multikinase inhibitor AT9283

enzyme-linked immunosorbent assay

immunohistochemistry staining method

laboratory biomarker analysis

pharmacological study

Darren Hargrave, MD

RATIONALE: AT9283 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PURPOSE: This phase I trial is studying the side effects and best dose of AT9283 in children and adolescents with relapsed and refractory solid tumors.

OBJECTIVES:

Primary

* To evaluate the safety and tolerability of Aurora kinase inhibitor AT9283 by characterizing the dose-limiting toxicities in children and adolescents with relapsed and refractory solid tumors.
* To determine the maximum-tolerated dose of this regimen in these patients.

Secondary

* To determine the pharmacokinetic parameters of this regimen in these patients.
* To demonstrate the pharmacodynamic (PD) activity of this regimen in these patients by studying its effects in surrogate tissue.
* To assess preliminary evidence of activity of this regimen by using appropriate objective tumor measurements in these patients.

Tertiary

* To demonstrate the PD activity of this regimen in these patients by studying its effects in both surrogate and tumor tissue (skin punch, bone marrow, and tumor biopsies).

OUTLINE: This is a multicenter, dose-escalation study.

Patients receive Aurora kinase inhibitor AT9283 IV over 72 hours on days 1-3. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.If a patient is benefiting from treatment with AT9283 (i.e. has stable or responding disease as measured by RECIST) and the benefit risk balance is considered acceptable then further treatment may be given.

Blood and skin tissue samples are collected at baseline and periodically during treatment for pharmacokinetic studies and pharmacodynamic and biomarker (M30, M65, pHH53, p53, PCNA and Ki67) analysis by IHC and ELISA assays.

After completion of study therapy, patients are followed up periodically.

Peer Reviewed and Funded or Endorsed by Cancer Research UK.

AT9283 in Children and Adolescents With Relapsed and Refractory Solid Tumors

A CCLG/Cancer Research UK Phase I Trial of AT9283 (a Selective Inhibitor of Aurora Kinases) Given for 72 Hours Every 21 Days Via Intravenous Infusion in Children and Adolescents With Relapsed and Refractory Solid Tumors

Cancer Research UK

Neoplasms

Symptoms and General Pathology

All Conditions

Blood and Lymph Conditions

Immune System Diseases

Rare Diseases

Neoplasm Metastasis

Recurrence

Leukemia

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Neoplasms by Histologic Type

Hematologic Diseases

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Acute Non Lymphoblastic Leukemia

Acute Graft Versus Host Disease

Childhood Acute Lymphoblastic Leukemia

Acute Leukemia of Ambiguous Lineage

Josef Vormoor

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.

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.

AT9283 in Treating Young Patients With Relapsed or Refractory Acute Leukemia

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 title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
AT9283 in Children and Adolescents With Relapsed and Refractory Solid Tumors	NCT00985868	Unspecified Chi...	multikinase inh... enzyme-linked i... immunohistochem... laboratory biom... pharmacological...	2 Years - 18 Years	Cancer Research UK
AT9283 in Treating Young Patients With Relapsed or Refractory Acute Leukemia	NCT01431664	Leukemia	multikinase inh... laboratory biom... pharmacological...	- 18 Years	Cancer Research UK

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