Protective Effect of Mangafodipir Against Oxaliplatin Neurotoxicity (MnDPDP-K04)

Evaluation of Mangafodipir Protective Activity Against Oxaliplatin Neurotoxicity

Oxaliplatin is a major antitumor agent but its use is limited by potentially disabling neurotoxicity, characterized by a sensitive defect in the extremities.Mangafodipir is a MRI contrast agent with antioxidant properties. Our previous laboratory works showed that mangafodipir is able to prevent hematologic toxicity of several chemotherapy agents, including oxaliplatin and to increase their antitumor activity. Preliminary clinical data suggested that mangafodipir could prevent oxaliplatin neurotoxicity.The primary purpose of the present study is to assess the protective effect of mangafodipir in patients who have a already moderate oxaliplatin neuropathy and in whom the continuation of this treatment is desirable because of significant antitumor effect.

Study Overview

• Status: Completed
• Conditions: Cancer; Neurotoxic Disorders
• Intervention / Treatment: Drug: Mangafodipir

Detailed Description

Phase 2 study aiming to assess the protective effect of mangafodipir against the oxaliplatine neuropathy.Population: Cancer patient who have a mild (grade 2) oxaliplatin neuropathy and in whom the continuation of oxaliplatin for at least 4 infusions is desirable will be include, whatever the location of the primitive tumor and the use of others anticancer agents.Treatment: Mangafodipir (0.5 ml/kg) is administered as a 30 minutes infusion just after each administration of oxaliplatin. The oxaliplatin dose (85 to 100 mg/m²) and the length of the infusion (2 hours) are the same that before the inclusion and modifications are not authorized during all the study participation. Primary objective: Neuropathy are clinically evaluated according to NCI-CTC criteria before each mangafodipir and oxaliplatin and thereafter one month after the last infusion. The primary criteria is the worst grade of oxaliplatin neuropathy experienced by each patient. The improvement of neuropathy is defined as a decrease by at least one grade of the severity of the neuropathy for at least 2 months.

Hypothesis: at least 50% of patients will experience an improvement or a stabilization of the oxaliplatin neuropathy while receiving the mangafodipir - oxaliplatin association.Treatment discontinuation: the treatment will be stopped if the neuropathy worsened by at least one grade, in case of tumor progression, intolerable toxicity, and patient wish.

Number of patients: it will be determined according to a simplified Gehan procedure: The inclusions will be stopped if no objective response (neuropathy improvement) is observed among the first 9 evaluable patients. If at least one response is observed, 16 more evaluable patients will be include. The total number of patients will be between 9 and 30 patients, including non evaluable patients.

Pharmacokinetic: Serum and intra- erythrocytes manganese concentration will be evaluated before each mangafodipir infusion in order to detect accumulation Pharmacodynamic: plasmatic total antioxidant activity, superoxide dismutase activity and lipid peroxidation will be assessed at the first cycle: before and after the administration of oxaliplatin and just after the perfusion of mangafodipir.

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Paris, France, 75014
    • Cochin

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• NCI CTC grade 2 or more neuropathy induced by oxaliplatine
• At least 18 years old
• ECOG PS: 2 or less
• Life expectancy longer than 3 months
• Written informed consent
• Adequate hematologic, liver and renal functions

Exclusion Criteria:

• Known hypersensibility to oxaliplatine
• Cancer resistant to oxaliplatine
• Fertile woman or man not willing to use adequate contraception
• Pregnant or lactating women
• Vitamin B6 administration within 48h prior to mangafodipir administration
• Uncontrolled infection
• Treatment with any other investigational agent, or participation in another clinical trial within 3 weeks prior to first administration of mangafodipir
• Evidence of any other disease or condition that contra-indicates the use of an investigational drug
• No Social Security insurance

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1	Drug: Mangafodipir; Mangafodipir (0.5 ml/kg) is administered as a 30 minutes infusion just after each administration of oxaliplatin. The oxaliplatin dose (85 to 100 mg/m²) and the length of the infusion (2 hours) are the same that before the inclusion and modifications are not authorized during all the study participation. During 4 months (8 administrations).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Maximal neuropathy severity (NCI-CTC score) established before each oxaliplatin injection	every 15 days

Secondary Outcome Measures

Outcome Measure	Time Frame
Number of oxaliplatin administration	every 15 days
Progression free survival (time from inclusion to cancer progression)	6 months

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Jerome Alexandre, MD, PhD, Assistance Publique - Hôpitaux de Paris

Publications and helpful links

General Publications

• Coriat R, Alexandre J, Nicco C, Quinquis L, Benoit E, Chereau C, Lemarechal H, Mir O, Borderie D, Treluyer JM, Weill B, Coste J, Goldwasser F, Batteux F. Treatment of oxaliplatin-induced peripheral neuropathy by intravenous mangafodipir. J Clin Invest. 2014 Jan;124(1):262-72. doi: 10.1172/JCI68730. Epub 2013 Dec 20.

Study record dates

Study Major Dates

• Study Start: June 1, 2008
• Primary Completion (Actual): January 1, 2010
• Study Completion (Actual): April 1, 2011

Study Registration Dates

• First Submitted: July 31, 2008
• First Submitted That Met QC Criteria: August 1, 2008
• First Posted (Estimate): August 4, 2008

Study Record Updates

• Last Update Posted (Estimate): December 16, 2011
• Last Update Submitted That Met QC Criteria: December 15, 2011
• Last Verified: July 1, 2011

More Information

Terms related to this study

• Keywords: Neuropathy; Oxaliplatin; Mangafodipir
• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Nervous System Diseases; Poisoning; Neurotoxicity Syndromes
• Other Study ID Numbers: P071203