Online Supplementary Information
Inclusion criteria

Signed written informed consent.

Male or female, ≥18 years.

Cancer which is refractory to standard therapies, or for which no standard therapies
exist, or for which the investigator feels no other active therapy is required for the
duration of the study. Inclusion is irrespective of stage of disease.

Histological or cytological confirmation of an advanced, solid, malignant tumour (or
lymphoma).

World Health Organization performance status 0–2 (those with performance status 2
must have been stable with no deterioration over the previous 2 weeks).

Evidence of post-menopausal status, permanent or surgically sterile, or negative
serum or urine pregnancy test for female patients of child-bearing potential. Women
will be considered post menopausal if they are over 50 years old and have been
amenorrheic for 12 months or more following cessation of all exogenous hormonal
treatments. Permanent sterilisation includes hysterectomy and/or bilateral
oopherectomy and/or bilateral salpingectomy, but excludes bilateral tubal occlusion.
Tubal occlusion is considered a highly effective method of birth control but does not
absolutely exclude the possibility of pregnancy. Women who have undergone tubal
occlusion should be managed as if they are of child-bearing potential (e.g. undergo
pregnancy testing as required by the study). Females of reproductive potential are
required to use reliable contraception.

Patients with measurable and non-measurable disease (according to RECIST
criteria) can be recruited.
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Exclusion criteria

Laboratory values (SI Units) as listed below:
o
ANC <1.5 x 109/L
o
platelets <100 x 109/L
o
haemoglobin (Hb) <9.0 g/dL
o
AST (SGOT) or ALT (SGPT) >2.5 x ULN if no demonstrable liver metastases
or >5 x ULN in the presence of liver metastases, total bilirubin (TBL) >1.5 x
ULN if no demonstrable liver metastases or >3 x ULN in the presence of liver
metastases
o
serum creatinine >1.5 x ULN or creatinine clearance ≤50 mL/min (measured
or calculated by Cockcroft-Gault method)
o
clinically relevant and treatment resistant abnormalities in potassium, sodium,
calcium (corrected for plasma albumin) or magnesium.

Patients must not have received prior chemotherapy, biological therapy, radiation
therapy, androgens, thalidomide, corticosteroids or other investigational anti-cancer
therapy within 21 days of entering the trial (not including palliative radiotherapy at
focal sites). Patients must have also recovered from previous chemo-associated
toxicities to grade 0–1 (with the exception of alopecia).

Treatment with any haemopoietic growth factors (e.g. G-CSF, GM-CSF) within 2
weeks prior to receiving study drug.

Active spinal cord compression as evidenced by clinical signs and/or oedema or
progressive growth demonstrated by imaging unless treated and stable off steroids
for at least 1 month prior to study treatment.

Patients with a peripheral neuropathy CTCAE grade >1 in the past 4 weeks.
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
Patients with a history of muscle diseases (including dermatomyositis, polymyositis,
inclusion body myositis, muscular dystrophy and metabolic myopathy).

Family history of myopathy.

Past history of brain metastases or current evidence of brain metastases.

Any evidence of severe or uncontrolled systemic conditions (e.g. severe hepatic
impairment, interstitial lung disease [bilateral, diffuse, parenchymal lung disease]) or
current unstable or uncompensated respiratory or cardiac conditions which makes it
undesirable for the patient to participate in the study or which could jeopardise
compliance with the protocol.

Patients with pre-existing renal disease including glomerulonephritis, nephritic
syndrome, Fanconi syndrome or renal tubular acidosis.

Patients with an abnormal fasting glucose value defined as >126 mg/dL (>7 mmol/L).

Patients with manifest diabetes type I and II or erythrocyte-HbA1c >6.5%.

Patients with uncontrolled hypercholesterolaemia or hypertriglyceridaemia (fasting
state) despite lipid-lowering therapy.

Evidence of active infection or active bleeding diatheses.

Patients who have experienced any of the following procedures or conditions in the
preceding 12 months:
o
coronary artery bypass graft
o
angioplasty
o
vascular stent
o
myocardial infarction (MI)
o
angina pectoris
o
congestive heart failure NYHA grade 2
o
uncontrolled hypertension (blood pressure >150/90 mmHg despite maximal
medical management)
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o
ventricular arrhythmias requiring continuous therapy
o
supraventricular arrhythmias including atrial fibrillation, which are uncontrolled
o
haemorrhagic or thrombotic stroke, including transient ischaemic attacks or
any other central nervous system bleeding.

Patients with an abnormal echocardiogram at baseline (left ventricular ejection
fraction [LVEF] <55% and shortening fraction [SF] <15%).

Patients with Torsades de Pointes either currently or within 2 weeks of study entry.

Patients with mean QTc interval >450ms from 3 ECGs using Fridericia's correction at
both screening visit and pre-dose on the first day of dosing.

Patients taking concomitant medications known to prolong QT interval or with factors
that increase the risk of QT prolongation or arrhythmic events (heart failure,
hyperkalaemia, personal or family history of long QT syndrome).

Uncontrolled severe thyroid hyperfunction or hypofunction.

Recent major surgery within 4 weeks prior to entry into the study (excluding the
placement of vascular access), or minor surgery within 2 weeks of entry into the
study.

Patients with documented cases of human immunodeficiency virus or hepatitis B
or C.

Involvement in the planning and conduct of the study (applies to both AstraZeneca
staff and staff at the study site).

Previous enrolment into the present study.

Patients receiving the following potent and moderate inhibitors and inducers of
CYP3A4/5 are excluded if they are taken within the stated washout periods:
o
inhibitors (competitive): ketoconazole, itraconazole, indinavir, saquinovir,
nelfinavir, atazanavir, amprenavir, fosamprenavir, troleandomycin,
telithromycin, fluconazole, nefazodone, cimetidine, aprepitant, miconazole,
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fluvoxamine (1 week minimum wash-out period), amiodarone (27 week
minimum wash-out period)
o
inhibitors (time dependent): erythromycin, clarithromycin, verapamil, ritonavir,
diltiazem (2 week minimum wash-out period)
o
inducers: phenytoin, rifampicin, St. John's Wort, carbamazepine,
dexamethasone, primidone, griseofulvin, carbamazepine, barbiturates,
troglitazone, pioglitazone, oxcarbazepine, nevirapine, efavirenz, rifabutin (3
week minimum wash-out period) and phenobarbitone (5 week minimum
wash-out period).

Potent and moderate inhibitors and inducers of CYP2C8 if taken within the stated
wash-out periods:
o
inhibitors: gemfibrozil, trimethoprim, glitazones, montelukast, quercetin (1
week minimum wash-out period)
o

inducers: rifampicin (3 week minimum wash-out period).
Has any other severe, acute or chronic medical or psychiatric condition or laboratory
abnormality that could increase the risk associated with study participation or study
drug administration or could interfere with the interpretation of the study results and,
in the judgment of the investigator, would make a patient inappropriate for entry in
this study.

Refractory nausea and vomiting, chronic gastrointestinal diseases (e.g. inflammatory
bowel disease) or significant bowel resection that would preclude adequate
absorption.

Clinical judgement by the investigator that the patient should not participate in the
study.
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