Safety and Tolerability of AP 12009, Administered I.V. in Patients With Advanced Tumors Known to Overproduce TGF-beta-2

The purpose of this dose-finding study is to evaluate the safety and tolerability of AP 12009. Two fixed dose-escalation schemes with predefined steps and increasing increments have been selected to determine the maximum tolerated dose (MTD) as well as the dose-limiting toxicity (DLT). At least two cycles of AP 12009 are administered intravenously in adult patients with no further acknowledged treatment options.

AP 12009 (trabedersen) is a phosphorothioate antisense oligodeoxynucleotide specific for the mRNA of human Transforming Growth Factor beta 2 (TGF-beta-2). The growth factor TGF-beta plays a key role in malignant progression of various tumors by inducing proliferation, invasion, metastasis, angiogenesis, and escape from immunosurveillance. In patients with pancreatic cancer, colorectal cancer, and metastatic melanoma the TGF-beta-2 overexpression is associated with disease stage, clinical prognosis, and the immunodeficient state of the patients.

Inclusion criteria

• Written informed consent.
• Age: 18-75 years.
• Male or non-pregnant, non-lactating female.
• a.Pancreatic cancer: Histologically or cytologically confirmed diagnosis, stage IVA or IVB (AJCC, 1997).

b. Melanoma: Histologically or cytologically confirmed diagnosis, stage III or IV (AJCC, UICC).

c. Colorectal cancer: Histologically or cytologically confirmed diagnosis, stage III or IV (AJCC, UICC), excluded from the last cohort.

• Patient is not or no longer amenable to established forms of therapy.
• At least one measurable lesion.
• Karnofsky performance status of at least 80%.
• Recovery from acute toxicity caused by any previous therapy.
• Adequate organ function as assessed by the following laboratory values:

• Serum creatinine and urea < 2 times the upper limit of normal (ULN).
• ALT and AST < 3 ULN (in case of a liver metastasis: < 5x ULN); alkaline phosphatase < 3 ULN; and bilirubin < 2.5 mg/dL.
• Prothrombin time < 1.5 INR and PTT < 1.5 times the upper limit of normal.
• Hemoglobin > 9 g/dL.
• Platelets > 100 x 10E9/L.
• WBC > 3.0 x 10E9/L.
• Absolute Neutrophil Count (ANC) > 1.5 x 10E9/L.

Exclusion criteria

• Patient unable to comply with the protocol regulations.
• Pregnant or lactating female.
• Antitumor radiation therapy within 12 weeks, tumor surgery within 4 weeks or any other therapy with established antitumor effects within 2 weeks prior to study entry.
• The patient takes or is likely to need other prohibited concomitant medication. Administration of corticosteroids should be strictly avoided during the course of the study.
• Patient's participation in another clinical trial with investigational medication within 30 days prior to study entry.
• History of brain metastases. In the case of suspected brain metastases a CT scan of the skull will be performed (not mandatory in asymptomatic patients).
• Clinically significant cardiovascular abnormalities such as refractory hypertension, congestive heart failure, unstable angina, or poorly controlled arrhythmia, or a myocardial infarction within 6 months prior to treatment.
• Gastric or duodenal ulcers within 6 months before study entry or is at risk of gastrointestinal ulceration due to high consumption of NSAIDs.
• An active infection with HIV, HBV, or HCV.
• Clinically significant acute viral, bacterial, or fungal infection.
• Acute medical problems that may be considered to become an unacceptable risk, or any conditions that might be contraindications for starting study treatment.
• History of allergies to reagents used in this study.
• Drug abuse or extensive use of alcohol.
• Significant psychiatric disorders/ legal incapacity or limited legal capacity.
• History of Long QT Syndrome or QTc time ≥ 480 msec in screening/baseline ECGs. The average QTc time is to be calculated from three separate ECGs performed prior to start of infusion: two ECGs performed at Screening/Baseline (with a minimum 1-hour interval in between) and one performed within 1 hour prior to start of infusion.