FDA Approval Sought for Ibrutinib in Pediatric Chronic Graft-Versus-Host Disease

US FDA

A supplemental new drug application (sNDA) has been submitted to the FDA seeking the approval of ibrutinib (Imbruvica) for the treatment of pediatric and adolescent patients aged 1 year and older with chronic graft-vs-host disease (cGVHD) following failure of 1 or more lines of systemic therapy.¹

A new drug application (NDA) has also been submitted for an oral suspension formulation of ibrutinib to serve as an alternative administration option for pediatric patients.

The applications were primarily supported by 3 years of data collected from the phase 1/2 iMAGINE trial (PCYC-1146-IM; NCT03790332), which showed that ibrutinib elicited an overall response rate (ORR) of 78% in 59 patients with relapsed or refractory, or new-onset moderate/severe cGVHD.

Notably, the pharmacokinetic (PK) data with the BTK inhibitor proved to be consistent with the adult dosing of the agent. Moreover, after 20 weeks, 70% of treatment-naïve patients and 58% of patients with relapsed/refractory disease continued to respond to treatment with the agent.

“It is important to empower patients and their families with evidence-based knowledge and I am encouraged by the results from the iMAGINE clinical trial of [ibrutinib],” Paul A. Carpenter, MD, attending physician at Seattle Children’s Hospital and study principal investigator, stated in a press release. “Results show that PK and safety were consistent with the known profile of [ibrutinib] and that of cGVHD. Efficacy results, including sustained response rates, were also encouraging.”

iMAGINE was comprised of 2 parts. To be eligible for enrollment to either part of the research, patients needed to have a history of allogeneic stem cell transplantation and a Karnofsky or Lansky performance status of 60 or higher.2

If patients had a single organ genitourinary involvement as the only manifestation of cGVHD, received an investigational agent within 28 days of enrollment, received donor lymphocyte infusion within 56 days of enrollment, had progressive underlying malignant disease or active post-transplant lymphoproliferative disease, an uncontrolled infection or active infections in need of syst4emic treatment, known bleeding disorders, or active hepatitis B or C virus, they were excluded.

Part A enrolled patients who were aged 1 to 12 years who had moderate or severe cGVHD following failure of 1 or more lines of systemic therapy. This group of patients was administered ibrutinib oral suspension or capsule at a starting once-daily dose of 120 mg/m2. Investigators determined the recommended pediatric equivalent dose (RPED) by escalating dosage of the agent to 240 mg/m2 after 2 weeks if no grade 3 or higher associated toxicity was noted.

The second part of the research, referred to as part B, enrolled patients aged 12 years to 22 years with moderate to severe cGVHD who were newly diagnosed or in whom 1 or more lines of systemic therapy had failed. These patients were given oral ibrutinib at a once-daily dose of 420 mg.

Notably, once the RPED dose was identified in part A, those in that portion of the study were permitted to be enrolled in part B.

Primary end points of the trial comprised PK and safety, and key secondary end points included ORR per 2014 National Institute of Health criteria, overall survival, duration of response, and patient-reported outcomes.

Previously, in August 2017, the FDA approved ibrutinib for the treatment of adult patients with cGVHD following the failure of 1 or more lines of systemic therapy.3 The regulatory decision was based on findings from the single-arm phase 1b/2 PCYC-1129 trial (NCT02195869), which showed that ibrutinib elicited an ORR of 67% (95% CI, 51%-80%) among 42 patients; this included a 21% complete response rate and a 45% partial response rate.

Moreover, clinically meaningful, and durable responses were observed in patients in whom at least 1 prior treatment had failed. Most responders were able to reduce steroid doses to an acceptable level.

References

1. AbbVie seeks new indication for IMBRUVICA (ibrutinib) in pediatric patients with chronic graft versus host disease (cGVHD). News release. AbbVie; February 28, 2022. Accessed February 28, 2022. https://prn.to/3pLGzxR
2. Phase 1/2 dose finding and safety study of ibrutinib in pediatric subjects with chronic graft versus host disease (cGVHD). ClinicalTrials.gov. Updated February 8, 2022. Accessed February 28, 2022. https://clinicaltrials.gov/ct2/show/NCT03790332
3. FDA approves treatment for chronic graft versus host disease. News release. FDA; August 2, 2017. Accessed February 28, 2022. https://prn.to/3hwOg69