A Phase I Study of Quizartinib Combined with Chemotherapy in Relapsed Childhood Leukemia: A Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) Study
A Phase I Study of Quizartinib Combined with Chemotherapy in Relapsed Childhood Leukemia: A Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) Study
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DOI：
10.1158/1078-0432.ccr-15-1998
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发表时间：
2016-08-15
影响因子：
11.5
通讯作者：
Brown, Patrick A.
中科院分区：
文献类型：
--
作者：
Cooper, Todd M.;Cassar, Jeannette;Brown, Patrick A.
目的：为了确定一个安全的和生物活性剂量的quizartinib（AC 220），一个有效的和选择性的III类受体酪氨酸激酶（RTK）FLT 3抑制剂，在与挽救性化疗的儿童复发性acutealemia.Experimental Design：Quizartinib口服给药后5天的高剂量阿糖胞苷和依托泊苷（AE）复发性AML或MLL重排ALL的儿童。采用3+3剂量递增设计确定安全和生物活性剂量。每周进行血浆抑制试验（PIA），以确定生物活性。结果：毒性与密集复发白血病方案一致。在40 mg/m2/d剂量下，6例患者中有1例出现剂量限制性毒性（DLT）（脂肪酶升高），在最高试验剂量60 mg/m2/d时，9例患者中有1例出现DLT（高胆红素血症）。在17例缓解可评价患者中，2例完全缓解（CR），1例完全缓解但血小板未恢复（CRp），1例完全缓解伴中性粒细胞和血小板不完全恢复（CRi），10例疾病稳定（SD），3例疾病进展（PD）。在7例FLT 3-ITD患者中，1例达到CR，1例达到CRp，1例达到Cri，4例达到SD。FLT 3-ITD患者，而非FLT 3野生型（WT）患者，在quizartinib后具有显著较低的原始细胞计数。所有患者的FLT 3磷酸化均被完全抑制。结论：Quizartinib加强化化疗在60 mg/m2/天剂量下耐受性良好，所有患者的FLT 3磷酸化均几乎完全抑制。有利的毒性特征、药效学活性和令人鼓舞的缓解率保证了quizartinib在FLT 3-ITD AML儿童中的进一步测试。(C)2016年AACR。
Purpose: To determine a safe and biologically active dose of quizartinib (AC220), a potent and selective class III receptor tyrosine kinase (RTK) FLT3 inhibitor, in combination with salvage chemotherapy in children with relapsed acute leukemia.Experimental Design: Quizartinib was administered orally to children with relapsed AML or MLL-rearranged ALL following 5 days of high-dose cytarabine and etoposide (AE). A 3+3 dose escalation design was used to identify a safe and biologically active dose. Plasma inhibitory assay (PIA) testing was performed weekly to determine biologic activity.Results: Toxicities were consistent with intensive relapsed leukemia regimens. One of 6 patients experienced a dose-limiting toxicity (DLT) at 40 mg/m(2)/day (elevated lipase) and 1 of 9 had a DLT (hyperbilirubinemia) at the highest tested dose of 60 mg/m(2)/day. Of 17 response evaluable patients, 2 had complete response (CR), 1 complete response without platelet recovery (CRp), 1 complete response with incomplete neutrophil and platelet recovery (CRi), 10 stable disease (SD), and 3 progressive disease (PD). Of 7 FLT3-ITD patients, 1 achieved CR, 1 CRp, 1 Cri, and 4 SD. FLT3-ITD patients, but not FLT3 wild-type (WT) patients, had significantly lower blast counts post-quizartinib. FLT3 phosphorylation was completely inhibited in all patients.Conclusions: Quizartinib plus intensive chemotherapy is well tolerated at 60 mg/m(2)/day with near complete inhibition of FLT3 phosphorylation in all patients. The favorable toxicity profile, pharmacodynamic activity, and encouraging response rates warrant further testing of quizartinib in children with FLT3-ITD AML. (C) 2016 AACR.