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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

Phase 1
18 Years
Open (Enrolling)
Advanced Solid Tumours

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Trial Information

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

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

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).

- Patient with a history of auto-immune disease or 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

- 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.

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

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

Safety Issue:


Principal Investigator

Professor Adrian Harris

Investigator Role:

Study Chair

Investigator Affiliation:

Oxford University Hospitals NHS Trust


United Kingdom: Medicines and Healthcare Products Regulatory Agency

Study ID:




Start Date:

October 2012

Completion Date:

April 2017

Related Keywords:

  • Advanced Solid Tumours
  • Phase I
  • Src/Abl inhibitor
  • Solid Tumours
  • Cancer
  • Neoplasms