efficacy and safety of iv rigosertib in mds patients with excess blasts progressing after azacitidine or decitabine

Conditions: Myelodysplastic Syndromes; Refractory Anemia With Excess Blasts; Chronic Myelomonocytic Leukemia; Cytopenia

Summary: this study will examine the effect intravenously administered rigosertib has on the relationship between bone marrow blasts response and overall survival in myelodysplastic syndromes (mds) patients who have 5-30% bone marrow blasts and who progressed on or after treatment with azacitidine or decitabine.


Eligibility criteria:
inclusion criteria: * diagnosis of mds confirmed within 6 weeks prior to screening according to who criteria or french-american-british (fab) classification. * mds classified as follows, according to who criteria and fab classification: * raeb-1 (5% to 9% bm blasts) * raeb-2 (10% to 19% bm blasts) * cmml (10% to 20% bm blasts) and white blood cells (wbc) \< 13,000/μl * raeb-t (20% to 30% bm blasts), meeting the following criteria: wbc \< 25,000/μl at study entry; or, stable white blood cell (wbc) at least 4 weeks prior to screening and not requiring intervention for wbc control with hydroxyurea, chemotherapy, or leukopheresis. * at least one cytopenia (absolute neutrophil count (anc) \< 1800/μl or platelet (plt) count \< 100,000/μl or hemoglobin (hgb) \< 10 g/dl). * progression (according to 2006 iwg criteria) at any time after initiation of subcutaneous or intravenous azacitidine or decitabine treatment per labeling during the past 2 years, defined as follows: * for patients with ˂ 5% bmbl, ≥ 50% increase in bmbl to ˃ 5% bmbl * for patients with 5-10% bmbl, ≥ 50% increase in bmbl to ˃ 10% bmbl * for patients with 10-20% bmbl, ≥ 50% increase in bmbl to ˃ 20% bmbl * for patients with 20-30% bmbl, ≥ 50% increase in bmbl to ˃ 30% bmbl * any of the following: ≥ 50% decrease from maximum remission/response levels in granulocytes or plt; decrease in hgb concentration by ≥ 2 g/dl; or, transfusion dependence, defined as administration of at least 4 rbc units in the past 8 weeks before screening (patients must have hgb values ˂ 9 g/dl prior to transfusion to be considered), in the absence of another explanation. * has failed to respond to, relapsed following, not eligible, or opted not to participate in bone marrow transplantation. * off all other treatments for mds for at least 4 weeks, except for azacitidine or decitabine. filgrastim (g-csf) and erythropoietin are allowed before and during the study as clinically indicated. * no medical need for induction chemotherapy. * eastern cooperative oncology group (ecog) performance status of 0, 1 or 2. * willing to adhere to the prohibitions and restrictions specified in this protocol. * patient must signed an informed consent form. exclusion criteria: * previous participation in a clinical study of iv or oral rigosertib. * anemia due to factors other than mds (including hemolysis or gastrointestinal \[gi\] bleeding) unless stabilized for 1 week after rbc transfusion. * any active malignancy within the past year, except basal cell or squamous cell skin cancer or carcinoma in situ of the cervix or breast. * uncontrolled intercurrent illness including. * active infection not adequately responding to appropriate therapy. * total bilirubin ≥ 1.5 mg/dl not related to hemolysis or gilbert's disease. * alt/ast ≥ 2.5 x upper limit of normal (uln). * serum creatinine ≥ 2.0 mg/dl. * ascites requiring active medical management including paracentesis, or hyponatremia (defined as serum sodium value of \<130 meq/l). * female patients who are pregnant or lactating. * patients who are unwilling to follow strict contraception requirements. * female patients with reproductive potential who do not have a negative urine beta-human chorionic gonadotropin (βhcg) pregnancy test at screening. * major surgery without full recovery or major surgery within 3 weeks of baseline/cycle 1 day 1 visit. * uncontrolled hypertension (defined as a systolic pressure ≥160 mmhg and/or a diastolic pressure ≥ 110 mmhg). * new onset seizures (within 3 months prior to baseline) or poorly controlled seizures. * any other concurrent investigational agent or chemotherapy, radiotherapy, or immunotherapy. * prior treatment with low-dose cytarabine during the past 2 years. * investigational therapy within 4 weeks of baseline/day 1 visit. * psychiatric illness or social situation that would limit the patient's ability to tolerate and/or comply with study requirements.

Keywords: international working group azacitidine decitabine