AT9283 in Treating Young Patients With Relapsed or Refractory Acute Leukemia

Sponsor

Cancer Research UK (Other)

Overall Status

Completed

CT.gov ID

NCT01431664

Collaborator

(none)

Enrollment

Locations

Duration (Months)

1.4

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Leukemia	Drug: multikinase inhibitor AT9283 Other: laboratory biomarker analysis Other: pharmacological study	Phase 1

Detailed Description

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

7 participants

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Sep 1, 2011

Actual Primary Completion Date :

Jul 1, 2014

Actual Study Completion Date :

Jul 1, 2014

Outcome Measures

Primary Outcome Measures

Maximum-tolerated dose and recommended phase II dose of multikinase inhibitor AT9283 []

Secondary Outcome Measures

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 []

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 18 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Royal Marsden Hospital	Surrey	London	United Kingdom	SM2 5PT
2	Birmingham Children's Hospital	Birmingham,		United Kingdom	B4 6NH
3	Leeds General Infirmary	Leeds		United Kingdom	LS1 3EX
4	Royal Manchester Children's Hospital	Manchester		United Kingdom	M13 9WL
5	Great North Children's Hospital, Royal Victoria Infirmary	Newcastle upon Tyne		United Kingdom	NE1 4LP