessed February 28, 2022. https://bit.ly/3K9GfAJ}