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.

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.

· 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)

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 orC.

· 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, 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.