5-azacitidine and Thalidomide for patients with Myelodysplastic Syndromes to assess safety and efficacy (MDS03)

Funding

Commercial sector/Industry,Pharmion Australia

Scientific enquiries

Dr Melita Kenealy

Brief Summary

5-azacitidine, a demethylating agent, has been approved for use in USA for treatment of Myelodysplastic Syndromes (MDS), with overall response rates of approximately 48%, a delay to progression to acute leukaemia or death and an improvement in quality of life. Thalidomide has also shown some activity as a single agent in MDS though with poor tolerance at doses above 100mg/day. Neither of these agents is currently routinely available in Australia for MDS. This trial aims to show the safety and to .... 5-azacitidine, a demethylating agent, has been approved for use in USA for treatment of Myelodysplastic Syndromes (MDS), with overall response rates of approximately 48%, a delay to progression to acute leukaemia or death and an improvement in quality of life. Thalidomide has also shown some activity as a single agent in MDS though with poor tolerance at doses above 100mg/day. Neither of these agents is currently routinely available in Australia for MDS. This trial aims to show the safety and tolerability of the combination of these two agents in MDS, with responses at least as good as single agent 5-azacitidine, and to investigate further the mechanisms by which these drugs work and whether we can predict which patients may be more likely to respond.
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Key Inclusion Criteria

1. Subjects with myelodysplastic syndrome (MDS), either de novo or treatment related 2. patients with refractory anaemia or refractory anaemia with ringed sideroblasts to meet one of the following additional criteria of marrow dysfunction:a. transfusion dependent or symptomatic anemia up to 3 monthsb. clinically significant thrombocytopenia; either significant bleeding, platelet transfusion dependency or thrombocytopenia with at least two counts less than or equal to 50x109/L at least 1 month ap .... 1. Subjects with myelodysplastic syndrome (MDS), either de novo or treatment related 2. patients with refractory anaemia or refractory anaemia with ringed sideroblasts to meet one of the following additional criteria of marrow dysfunction:a. transfusion dependent or symptomatic anemia up to 3 monthsb. clinically significant thrombocytopenia; either significant bleeding, platelet transfusion dependency or thrombocytopenia with at least two counts less than or equal to 50x109/L at least 1 month apartc. significant neutropenia with absolute neutrophil count = 1.0 x 109/L on at least 2 occasions 1 month apart (those patients with refractory anaemia with excess blasts, refractory anaemia with excess blasts in transformation and chronic myelomonocytic leukaemia are not required to meet the above additional criteria). 4. life expectancy 3 months or over5. Eastern Cooperative Oncology Group performance status 0-26. adequate hepatic function as defined by bilirubin = 1.5 x the upper limit of normal and aspartate aminotransferase & alanine aminotransferase = 2 x upper limits of normal 7. adequate renal function 8. provision of written informed consent prior to registration9. males with a female partner of childbearing potential must agree to use at least 2 effective contraceptive methods throughout the study and for 30 days following the date of last dose 10. women of childbearing potential may participate providing they agree to use at least 2 effective contraceptive methods throughout the study and for 30 days following completion, and have a negative serum pregnancy test within 21 days prior to commencement of study treatment.
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Key Exclusion Criteria

1. bone marrow blast count 30% or more2. Grade 3-4 peripheral neuropathy3. prior stem cell transplantation4. prior treatment with thalidomide or its analogues within 30 days of commencing treatment on trial5. any prior treatment with 5-azacitidine, decitabine or any known demethylating agent6. treatment with Granulocyte colony stimulating factor in the 21 days prior to Day 1, androgenic hormones in 14 days prior to Day 1 or any investigational agent in the 30 days prior to Day 17. any serious me .... 1. bone marrow blast count 30% or more2. Grade 3-4 peripheral neuropathy3. prior stem cell transplantation4. prior treatment with thalidomide or its analogues within 30 days of commencing treatment on trial5. any prior treatment with 5-azacitidine, decitabine or any known demethylating agent6. treatment with Granulocyte colony stimulating factor in the 21 days prior to Day 1, androgenic hormones in 14 days prior to Day 1 or any investigational agent in the 30 days prior to Day 17. any serious medical condition which the investigator feels may interfere with the procedures or evaluations of the study8. history of other malignancy within 5 years, except if local disease completely excised with a high probability of cure 9. hepatic tumour or advanced liver disease10. significant cardiac or respiratory disease 11. known active viral infection with human immunodeficiency virus or viral hepatitis B12. known or suspected hypersensitivity to 5-azacitidine, mannitol or thalidomide13. pregnant or breastfeeding females 14. patients unwilling or unable to comply with study protocol15. current participation in another therapeutic clinical trial.
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