AT9283 in Treating Young Patients With Relapsed or Refractory Acute Leukemia

Study Overview
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Brief Summary
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RATIONALE: AT9283 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. PURPOSE: This phase I/IIa clinical trial is studying the side effects and best dose of AT9283 in treating young patients with relapsed or refractory acute leukemia.

Detailed Description
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OBJECTIVES: Primary To identify the maximum-tolerated dose and recommended phase IIb dose of multikinase inhibitor AT9283 in pediatric patients with relapsed or refractory acute leukemia. Secondary To evaluate the safety and tolerability of this drug in these patients. To document evidence of efficacy of this drug in these patients. To investigate the pharmacokinetic profile of this drug in plasma in these patients. Tertiary To assess target kinase inhibition by multikinase inhibitor AT9283 in these patients. To identify potential predictive molecular biomarkers in these patients. OUTLINE: This is a multicenter study. Patients receive multikinase inhibitor AT9283 IV continuously over 72 hours. Treatment repeats every 21 days* for 6 courses in the absence of disease progression or unacceptable toxicity. Patients achieving benefit of treatment may continue for up to 6 more courses at the discretion of the chief/principal investigator. NOTE: *Course length may be extended to a maximum 42 days to allow for recovery of blood counts. Intrathecal therapy is permitted from course 2 onwards in patients with ALL. Blood specimens are collected for pharmacokinetic and pharmacodynamic studies including molecular predictive biomarkers and ex vivo and in vivo measurement of kinase inhibition assessments. After completion of study treatment, patients are followed up for 42 days or until recovery of blood counts (whichever is the sooner). Peer Reviewed and Funded or Endorsed by Cancer Research UK.

Official Title
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A Cancer Research UK Phase I/IIa Trial of AT9283 (A Selective Inhibitor of Aurora Kinases) Given Over 72 Hours Every 21 Days Via Intravenous Infusion in Children and Adolescents Aged 6 Months to 18 Years With Relapsed and Refractory Acute Leukemia

Conditions
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Leukemia

Intervention / Treatment
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* Drug: multikinase inhibitor AT9283
* Other: laboratory biomarker analysis
* Other: pharmacological study


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed acute leukemia according to the following criteria: Acute lymphoblastic leukemia (ALL) meeting any of the following criteria: Second relapse Refractory to induction therapy for first relapse Third or subsequent relapse Acute myeloid leukemia (AML) meeting any of the following criteria: Second or subsequent relapse Refractory to an induction therapy for first relapse Without a curative treatment option Other type of acute leukemia meeting any of the following criteria: First or subsequent relapse Refractory to induction therapy Not eligible for any therapy of higher curative potential No chronic myeloid leukemia (CML) Patients in relapse must have ≥ 5% blasts in the bone marrow Patients with refractory disease following induction must have ≥ 20% blasts in the bone marrow No evidence of CNS disease PATIENT CHARACTERISTICS: Karnofsky performance status (PS) 50-100% OR Lansky PS 50-100% Life expectancy ≥ 8 weeks Serum bilirubin < 1.5 times upper limit of normal (ULN) ALT or AST < 2.5 times ULN (5 times ULN if due to leukemic infiltration of the liver) Creatinine clearance ≥ 60 mL/min Not pregnant or nursing Negative pregnancy test Fertile female patients must use 2 of the following combined forms of contraception (oral, injected, or implanted hormonal contraception and condom OR intra-uterine device and condom OR diaphragm with spermicidal gel and condom) before, during, and for 6 months after completion of study therapy Male patients must use 1 form of highly effective contraception (condom plus spermicidal gel) during and for 6 months after completion of study therapy Men with pregnant or lactating partners should be advised to use barrier-method contraception (condom plus spermicidal gel) No serological positivity for hepatitis B, hepatitis C, or HIV No congenital heart disease, with the exception of patent foramen ovale or small muscular ventricular septal deficit (within the first year of life) No uncontrolled arterial hypertension (defined as a systolic blood pressure [BP] and/or diastolic BP ≥ 95th percentile for age and height) No fractional shortening of ≤ 29% on echocardiogram No active graft-vs-host disease No current non-malignant systemic disease considered high medical risk, including any of the following: Active uncontrolled infection Unstable or uncompensated respiratory or cardiac condition that makes study participation undesirable No other condition that, in the Investigator's opinion, would not make the patient a good candidate for the clinical trial PRIOR CONCURRENT THERAPY: Recovered from toxicity of prior therapy, including toxicity following hematopoietic stem cell transplantation Alopecia or certain grade 1 toxicities allowed at the discretion of the Investigator A maximum of 2 days of hydroxycarbamide 10-20 mg/kg/day (or according to local practice) in patients with AML and hyperleukocytosis allowed At least 7 days since prior investigational drugs (except antibodies for which a 4-week window must be observed) At least 7 days since prior protein kinase inhibitors and intrathecal therapy Concurrent intrathecal therapy allowed from course 2 onwards in patients with ALL At least 14 days since prior cytotoxic therapy, including vincristine and other anti-neoplastics No prior major thoracic or abdominal surgery from which the patient has not yet recovered No prior aurora kinase inhibitor No concurrent steroid therapy Multikinase inhibitor AT9283 administration may be commenced once steroids have started; however, steroids may not be started once multikinase inhibitor AT9283 has started Up to 5 days of prior oral dexamethasone (6 mg/m^2) for patients with ALL experiencing a rapid rise in blast count allowed No other concurrent interventional clinical study Participation in an observational study allowed No other concurrent anticancer therapy or investigational drugs

Ages Eligible for Study
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Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: multikinase inhibitor AT9283|nan|
|Other: laboratory biomarker analysis|nan|
|Other: pharmacological study|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum-tolerated dose and recommended phase II dose of multikinase inhibitor AT9283 |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events to multikinase inhibitor AT9283 and grading severity according to NCI CTCAE Version 4.02 |  |  | 
| Partial remission, complete remission, or complete remission with incomplete bone marrow recovery using disease-specific criteria based on ANC, platelets, and % blasts in the bone marrow |  |  | 
| Plasma concentration measurement of multikinase inhibitor AT9283 |  |  | 
| Tertiary outcome(s) - Ex vivo and in vivo measurement of kinase inhibition using Plasma Inhibitory Activity (PIA) assay, phosphorylated STAT5 assay, and skin-punch biopsy (measuring pHH3, p53, PCNA, Ki67 levels) |  |  | 
| Results of established and novel prognostic biomarkers (genetic mutations of JAK 1, 2, 3, FLT3, IKAROS, and BCR/ABL) linking to observed responses |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent childhood acute lymphoblastic leukemia, recurrent childhood acute myeloid leukemia, acute leukemias of ambiguous lineage, acute undifferentiated leukemia, secondary acute myeloid leukemia