A phase I/II trial of AT9283, a selective inhibitor of aurora kinase in children with relapsed or refractory acute leukemia: challenges to run early phase clinical trials for children with leukemia
Britta VormoorGareth J. VealMartin J. GriffinAlan V. BoddyJulie IrvingLynne MintoMarian CaseUdai BanerjiKaren E. SwalesJennifer TallAndrew S. MooreM. ToguchiGary D ActonKaren DyerClaire SchwabChristine J. HarrisonJohn D. GraingerDonna LancasterPamela KearnsDarren HargraveJosef Vormoor
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Abstract:
Abstract Aurora kinases regulate mitosis and are commonly overexpressed in leukemia. This phase I/IIa study of AT9283, a multikinase inhibitor, was designed to identify maximal tolerated doses, safety, pharmacokinetics, and pharmacodynamic activity in children with relapsed/refractory acute leukemia. The trial suffered from poor recruitment and terminated early, therefore failing to identify its primary endpoints. AT9283 caused tolerable toxicity, but failed to show clinical responses. Future trials should be based on robust preclinical data that provide an indication of which patients may benefit from the experimental agent, and recruitment should be improved through international collaborations and early combination with established treatment strategies.Keywords:
Refractory (planetary science)
Pharmacodynamics
Aurora A kinase
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OBJECTIVE To study the analgesia effects and pharmacodynamics of Wutou injection.METHODS The mice were treated ip once with Wutou injection (2 mg·kg -1 ) and morphine (10 mg·kg -1 ) was used as the positive control.The changes of reactive latent period on hot-plate were observed.The apparent parameters of pharmacodynamics were estimated based on the time-effect curve.RESULTS The Wutou injection had analgesic effect obviously.Its effect-time curve ws conformed to one-compartment modle of extravascular administration.The apparent parameters of the pharmacodynamics were: K a=0.026539 min -1 ; t 1/2a =26.12 min; k e=0.007968 min -1 ; t 1/2E =87 min; t max =80.16 min; E max =149.24 ΔE%(58.27 s),respectively.CONCLUSION The Wutou injection had analgesic effect obviouly.The parameters of pharmacodynamics may be helpful for physicians clinic.
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Eleven patients with acute leukemia, refractory to all previous chemotherapy, were treated with acridinyl anisidide (m-AMSA). Seven patients received m-AMSA i.v. as a single agent at 150 mg/m2 daily for 4 to 7 days, and 4 patients received m-AMSA at 90 mg/m2 daily for 3 days in combination with thioguanine and cytosine arabinoside. Four of the nine patients with acute nonlymphoblastic leukemia responded to the treatment, and complete remission was obtained in three of them. One of these patients remained in complete remission 5 months after therapy. Three of the four responding patients received m-AMSA as a single agent. Two patients with resistant acute lymphoblastic leukemia did not respond. As in earlier trials with m-AMSA reported by others, about one-third of our refractory patients responded, which justifies the future use of this agent in refractory leukemia and in other regimens for the induction of remission in acute leukemia. Despite minimal cardiotoxicity of the drug, evidence of its cardiotoxic potential is recorded.
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Amsacrine
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Objective To study the relation between multidrug resistance gene mdrl and curative effects of chemotherapy and pro gnosis in children with acute leukemia.Methods mdrl mRNA expression in 33 children with acute leukemia was observed closely by semi-quantitative m ethod-RT-PCR,and the levels of mdrl were evaluated with the ratio of mdrl/β2M.Results The mRNA positive rate and ex pression levels of mdrl in refractory and relapse cases were significantly higher than those in first-visit and remission cases.Conclusion The expression lev els of mdrl mRNA might be related to refractory de gree and relapse in leukemia,which also has clinical guid ance significance in selecting chemotherapy methods and predicting prognosis.
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TPS4592 Background: Progress in developing new effective therapies in advanced and relapsing urothelial cancer has been stagnant in the last few decades and a paradigm shift is desperately needed. Aurora kinase-A overexpression has been previously described in bladder cancer and spindle checkpoint dysregulation is a common feature of human UC. Alisertib (Millennium Inc.) is an orally available, selective small molecule inhibitor of Aurora A kinase. Single agent and combination treatment of MLN8237 with either paclitaxel (TXL) or gemcitabine synergistically reduced UC cell viability compared with either drug alone. Hence, sequential application of MLN8237 and TXL warrants clinical investigation. Phase 1 trials of both single agent and the combination with TXL defined the recommended doses for phase 2 trials. Methods: A multistep approach will be adopted for this Phase 2 trial. A single-group run-in phase will be conducted first with Alisertib 50 mg orally BID for 7 days, followed by 14d rest until disease progression. In case of activity, a confirmatory randomized (1:1) trial of weekly TXL plus either Alisertib or Placebo will follow, incorporating efficacy and futility boundaries for early stopping. In a single-blind design, TXL will be given on days 1,8,15 q4wks at the dose of 60 mg/m2 with alisertib and 80 mg/m2 with placebo. Alisertib dose will be 40 mg BID days 1-3, 8-10 and 15-17, q4wks. In the single-arm phase, primary endpoint (EP) will be RECIST 1.1 response-rate. 20 pts will be accrued, ≥3 responses will be required (10% type I and 20% type II error costraints). An accrual of 110 pts is foreseen in the randomized phase. Primary EP: progression-free survival (PFS), assuming an improvement in PFS from a median of 2.5 months (H0) to a median of 4.5 months (H1) (44% hazard rate reduction, 10% drop out rate). Eligibility will include diagnosis of metastatic UC and failure of 1-2 CT regimens (single-arm) or 1 prior CT only (randomized phase). A relapse within 6 months of a peri-operative CT will be counted as 1 line. Computed tomography and PET will be done every 2 cycles (2 months). Additional pharmacodynamic and translational analyses are planned on pre- post- blood and tissue samples. Clinical trial information: 2014-000557-36.
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Aurora inhibitor
Aurora A kinase
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In spite of continuous progress in the therapy of acute leukemia,relapses still occur frequently both in children and adults.A high incidence of relapses following induction chemotherapy is a major hindrance to patients' survival in acute leukemia.Refractory acute leukemia is almost invariably fatal and the treatment of patients with refractory or recurrent acute leukemia remains challenging.In this article,the progress in diagnostic criteria,immunology,cytogenetics,molecular biology,mul- tidrug resistance and therapy of refractory acute leukemia was summarized.Traditional Chinese medicine (TGM) plays an impor- tant role in the treatment of refractory acute leukemia,which,in combination with chemotherapy,can improve the remission rate for patients.The probability of relapse was reduced when patients had been assigned to be treated with TCM along with chemotherapy.The patients might particularly benefit from the procedure.Tberefore,it is believed that in clinical application and commercial development,TCM has a potential future,which is worth further studying.
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Induction chemotherapy
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Objective:To investigate the influence on the pharmacodynamics of Danggui powder processed by mini-grinding. Methods;The pharmacodynamics were measured by the methods of hemorrhagic iron-deficency anemia model and isolated uterine smooth muscle of mice. Results:The mini-grinded was markedly outbalance the traditional in the parameters. Conclusion: The pharmacodynamics of Danggui powder can be obviously improved by mini-grinding.
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Objective To explore the therapeutic protocol for refractory acute leukemia.Methods Fifteen cases of refractory acute leukemia were treated with HAEG regimen,which consisted of Har1 mg/d(d1～10),Ara-C 30 mg/d(d1～14),VP-16 50 mg/d(d1～5),G-CSF 150 mg/d(d1～14).Results Eight patients(53.3%) achieved complete remission,2(13.4%)did partial remission,overall effective rate was 66.7%.Conclusion HAEG regimen in treatment of refractory acute leukemia is an effective means.
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OBJECTIVE:To evaluate the pharmacodynamics and therapeutic effect of Jiakang Ⅰ oral liquid.METHODS:The drug actions of tapazole,NS and Jiakang Ⅰ were compared in the animal model of hyperthyroidism.205 hyperthyroidism cases were treated with Jiakang Ⅰ in a double blind design and the therapeutic effect was observed.RESULTS:Pharmacodynamic observation revealed that Jiakang Ⅰ could decreased T3,T4 and increase TSH significantly in rats.Compared with control group treated with tapazole or NS,in Jiakang Ⅰ group,T3 and T4 were obviously reduced and TSH was increased and the clinical symptoms were alleviated without any marked adverse reaction.CONCLUSION:The hyperthyroidism animal model can be applied to evaluating the pharmacodynamic effect of Jiakang Ⅰ.This drug has satisfactory therapeutic effect on hyperthyroidism.
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Objective To explore the therapeutic protocol for patients with refractory/recurrent acute leukemia.MethodsTwenty-three cases of refractory acute leukemia were treated with HEAG regimen,which consisted of Hht 1-2 mg/(m2·d)(d1～14),Ara-C 30 mg/(m2·d)(d1～14),G-CSF 150 mg/(m2·d)(d1～14),and VP-16 50 ～100 mg/(m2·d)(d1～4).ResultsTwelve patients(52.2%)achieved complete remission,2 patients(8.7%)did partialremission,overan effective rate was 60.8%.ConclusionHEAG regimen in treatment of refractory/recurrent acute leukemia is an effective means.
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