A Phase I/II Clinical Trial of PXD101 in Combination With Doxorubicin in Patients With Soft Tissue Sarcomas

Inclusion criteria

• Signed consent of an IEC (Independent Ethics Committee)-approved Information consent form
• A. For the dose escalation phase: Patients with histological or cytological confirmed solid tumours (including sarcomas), for which there is no known curative therapy B. For the MTD expansion phase: Patients with an established diagnosis of soft tissue sarcoma in need of first line chemotherapy and with measurable disease
• Performance status (ECOG) ≤ 2
• Life expectancy of at least 3 months
• Age ≥ 18 years
• Acceptable liver, renal and bone marrow function including the following:

• Bilirubin ≤ 1.5 times upper limit of normal (ULN)
• AST ([Aspartate Amino Transferase]](SGOT), ALT (SGPT) and Alkaline Phosphatase ≤ 3 times upper limit of normal (if liver metastases are present, then ≤ 5 x ULN is allowed)
• Serum creatinine ≤ 1.5 times upper limit of normal (ULN)
• Leucocytes > 2.5 x 109/ L, neutrophils > 1.0 x 109/L, platelets > 100 x 109/L
• Haemoglobin > 9.0 g/dL or > 5.6 mmol/l
• Acceptable coagulation status: PT and APTT ([activated partial thromboplastin time ]) within ≤ 1.5 times upper limit of normal or in the therapeutic range if on anticoagulation.
• A negative pregnancy test for women of childbearing potential. For men and women of child producing potential, the use of effective contraceptive methods during the study is required
• Serum potassium within normal range

Exclusion criteria

• Treatment with investigational agents within the last 4 weeks
• Prior anticancer therapy, within the last 3 weeks of trial dosing including chemotherapy, radiotherapy, endocrine therapy or immunotherapy
• Co-existing active infection or any co-existing medical condition likely to interfere with trial procedures, including significant cardiovascular disease (New York Heart Association Class III or IV cardiac disease, myocardial infarction within the past 6 months, unstable angina, congestive heart failure requiring therapy, unstable arrhythmia or a need for anti-arrhythmic therapy, or evidence of ischemia on ECG, marked baseline prolongation of QT/QTc ([corrected QT interval ]) interval, e.g., repeated demonstration of a QTc interval > 500 msec; Long QT Syndrome; the required use of concomitant medication on PXD101 infusion days that may cause Torsade de Pointes.
• Altered mental status precluding understanding of the informed consent process and/or completion of the necessary studies
• Concurrent second malignancy
• History of hypersensitivity to doxorubicin
• A. For dose escalation phase: More than two prior doses of anthracycline, more than three prior lines of chemotherapy given for metastatic disease B. For MTD expansion phase: Prior chemotherapy
• Bowel obstruction or impending bowel obstruction
• Known HIV positivity
• LVEF ([left ventricular ejection fraction]) below normal range (45% by MUGA)
• Presence of metastatic disease that, in the opinion of the investigator, would require palliative treatment within 4 weeks of enrolment