addition of vorinostat to azacitidine in higher risk mds a phase ii add-on study in patients with azacitidine failure

Conditions: Myelodysplastic Syndrome

Summary: azacytidine (aza) is the current standard of care for frontline patient treated with high-risk mds and is clinically active in all type of mds, however, 50% of the patients will never respond. vorinostat is an orally available hdac inhibitor with clinical activity in mds and proven in vitro synergy with aza. patient treated upfront with a combination of this agents have shown more responses based on phase i/ii data. in the present study, we will use the combination of these two drugs to try to create a synergetic effect and generate a response for patients who experienced treatment failure after aza. all eligible patients will be treated with azacitidine and oral vorinostat for 6 cycles of 28 days. study design

patients who meet eligibility criteria will be administered vorinostat orally at 300mg two times daily for 7 days as outlined in table 1.1. 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. patients will receive 6 cycles unless progression is documented. patients with a complete remission (cr), partial remission (pr), or hematological improvement (hi), will be treated until progression.

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 \ 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.