Search

e18319 Background: ICH E6 (R2) has increased the level of scrutiny that we have for the data we collect in clinical trials. The emphasis is on quality-by-design with a quality management system to be incorporated and a focus on using a risk-based approach. This can be time-consuming and expensive - though the goal of this addendum is to improve quality AND efficiency, whilst ensuring patient safety and integrity of trial results. We therefore, piloted a proactive, concise and consistent method for utilizing a risk-based approach with central monitoring. Methods: Our method included 1) identifying risks within our data with 8 standard Key Risk Indicators (KRIs) across different study phases and different therapeutic areas together with 2) an off-the-shelf web-based tool for uniform and efficient review by a team of central monitors to assess which data may need more examination. These 8 KRIs are indicated in the list below, in order of the categories within the TransCelerate Risk Assessment and Categorization Tool: (S)AE rates, Enrollment Rates, Screen Failure Rates, Discontinuation Rate, Protocol Deviation Rates, Overdue Query Rate, Data Latency, and Identification of Potential Fraudulent data. Results: 15 studies were configured with the same KRIs and Visual Analytics; histograms, line- and pie-charts and data tables allowing for interactive data visualization and drill down. This represents research across different Phases 1-3 and observational studies. Based upon qualitative survey analysis from the central monitoring team 5/8 KRIs were found to be extremely valuable to focus on study quality, identifying earlier issues in study conduct for the project teams and Sponsors, while the remaining 3 were less valuable. Conclusions: We Our Risk Management team aims to increase the quality of data and ease of implementation of ICHE6 (R2) by focusing on the areas that matter the most, however identifying those areas and managing those data can sometimes be challenging. Through this innovation we have proven some core KRIs of trials that should be most closely monitored to aid decision making and will continue to evaluate to develop core oncology specific KRIs that will allow a more consistent review of data.

In vitro, bexarotene inhibits the proliferation of non-M3 AML cell lines and induces differentiation of leukemic blasts. Our previous phase I study in non-M3 AML showed evidence of leukemic response as manifested by reduction in bone marrow blast counts (15% response rate), improved platelet counts (41%) and improved neutrophil counts (26%). Based on these results, a phase II trial in non-M3 AML was initiated at the phase I MTD. In the current phase II trial, bexarotene (300mg/m2) was administered daily as monotherapy until disease progression or unacceptable side effects occurred. Fourteen patients have been enrolled: 8M/6F, median age 74 (range 20–83), 9 secondary AML (MDS or prior chemotherapy), 9 primary refractory or relapsed < 1 year after induction, 5 no prior induction chemotherapy, 5 requiring hydroxyurea at the time of enrollment for leukemic blast control, 4 prior allogeneic stem cell transplant, 12 blood transfusion dependent, 11 platelet transfusion dependent, and 8 neutropenic. Overall, no significant adverse events were noted. All patients received prophylactic antihyperlipidemic agents and achieved good lipid control. Two patients developed mild hypothyroidism related to bexarotene. Five patients were evaluable with bone marrow biopsy at 2 months: 1 50% reduction in absolute blasts, 1 SD and 3 PD. Similar to data from our prior phase I study, evidence of clinical activity was manifested as platelet count response in 1 patient and neutrophil increases attributable to bexarotene in 2 patients. When combining the results of our phase I experience (27 patients) with our phase II data (14 patients), there is a suggestion of increased activity in patients with 5q minus abnormalities with 4/7 (57%) benefiting (2 BM response, 4 neutrophil improvements and 1 platelet response). Conversely rates of clinical benefit were lower in patients with multiple (>3) cytogenetic abnormalities (2/13), relapse after stem cell transplant (1/9) or requiring hydroxyurea for peripheral blast control at the time of study enrollment (0/10). Bexarotene is very well tolerated at the dose level studied. Early evidence for clinical activity has been seen as exemplified by improvement in platelet count, increased neutrophil counts and decreased bone marrow blasts. In summary, we conclude that bexarotene is an active agent in a subgroup of patients with AML. Study enrollment continues with amended inclusion criteria to focus on patients more likely to benefit from treatment.