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

February 13, 2019 updated by: Isarna Therapeutics GmbH

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.

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Actual)

62

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

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

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 75 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: NA
  • Interventional Model: SINGLE_GROUP
  • Masking: NONE

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
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

Outcome Measure
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.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Isarna Therapeutics GmbH

Investigators

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

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2005

Primary Completion (ACTUAL)

November 1, 2011

Study Completion (ACTUAL)

November 1, 2011

Study Registration Dates

First Submitted

February 12, 2009

First Submitted That Met QC Criteria

February 12, 2009

First Posted (ESTIMATE)

February 13, 2009

Study Record Updates

Last Update Posted (ACTUAL)

February 15, 2019

Last Update Submitted That Met QC Criteria

February 13, 2019

Last Verified

February 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • AP 12009-P001

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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