Addition of Vorinostat to Azacitidine in Higher Risk MDS a Phase II add-on Study in Patients With Azacitidine Failure (GFM-AZA-VOR)
Myelodysplastic Syndrome
About this trial
This is an interventional treatment trial for Myelodysplastic Syndrome
Eligibility Criteria
Inclusion Criteria:
- Myelodysplastic syndrome (WHO and FAB classified) including: RA, RARS, RCMD, RCMD-RS RAEB , RAEB-t and CMML with WBC < 13000/mm3)
- IPSS score 1.5 or higher (IPSS intermediate-2 and high risk categories) at the beginning of azacitidine,
- Absence of response (CR, PR, marrow CR or HI according to IWG 2006) after a minimum of 6 cycles of azacitidine single agent at 75 mg/m²/d for 7 days per cycle. Patients with a previous dose reduction of AZA may be eligible if the maximum tolerated dose was equal to or above 350mg/m2/cycle (i.e. 50 mg/m²/d for 7 days or 75mg/m2/d for 5 days).
- Age more or egal to 18 years
- ECOG performance status ≤ 2 (cf. appendix 2);
- Patient must have adequate organ function as indicated by the following laboratory values
Renal Serum creatinine or calculated creatinine clearancea < 2 mg/dl OR ≥ 60 mL/min for patients with creatinine levels > 1.5 X institutional ULN Hepatic
Serum total bilirubin ≤ 2.5 X ULN OR direct bilirubin ≤ ULN for patients with total bilirubin levels ≥ 2 mg/dL.
AST (SGOT) and ALT (SGPT) ≤ 2.5 times ULN Alkaline Phosphatase ≤ 5 X ULN If > 2.5 X ULN, then liver fraction should be ≤ 2.5 X ULN a Creatinine clearance should be calculated per institutional standard.
- Patient is known to not be refractory to platelet transfusions.
- Patient ineligible for allogeneic hematopoietic stem cell transplantation at the time of inclusion in the study
- Adherence to the study visit schedule;
- Women of childbearing potential must:
Agree to use effective contraception without interruption throughout the study and for a further 3 months after the end of treatment;
- Men must: Agree to not conceive during the treatment and to use effective contraception during the treatment period (including periods of dose reduction or temporary suspension) and for a further 3 months after the end of treatment if their partner is of childbearing potential.
Agree to learn about the procedures for preservation of sperm.
Exclusion Criteria:
- Patient had prior treatment with an HDAC inhibitor (e.g., depsipeptide or NSC-630176, MS 275, LAQ-824, PXD-101, LBH589, MGCD0103, CRA024781, etc). Patients who have received compounds with HDAC inhibitor-like activity, such as valproic acid, as anti-tumor therapy should not enroll in this study. Patients who have received such compounds for other indications, e.g. valproic acid for epilepsy, may enroll after a 30-day washout period.
- Severe infection or any other uncontrolled severe condition.
- Last dose of AZA was given more than 3 months before entering the trial.
- Patient already enrolled in another therapeutic trial of an investigational drug
- HIV infection or active hepatitis B or C.
- Patient has a known allergy or hypersensitivity to any component of vorinostat or azacitidine.
- Active cancer, or cancer during the year prior to trial entry other than basal cell carcinoma or carcinoma in situ of the cervix or breast.
- Less than 30 days since prior treatment with growth factors (EPO, G-CSF) or non-cytotoxic agents (including low-dose oral chemotherapy); in the event of prior treatment with cytotoxic or demethylating agents, an interval of 3 months is required;
- Patient is on any systemic steroids that have not been stabilized to the equivalent of ≤ 10 mg/day prednisone during the 4 weeks prior to the start of the study drugs.
- Patients with clinical evidence of CNS leukemia.
- Patient has a history of GI surgery or other procedures that might interfere with the absorption or swallowing of the study drugs.
- Women who are or could become pregnant, or who are currently breastfeeding
- Patient eligible for allotransplantation at the time of inclusion.
Sites / Locations
- CHU d'Angers
- CH Annecy
- Hôpital Avignon
- Centre hospitalier de la côte Basque
- Hôpital Avicenne
- CHU de Grenoble
- CH Le mans
- CH Lyon Sud
- IPC-Unité d'Hématologie 3
- CHU Nantes
- Hôpital Archet1
- GHU Caremeau
- Hôpital Saint Louis
- Hopital Saint Louis - AP-HP, Hematology Dpt
- Hôpital Saint-Louis
- Hopital Cochin-Hematology
- Centre Hospitalier Joffre
- CHU de Haut-Lévèque
- Centre Henri Becquerel
- Hopital Purpan-Medecine interne
- Hôpital PURPAN, Service d'Hématologie Clinique
- CHU Bretonneau
- CH de Valence
- CHU Brabois
Arms of the Study
Arm 1
Experimental
Azacitidine and oral vorinostat
Patients who meet eligibility criteria will be administered vorinostat orally at 300mg two times daily for 7 days. AZA will be administered SC at 75 mg/m2/day x 7 consecutive days or at maximum tolerated dose if a dose reduction of AZA was needed before entering the trial with a minimum dose of 50mg/m2/d for 7 consecutive days. Each cycle will last 28 days with AZA starting on day 1 of each cycle and vorinostat starting on day 3.