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

Sponsor

Isarna Therapeutics GmbH (Industry)

Overall Status

Completed

CT.gov ID

NCT00844064

Collaborator

(none)

Enrollment

Locations

Arm

Duration (Months)

6.2

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

In this national Phase I dose-escalation study the safety and tolerability of AP 12009 is evaluated in adult patients with advanced tumors known to overproduce TGF-β2, who are not or no longer amenable to established therapies.

Condition or Disease	Intervention/Treatment	Phase
Pancreatic Neoplasms Melanoma Colorectal Neoplasms	Drug: AP 12009	Phase 1

Detailed Description

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

62 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

An Open-Label, Multicenter Dose-Escalation Study to Evaluate the Safety and Tolerability of AP 12009 (Trabedersen), Administered Intravenously in Patients With Advanced Tumors Known to Overproduce TGF-β2.

Study Start Date :

Jan 1, 2005

Actual Primary Completion Date :

Nov 1, 2011

Actual Study Completion Date :

Nov 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: AP 12009	Drug: AP 12009 Initial scheme: AP 12009 (trabedersen), dose escalation scheme, continuous intravenous infusion (7 days), every other week, up to 10 cycles. Modified scheme: AP 12009 (trabedersen), dose escalation scheme, continuous intravenous infusion (4 days), every other week, up to 10 cycles

Arm

Intervention/Treatment

Experimental: AP 12009

Drug: AP 12009

Initial scheme: AP 12009 (trabedersen), dose escalation scheme, continuous intravenous infusion (7 days), every other week, up to 10 cycles. Modified scheme: AP 12009 (trabedersen), dose escalation scheme, continuous intravenous infusion (4 days), every other week, up to 10 cycles

Outcome Measures

Primary Outcome Measures

To determine the maximum tolerated dose (MTD) as well as the dose-limiting toxicity (DLT) of two cycles of AP 12009 administered intravenously at weekly intervals and for four days every other week. []

Secondary Outcome Measures

To determine the safety and tolerability of AP 12009 administered intravenously at weekly intervals and for four days every other week. []
To assess the plasma pharmacokinetic profile of AP 12009 administered intravenously at weekly intervals and for four days every other week. []
To establish a suitable determination method and to assess the urine pharmacokinetic profile of AP 12009 administered intravenously for four days every other week. []
To determine the effect of AP 12009 administered intravenously at weekly intervals and for four days every other week on TGF-β2 plasma concentration levels. []
To determine the potential antitumor activity of AP 12009 administered intravenously at weekly intervals and for four days every other week, as assessed by the effect on tumor size and tumor markers. []

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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).

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

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Universitätsmedizin Berlin Charité	Berlin	Germany	10117
2	Universitätsklinik und Poliklinik für Innere Medizin I	Halle (Saale)	Germany	06120
3	Hautklinik der Ruprecht-Karls-Universität Heidelberg	Heidelberg	Germany	69115
4	Universitätsklinikum Schleswig-Holstein	Kiel	Germany	24105
5	Krankenhaus rechts der Isar, II. Medizinische Klinik und Poliklinik	München	Germany	81675
6	Universität Münster, Klinik und Poliklinik für Hautkrankheiten	Münster	Germany	48149
7	Klinik und Poliklinik für Innere Medizin I	Regensburg	Germany	93042
8	Klinik und Poliklinik für Dermatologie	Regensburg	Germany	93053
9	Universitäts-Hautklinik, Sektion Dermatologische Onkologie	Tübingen	Germany	72076
10	Universitätsklinikum Ulm, Zentrum für Innere Medizin	Ulm	Germany	89081