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)

被引：100

作者：

Loh, Mignon L. ^{[1
,2
]}

Tasian, Sarah K. ^{[3
,4
,5
,6
,7
]}

Rabin, Karen R. ^{[8
]}

Brown, Patrick ^{[9
,10
]}

Magoon, Daniel ^{[9
,10
]}

Reid, Joel M. ^{[11
]}

Chen, Xuejun ^{[12
]}

Ahern, Charlotte H. ^{[13
]}

Weigel, Brenda J. ^{[14
]}

Blaney, Susan M. ^{[8
]}

机构：

[1] UCSF Benioff Childrens Hosp, Dept Pediat, San Francisco, CA 94143 USA

[2] Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USA

[3] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA

[4] Childrens Hosp Philadelphia, Ctr Childhood Canc Res, Philadelphia, PA 19104 USA

[5] Univ Penn, Dept Pediat, Perelman Sch Med, Philadelphia, PA 19104 USA

[6] Univ Penn, Abramson Canc Ctr, Perelman Sch Med, Philadelphia, PA 19104 USA

[7] Univ Penn, Dept Pediat, Div Oncol, Perelman Sch Med, Philadelphia, PA 19104 USA

[8] Baylor Coll Med, Texas Childrens Canc Ctr, Div Pediat Hematol Oncol, Houston, TX 77030 USA

[9] Johns Hopkins Univ, Sch Med, Dept Oncol, Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD 21205 USA

[10] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA

[11] Mayo Clin, Coll Med, Rochester, MN USA

[12] Incyte Corp, Wilmington, DE USA

[13] Childrens Oncol Grp, Arcadia, CA USA

[14] Univ Minnesota, Minneapolis, MN USA

来源：

PEDIATRIC BLOOD & CANCER | 2015年 / 62卷 / 10期

关键词：

childhood cancer; JAK inhibitor; pediatric; pharmacokinetics; ruxolitinib; ACUTE LYMPHOBLASTIC-LEUKEMIA; ESSENTIAL THROMBOCYTHEMIA; POLYCYTHEMIA-VERA; B-PROGENITOR; CRLF2; INHIBITOR; MUTATIONS; KINASE; REARRANGEMENT; INCB018424;

D O I：

10.1002/pbc.25575

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

BackgroundRuxolitinib, an orally bioavailable JAK1/JAK2 inhibitor, may treat cancers with CRLF2 and/or JAK pathway mutations. ProcedureA 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 50mg/m(2)/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). ResultsForty-nine patients were enrolled, 28 with STs (dose escalation cohort) and 21 with HMs. Ruxolitinib was well-tolerated with one DLT per cohort of six patients at dose levels (DLs) 2-5. One patient with an 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. ConclusionRuxolitinib was well tolerated in children with refractory cancer. The recommended phase 2 dose for continuous BID oral administration is 50mg/m(2)/dose. Subsequent evaluation of ruxolitinib in combination with cytotoxic chemotherapy in children, adolescents, and young adults with JAK-mutant leukemias is planned. Pediatr Blood Cancer 2015;62:1717-1724. (c) 2015 Wiley Periodicals, Inc.

引用

页码：1717 / 1724

页数：8

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