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

Study Description

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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

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	62 participants
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 :	January 2005
Actual Primary Completion Date :	November 2011
Actual Study Completion Date :	November 2011

Arms and Interventions

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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

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Primary Outcome Measures :

1. 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 :

1. To determine the safety and tolerability of AP 12009 administered intravenously at weekly intervals and for four days every other week.
2. To assess the plasma pharmacokinetic profile of AP 12009 administered intravenously at weekly intervals and for four days every other week.
3. To establish a suitable determination method and to assess the urine pharmacokinetic profile of AP 12009 administered intravenously for four days every other week.
4. 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.
5. 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

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Ages Eligible for Study:	18 Years to 75 Years (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

1. Written informed consent.
2. Age: 18-75 years.
3. Male or non-pregnant, non-lactating female.

4. 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.

5. Patient is not or no longer amenable to established forms of therapy.
6. At least one measurable lesion.
7. Karnofsky performance status of at least 80%.
8. Recovery from acute toxicity caused by any previous therapy.

9. 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:

1. Patient unable to comply with the protocol regulations.
2. Pregnant or lactating female.
3. 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.
4. 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.
5. Patient's participation in another clinical trial with investigational medication within 30 days prior to study entry.
6. 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).
7. 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.
8. Gastric or duodenal ulcers within 6 months before study entry or is at risk of gastrointestinal ulceration due to high consumption of NSAIDs.
9. An active infection with HIV, HBV, or HCV.
10. Clinically significant acute viral, bacterial, or fungal infection.
11. Acute medical problems that may be considered to become an unacceptable risk, or any conditions that might be contraindications for starting study treatment.
12. History of allergies to reagents used in this study.
13. Drug abuse or extensive use of alcohol.
14. Significant psychiatric disorders/ legal incapacity or limited legal capacity.
15. 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

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Locations

Germany
Universitätsmedizin Berlin Charité
Berlin, Germany, 10117
Universitätsklinik und Poliklinik für Innere Medizin I
Halle (Saale), Germany, 06120
Hautklinik der Ruprecht-Karls-Universität Heidelberg
Heidelberg, Germany, 69115
Universitätsklinikum Schleswig-Holstein
Kiel, Germany, 24105
Krankenhaus rechts der Isar, II. Medizinische Klinik und Poliklinik
München, Germany, 81675
Universität Münster, Klinik und Poliklinik für Hautkrankheiten
Münster, Germany, 48149
Klinik und Poliklinik für Innere Medizin I
Regensburg, Germany, 93042
Klinik und Poliklinik für Dermatologie
Regensburg, Germany, 93053
Universitäts-Hautklinik, Sektion Dermatologische Onkologie
Tübingen, Germany, 72076
Universitätsklinikum Ulm, Zentrum für Innere Medizin
Ulm, Germany, 89081

Sponsors and Collaborators

Isarna Therapeutics GmbH

Investigators

Study Chair:	Helmut Oettle, MD	Charité Berlin Campus Virchow-Klinikum

More Information

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Responsible Party:	Isarna Therapeutics GmbH
ClinicalTrials.gov Identifier:	NCT00844064 History of Changes
Other Study ID Numbers:	AP 12009-P001
First Posted:	February 13, 2009
Last Update Posted:	November 21, 2011
Last Verified:	November 2011

Keywords provided by Isarna Therapeutics GmbH:

Pancreatic cancer; Metastatic melanoma; Advanced tumor; Targeted therapy	Antisense; Transforming Growth Factor beta 2; Dose escalation

Additional relevant MeSH terms:

Neoplasms; Melanoma; Colorectal Neoplasms; Pancreatic Neoplasms; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Nerve Tissue; Nevi and Melanomas; Intestinal Neoplasms; Gastrointestinal Neoplasms	Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Endocrine Gland Neoplasms; Pancreatic Diseases; Endocrine System Diseases; Trabedersen; Antineoplastic Agents