AT9283 in Children and Adolescents With Relapsed and Refractory Solid Tumors

November 27, 2019 updated by: Cancer Research UK

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Actual)

33

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United Kingdom
    • England
      • Birmingham, England, United Kingdom, B4 6NH
        • Birmingham Children's Hospital
      • Leeds, England, United Kingdom, LS9 7TF
        • Leeds General Infirmary
      • Manchester, England, United Kingdom, M27 4HA
        • Royal Manchester Children's Hospital
      • Newcastle-Upon-Tyne, England, United Kingdom, NE1 4LP
        • Great North Children's Hospital, Royal Victoria Infirmary
      • Sutton, England, United Kingdom, SM2 5PT
        • Royal Marsden - Surrey

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

2 years to 18 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

DISEASE CHARACTERISTICS:

  • Histologically confirmed solid tumor meeting 1 of the following criteria:

    • Refractory to conventional treatment
    • Disease for which no conventional therapy exists
  • Patients with CNS tumors must be on a stable or decreasing dose of dexamethasone for ≥ 1 week before study entry

PATIENT CHARACTERISTICS:

  • WHO performance status (PS) 0-2 OR Lansky Play PS 70-100% (> 50% is acceptable if it is due to a stable neurological deficit or CNS tumor)
  • Life expectancy ≥ 12 weeks
  • ANC ≥ 1,000/mm^3
  • Platelet count ≥ 100,000/mm^3
  • Hemoglobin ≥ 9.0 g/dL
  • Serum bilirubin < 1.5 times upper limit of normal (ULN)
  • Creatinine kinase normal
  • ALT or AST < 2.5 times ULN (≤ 5 times ULN if due to tumor)
  • Creatinine clearance/EDTA-measured GFR ≥ 60 mL/min
  • Sufficient blood volume to undergo the blood-sampling regimen specified by the protocol that, in the opinion of the investigator, will not jeopardize patient's safety
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use 2 methods of effective contraception 4 weeks before, during, and for 6 months after completion of study therapy
  • Not at high medical risk because of non-malignant systemic disease, including active uncontrolled infection
  • Not known to be serologically positive for hepatitis B or C or HIV
  • Fractional shortening of > 29% on echocardiogram
  • LVEF ≥ 50%
  • No history of allergy or auto-immune disease
  • No congenital heart disease
  • No other condition that, in the investigator's opinion, would not make the patient a good candidate for the clinical trial

PRIOR CONCURRENT THERAPY:

  • See Disease Characteristics
  • Recovered from prior therapy
  • More than 4 weeks since prior radiotherapy (except for palliative reasons), endocrine therapy, immunotherapy, or chemotherapy (6 weeks for investigational medicinal products, 2 weeks for vincristine)
  • More than 3 months since prior autologous stem cell transplantation
  • No prior allogenic bone marrow transplantation
  • No prior extensive radiotherapy to > 25% of bone marrow
  • No prior Aurora kinase inhibitor
  • No prior major thoracic or abdominal surgery from which the patient has not yet recovered

  • No prior or concurrent participation in another interventional clinical trial

    • Participation in an observational study allowed
  • No other concurrent anticancer therapy or investigational drugs

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Dose-limiting toxicities
Maximum-tolerated dose

Secondary Outcome Measures

Outcome Measure
Pharmacokinetic parameters and the correlation between them and toxicity and/or efficacy
The magnitude and duration of biomarkers (M30 and M65 ELISA) change after AT9283 administration
Objective tumor response according to RECIST criteria

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Cancer Research UK

Investigators

  • Principal Investigator: Darren Hargrave, MD, Great Ormond Street Hospital For Children NHS Foundation Trust

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

September 1, 2009

Primary Completion (Actual)

January 25, 2016

Study Completion (Actual)

November 20, 2019

Study Registration Dates

First Submitted

September 26, 2009

First Submitted That Met QC Criteria

September 26, 2009

First Posted (Estimate)

September 29, 2009

Study Record Updates

Last Update Posted (Actual)

November 29, 2019

Last Update Submitted That Met QC Criteria

November 27, 2019

Last Verified

November 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CDR0000653387
  • UKM-ICRF-CR0708-11
  • CRUK-CR0708-11
  • EUDRACT-2008-005542-23
  • EU-20980

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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