Intensified Azacitidine in High Risk Myelodysplastic Syndrome (MDS)

Sponsor

Groupe Francophone des Myelodysplasies (Other)

Overall Status

Completed

CT.gov ID

NCT01305460

Collaborator

(none)

Enrollment

Locations

Arm

52.4

Actual Duration (Months)

1.3

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

A phase I/II study of the efficacy and safety of an intensified schedule of Azacitidine (Vidaza®) in intermediate-2 and high risk MDS patients.

Condition or Disease	Intervention/Treatment	Phase
Myelodysplastic Syndrome	Drug: Azacitidine	Phase 1/Phase 2

Detailed Description

The study is an open-label, multicenter phase I/II study.

Treatment Regimen, Dosage and Duration:

Treatment will consist of azacitidine 75mg/m2/d for 5 days every 14 days for 4 cycles (azacitidine-14, cycles 1-4).

Patients achieving CR or PR will be then treated with 4 cycles of azacitidine 75mg/m2/d for 5 days administered every 21 days (azacitidine-21, cycles 5 to 8) followed by cycles of azacitidine 75mg/m2/d for 7 days administered every 28 days (azacitidine-28, cycles 9 and beyond), to be continued until progression/relapse or toxicity arises).
Patients not obtaining CR or PR after the initial 4 cycles of azacitidine-14 will continue to receive azacitidine 75mg/m2/d for 5 days every 14 days for 4 additional cycles (cycles 5 to 8). If they achieve CR, PR or HI after 8 cycles, they will then be treated with azacitidine 75mg/m2/d for 5 days every 21 days (azacitidine-21, cycles 9 to

and subsequently cycles of azacitidine 75mg/m2/d for 7 days administered every 28 days (azacitidine-28, cycles 13 and beyond) until progression/relapse or toxicity arises.

Patients not obtaining CR, PR or HI after 8 cycles of azacitidine-14 will go "off-study".

Number of patients to be included:

The trial will enroll at least 27 patients (phase I of the trial) and a maximum of 81 patients (phase II of the trial). A safety analysis will be performed by an independent DSMB after inclusion of 9, 18 and 27 patients. This safety analysis will focus particularly on the clinical consequences of cytopenias. Moreover, a teleconference will be organized twice monthly between the PI and investigators to share safety observations and take appropriate actions if needed. CRFs will be collected every cycle focusing particularly on the safety of this dose intensified study. All AE and SAE will be reported to the DSMB upon reception.

Primary Endpoint:

-Response rate (including CR and PR) according to IWG 2006 criteria for MDS after 4 and 8 cycles 75mg/m2/d azacitidine administered every 2 weeks.

Secondary Endpoints:

Safety/toxicity profile of azacitidine administered every 14 days (NCI-CTAE)
Responses (CR, PR, marrow CR, HI) according to IWG 2006 criteria and their duration
Overall survival and progression (IPSS/AML) free survival.

Sample Size and Duration of Trial:

The first stage of the trial will include 27 patients. The trial will be terminated if 9 or fewer responses are observed. Otherwise, additional patients will be recruited in the second stage until a total sample size of 81 patients is reached.

Duration of inclusion: 24 months for 81 patients Duration of follow-up: 24 months

Study Design

Study Type:

Interventional

Actual Enrollment :

27 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase I/II Study of the Efficacy and Safety of an Intensified Schedule of Azacitidine (Vidaza®) in Intermediate-2 and High Risk MDS Patients

Actual Study Start Date :

Jul 5, 2011

Actual Primary Completion Date :

Dec 1, 2011

Actual Study Completion Date :

Nov 16, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Azacitidine intensified dose	Drug: Azacitidine Treatment will consist of azacitidine 75mg/m2/d for 5 days every 14 days for 4 cycles. Patients achieving CR or PR will be then treated with 4 cycles of azacitidine 75mg/m2/d for 5 days every 21 days followed by cycles of azacitidine 75mg/m2/d for 7 days administered every 28 days (cycles 9 and beyond), to be continued until progression/relapse or toxicity arises. Patients not obtaining CR or PR after the initial 4 cycles of azacitidine-14 will continue to receive azacitidine 75mg/m2/d for 5 days every 14 days for 4 additional cycles (cycles 5 to 8). If they achieve CR, PR or HI after 8 cycles, they will then be treated with azacitidine 75mg/m2/d for 5 days every 21 days (cycles 9 to 12) and subsequently cycles of azacitidine 75mg/m2/d for 7 days administered every 28 days (cycles 13 and beyond) until progression/relapse or toxicity arises. Patients not obtaining CR, PR or HI after 8 cycles of azacitidine-14 will go "off-study". Other Names: Vidaza

Arm

Intervention/Treatment

Experimental: Azacitidine intensified dose

Drug: Azacitidine

Treatment will consist of azacitidine 75mg/m2/d for 5 days every 14 days for 4 cycles. Patients achieving CR or PR will be then treated with 4 cycles of azacitidine 75mg/m2/d for 5 days every 21 days followed by cycles of azacitidine 75mg/m2/d for 7 days administered every 28 days (cycles 9 and beyond), to be continued until progression/relapse or toxicity arises. Patients not obtaining CR or PR after the initial 4 cycles of azacitidine-14 will continue to receive azacitidine 75mg/m2/d for 5 days every 14 days for 4 additional cycles (cycles 5 to 8). If they achieve CR, PR or HI after 8 cycles, they will then be treated with azacitidine 75mg/m2/d for 5 days every 21 days (cycles 9 to 12) and subsequently cycles of azacitidine 75mg/m2/d for 7 days administered every 28 days (cycles 13 and beyond) until progression/relapse or toxicity arises. Patients not obtaining CR, PR or HI after 8 cycles of azacitidine-14 will go "off-study".

Other Names:

Vidaza

Outcome Measures

Primary Outcome Measures

Response rate (including CR and PR) according to IWG 2006 criteria for MDS after 4 and 8 cycles 75mg/m2/d azacitidine administered every 2 weeks. [2 months]
After 4 courses treatment

Secondary Outcome Measures

Safety/toxicity profile of azacitidine administered every 14 days (NCI-CTAE) [1-24 months]
After each course of treatment until end of treatment.
Responses (CR, PR, marrow CR, HI) according to IWG 2006 criteria and their duration. [2-4 months]
After 4 and 8 courses of treatment.
Overall survival and progression (IPSS/AML) free survival. [2 months and further]
After 4 course of treatment.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

MDS defined according to WHO classification (also including RAEB-T according to FAB classification) (see appendix 1) with intermediate-2 or high risk IPSS (see appendix 1).
Age ≥ 18 years and <75 years.
Must understand and voluntarily sign an informed consent form.
Must be able to adhere to the study visit schedule and other protocol requirements.
Patients must have ECOG performance status (PS) of 0 - 2, and no major comorbidities preventing administration of an intensified regimen of azacitidine.
Women of child-bearing potential (i.e., women who are pre-menopausal or not surgically sterile) must :
Have a negative serum or urine pregnancy test within 2 weeks prior to beginning treatment on this study. Lactating patients are excluded.
Agree to use, and to be able to comply with, effective contraception without interruption, 4 weeks before starting study drug throughout the entire duration study drug therapy (including doses interruptions) and for 3 months after the end of the study drug therapy.
Male patients must :
Agree the need for the use of a condom if engaged in sexual activity with a woman of childbearing potential during the entire period of treatment, even if disruption of treatment and during 3 months after end of treatment.
Agree to learn about the procedures for preservation of sperm before starting treatment.
Creatinine < 1.5 N or estimated clearance of creatinine above 30 ml/min.
Serum aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) or alanine transaminase (ALT)/serum glutamate pyruvate transaminase (SGPT) < 3.0 x upper limit of normal (ULN).
Serum total bilirubin < 1.5 mg/dL. (except for unconjugated hyperbilirubinemia due to Gilbert's disease or secondary to MDS-related dyserythropoiesis).
Health insurance

Exclusion Criteria:

Patients with a history of myeloproliferative syndrome or CMML.
Known positive status for human immunodeficiency virus (HIV) or hepatitis B or C.
Pregnant and lactating patients are excluded because the effects of azacitidine on a fetus or a breast-fed child are unknown.
Uncontrolled intercurrent illness including, but not limited to uncontrolled infection, symptomatic congestive heart failure (NYHA > II), cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
Patients receiving any other standard or investigational cytotoxic treatment for their hematologic malignancy in the last 8 weeks
Any medical condition which in the opinion of the investigator places the patient at an unacceptably high risk for toxicities of an intensified regimen of azacitidine.
Less than 6 months since prior allogeneic bone marrow transplantation.
Less than 3 months since prior autologous bone marrow or stem cell transplantation
Active cancer or prior history of malignancy other than MDS (except basal cell or squamous cell carcinoma or carcinoma in situ of the cervix or breast) unless the subject has been free of disease for ≥ 3 years.
Prior treatment with azacitidine.
Known allergy/intolerance to azacitidine or mannitol.
ECOG > 2.
Life expectancy of less than 3 months.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	CHU d'Amiens	Amiens	France	80054
2	Centre Hospitalier de La Cote Basque	Bayonne	France	64100
3	Hôpital Avicenne	Bobigny	France	93009
4	Centre henri Mondor	Creteil	France	94010
5	CHU Albert Michallon - Service d'Hématologie Clinique	Grenoble	France	38043
6	Centre Hospitalier du Mans	Le Mans cedex	France	72037
7	Hôpital Huriez	Lille	France	59037
8	Hôpital Paoli Calmettes	Marseille	France	13273
9	Centre Hospitalier de Meaux	Meaux	France	77100
10	CHU Brabois	Nancy	France	54511
11	CHU de nantes	Nantes	France	44093
12	Hôpital l'Archet de Nice	Nice	France	06202
13	Hôpital Cochin	Paris	France	75004
14	Hôpital Saint Louis	Paris	France	75010
15	Hopital Saint Louis - AP-HP, Hematology Dpt	Paris	France	75475
16	CHU de Haut-Lévèque	Pessac	France	33604
17	CHU de Poitiers	Poitiers	France	86021
18	CHRU Annecy Hospital	Pringy	France	74374
19	Hôpital Pontchaillou	Rennes	France	35033
20	Hopital Purpan Service d'Hématologie Clinique	Toulouse	France	31059
21	CH de Valence	Valence	France	26953

Sponsors and Collaborators

Groupe Francophone des Myelodysplasies

Investigators

Study Chair: Lionel Adès, MD, Groupe Francophone des Myélodysplasies
Principal Investigator: Simone Boehrer, MD, Groupe Francophone des Myélodysplasies