DiNardo CD, et al. - Researchers aimed to investigate the safety and preliminary efficacy of venetoclax with decitabine or azacitidine among elderly patients with previously untreated acute myeloid leukaemia. In this underserved patient population, venetoclax plus hypomethylating agent therapy appeared to be a novel, well-tolerated regimen with promising activity. Evaluation of expansion cohorts was in progress at 400 mg and 800 mg doses using both hypomethylating agent combinations.

Methods

• The researchers enrolled previously untreated patients (65 years and over) with acute myeloid leukaemia who were ineligible for standard induction therapy, into this non-randomised, open-label, phase 1b study.
• For this study, patients were required to have an Eastern Cooperative Oncology Group performance status of 0-2 and either intermediate-risk or poor-risk cytogenetics.
• They enrolled patients into 1 of 3 groups for the dose-escalation phase of this study:
  • Group A (venetoclax and intravenous decitabine 20 mg/m² [days 1–5 of each 28-day cycle]),
  • Group B (venetoclax and subcutaneous or intravenous azacitidine 75 mg/m² [days 1-7 of each 28-day cycle]), and
  • Group C (a venetoclax and decitabine substudy with the oral CYP3A inhibitor posaconazole, 300 mg twice on cycle 1, day 21, and 300 mg once daily from cycle 1, days 22–28, to evaluate its effect on venetoclax pharmacokinetics).
• With at least 3 evaluable patients enrolled per cohort, dose escalation followed a standard 3 + 3 design; daily target doses of venetoclax for groups A and B were 400 mg (cohort 1), 800 mg (cohorts 2 and 3), and 1200 mg (cohort 4), and 400 mg for group C.
• The safety and pharmacokinetics of venetoclax plus decitabine or azacitidine, and to determine the maximum tolerated dose and recommended phase 2 dose were the primary endpoints.
• The preliminary anti-leukaemic activity of venetoclax with decitabine or azacitidine through the analysis of overall response, duration of response, and overall survival were included as secondary endpoints.
• Safety, pharmacokinetics, and anti-leukaemic activity were analyzed in all patients who received 1 or more venetoclax doses.

Results

• The researchers enrolled 57 patients in the study.
• Between Nov 19, 2014, and Dec 15, 2015, 23 patients in group A and 22 patients in group B were enrolled.
• Twelve patients in group C were enrolled between June 14, 2015, and Jan 16, 2016.
• The most common grade 3-4 treatment-emergent adverse events were thrombocytopenia (27 [47%] of 57 patients; 9 in group A, 13 in group B, and 5 in group C), febrile neutropenia (24 [42%] of 57; 11 in group A, 10 in group B, and 3 in group C), and neutropenia (23 [40%] of 57; 12 in group A, 8 in group B, and 3 in group C), as of data cutoff on June 15, 2016.
• Febrile neutropenia (seven [30%] of 23 patients vs 7 [32%] of 22) was the most common serious treatment-emergent adverse event in groups A and B, while in group C it was lung infection (4 [33%] of 12 patients).
• Treatment-related adverse events were reported in 49 (86%) of 57 patients.
• The most common treatment-related adverse events in groups A and B included nausea (12 [52%] patients vs 7 [32%] patients), fatigue (6 [26%] patients vs 7 [32%]), and decreased neutrophil count (6 [26%] patients vs 6 [27%]), while in group C the most common were nausea (7 [58%] of 12 patients), leucopenia (6 [50%]), vomiting (5 [42%]), and decreased platelet count (5 [42%]).
• The maximum tolerated dose was not reached.
• Findings recommended a phase 2 dose of 400 mg once a day or 800 mg with an interrupted dosing schedule (safety expansion).
• Within 30 days of the first venetoclax dose, 4 (7%) of 57 patients had died due to sepsis (group B), bacteraemia (group A), lung infection (group C), and respiratory failure (group A).
• Tumour lysis syndrome was not observed.
• They found no substantial effect of decitabine and azacitidine on venetoclax exposures.
• In this study, 35 (61%; 95% CI 47·6–74·0) of 57 patients achieved complete remission or complete remission with incomplete marrow recovery.
• Twenty-seven (60%; 95% CI 44·3–74·3) of 45 patients had complete remission or complete remission with incomplete marrow recovery in groups A and B.