A Study of Combined Deferasirox, Vitamin D and Azacytidine in High Risk MDS (GFM-EXVD-AZA)

Phase I-II Study of Association of Deferasirox, Vitamin D and Azacytidine as Treatment of High Risk MDS (IPSS Int-2 and High)

Determinate safety and response rate of the association Deferasirox -Vitamine D - Azacitidine in treatment of high risk MDS

Deferasirox Exjade:

The dose of Deferasirox will be assigned according to the ferritin level. Dose escalation is scheduled during the phase I, with 5 additional patients per group.

The maximal tolerated dose of Deferasirox will be required for the phase II of the study.

The first dose will be assigned according to the ferritin level of the patient at time of inclusion:

5 mg/kg/d if the ferritin is >300ng/ml and < 1000ng/ml in Group 1 10 mg/kg/d if the ferritin is ≥1000ng/ml) in Group 2

Group 1 : Ferritin 300 to 1000ng /ml:

• cohort 1 : 5 mg/kg/d
• cohort 2 : 10mg/kg/d
• cohort 3 : 15 mg/kg/d

Group 2 : Ferritin > 1000ng /ml:

• cohort 1 : 10 mg/kg/d
• cohort 2 : 15mg/kg/d

• cohort 3 : 20 mg/kg/d

  5 patients will be treated by cohort. In absence of toxicity (extra-hematological toxicity grade 3 or 4 or hematological grade 4), 5 additional patients will be included in the next cohort.

Deferasirox will be administrated once daily during all the study period. Uvedose will be administrated once weekly during all the study period (100.000 UI P.O).

Azacitidine will be administrated sc at 75 mg/m²/d, during 7 days, J1 to J7 of each cycles(One cycle is 28 days)

During phase I and II, Deferasirox will always be associated with Vitamin D and Azacitidine

Patients will be received 6 cycles of treatment (except if progression, unacceptable toxicity or withdrawn of patients occured) After 3 and 6 cycles, an evaluation will be done to evaluate the efficacy of the treatment.

No dose modification of deferasirox will be done after 3 cycles of treatment except in case of progression). After 6 cycles, patients with CR, PR, marrow CR or HI will be treated with the same dose of Deferasirox until progression .

Study Overview

• Status: Unknown
• Conditions: MDS
• Intervention / Treatment: Drug: Deferasirox, Vitamin D and Azacitidine

Detailed Description

Deferasirox will be administrated once daily in the morning on an empty stomach, 30 minutes before meal.

Deferasirox will be stopped if the ferritin level is under 100 ng/ml,and could be restarted is the ferritin level increase to 200 ng/ml

Uvedose dose could be adjusted according to the phosphocalcic metabolism parameters and the plasma Vitamin D3 level.

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Gent, Belgium, 9000
    • Gent
• France
  • Bayonne, France, 64100
    • Centre Hospitalier de la Cote Basque
  • Bobigny, France, 93009
    • Hôpital Avicenne
  • Boulogne sur Mer, France
    • Centre Hospitalier de Boulogne Sur Mer
  • Le MANS, France
    • CHU Le Mans
  • Lille, France, 59020
    • Hôpital Saint Vincent de Paul
  • Limoges, France, 87042
    • Chu Limoges
  • Nancy, France, 54511
    • CHU Brabois
  • Nantes, France, 44093
    • CHU Nantes
  • Nantes, France
    • Centre Catherine de Sienne
  • Paris, France, 75010
    • Hopital Saint Louis
  • Paris, France, 75679
    • Hopital Cochin
  • Paris, France, 75743
    • Hopital Necker
  • Poitiers, France, 86021
    • CHU Poitiers
  • Toulouse, France
    • IUCT Oncopole Toulouse

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:

• High risk MDS, according to OMS classification
• High risk CMML (WBC < 13 G/L)
• AREBT of the FAB classification with less than 30% of blastes
• IPSS>=1.5 (int-2 and high risk)
• Age >=18y
• Performance status<=2 (ECOG)
• Bilirubin and transaminase < 1.5 x ULN
• Normal renal function
• Patient not eligible for Allogeneic stem cell transplant
• Male and female patients must use an effective contraceptive method during the study and for a minimum of 3 months after study treatment.
• Agree the need for the use of a condom if engaged in sexual activity with a pregnant woman or a woman of childbearing potential. during the entire period of treatment, even if disruption of treatment and during 3 months after end of treatment
• Male patient: Agree not to conceive during treatment and study drug therapy (including doses interruptions) and for 3 months after the end of the study drug therapy
• Agree not to donate semen during study drug therapy and for one week after end of study drug therapy.
• Agree to learn about the procedures for preservation of sperm,before starting treatment
• Patient be able to adhere to the study visit schedule and other protocol requirements

Exclusion Criteria:

• Active infection or uncontrolled disease
• Use of cytotoxic chemotherapeutic agents or experimental agents(agents that are not commercially available) for the treatment of MDS within 28 days. In case of used of cytotoxic chemotherapeutic agents or hypomethylating agent a wash out of 3 mont is required.
• Active Cancer or Cancer within one year before inclusion
• Previous calcic urinary lithiasis
• Previous hyperparathyroid primitive disease or uncontrolled
• Hypercalcemia, hyperphosphoremia, hypervitaminosis D
• Patient already include in another experimental study
• Active infection by HIV, hepatite B or C
• Pregnant or lactating females
• Patient not able (medical/psychiatric) to understand and sign the written consent
• Patients with a ferritin level less than 300ng/ml
• Patient eligible for an Allogeneic stem cell transplant

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: ferritin level >300ng/ml and < 1000ng/ml; Patients will be included in 2 groups according to the ferritin level at time of inclusion. Patients with the ferritin level >300ng/ml and < 1000ng/ml, will be included in Group 1. Interventions: Deferasirox, Vitamin D (100000/week) and Azacitidine (75 mg/kg/day Day1 today 7) 5 patients in each cohort: Cohort 1: Deferasirox: 5mg/kg/d Cohort 2: Deferasirox: 10mg/kg/d Cohort 3: Deferasirox: 15mg/kg/d	Drug: Deferasirox, Vitamin D and Azacitidine; association of Deferasirox (group 1: 5-10-15/mg/kg/day according to dose level group), Vitamine D (100000U/week) and Azacitidine (75 mg/kg/day day1-day7); Other Names: Vidaza; Exjade; VitaminD
EXPERIMENTAL: ferritin level > 1000ng/ml; Patients will be included in 2 groups according to the ferritin level at time of inclusion. Patients with the ferritin level > 1000ng/ml, will be included in Group 2. Intervention: Deferasirox, Vitamin D (100000/week) and Azacitidine (75 mg/kg/day Day1 today 7) 5 patients in each cohort: Cohort 1: Deferasirox: 10mg/kg/d Cohort 2: Deferasirox: 15mg/kg/d Cohort 3: Deferasirox: 20mg/kg/d	Drug: Deferasirox, Vitamin D and Azacitidine; association of Deferasirox (group 1: 5-10-15/mg/kg/day according to dose level group), Vitamine D (100000U/week) and Azacitidine (75 mg/kg/day day1-day7); Other Names: Vidaza; Exjade; VitaminD

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To determine the maximal tolerated dose(MTD	patient will be evaluable after at least one cycle. Treatment will be administrated during 6 month and responders will be treated until progression or death	6 month of treatment

Collaborators and Investigators

• Sponsor: Groupe Francophone des Myelodysplasies
• Collaborators: Novartis
• Investigators: Principal Investigator: Olivier Hermine, MD, Necker Hospital (Paris); Study Director: Pierre Fenaux, MD, Saint Louis Hospital (Paris); Study Chair: Felipe Suarez, MD, Necker Hospital (Paris)

Study record dates

Study Major Dates

• Study Start (ACTUAL): February 1, 2013
• Primary Completion (ANTICIPATED): February 1, 2019
• Study Completion (ANTICIPATED): February 1, 2019

Study Registration Dates

• First Submitted: October 24, 2012
• First Submitted That Met QC Criteria: October 30, 2012
• First Posted (ESTIMATE): October 31, 2012

Study Record Updates

• Last Update Posted (ACTUAL): January 10, 2018
• Last Update Submitted That Met QC Criteria: January 9, 2018
• Last Verified: January 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Micronutrients; Vitamins; Bone Density Conservation Agents; Chelating Agents; Sequestering Agents; Iron Chelating Agents; Vitamin D; Azacitidine; Deferasirox
• Other Study ID Numbers: GFM-EXVD-AZA-2011-005623-41

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO