Investigators often send reports to sponsors that incorrectly categorize adverse event (AE)s as serious or attribute AEs to investigational drugs. Such errors can contribute to high volumes of uninformative investigational new drug safety reports that sponsors submit to the US Food and Drug Administration and participating investigators, which strain resources and impede the detection of valid safety signals. To improve the quality of serious AE (SAE) reporting by physician-investigators and research staff, ASCO developed and tested a Decision Aid.A preliminary study with crossover design was conducted in a convenience sample. Physician-investigators and research staff were randomly assigned to receive case studies. Case studies were assessed for seriousness and attribution, first unassisted and then with the Decision Aid. Participants completed a feedback survey about the Decision Aid. Effectiveness of reporting and attribution are reported as odds ratios (ORs) with 95% CI. Power to detect associations was limited because of a small sample size.The Decision Aid did not significantly affect accuracy of determining seriousness (OR, 0.87; 95% CI, 0.31 to 2.46), but it did significantly increase accuracy of attributing an SAE to a drug (OR, 3.60; 95% CI, 1.15 to 11.4). Most of the 29 participants reported that the Decision Aid was helpful (93%) and improved decision-making time (69%) and confidence in reporting (83%), and that they would use the Decision Aid in practice (83%).The Decision Aid shows promise as a method to improve the quality of SAE attribution, which may improve the detection of valid safety signals and reduce the administrative burden of uninformative investigational new drug safety reports. Study of the Decision Aid in a larger sample with analysis stratified by participant role and SAE reporting experience would further assess the tool's impact.
<p>This figure shows (A) Proportion of circulating CD34+ stem cells (% of living cells, all patients combined). (B) Proportion of circulating CD138+ myeloma cells (% of living cells, all patients combined) (C) Distribution of CD34+ stem cells in responding vs. non-responding group (% of living cells). (D) Distribution of CD138+ myeloma cells in responding vs. non-responding group (% of living cells).</p>
5558 Background: IMGN853 (mirvetuximab soravtansine) is a FRα-targeting ADC comprising a FRα-binding antibody and potent maytansinoid, DM4. Methods: This Phase 1 trial is being conducted to determine safety, pharmacokinetics (PK), pharmacodynamics, maximum tolerated dose, recommended phase 2 dose (RP2D) and evidence of activity of IMGN853 in pts with EOC or other FRa-positive solid tumors. As previously reported, the occurrence of ocular adverse events (AEs) was associated with peak drug exposure and pt weight. Dosing by adjusted ideal body weight (AIBW) instead of total body weight (TBW) was implemented to decrease PK variability. Two dosing schedules are being evaluated; (A) once every 3 weeks and (B) Days 1, 8, and 15, every 4 weeks. Results: Fifty nine pts enrolled to dose escalation to date, 44 (30 TBW; 14 AIBW) pts in A, 16 (AIBW) in B. RP2D for A was determined to be 6.0 mg/kg, while dose finding in B continues. Exposure to IMGN853 increased with an increase in dose in a more than dose-proportional manner indicating non-linear PK. AIBW dosing enabled better control of drug exposure, with more pts treated within a clinically relevant therapeutic window. The majority of AEs have been CTCAE grade 1 or 2, generally similar across both schedules: included GI events, ocular events, cough, fatigue, and neuropathy in > = 20% of patients. Nausea, vomiting and headache may be more common on schedule B. Diarrhea may be more common on schedule A. Preliminary evidence of clinical benefit (CB) (partial PR or complete CR response, CA125 response, SD ≥ 6 cycles) has been observed with both schedules during escalation. In A, CB was observed in 11/44 pts: 4 PRs; 2 confirmed CA125 responses; 5 SD, 2 for 10 cycles. In B, 5/15 evaluable pts had CB: 1 PR; 4 SD, 3 with confirmed CA125 response; six pts remain on study. Benefit was seen in epithelial and transitional cell ovarian cancer, endometrial cancer and NSCLC. Conclusions: With both schedules,IMGN853 demonstrates encouraging clinical activity in heavily pretreated patients during dose escalation with a manageable AE profile. A RP2D has been identified for schedule A, while schedule B continues dose finding. Clinical trial information: NCT01609556.
The cardiovascular, renal, pulmonary, and dermatologic toxicities of interleukin-2 (IL-2) and gamma-interferon (IFN) are well described. However, autoimmune toxicities have only recently been noticed. The authors report the development of warm autoantibodies against erythrocytes in a patient receiving IL-2 (3.75 × 106 cetus units/m2 intravenous bolus three times per week) and gamma-IFN (0.1 mg/m2 subcutaneously three times per week) for metastatic renal cell carcinoma. Other potential causes of autoantibody formation, such as drugs, infection, and collagen vascular disease, were excluded. Both gamma-IFN and IL-2 have the potential to trigger or exacerbate autoimmunity due to either aberrant expression of restricted antigens or inhibition of normal cellular immune suppressor mechanisms.
Aims We evaluated the potential effect of sonidegib at an oral dose of 800 mg once daily (QD) on the pharmacokinetics (PK) of the probe drugs warfarin (CYP2C9) and bupropion (CYP2B6). Methods This was a multicentre, open‐label study to evaluate the effect of sonidegib on the PK of the probe drugs warfarin and bupropion in patients with advanced solid tumours. Cohort 1 patients received a single warfarin 15‐mg dose on Day 1 of the run‐in period and on Cycle 2 Day 22 (C2D22) of sonidegib administration. Cohort 2 patients received a single bupropion 75‐mg dose on Day 1 of run‐in period and on C2D22 of sonidegib administration. Sonidegib 800 mg QD oral dosing began on Cycle 1 Day 1 of a 28‐day cycle after the run‐in period in both cohorts. Results The geometric means ratios [90% confidence interval] for (S)‐ warfarin with and without sonidegib were: area under the concentration–time curve from time 0 to infinity (AUC inf ) 1.15 [1.07, 1.24] and maximum plasma concentration (C max ) 0.88 [0.81, 0.97]; and for ( R) ‐warfarin were: AUC inf 1.10 [0.98, 1.24] and C max 0.93 [0.87, 1.0]. The geometric means ratios [90% confidence interval] of bupropion with and without sonidegib were: AUC inf 1.10 [0.99, 1.23] and C max 1.16 [0.95, 1.42]. Sonidegib 800 mg had a safety profile that was similar to that of lower dose sonidegib 200 mg and was unaffected by single doses of the probe drugs. Conclusions Sonidegib dosed orally at 800 mg QD (higher than the Food and Drug Administration‐approved dose) did not impact the PK or pharmacodynamics of warfarin (CYP2C9 probe substrate) or the PK of bupropion (CYP2B6 probe substrate).
We describe how mobile and ubiquitous computation models have been applied, with the aim of solving some technological traditional problems in the domain of public passenger road transport.Those problems are due to a weak integration of the information systems aboard.The introduced models have permitted us to solve our integration problems, and, consequently, we have managed to improve the business in a variety of domains.Particularly, the application of those models have benefited on-board mobile information systems and user information systems.
