A clinical trial for patients with acute myeloid leukemia or myelodysplastic syndromes not eligible for standard clinical trials

Abstract

Most clinical trials exclude patients with poor performance or comorbidities. To study whether patients with these characteristics can be treated within a clinical trial, we conducted a study for patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) with poor performance, organ dysfunction or comorbidities. Primary endpoint was 60-day survival. Study included stopping rules for survival and response. Treatment consisted on a combination of azacitidine and vorinostat. Thirty patients (16 with MDS, 14 with AML) were enrolled. Median follow-up was 7.4 months (0.3-29). Sixty-day survival was 83%. No stopping rules were met. Main adverse events (AEs) were grades 1 and 2 gastrointestinal toxicities. In view of these results, we expanded the study and treated 79 additional patients: 27 with azacitidine (AZA) and 52 with azacitidine and vorinostat (AZA+V). Median follow-up was 22.7 months (12.6-47.5). Sixty-day survival rate was 79% (AZA=67%, AZA+V=85%, P=0.07). Median overall survival was 7.6 months (4.5-10.7). Median event-free survival was 4.5 months (3.5-5.6). Main AEs included grades 1 and 2 gastrointestinal toxicities. Our results suggest this subset of patients can be safely treated within clinical trials and derive clinical benefit. Relaxation of standard exclusion criteria may increase the pool of patients likely to benefit from therapy.

Myelodysplastic syndromes: 2018 update on diagnosis, risk‐stratification and management

“…Because the HMAs are the standard of care in front line higher risk MDS, a number of studies are being conducted to test combinations. Agents used in combinations include the histone deacetylase inhibitors such as pracinostat, vorinostat and panobinostat and lenalidomide . So far none of these combinations has been shown to be superior to single agent HMA.…”

A call for action: Increasing enrollment of untreated patients with higher‐risk myelodysplastic syndromes in first‐line clinical trials

“…48 One recent analysis of randomized trials in patients with hematologic malignancies published in a high-impact journal found that there was no association between known drug side effects and eligibility criteria, nor between eligibility criteria and adverse events actually observed in those trials. 50 In this study, the main adverse events observed were grade 1 to 2 gastrointestinal side effects and stopping rules for survival, response, and toxicity were not reached. 50 In this study, the main adverse events observed were grade 1 to 2 gastrointestinal side effects and stopping rules for survival, response, and toxicity were not reached.…”

“…49 A recent clinical trial of azacitidine plus vorinostat that included patients with MDS and AML with poor performance status, serious comorbidities, or organ dysfunction confirmed the feasibility and safety of treating this subgroup of patients in a clinical trial. 50,51 These results argue for a relaxation of inclusion criteria to offer participation in clinical trials to more patients with MDS, especially for more advanced clinical trials that accrue in community practices. A performance score of 3, a creatinine or bilirubin concentration of 2 mg/dL, the presence of another malignancy, and an Adult Comorbidity Evaluation-27 (ACE-27) index score of 2 or 3 did not appear to adversely affect 60-day survival, OS, or event-free survival.…”

“…A performance score of 3, a creatinine or bilirubin concentration of 2 mg/dL, the presence of another malignancy, and an Adult Comorbidity Evaluation-27 (ACE-27) index score of 2 or 3 did not appear to adversely affect 60-day survival, OS, or event-free survival. 50,51 These results argue for a relaxation of inclusion criteria to offer participation in clinical trials to more patients with MDS, especially for more advanced clinical trials that accrue in community practices. Achieving this requires stronger collaboration and the advocacy of leading MDS investigators to help the pharmaceutical companies in designing more "pragmatic" clinical trial protocols with the goals of expanding access of trials to patients instead of just focusing on using the most stringent eligibility criteria to select the "Olympic athletes" of patients with MDS with the sole goal of achieving drug approval.…”

New drugs in AML: uses and abuses

“…Building on these observations, Montalban-Bravo et al reported an innovative phase-2 study of 109 subjects with AML or MDS ineligible for standard trials for the aforementioned reasons [20]. The study was designed to stop if the 50% 60-day survival rate for similar subjects not treated on a protocol was exceeded.…”