A phase 1 dosing study of ruxolitinib in children with relapsed or refractory solid tumors, leukemias, or myeloproliferative neoplasms: A Children's Oncology Group phase 1 consortium study (ADVL1011)

Abstract

Background Ruxolitinib, an orally bioavailable JAK1/JAK2 inhibitor, may treat cancers with CRLF2 and/or JAK pathway mutations. Procedure A phase 1 trial of ruxolitinib was performed to determine the maximum-tolerated or recommended phase 2 dose, dose-limiting toxicities (DLTs), pharmacokinetics (PK), and pharmacodynamics (PD) in children with recurrent/refractory solid tumors (STs). Ruxolitinib was administered twice daily (BID) in 28-day cycles at five dose levels (15, 21, 29, 39, and 50 mg/m2/dose). PK and PD studies were performed during Cycle 1. Toxicity, preliminary efficacy, and PK/PD were also assessed in children with relapsed/refractory hematologic malignancies (HMs). Results Forty-nine patients were enrolled, 28 with STs (dose escalation cohort) and 21 with HMs. Ruxolitinib was well-tolerated with one DLT per cohort of 6 patients at dose levels (DLs) 2-5. One patient with a ST had grade 5 multi-organ failure at DL2. One patient each at DL3 and DL4 had a grade 4 neutropenia, and one patient at DL5 had a grade 4 creatinine phosphokinase elevation. No objective responses were observed in patients with STs. One patient with polycythemia vera achieved a partial response and received 18 cycles of ruxolitinib. The PK of ruxolitinib were similar to that in adults. Partial inhibition of phosphorylated JAK2, STAT5, and S6 was observed in in vitro plasma inhibitory activity PD assay. Conclusion Ruxolitinib was well-tolerated in children with refractory cancer. The recommended phase 2 dose for continuous BID oral administration is 50 mg/m2/dose. Subsequent evaluation of ruxolitinib in combination with cytotoxic chemotherapy in children, adolescents, and young adults with JAK-mutant leukemias is planned.

Therapeutic effect of JAK1/2 blockade on the manifestations of hemophagocytic lymphohistiocytosis in mice

“…In the phase 1 and phase 2 clinical trials reported to date, twice-daily doses of 15 to 50 mg/m 2 in children and 25 mg in adults were well tolerated. 44,58,59 These values are equivalent to the twice-daily therapeutic oral dose of 1 mg/kg per mouse used in the present study. Our dose level was high enough to downregulate STAT1 activation in circulating MNCs, correct all the clinical and biological manifestations of HLH, and significantly improve Prf1 2/2 mice survival, although no pharmacological data were collected in the present study.…”

Co-occurrence of CRLF2-rearranged and Ph+ acute lymphoblastic leukemia: a report of four patients

“…It is possible that a higher dose of ruxolitinib may be required for optimal inhibition of JAK-STAT signaling in patients with Ph-like ALL overexpressing CRLF2, as often utilized in pediatric patients with Phlike ALL. 16 JAK inhibition with novel type II JAK inhibitors which stabilizes JAK2 in an inactive conformation have shown to suppress the growth of CRLF2+ B-ALL cells, and could be explored therapeutically.…”

Ph-like acute lymphoblastic leukemia: a high-risk subtype in adults

“…6,7,19 Thus, genomic characterization of Ph-like ALL has significant therapeutic implications with the emerging use of kinase inhibitors in this patient population. 6,7,16,[20][21][22][23] Therefore, it is imperative to establish the incidence and clinical/genomic features of Ph-like ALL in adults. Here, we report the genomic characteristics and outcomes of adult patients with Ph-like ALL uniformly treated with a hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) or an augmented BerlinFrankfurt-Münster (BFM) regimen at a single institution.…”