KEY TAKEAWAYS
- The phase 1/2 REACH4 study evaluated ruxolitinib in pediatric patients with grade II-IV treatment-naïve or steroid-refractory aGvHD.
- Phase 1 evaluated ruxolitinib’s pharmacokinetics and set an age-based RP2D for Groups 2-4. Phase 2 analyzed ruxolitinib’s ORR on day 28, with a secondary focus on the sustained ORR on day 56.
- The study suggested that ruxolitinib’s ORR was in line with previous REACH2 findings and other studies on pediatric patients, with its safety profile meeting expectations for this group.
Corticosteroids are the primary treatment for acute graft-vs-host disease (aGvHD), but only 30-50% of patients (pts) see benefits. In the REACH2 study, ruxolitinib showed better overall response rates (ORR) compared to other treatments for patients aged 12 and above with steroid-resistant aGvHD. The REACH4 phase 1/2 study assessed ruxolitinib in pediatric patients with grade II-IV aGvHD, either treatment-naïve or steroid-refractory.
In REACH4, pts were divided into four age-based groups. All received ruxolitinib alongside corticosteroids, sometimes with a calcineurin inhibitor, for 24 weeks or until they stopped. Group 1 teens took ruxolitinib 10 mg two times daily. Starting doses for Groups 2 and 3 were 5 mg twice daily and 4 mg/m2 twice daily. The primary aim of Phase 1 was determining ruxolitinib’s pharmacokinetics and suggesting an age-appropriate recommended Phase 2 Dose (RP2D) for Groups 2-4. Phase 2’s main goal was to evaluate ruxolitinib’s ORR on day 28; another aim was to determine the ORR’s longevity on day 56. When determining the phase 2 dose, pharmacokinetic data were used. All other findings were considered after all pts completed or exited the 24-week treatment (last data checked on 22 February 2022).
Of the 45 pts given ruxolitinib, 64.4% had grade II aGvHD, 26.7% had grade III, and 8.9% had grade IV. Steroid-resistance was seen in 71.1%, while 28.9% had not undergone treatment. The median ruxolitinib treatment span was 117 days. At week 24, 48.9% finished treatment, 66.7% moved to long-term monitoring, and 51.1% stopped due to ineffectiveness (26.7%), adverse effects (22.2%), or disease recurrence (2.2%).
Ruxolitinib exposure (AUClast and Cmax) was consistent across age groups. The starting doses were confirmed as RP2Ds for Groups 2 and 3. However, RP2D for Group 4 (from 28 days to less than 2 years) is still uncertain.
Early analysis showed an 84.4% ORR in all pts on day 28, maintaining at 66.7% on day 56. Among those untreated, the ORRs on days 28 and 56 were 69.2% and 61.5%, respectively. For the steroid-resistant group, the rates were 90.6% and 68.8%. No new safety issues were reported, and no graft failures were confirmed.
The recommended phase 2 doses (RP2D) of 5 mg and 4 mg/m2 twice daily for ruxolitinib (predicted by physiologically based pharmacokinetics [PBPK]) were validated for Groups 2 and 3. Ruxolitinib’s high ORR aligned with earlier findings in REACH2 and retrospective pediatric studies. The drug’s safety profile was as anticipated for this demographic.
Source: https://ebmt2023.abstractserver.com/program/#/details/presentations/1645
Clinical Trial: https://classic.clinicaltrials.gov/ct2/show/NCT03491215
Locatelli, F., Kang, H.J., Bruno, B., Gandemer, V., Rialland, F., Faraci, M., Takahashi, Y., Koh, K., Bittencourt, H., Cleary, G., Rosko, C., Roussou, P., Pierre, A.S., Prahallad, A., Diaz-de-Heredia, C. Paed3-05 RUXOLITINIB IN PEDIATRIC PATIENTS WITH TREATMENT-NAÏVE OR STEROID-REFRACTORY ACUTE GRAFT-VERSUS-HOST DISEASE: PRIMARY FINDINGS FROM THE PHASE I/II REACH4 STUDY.
