Phase Ib study of venetoclax with decitabine or azacitidine in elderly AML patients

In the February 2018 issue of Lancet Oncology, Courtney D. DiNardo from The University Texas MD Anderson Cancer Center, Houston, TX, and colleagues reported data from a dual-stage, non-randomized phase Ib study (NCT02203773), which is assessing the safety and preliminary efficacy of venetoclax (VEN), a BCL2 inhibitor, in combination with decitabine (DEC) or azacitidine (AZA) in previously untreated older Acute Myeloid Leukemia (AML) patients who are ineligible for standard induction therapy.

A total of 57 previously untreated AML patients with a median age of 75 years (range, 71 – 80 years) were enrolled in this study. Dose-escalation phase of this study comprised of two primary groups including group A (VEN plus DEC [20 mg/m², days 1–5], n = 23) and group B (VEN plus AZA [75 mg/m² days 1–7], n = 22) who were enrolled between November 2014 – December 2015. A third group (group C, n = 12) who were enrolled between June 2015 – January 2016 was included as a sub-study in order to assess the interaction of VEN plus DEC administered with a strong oral CYP3A inhibitor, posaconazole (300 mg twice on cycle 1, day 21, and 300 mg once daily from cycle 1, days 22–28).

Dose escalation followed a standard 3 + 3 design with a minimum of three evaluable patients enrolled per cohort. Daily target doses of VEN 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.

Key findings at data cut-off on June 15 2016:

• Safety

  • Most common grade 3–4 Treatment-Emergent Adverse Events (TEAEs) were thrombocytopenia (47% [group A, n = 9, group B, n = 13, group C, n = 5]), febrile neutropenia (42% [group A, n = 11, group B, n = 10, group C, n = 3]) and neutropenia (40% [group A, n = 12, group B, n = 8, group C, n = 3])
  • Febrile neutropenia was the most common serious TEAE in groups A (30%) and B (32%), compared with lung infection in group C (33%)
  • 30-day mortality rate: 7% (4/57)
    • Death occurred due to sepsis (n = 1, group B), bacteremia (n = 1, group A), lung infection (n = 1, group C) and respiratory infection (n = 1, group C)
  • Treatment-related Adverse Events (AEs) occurred in 86% of patients
    • Most common treatment-related AEs in group A and B include nausea (42%), neutropenia (40%), thrombocytopenia (36%), fatigue (29%), diarrhea (27%) and decreased appetite (20%)
    • Most common treatment-related AEs in group C include nausea (58%), thrombocytopenia (50%), vomiting (42%), diarrhea (25%), and anemia (25%)
  • Maximum tolerated dose: not reached
  • Recommended phase 2 dose: 400 mg or 800 mg with an interrupted dosing schedule

• Efficacy

  • Complete Remission (CR) or CR with incomplete marrow recovery (CR/CRi) in all patients: 61% (35/57)
  • CR/CRi in group A, B, and C were 61% (14/23), 59% (13/23) and 67% (8/12) respectively
  • Median overall survival for group A and B combined was 15.2 months

In summary, this is the first study combining VEN plus Hypomethylating Agents (HMA), AZA or DEC in elderly AML patients. VEN plus AZA or DEC was “well tolerated” in newly diagnosed patients with AML who are unfit for standard chemotherapy.  Additionally, the preliminary efficacy observed with VEN plus AZA or DEC was “promising” with a low early mortality rate.

Key limitations of this study include the small size of patients treated in each cohort and lack of molecular data. Due to the sample size, the authors suggested that the findings of their study needs to be confirmed in a larger and randomized study. DiNardo et al. concluded by noting that “further evaluation of the 400 mg and 800 mg doses of VEN in an expansion phase of this study is ongoing and will provide additional insight into the safety and efficacy of these combinations”.

In an accompanying commentary in this same issue of Lancet Oncology, Carsten Müller-Tidow and Richard F. Schlenk from Heidelberg University, DE, commented on the findings of this study. They noted that the response rates observed in this study were “remarkable” especially in this difficult to treat AML patients. Additionally, the CR rates observed in this study were double compared to the rates observed with single agent HMA in similar AML population with manageable toxicity.  

Müller-Tidow and Schlenk further questioned the impact of these data by DiNardo et al. on therapy for AML patients. They noted that “initially, more patients should be treated with the hypomethylating agent– venetoclax combination, and these trials are ongoing”. They further concluded that the “preliminary data provided by DiNardo and colleagues suggests that the combination of HMA drugs and VEN is effective in AML therapy”.