Idarubicin Combined to Azacitidine in Int-2 or High Risk Myelodysplastic Syndromes

A Phase I-II Study of the Efficacy and Safety of Idarubicin Combined to Azacitidine in Int-2 or High Risk Myelodysplastic Syndromes

Patients will receive escalating doses of ldarubicin combined to Azacitidine given at the FDA/EMEA approved Schedule and dosing.

For the Phase I study :

Determine the safety and tolerance of escalating doses of Idarubicin combined to Azacitidine in patients with INT-2 or higher risk MDS.

For the phase II study:

Primary: Evaluate rate and duration of response (according to IWG 2006 criteria and IWG 2000 criteria) to the combination of Idarubicin and Azacitidine in patients with INT-2 or higher risk MDS

Study Overview

• Status: Completed
• Conditions: High Grade Myelodysplastic Syndrome Lesions
• Intervention / Treatment: Drug: azacitidine and idarubicin

Detailed Description

Patients will receive ldarubicin combined to Azacitidine.

• The first 10 patients will receive Idarubicin 5 mg/m2/d on day 8 of each cycle of Azacitidine 75 mg/m2/d CI during 7 days (First Cohort ).
• Progression or not to the next cohort of 10 patients : Idarubicin 10 mgm2/d on day 8 of each cycle of Azacitidine 75 mg/m2/d CI during 7 days (Second cohort of 10 patients), will be decided after completion of the first cohort, after review of hematological toxicity by an independent safety review committee (SRC).
• The next 21 patients will be treated either according to the first or second cohort schedule of Idarubicin, after review of hematological toxicity and efficacy by an independent safety review committee (SRC).

• Study Type: Interventional
• Enrollment (Actual): 41
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• France
  • Amiens, France, 80054
    • CHU d'Amiens
  • Angers, France, 49033
    • CHU d'Angers
  • Bayonne, France, 64100
    • Hopital de la cote Basque
  • Bobigny, France, 93009
    • Hôpital Avicenne
  • Caen, France, 14033
    • CHRU de Caen - Hôpital Côte de Nacre
  • Clermont-Ferrand, France, 63000
    • CHU Estaing
  • Dijon, France, 21000
    • CHU Dijon Hôpital d'enfants
  • Grenoble, France, 38043
    • Chu Albert Michallon
  • Le Mans, France, 72000
    • CH Le mans
  • Limoges, France, 87042
    • CHU de Limoges
  • Lyon, France, 69495
    • Centre Hospitalier Lyon Sud
  • Marseille, France, 13009
    • Institut Paoli-Calmette
  • Nancy, France, 54511
    • CHU Brabois
  • Nantes, France, 44093
    • Chu Hotel Dieu
  • Nice, France, 06202
    • CHU NICE, Hôpital l'Archet
  • Paris, France, 75012
    • Hopital Saint Antoine
  • Paris, France, 75014
    • Hopital Cochin
  • Paris, France, 75010
    • Hôpital saint louis - Hématologie Clinique
  • Paris, France, 75010
    • Hôpital Saint Louis - Hématologie Séniors
  • Perpignan, France, 66046
    • Centre Hospitalier Joffre
  • Poitiers, France, 86021
    • CHU De Poitiers
  • Périgueux, France, 24019
    • CH de Périgueux
  • Rennes, France, 35033
    • Hopital Pontchaillou
  • Rouen, France, 76038
    • Centre Henri Becquerel
  • Strasbourg, France, 67098
    • Hôpital Hautepierre
  • Toulouse, France, 31059
    • Hôpital PURPAN - Hématologie Clinique
  • Toulouse, France, 31059
    • Hôpital Purpan - Médecine Interne
  • Tours, France, 37000
    • Hopital Bretonneau
  • Valence, France, 26953
    • CH de Valence
  • Villejuif, France, 94805
    • Institut Gustave Roussy
  • Bordeaux - Pessac
    • Pessac, Bordeaux - Pessac, France, 33604
      • CHU de Haut-Lévèque
• Tunisia
  • Tunis, Tunisia
    • Hôpital Aziza Othmana

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:

• Documented diagnosis of MDS, or CMML with WBC < 13,000/mm3 that meets IPSS criteria for intermediate-2 or high-risk disease,
• IPSS score ≥1.5
• Myocardial function do not contraindicate the use of idarubicin
• Age ≥ 18 years
• Performance Status ≤2 according to ECOG.
• Serum creatinine < 1.5 x ULN and normal levels of electrolytes (serum sodium 136-145 mmol/l, Potassium 3,5-4,5 mmol/l, alkaline Reserve 23-29 mmol/l, , Calcium 2,15-2,5 mmol/l, Phosphore 0,87-1,45 mmol/l) Serum aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) or alanine transaminase (ALT)/serum glutamate pyruvate transaminase (SGPT) < 1.5 x upper limit of normal (ULN)
• Serum total bilirubin < 1.5 x ULN.
• Must be able to adhere to the study visit schedule and other protocol requirements
• Signed informed consent.

Female subjects of childbearing potential must:

• Accept effective contraception without interruption throughout the duration of study and up to three months after the end of treatment.

Male subjects must

• Agree to use condoms throughout study drug therapy, during any dose interruption and for one week after cessation of study therapy and up to three months after the final treatment if their partner is of childbearing potential and has no contraception.
• Agree to learn the procedures for preservation of sperm

Exclusion Criteria:

• Uncontrolled infection
• Prior therapy with anthracycline for MDS.
• Eligible for an allogeneic stem cell transplantation.
• Prior therapy with demethylating agents within the last 3 months
• Prior therapy with Hematopoietic growth factor (ESA or G-CSF) agents or cytotoxic agents (oral chemotherapy, low doses AraC) within the last 30 days.
• Prior history of malignancy other than MDS (except basal cell or squamous cell carcinoma or carcinoma in situ of the cervix or breast)
• Pregnant or lactating females
• Known HIV-1 positivity
• Contra-indication to Anthracyclines

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

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: azacitidine 75mg/m²/d + idarubicin 5mg/m²/d; phase I : palier 1 have 10 patients and palier 2 have to 10 patients. palier 1: Ida 5mg/m²/d (D8) + AZACITIDINE 75mg/m²/d (D1-D7)	Drug: azacitidine and idarubicin; azacitidine:100mg, 75mg/m²/d, during 7days every 28 days (D1-D7). Idarubicin: 5mg/ml, 5mg/m²/d (palier1) or 10mg/m²/d (palier2), D8
Experimental: Azacitidine 75mg/m²/d + idarubicin 10mg/m²/d; palier 2: Ida 10mg/m²/d (D8)+ Azacitidine 75mg/m²/d (D1-D7)	Drug: azacitidine and idarubicin; azacitidine:100mg, 75mg/m²/d, during 7days every 28 days (D1-D7). Idarubicin: 5mg/ml, 5mg/m²/d (palier1) or 10mg/m²/d (palier2), D8

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
To determined tolerance and dose limiting toxicities to idarubicin and azacitidine association.	After 12 weeks treatment

Secondary Outcome Measures

Outcome Measure	Time Frame
to determined overall response rate and response duration	After six months

Collaborators and Investigators

• Sponsor: Groupe Francophone des Myelodysplasies
• Investigators: Principal Investigator: Lionel ADES, PHD,MD, GFM: Groupe Francophone des Myélodysplasies

Study record dates

Study Major Dates

• Study Start (Actual): December 30, 2010
• Primary Completion (Actual): June 1, 2011
• Study Completion (Actual): May 9, 2016

Study Registration Dates

• First Submitted: February 25, 2011
• First Submitted That Met QC Criteria: February 25, 2011
• First Posted (Estimate): February 28, 2011

Study Record Updates

• Last Update Posted (Actual): June 7, 2017
• Last Update Submitted That Met QC Criteria: June 6, 2017
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Keywords: myelodysplastic syndrome, azacitidine, idarubicin
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Disease; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Syndrome; Myelodysplastic Syndromes; Preleukemia; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Azacitidine; Idarubicin
• Other Study ID Numbers: GFM-AZA-IDA-09

Plan for Individual participant data (IPD)

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