A Clinical Trial on Topotect® (Dexrazoxane) in the Treatment of Accidental Extravasation of Anthracyclines

• ClinicalTrials.gov Identifier: NCT00548704
• Recruitment Status: Completed
• First Posted: October 24, 2007
• Last Update Posted: October 21, 2015
• Sponsor: Onxeo
• Information provided by (Responsible Party): Onxeo

Study Description

Brief Summary:

The purpose of this study is

• To prevent progression of a lesion caused by anthracycline extravasation into necrosis, which would require surgical intervention
• To prevent development of deep tissue necrosis and destruction leading to impaired limb function and neurological deficit
• To prevent postponement of the scheduled cancer treatment due to the treatment of the extravasation

Condition or disease	Intervention/treatment	Phase
Extravasation	Drug: Dexrazoxane	Phase 2; Phase 3

Detailed Description:

Accidental extravasation of anthracyclines, e.g. doxorubicin and its derivative epirubicin, may cause progressive tissue destruction including serious damage of the skin, the subcutaneous tissue, muscles, and nerves.

The patient may suffer from acute local symptoms such as pain and swelling, which may progress into blistering and necrosis. Subsequently dysesthesia, skin atrophy, disfigurement, and impaired limb function may be the consequence.

Surgical removal of all affected tissue is required and the debridement often necessitates split skin grafting. The patient is thus subjected to the distress of major surgery, which in turn leads to delay of further cytotoxic treatment.

Preclinical animal studies as well as a clinical multicenter phase II trial have demonstrated a highly significant efficacy of dexrazoxane in preventing tissue destruction caused by anthracyclines.

This confirmatory trial will determine the effect of Topotect® (dexrazoxane) as an acute antidote in patients with anthracycline extravasation.

Orphan drug status TopoTarget A/S was granted designation for Topotect® as an orphan medical product for the treatment of anthracycline extravasations by the European Commission in September 2001 and by the FDA in ???.

Purpose

Primary objectives:

• To prevent progression of the anthracycline extravasation lesion as tissue ulceration and necrosis requiring surgical intervention

Secondary objectives:

• To prevent development of deep tissue necrosis and destruction leading to late sequelae as impaired limb function and neurological deficit
• To prevent postponement of the scheduled cancer treatment due to the treatment of the extravasation
• To evaluate the tolerance to and/or toxicity of Topotect® used for this indication, according to the indicated schedule

Trial design This is an open-label, non-randomised phase II/III trial. Thirty -five evaluable patients with anthracycline extravasations will be treated.

Extravasation is determined by the presence of pain, and/or swelling, and/or redness at the site where anthracycline leakage is suspected to have occurred. The extravasations are subsequently confirmed in each patient by fluorescence microscopy of at least two punch biopsies at the time of the accident.

Success criteria The prevention of surgical intervention, necrosis and late sequelae evaluated 3 months after the extravasation.

Safety features

• Toxicity caused by Topotect® will be examined by haematology and blood chemistry, questions are asked on any discomfort. Scheduled clinical examinations are performed
• A systematic clinical evaluation of the marked area of skin covering the area of extravasation will be performed in order to evaluate the need for surgery
• Sequential colour photographs of the involved skin will be taken

Medical Treatment Patients are treated with intravenous infusion of Topotect® administered once daily on three consecutive days at the following doses: 1,000 mg/m2 + 1,000 mg/m2 + 500 mg/m2. The first dose is administered as soon as possible and within 6 hours of the extravasation and the next two doses at 24 and 48 hours after the first infusion.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 57 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Clinical Trial on Topotect® (Dexrazoxane) in the Treatment of Accidental Extravasation of Anthracycline Anti-cancer Agents
• Study Start Date: April 2002
• Actual Primary Completion Date: August 2005
• Actual Study Completion Date: August 2005

Arms and Interventions

Intervention Details:

• Drug: Dexrazoxane
  Other Name: Totect

Outcome Measures

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. All cancer patients treated with anthracyclines
2. Informed consent must be obtained from the patient

3. Patients suspected to have been exposed to extravasation (leakage) of anthracycline, defined as:

   1. A primary assessment by the physician on duty, which would activate the standard departmental procedure for treatment of anthracycline extravasation.
   2. The presence of at least one of the following symptoms: pain, swelling or redness at the site where the anthracycline leakage is suspected to have occurred.
4. Suspicion of anthracycline extravasation from a central venous access device
5. The Topotect® infusion must be started < 6 hours after the accident
6. 18 years of age or older
7. Performance status (PS) < 2

Exclusion Criteria:

1. Known allergy towards dexrazoxane
2. Reasonable suspicion of extravasation by other compounds than anthracyclines through the same intravenous access, e.g. vincristine, mitomycin, and vinorelbine, all of which may cause ulceration
3. AST (aspartate aminotransferase) or ALT (alanine aminotransferase), bilirubin, LDH (lactate dehydrogenase), alkaline phosphatase >3 x upper normal value
4. Neutrophils CTC (common toxicity criteria) ≥ grade 2. (neutrophils 1.5 x 109/L, ≥1,500/mm3)
5. Platelets CTC ≥ grade 2. (platelets ≥75.0 x 109/L, <75,000/mm3).
6. Topical use of DMSO (dimethylsulfoxide) at the area of the accident
7. Administration of dexrazoxane within the last 3 weeks
8. Pregnant or nursing women
9. Women of childbearing age and potential, who do not use an efficient contraceptive (e.g. the Pill or a diaphragm plus a spermicide) for at least 3 months prior to the start of trial medication

Contacts and Locations

Locations

Denmark

Aalborg Hospital South

Aalborg, Denmark, 9100

Aarhus County Hospital

Aarhus, Denmark, 8000 C

Aarhus Municipality Hospital

Aarhus, Denmark, 8000 C

Rigshospitalet, Haematology Department

Copenhagen, Denmark, 2100

Rigshospitalet, Oncology Department

Copenhagen, Denmark, 2100

Esbjerg District Hospital

Esbjerg, Denmark, 6700

Herlev County Hospital, Haematology Department

Herlev, Denmark, 2730

Herlev County Hospital, Oncology Department

Herlev, Denmark, 2730

Hilleroed Hospital

Hilleroed, Denmark, 3400

Naestved District Hospital

Naestved, Denmark, 4700

Odense University Hospital

Odense, Denmark, 5000 C

Roskilde County Hospital

Roskilde, Denmark, 4000

Soenderborg Hospital

Soenderborg, Denmark, 6400

Vejle Hospital

Vejle, Denmark, 7100

Viborg Hospital

Viborg, Denmark, 8800

Germany

Evangelisches Bethesda Krankenhaus

Essen Borbak Statt, Germany, 45355

Klinik für Gynäkologie und Geburtshilfe

Frankfurt am Main, Germany, 60590

Klinik und Poliklinik für Innere Medizin

Hamburg, Germany, 20246

Medizinische Hochschule Hannover

Hannover, Germany, 30659

Universitäts Frauenklinik

Kiel, Germany, 24105

Universitäts Medizinische Klinik

Kiel, Germany, 24105

Frauenklinik com Roten Kreuz

Munich, Germany, 80637

Universitäts Frauenklinik

Rostock, Germany, 18057

Klinik für Gynäkologie und Gynäkologische Onkologie

Wiesbaden, Germany, 65199

Italy

Ospedale G.B. Morgagni L. Pierantoni

Forli, Italy, 47100

Presidio Ospedaliero di Ravenna

Ravenna, Italy, 48100

Ospedale degli Infermi

Rimini, Italy, 47037

Ospedali Riuniti

Trieste, Italy, 34100

Netherlands

Netherland Cancer Institute

Amsterdam, Netherlands, 1066 CX

University Hospital

Groningen, Netherlands, 9700 RB

Willem Alexander Hospital

Hertogenbosch, Netherlands, 5223 GV

Poland

Centre of Oncology - Krakow Division

Krakow, Poland, 31-115

Maria Sklodowska-Curie Memorial Cancer Center

Warsaw, Poland, 02-781

Dolnoslaski Centrum Onkologii oddzial Chemoterapii

Wroclaw, Poland, 53-413

Sponsors and Collaborators

Onxeo

Investigators

• Principal Investigator: Henning T Mouridsen, MD, Dr. med.; Rigshospitalet, The Finsen Centre 5074, Blegdamsvej 9, DK-2100 Copenhagen

More Information

Publications of Results:

Mouridsen HT, Langer SW, Buter J, Eidtmann H, Rosti G, de Wit M, Knoblauch P, Rasmussen A, Dahlstrøm K, Jensen PB, Giaccone G. Treatment of anthracycline extravasation with Savene (dexrazoxane): results from two prospective clinical multicentre studies. Ann Oncol. 2007 Mar;18(3):546-50. Epub 2006 Dec 21.

• Responsible Party: Onxeo
• ClinicalTrials.gov Identifier: NCT00548704
• Other Study ID Numbers: TT02
• First Posted: October 24, 2007
• Last Update Posted: October 21, 2015
• Last Verified: November 2013

Keywords provided by Onxeo:

Extravasation; Anthracyclines

Additional relevant MeSH terms:

Dexrazoxane; Razoxane; Antineoplastic Agents; Cardiotonic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Protective Agents; Physiological Effects of Drugs; Antimitotic Agents; Mitosis Modulators