A Cancer Research UK Phase I Trial to Evaluate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Aurora B Inhibitor GSK1070916A in Patients With Advanced Solid Tumors
Eligibility criteria The patient must fulfil the eligibility criteria (listed in Section
4.1.1 and 4.1.2).
Additional eligibility criteria must be fulfilled for the expanded MTD cohort (listed in
4.1.1 Inclusion criteria:
1. Histologically or cytologically proven solid tumour refractory to conventional
treatment, or for which no conventional therapy exists
2. Life expectancy of at least 3 months
3. World Health Organisation (WHO) performance status of 0 or 1
4. 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
goes on study. Laboratory Test Value required Haemoglobin
(Hb) ≥ 10.0 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 unless raised due to tumour
in which case up to 5 x ULN is permissible Calculated creatinine clearance
(preferably measured by EDTA/ DTPA (isotope method) otherwise to be calculated using
Wright formula) ≥ 50 mL/min (uncorrected value)
5. 18 years or over
6. Written (signed and dated) informed consent and be capable of co-operating with
treatment and follow-up
4.1.2 Exclusion criteria:
1. Radiotherapy (except for palliative reasons), endocrine therapy, immunotherapy or
chemotherapy during the previous four weeks (six weeks for nitrosoureas, Mitomycin-C
and six weeks for investigational medicinal products) before treatment.
2. 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 Drug
Development Office (DDO) should not exclude the patient.
3. Known brain metastases.
4. Patients on therapeutic anti-coagulation with warfarin are excluded. (1mg warfarin
for line maintenance is acceptable; conversion to low molecular weight heparin is
acceptable but must be done a minimum of seven days prior to the first dose of study
5. Ability to become pregnant (or already pregnant or lactating). However, those female
patients who have a negative serum or urine pregnancy test before enrolment and agree
to use two highly effective forms of contraception (oral, injected or implanted
hormonal contraception and condom, have a intra-uterine device and condom, diaphragm
with spermicidal gel and condom) for four weeks before entering the trial, during the
trial and for six months afterwards are considered eligible.
6. 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
[condom plus spermicide] during the trial and for six months afterwards). Men with
pregnant or lactating partners should be advised to use barrier method contraception
(e.g. condom plus spermicidal gel) to prevent exposure to the foetus or neonate.
7. Major thoracic or abdominal surgery from which the patient has not yet recovered.
8. At high medical risk because of non-malignant systemic disease including active
9. Known to be serologically positive for hepatitis B, hepatitis C or human
immunodeficiency virus (HIV).
10. QTc interval ≥ 450 msecs for men and ≥ 470 msecs for women or other clinically
significant electrocardiogram (ECG) abnormalities (QTc preferably calculated using
the algorithm in Appendix 6).
11. Use of medicines known to prolong QTc within 14 days prior to the first dose of study
drug (see Category 1 of Appendix 5).
12. Previous exposure to aurora kinase inhibitors
13. Concurrent congestive heart failure, prior history of class III/ IV cardiac disease
(New York Heart Association [NYHA] - refer to Appendix 4)
14. History of cardiac ischaemia, cardiac arrhythmias, coronary angioplasty or stenting
in the previous 12 months. Patients currently on medication for cardiac arrhythmias
are also excluded.
15. Patients with a known left ventricular ejection fraction (LVEF) <50%. A multi-gated
acquisition (MUGA) scan or echocardiogram must be performed if clinically indicated.
16. Any other condition which in the Investigator‟s opinion would not make the patient a
good candidate for the clinical trial.
17. Is a participant or plans to participate in another interventional clinical study,
whilst taking part in this Phase I study of GSK1070916A. Participation in an
observational study would be acceptable.
4.1.3 Additional inclusion / exclusion criteria for expanded MTD cohort:
Once tolerability has been confirmed in the initial three to six patients of the MTD,
further patients in this expanded cohort must either consent to have tumour biopsies taken
or having FDG PET-CT and DW/DCE-MRI scans performed. The minimum number of patients
required in each part of the expansion cohort is six. The following additional inclusion /
exclusion criteria will apply.
For patients consenting to tumour biopsies:
1. Additional written (signed and dated) informed consent for tumour biopsies must be
2. The patient‟s tumour should be amenable to biopsy.
For patients consenting to FDG PET-CT and DW/DCE-MRI scans:
3. Additional written (signed and dated) informed consent for FDG PET-CT and DW/DCE-MRI
scans must be given.
4. Patients with diabetes must have their condition under good control (blood sugar less
5. Patients must be able to tolerate / comply with imaging protocol (i.e. patients with
high levels of pain, urinary incontinence, or claustrophobia etc should be excluded).
6. Patients with tumours known to be poorly FDG avid (e.g. mucinous adenocarcinoma, well
differentiated neuroendocrine or hepatocellular carcinoma) or falsely negative (e.g.
all tumours less than 5-6mm) are excluded. Refer to Appendix 7 for full list of
7. Patients with implanted metallic devices (e.g. pacemaker) are excluded.