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Advanced Solid TumoursPhase 1AZD0424NCT01668550

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

A Phase 1 study testing AZD0424 in people with Advanced Solid Tumours, run by Cancer Research UK at 3 sites in United Kingdom.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

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 Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Advanced Solid Tumours
What is being tested?
AZD0424
Type of treatment
Pill or oral medicine
How many people
43 participants
Where
3 sitesUnited Kingdom
Study dates
Oct 2012to May 2016
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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)

Who cannot join

  • 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.
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  • 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.

Trial locations and contacts

3 sites in 1 country.

United Kingdom3 sites

  • Belfast City Hospital

    Belfast

  • Edinburgh Cancer Centre - Western General Hospital

    Edinburgh

  • Oxford University Hospitals NHS Trust

    Oxford

Other trials in United Kingdom

About this study

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

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

Read the 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 (up to six additional patients may be recruited in order to provide paired tumour biopsies for PD analysis).
  • Combination arm dose escalation: Provided that it is deemed appropriate (after review of available clinical data from the monotherapy part of the trial, and available preclinical and published data on the combination), a Phase Ia dose escalation arm of AZD0424 in combination with the selected agent will proceed to determine the MTD for the combination and a recommended Phase II dose.
  • Combination arm dose expansion: Phase Ib combination arm using the recommended Phase II dose for both AZD0424 and the combination agent.
Being tested
AZD0424
Keywords
Phase I, Src/Abl inhibitor, Solid Tumours, Cancer
Medical subject headings
Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • AZD0424Drug

    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.

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Establishing the Maximum Tolerated Dose (MTD) of AZD0424 alone and in combination

  2. Determining the causality and duration of adverse events observed during the study according to NCI CTCAE Version 4.02

Secondary outcomes (4)

  1. Determining the correlation between PK studies and toxicity and/or efficacy.

  2. 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

  3. 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.

  4. 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.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted20 Aug 2012 (estimated)
  2. Study startOct 2012
  3. Primary completionMay 2016
  4. Study completionMay 2016

Why it stopped: Single agent phase completed, insufficient supportive preclinical data to proceed with combination phase

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
43 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01668550
Sponsor's protocol ID
CRUKD/07/061
Acronym
AZD0424
Status last verified
Jul 2016
First submitted
31 May 2012
Last updated
5 Feb 2018
Results posted
No
Data monitoring committee
No

Publications

  • Woodcock VK, Clive S, Wilson RH, Coyle VM, Stratford MRL, Folkes LK, Eastell R, Barton C, Jones P, Kazmi-Stokes S, Turner H, Halford S, Harris AL, Middleton MR. A first-in-human phase I study to determine the maximum tolerated dose of the oral Src/ABL inhibitor AZD0424. Br J Cancer. 2018 Mar 20;118(6):770-776. doi: 10.1038/bjc.2017.484. Epub 2018 Feb 13.

    PubMed 29438361

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing AZD0424 in people with Advanced Solid Tumours, run by Cancer Research UK at 3 sites in United Kingdom.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 12 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 5 Feb 2018. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was stopped early (reason given: Single agent phase completed, insufficient supportive preclinical data to proceed with combination phase). Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Establishing the Maximum Tolerated Dose (MTD) of AZD0424 alone and in combination. The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01668550, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Feb 2018.

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