Rigosertib versus best supportive care for patients with high-risk myelodysplastic syndromes after failure of hypomethylating drugs (ONTIME): a randomised, controlled, phase 3 trial.

BACKGROUND: Hypomethylating drugs are the standard treatment for patients with high-risk myelodysplastic syndromes. Survival is poor after failure of these drugs; there is no approved second-line therapy. We compared the overall survival of patients receiving rigosertib and best supportive care with that of patients receiving best supportive care only in patients with myelodysplastic syndromes with excess blasts after failure of azacitidine or decitabine treatment. METHODS: We did this randomised controlled trial at 74 hospitals and university medical centres in the USA and Europe. We enrolled patients with diagnosis of refractory anaemia with excess blasts (RAEB)-1, RAEB-2, RAEB-t, or chronic myelomonocytic leukaemia based on local site assessment, and treatment failure with a hypomethylating drug in the past 2 years. Patients were randomly assigned (2:1) to receive rigosertib 1800 mg per 24 h via 72-h continuous intravenous infusion administered every other week or best supportive care with or without low-dose cytarabine. Randomisation was stratified by pretreatment bone marrow blast percentage. Neither patients nor investigators were masked to treatment assignment. The primary outcome was overall survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT01241500. FINDINGS: From Dec 13, 2010, to Aug 15, 2013, we enrolled 299 patients: 199 assigned to rigosertib, 100 assigned to best supportive care. Median follow-up was 19·5 months (IQR 11·9-27·3). As of Feb 1, 2014, median overall survival was 8·2 months (95% CI 6·1-10·1) in the rigosertib group and 5·9 months (4·1-9·3) in the best supportive care group (hazard ratio 0·87, 95% CI 0·67-1·14; p=0·33). The most common grade 3 or higher adverse events were anaemia (34 [18%] of 184 patients in the rigosertib group vs seven [8%] of 91 patients in the best supportive care group), thrombocytopenia (35 [19%] vs six [7%]), neutropenia (31 [17%] vs seven [8%]), febrile neutropenia (22 [12%] vs ten [11%]), and pneumonia (22 [12%] vs ten [11%]). 41 (22%) of 184 patients in the rigosertib group and 30 (33%) of 91 patients in the best supportive care group died due to adverse events and three deaths were attributed to rigosertib treatment. INTERPRETATION: Rigosertib did not significantly improve overall survival compared with best supportive care. A randomised phase 3 trial of rigosertib (NCT 02562443) is underway in specific subgroups of patients deemed to be at high risk, including patients with very high risk per the Revised International Prognostic Scoring System criteria. FUNDING: Onconova Therapeutics, Leukemia & Lymphoma Society.

Initiation of epoetin-alpha therapy at a starting dose of 120,000 units once every 3 weeks in patients with cancer receiving chemotherapy: an open-label, multicenter study with randomized and nonrandomized treatment arms.

BACKGROUND: Epoetin-alpha initiated once weekly, followed by once-every-3-weeks maintenance, was effective and well tolerated for chemotherapy-induced anemia. This study evaluated a starting dose of epoetin-alpha 120,000 U once every 3 weeks for chemotherapy-induced anemia using early and late initiation regimens. METHODS: Patients with baseline hemoglobin 11.0-12.0 g/dL were randomly assigned to early intervention with immediate epoetin-alpha (n = 68) or to standard intervention with epoetin-alpha when hemoglobin decreased to <11 g/dL (n = 68). A third group of patients with baseline hemoglobin <11 g/dL (n = 50) were enrolled but not randomized; epoetin-alpha was initiated immediately. The primary endpoint was mean proportion of hemoglobin values within the target range (11.0-13.0 g/dL) among randomized patients. RESULTS: The mean proportion of hemoglobin values in range through week 16 was 60% in each randomized group. Mean hemoglobin by week showed similar increases over the study. Blood transfusions were administered in 9%, 8%, and 24% of patients in the early, standard, and nonrandomized groups. Mean epoetin-alpha doses were similar between treatment groups. Dose reductions and withholds were more common in the early intervention group. Adverse events (eg, diarrhea, fatigue, nausea) were consistent with the safety profile for epoetin-alpha . Clinically relevant thrombotic vascular events (regardless of relationship to study treatment) were reported for 9%, 12%, and 12% of patients in the early, standard, and nonrandomized groups. CONCLUSIONS: Early and standard intervention with epoetin-alpha, administered once every 3 weeks, increased and maintained hemoglobin levels within 11.0-13.0 g/dL in patients with chemotherapy-induced anemia.

An extended maintenance dosing regimen of epoetin alfa 80,000 U every 3 weeks in anemic patients with cancer receiving chemotherapy.

BACKGROUND: The purpose of this study was to evaluate the safety and efficacy of epoetin alfa (EPO) at an initial dose of 60,000 Units (U) once weekly (QW) followed by extended dosing of 80,000 U every 3 weeks (Q3W) in patients with chemotherapy-induced anemia (CIA). MATERIALS AND METHODS: Anemic patients (hemoglobin [Hb] < or = 11 g/dl) receiving Q3W chemotherapy for nonmyeloid malignancy were enrolled in this prospective, open-label, single-arm study to receive EPO 60,000 U subcutaneously (SC) QW (initial dosing phase [IDP]) until a target Hb level of 12 g/dl was reached (maximum 12 weeks). Patients who achieved an Hb level of 12 g/dl at any point during the IDP then entered the extended dosing phase (EDP; EPO 80,000 U SC Q3W). Maximum study duration (IDP + EDP) was 24 weeks. The primary endpoint was the proportion of patients achieving a hematopoietic response (Hb increase > or = 2 g/dl from baseline or Hb > or = 12 g/dl) during the IDP. RESULTS: One hundred fifteen patients were enrolled. During the IDP, 76% (84/110) of patients achieved a hematopoietic response, and 15% (17/115) received red blood cell (RBC) transfusion. Sixty-three percent (73/115) of patients entered the EDP, and 88% (64/73) of these patients maintained a mean Hb level > 11.0 and < or =13.0 g/dl. Two of 73 patients received RBC transfusion during the EDP. Adverse events were consistent with the underlying disease and chemotherapy treatment. CONCLUSION: These results suggest that initiation of EPO 60,000 U SC QW is effective in the treatment of CIA and that EPO 80,000 U SC Q3W can be an effective extended dosing option.

An extended dosing regimen of epoetin alfa 60,000 units every 2 weeks in anemic patients with cancer receiving chemotherapy.

PURPOSE: This open-label study evaluated the safety and efficacy of epoetin alfa 60,000 U once weekly Initialsly followed by 60,000 U every 2 weeks in anemic patients with cancer receiving chemotherapy. PATIENTS AND METHODS: Patients receiving weekly or every- 4-weeks chemotherapy regimens for nonmyeloid malignancy and with hemoglobin (Hb) level /= 1 dose of epoetin alfa. Sixty-eight percent of patients had hematopoietic response (Hb increase >/= 2 g/dL from baseline or Hb level >/= 12 g/dL during the IDP; primary endpoint). Eighty-four patients entered the EDP; 74 of 84 patients (88%) maintained average Hb level between 11 g/dL and 13 g/dL up to time of withdrawal or study completion. Adverse events were consistent with the underlying disease process and chemotherapy treatment. Six patients (4.7%) in the IDP and 8 patients (9.5%) in the EDP experienced clinically relevant thrombotic vascular events. CONCLUSION: In this study, approximately 90% of patients receiving an extended dosing regimen of epoetin alfa 60,000 U every 2 weeks were able to maintain Hb level between 11 g/dL and 13 g/dL.

Randomized, open-label comparison of epoetin alfa extended dosing (80 000 U Q2W) vs weekly dosing (40 000 U QW) in patients with chemotherapy-induced anemia.

OBJECTIVE: This randomized, open-label, multicenter study compared the efficacy and safety of epoetin alfa (EPO) 80 000 U every 2 weeks (Q2W) to the FDA-approved regimen of 40 000 U weekly (QW) in patients with chemotherapy-induced anemia. RESEARCH DESIGN AND METHODS: A total of 310 patients with nonmyeloid malignancy and baseline hemoglobin (Hb)

An open-label pilot study to evaluate a flexible dosing regimen of epoetin alfa for the treatment of chemotherapy-induced anemia: 60,000 units weekly followed by 60,000 units every 2 weeks.

PURPOSE: This open-label, single-arm pilot study assessed the safety and efficacy of administering an Initials epoetin alfa dose of 60,000 U subcutaneously once weekly (Initials dosing phase [IDP]) followed by an extended dose regimen of 60,000 U subcutaneously every 2 weeks (extended dosing phase [EDP]). PATIENTS AND METHODS: Patients who had a hematologic response, defined as hemoglobin (Hb) level increase >/= 1 g/dL from week 1 baseline at any time during the 4-week IDP (the primary efficacy endpoint), were eligible to enter the EDP at week 5 and receive every-other-week treatment for up to 12 additional weeks. Patients who did not exhibit this increase in the IDP were withdrawn. RESULTS: Fifty-one patients were enrolled; the mean baseline Hb level was 10.1 g/dL +/- 0.79 g/dL. Thirty-three patients (64.7%) met the primary efficacy endpoint of Hb increase >/= 1 g/dL during the IDP; 29 patients (56.9%) proceeded to the EDP. Mean Hb level at entry to the EDP was 12.4 g/dL +/- 0.99 g/dL. Further Hb increase in the EDP (average Hb level >/= week 5 Hb value) was achieved in 12 of 29 patients (41.4%). Final Hb value for patients in the EDP was 11.7 g/dL +/- 1.28 g/dL. Four patients received a total of 5 red blood cell transfusions during the study. Epoetin alfa was well tolerated and had a safety profile similar to that observed with labeled dosing. Two patients experienced a clinically relevant thrombotic vascular event. CONCLUSION: RESULTS from this pilot study suggest that higher Initials weekly dosing of epoetin alfa followed by extended dosing is safe and effective for treating chemotherapy-induced anemia.