LAUSR

Introduction The measurement, analysis, and communication of treatment-related symptoms and their impact on the functioning of individuals in clinical trials is an area of interest to the medical community, the Food and Drug Administration and other regulatory agencies. Inclusion of GAs and PROs in early phase trials can characterize the heterogeneity of aging and guide development of therapies to benefit older adults. Despite evidence that GAs and PROs are feasible and predictive of outcome, few early phase trials have integrated them to inform on treatment tolerance. The aim of this analysis is to describe changes in GAs and PROs among older adults with R/R AML in a Phase 1b trial of BCL2 inhibitor venetoclax (Ven) with either MEK inhibitor cobimetinib (cobi) or MDM2 antagonist idasanutlin (idasa) (NCT02670044). Methods Patients (pts) aged ≥60 yrs who were ineligible for cytotoxic therapy/allogeneic stem cell transplant were enrolled in this open-label, multicenter study, designed to evaluate the safety, tolerability, and efficacy of Ven+cobi/idasa in R/R or secondary AML. GA measures were Short Physical Performance Battery (SPPB; gait speed, balance tests, chair stands), Hematopoietic Cell Transplant-Comorbidity Index (HCT-CI) and Short Blessed Orientation Test (SBOT). Treatment-related symptoms were assessed via the PRO version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), administered electronically throughout treatment. GAs were administered at screening, Cycle (C) 2 Day (D) 1, C3D1, and C7D1; PRO-CTCAE was administered at C1D1, weekly during C1, for the first 3 weeks of C2 and C3, and monthly starting at C4D1. Mean GA scores were calculated over time for each treatment arm and pt-level heatmaps were created. The 'frequency', 'severity', 'interference', and 'presence' of PRO-CTCAE symptoms were reported at each assessment, with a longitudinal analysis to understand how symptoms changed over the course of treatment. Results As of April 6 2018, 64 pts had been treated with either Ven+cobi or Ven+idasa. Baseline characteristics were comparable between arms; respectively: median age, 72, 74 yrs; ECOG performance status 0-1, 83%, 82%; refractory disease, 63%, 56%. GA and PRO data were available in 52 and 38 pts, respectively. Screening of GAs identified a physically frail (mean SPPB score <9), cognitively intact (mean SBOT scores <4) pt population with comorbidities (Table 1). At baseline, PRO-CTCAE showed that >70% of pts 'never' or 'rarely' experienced nausea, vomiting or diarrhea; >75% and >50% reported 'none' or 'mild' decreased appetite and fatigue, respectively. In both arms, pt numbers reduced over C1-3, with 8 pts in the Ven+cobi and 6 pts in the Ven+idasa arms providing data at C3D1; this was largely due to attrition on study. Pts reported that their worst post-baseline symptom was 'frequent' or 'almost constant' symptoms of nausea (55%), diarrhea (71%), and vomiting (5%) at some point, and 'severe' or 'very severe' decreased appetite (55%) or fatigue (55%). Variations in the worst post-baseline symptoms were observed between treatment arms, although this was not statistically tested. Symptoms tended to increase and decrease with the start and end of each treatment cycle and appeared worse during C1 for Ven+cobi (Figure 1). Despite differences in symptoms during the cycle, there did not appear to be changes in mean SPPB scores from baseline to C2, no cognitive impairment during treatment, and little to no increase in comorbidity burden. These results may be influenced by a reduction in pt numbers in each treatment arm over subsequent assessments. Conclusion PROs from this Phase 1b study indicate an increased frequency of treatment-related symptoms, in particular, nausea, diarrhea, vomiting, decreased appetite and fatigue, in older AML pts treated with Ven+cobi or Ven+idasa compared with pre-treatment. PROs and GAs can provide additional complementary insight into the older pt's treatment experience on early phase clinical trials that can inform design of later-phase studies. However, strategies to address missing data will be important for maximizing value gained. Klepin: Genentech Inc: Consultancy. Campinha-Bacote:Genentech Inc: Employment. Hong:Genentech Inc/Roche: Employment, Other: Ownership interests PLC. Phuong:Genentech Inc: Employment, Equity Ownership, Other: Ownership interests PLC. Wang:Genentech Inc: Employment; F. Hoffmann-La Roche Ltd: Equity Ownership. Mobasher:F. Hoffmann-La Roche Ltd: Other: Ownership interests non-PLC; Genentech Inc: Employment. Trask:Genentech Inc: Employment; F. Hoffmann-La Roche: Employment.