Rigosertib in combination with azacitidine in patients with myelodysplastic syndromes or acute myeloid leukemia: Results of a phase 1 study.

Phase 1 results from a Phase 1/2 study comprise 18 patients with myelodysplastic syndromes (MDS; n = 9), acute myeloid leukemia (AML; n = 8), and chronic myelomonocytic leukemia (CMML; n = 1) who were either hypomethylating agent naïve (n = 10) or relapsed/refractory following prior hypomethylating agent therapy (n = 8) (NCT01926587). Patients received oral rigosertib, an inhibitor of Ras-effector pathways, in 3 successive cohorts (140 mg twice daily, 280 mg twice daily, or 840 mg/day [560 mg morning/280 mg evening]) for 3 weeks of a 4-week cycle. Patients received parenteral azacitidine (75 mg/m2/day × 7 days) during the second week; the cycle repeated every 4 weeks. The combination was well tolerated for a median of 4 (range 1-41) cycles, with 72% of patients experiencing ≥1 serious adverse events. No dose-limiting toxicities were observed. Thus, no maximum tolerated dose was reached. The most frequently reported adverse events were diarrhea (50%), constipation, fatigue, and nausea (each 44%), and pneumonia and back pain (each 33%). Sequential administration demonstrated an overall response rate of 56% in evaluable patients, with responses observed in 7/9 MDS/CMML patients (78%) and 2/7 AML patients (29%). Further clinical studies are warranted to investigate this doublet therapy in patients with myeloid malignancies.

A phase 1/2 study of rigosertib in patients with myelodysplastic syndromes (MDS) and MDS progressed to acute myeloid leukemia.

This Phase 1/2, dose-escalating study of rigosertib enrolled 22 patients with higher-risk myelodysplastic syndromes (MDS) (n=9) and acute myeloid leukemia (AML; n=13) who had relapsed or were refractory to standard therapy and for whom no second-line therapies were approved. Patients received 3- to 7-day continuous intravenous infusions of rigosertib, an inhibitor of Ras-effector pathways that interacts with the Ras-binding domains, common to several signaling proteins including Raf and PI3 kinase. Rigosertib was administered at doses of 650-1700mg/m2/day in 14-day cycles. Initial dose escalation followed a Fibonacci scheme, followed by recommended phase 2 dose confirmation in an expanded cohort. Rigosertib was well tolerated for up to 23 cycles, with no treatment-related deaths and 18% of patients with related serious adverse events (AEs). Common AEs were fatigue, diarrhea, pyrexia, dyspnea, insomnia, and anemia. Rigosertib exhibited biologic activity, with reduction or stabilization of bone marrow blasts and improved peripheral blood counts in a subset of patients. Ten of 19 evaluable patients (53%) demonstrated bone marrow/peripheral blood responses (n=4 MDS, n=1 AML) or stable disease (n=3 MDS, n=2 AML). Median survival was 15.7 and 2.0 months for responders and non-responders, respectively. Additional studies of rigosertib are ongoing in higher-risk MDS (NCT00854646).

Analysis of professional competencies for the clinical research data management profession: implications for training and professional certification.

OBJECTIVE: To assess and refine competencies for the clinical research data management profession. MATERIALS AND METHODS: Based on prior work developing and maintaining a practice standard and professional certification exam, a survey was administered to a captive group of clinical research data managers to assess professional competencies, types of data managed, types of studies supported, and necessary foundational knowledge. RESULTS: Respondents confirmed a set of 91 professional competencies. As expected, differences were seen in job tasks between early- to mid-career and mid- to late-career practitioners. Respondents indicated growing variability in types of studies for which they managed data and types of data managed. DISCUSSION: Respondents adapted favorably to the separate articulation of professional competencies vs foundational knowledge. The increases in the types of data managed and variety of research settings in which data are managed indicate a need for formal education in principles and methods that can be applied to different research contexts (ie, formal degree programs supporting the profession), and stronger links with the informatics scientific discipline, clinical research informatics in particular. CONCLUSION: The results document the scope of the profession and will serve as a foundation for the next revision of the Certified Clinical Data Manager TM exam. A clear articulation of professional competencies and necessary foundational knowledge could inform the content of graduate degree programs or tracks in areas such as clinical research informatics that will develop the current and future clinical research data management workforce.