A Phase I Study of AZD0424 Alone and in Combination in Advanced Solid Tumours

This study is currently recruiting participants. (see Contacts and Locations)
Verified October 2013 by Cancer Research UK
Sponsor:
Information provided by (Responsible Party):
Cancer Research UK
ClinicalTrials.gov Identifier:
NCT01668550
First received: May 31, 2012
Last updated: October 29, 2013
Last verified: October 2013
  Purpose

The purpose of this study is to determine the maximum tolerated dose of the oral Src/Abl inhibitor AZD0424, and to find tolerable and effective AZD0424 combination regimens for the treatment of advanced solid tumours


Condition Intervention Phase
Advanced Solid Tumours
Drug: AZD0424
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Cancer Research UK Phase I Study to Determine the Maximum Tolerated Dose of the Oral Src/Abl Inhibitor AZD0424, and to Identify Tolerable and Effective AZD0424 Combination Regimens for the Treatment of Advanced Solid Tumours

Resource links provided by NLM:


Further study details as provided by Cancer Research UK:

Primary Outcome Measures:
  • Establishing the Maximum Tolerated Dose (MTD) of AZD0424 alone and in combination [ Designated as safety issue: Yes ]
  • Determining the causality and duration of adverse events observed during the study according to NCI CTCAE Version 4.02 [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Determining the correlation between PK studies and toxicity and/or efficacy. [ Designated as safety issue: No ]
  • Measurement of urinary and serum N terminal Telopeptide (NTx) and serum C-terminal peptide (CTx) levels before the first AZD0424 administration and then following first AZD0424 administration, to evaluate bone turnover [ Designated as safety issue: No ]
  • Measurement of the following biomarkers in tumour tissue before and after the first AZD0424 administration: p-Src, MKI67 (Ki-67), p-PAX, p-CRKL, p-FAK. [ Designated as safety issue: No ]
  • Evaluate responses (stable disease (SD), partial response (PR) or complete response (CR)) in any of the patients as determined by Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. [ Designated as safety issue: No ]

Estimated Enrollment: 96
Study Start Date: October 2012
Estimated Study Completion Date: April 2017
Estimated Primary Completion Date: April 2017 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: AZD0424

    AZD0424 will be administered as a flat dose orally once a day. One treatment cycle consists of 28 days of continuous drug administration with AZD0424, with the flexibility to introduce treatment breaks if required due to cumulative toxicity.

    Combination agents and treatment regimen with AZD0424 will be confirmed and approved at a later date.

Detailed Description:

AZD0424 is a potent orally available, potent (IC50 approximately 4 nM) inhibitor of Src and ABL1 kinases with additional activity against Src family kinase (SFK) members including Yes and Lck. AZD0424 was selective for SFKs and ABL1 kinase over C-terminal Src kinase (a negative regulator of Src) and a range of other kinase targets. The anti-cancer activity of AZD0424 is thought to be mediated primarily by anti-migratory and anti-invasive signalling and, as such, it is expected that in the late stage cancer setting strong signals of efficacy with this compound used as a single agent are unlikely, requiring it to be administered in combination with other anti-cancer agents.

In summary the study will be performed in four main stages:

  • AZD0424 monotherapy, dose escalation: Phase Ia single agent (AZD0424) dose escalation study to determine the MTD.
  • AZD0424 monotherapy, dose expansion: Phase Ib single agent dose expansion at MTD.
  • Combination arm(s) dose escalation: Provided that it is deemed appropriate (post review of available clinical data from the monotherapy dose escalation and available preclinical and published data on the combinations), up to three Phase Ia dose escalation arms of AZD0424 in combination with selected agent(s) will proceed to determine the MTD for the combination and a recommended Phase II dose.
  • Combination arm(s) dose expansion: Up to three Phase Ib combination arm(s) as appropriate using the recommended Phase II dose for both AZD0424 and the combination agent.
  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically or cytologically proven solid tumour, refractory to conventional treatment, or for which no conventional therapy exists or is declined by the patient or for whom there is the prospect of clinical benefit
  • Life expectancy of at least 12 weeks
  • World Health Organisation (WHO) performance status of 0-2
  • Haematological and biochemical indices within the ranges shown below. These measurements must be performed within one week (Day -7 to Day 1) before the patient receives AZD0424

    • Haemoglobin (Hb) ≥ 9.0 g/dL
    • Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
    • Platelet count ≥ 100 x 109/L
    • Serum bilirubin ≤ 1.5 x upper limit of normal (ULN)
    • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x (ULN) Either: Calculated creatinine clearance ≥ 50 mL/min Or Or Isotope Clearance measurement ≥ 50 mL/min (uncorrected)
  • 18 years or over
  • Written (signed and dated) informed consent and be capable of co-operating with treatment and follow-up
  • MTD Expansion cohorts only: A tumour which is safely accessible for biopsy (single and combination)
  • Single Agent Expansion cohort only: patient must be willing and capable to have [18F]FDGPET-CT imaging performed within two weeks of first AZD0424 administration and again two weeks after first AZD0424 administration.

Exclusion Criteria:

  • Radiotherapy (except for palliative reasons), endocrine therapy, immunotherapy or chemotherapy during the previous four weeks (six weeks for nitrosoureas, Mitomycin-C and four weeks for investigational medicinal products) before treatment.
  • Ongoing toxic manifestations of previous treatments. Exceptions to this are alopecia or certain Grade 1 toxicities, which in the opinion of the Investigator and the DDO should not exclude the patient.
  • Symptomatic brain metastases (if brain metastases are present they must have been stable for > 3 months).
  • Patients with evidence of interstitial lung disease (bilateral, diffuse, parenchymal lung disease).
  • Patients with a peanut allergy will be excluded.
  • Ability to become pregnant (or already pregnant or lactating). However, those female patients who have a negative serum or urine pregnancy test before enrollment and agree to use two highly effective forms of contraception as detailed in the protocol are considered eligible.
  • Male patients with partners of child-bearing potential (unless they agree to take measures not to father children by using one form of highly effective contraception as detailed in the protocol). Men with pregnant or lactating partners should be advised to use barrier method contraception (for example, condom plus spermicidal gel) to prevent exposure to the foetus or neonate.
  • Major thoracic or abdominal surgery from which the patient has not yet recovered.
  • At high medical risk because of non-malignant systemic disease including active uncontrolled infection.
  • Known to be serologically positive for hepatitis B, hepatitis C or human immunodeficiency virus (HIV).
  • Resting ECG with measurable QTc interval of >480 msec (mean value and manually verified) of at least 3 time points within a 24 hour period.
  • Concurrent hypotension defined as a baseline supine blood pressure (BP) systolic < 90 mmHg.
  • Concurrent congestive heart failure, prior history of class III/ IV cardiac disease (New York Heart Association [NYHA]), prior history of cardiac ischaemia or prior history of cardiac arrhythmia within 6 months. Coronary angioplasty or stenting in the previous 12 months.
  • Is a participant or plans to participate in another interventional clinical trial, whilst taking part in this Phase Ia/Ib study of AZD0424 single agent and in combination. Participation in an observational, counseling or psychological trial would be acceptable.
  • Any other condition which in the Investigator's opinion would not make the patient a good candidate for the clinical trial.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01668550

Contacts
Contact: Helen Turner 0203 469 6947 ext 6947 helen.turner@cancer.org.uk

Locations
United Kingdom
Belfast City Hospital Not yet recruiting
Belfast, United Kingdom
Contact: Dr Richard Wilson         
Edinburgh Cancer Centre - Western General Hospital Recruiting
Edinburgh, United Kingdom
Contact: Dr Sally Clive         
Oxford University Hospitals NHS Trust Recruiting
Oxford, United Kingdom
Contact: Professor Mark Middleton         
Sponsors and Collaborators
Cancer Research UK
Investigators
Study Chair: Professor Adrian Harris Oxford University Hospitals NHS Trust
  More Information

No publications provided

Responsible Party: Cancer Research UK
ClinicalTrials.gov Identifier: NCT01668550     History of Changes
Other Study ID Numbers: CRUKD/07/061
Study First Received: May 31, 2012
Last Updated: October 29, 2013
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency
United Kingdom: Research Ethics Committee

Keywords provided by Cancer Research UK:
Phase I
Src/Abl inhibitor
Solid Tumours
Cancer

Additional relevant MeSH terms:
Neoplasms

ClinicalTrials.gov processed this record on July 22, 2014