PB2355 A PHASE I/II, OPEN‐LABEL, SINGLE‐ARM, STUDY OF RUXOLITINIB ADDED TO CORTICOSTEROIDS IN PEDIATRIC PATIENTS WITH ACUTE GRAFT‐VS‐HOST DISEASE AFTER ALLOGENEIC STEM CELL TRANSPLANTATION (REACH‐4)

Background: Graft‐vs‐host disease (GvHD) is a major limitation to the success of allogeneic stem cell transplantation, a curative immunotherapy commonly used for treating malignant/nonmalignant hematologic disorders. Despite prophylaxis with immunosuppressive agents, 20%–40% of pediatric patients develop grade II–IV acute GvHD (aGvHD); of these, 30%–50% respond to systemic corticosteroids (CS) as the initial standard of care, thus augmenting an unmet need for optimal and/or novel therapies in treatment (Tx)‐naïve and steroid‐refractory (SR) aGvHD pediatric patients. Recently published data have demonstrated the clinical efficacy of ruxolitinib when added to immunosuppressive therapy in adult and adolescent SR aGvHD patients (ongoing REACH‐1 study; Zeiser 2015). Further, SR aGvHD pediatric patients have shown encouraging overall response rates (ORRs) with ruxolitinib compared with CS ± calcineurin inhibitor alone (Khandelwal 2017). These data, along with an ongoing trial evaluating the efficacy of ruxolitinib versus the best available therapy in adult and adolescent SR aGvHD patients (REACH‐2), provide a substantial rationale that ruxolitinib may provide a better disease response with clinical benefits while being steroid‐sparing in pediatric patients. Aims: To assess the safety, activity, and pharmacokinetics (PK) of ruxolitinib Tx with CS in Tx‐naïve and SR aGvHD patients and define a recommended Phase II dose (RP2D) for patients aged ≥28 days to <18 years (y). Methods: REACH‐4 is a Phase I/II open‐label, single‐arm, multicenter study of ruxolitinib added to CS in pediatric grade II–IV aGvHD patients, across 4 groups based on age (Group 1: ≥12 to <18 y, Group 2: ≥6 to <12 y, Group 3: ≥2 to <6 y and Group 4: ≥28 days to <2 y) to allow appropriate dosing based on available data ( Figure ). Before Tx initiation, organ staging of aGvHD will be performed according to the updated National Institutes of Health criteria (Harris et al., 2016). The scoring of response will be relative to the organ stage at the start of the study Tx. Ruxolitinib doses and Tx schedule are shown in Table . The primary objective of Phase I is to assess the PK parameters of ruxolitinib and define an age‐appropriate RP2D for groups 2–4. Patients in Group 1 will be enrolled directly at ruxolitinib 10 mg twice daily (BID), which is already considered the RP2D for this group. PK parameters used to define the RP2D for Groups 2–4 will be compared with information from adult and adolescent aGvHD patients treated with ruxolitinib in another study (CINC424C2301). Data from patients >2 y will be analyzed to determine the administered dose in Group 4. The primary objective of Phase II is to measure the activity of ruxolitinib by ORR at Day 28. The study will also assess the rate of durable ORR at Day 56 (proportion of all patients who achieve a complete response [CR] or partial response [PR] at Day 28 and maintain a CR or PR at Day 56). All patients will be treated for 24 weeks or until early discontinuation and followed for additional 18 months. PK data from patients in Groups 1–3 will allow for comparisons between pediatric and adult patients. In Phase II, ≥39 patients (regardless of age and including ≥40% Tx‐naïve patients and 40% SR aGvHD patients) will be enrolled. Patients enrolled at the RP2D in Phase I will be added in the count of 39 patients. Results: Trial in progress. Summary/Conclusion: REACH‐4 is currently recruiting (ClinicalTrials.gov: NCT03491215).