Phase II trial results of abexinostat in R/R NHL and CLL

In January 2017, Vincent Ribrag from the Institut de Cancérologie Gustave Roussy, Paris, and colleagues published in Haematologica the results of a phase II study of abexinostat in the treatment of R/R Non-Hodgkin Lymphoma (NHL) and CLL. Abexinostat is a Histone Deacetylase (HDAC) inhibitor that has different pharmacodynamics and regimen to other HDAC inhibitors. The authors aim was to assess the efficacy and safety of a two-week-on-one-week-off treatment schedule using 45 mg/m² twice per day until Progressive Disease (PD) or intolerable toxicity.

Key Highlights:

• Overall 100 R/R pts enrolled: 18 FL, 18 TCL, 17 DLBCL, 16 MCL, 16 CLL, and 15 MZL and other subtypes
• Excluded 13 pts without baseline or minimum one post-baseline tumor evaluation from efficacy evaluation
• Efficacy: Overall ORR = 28% (95% CI: 19%–38%), CR = 5%
  • ORR FL = 56% (95% CI: 30%­­–80%)
    • Median duration of response = 16 months
    • mPFS = 10.2 months, mOS = not reached
  • ORR TCL = 40% (95% CI: 16%–68%)
    • Median duration of response = 11.5 months
    • mPFS = 5.5 months, mOS = 17.8 months
  • ORR DLBCL = 31% (95% CI: 11%–59%)
    • Median duration of response = 1.9 months
    • mPFS = 2.8 months, mOS = 10.2 months
  • MCL and MZL had 15% response rate
  • No responses in CLL
• Safety:
  • Drug-related AEs reported by 98% pts, ≥ Grade 3 AEs in 82% (80% thrombocytopenia, 27% neutropenia, 12% anemia)
  • Serious AEs reported by 73% pts, ≥ Grade 3 SAEs in 70% (54% thrombocytopenia, 11% neutropenia, 7% anemia)
  • During study 5 deaths unrelated to treatment
  • Serious AEs and Grade 3 or higher AEs were both more common in pts with lower than median body surface area (below 1.8m²) compared with those above the median
  • AEs resulted in 29% pts discontinuing, 21% dose reducing
• Withdrawals: 56% pts due to PD, 25% due to AE

In conclusion, the authors state that the changes in the treatment regimen to two-week-on-one-week-off resulted in a greater frequency of Grade 3 or higher AEs compared to a previous phase I/II study, which used a one-week-on-one-week-off regimen e.g. thrombocytopenia 80% vs 20% pts. However, the authors conclude by stating that abexinostat is a clinically active drug in the treatment of R/R NHL, and that abexinostat showed “good tolerability during prolonged drug administration” with the caveat that a less intense dosing regimen might reduce toxicity.

Abstract:

Histone deacetylase inhibitors are members of a class of epigenetic drugs that have proven activity in T-cell malignancies, but little is known about their efficacy in B-cell lymphomas. Abexinostat is an orally available hydroxamate-containing histone deacetylase inhibitor that differs from approved inhibitors; its unique pharmacokinetic profile and oral dosing schedule, twice daily 4 hours apart, allows for continuous exposure at concentrations required for efficient tumor cell killing. In this phase 2 study, patients with relapsed/refractory non-Hodgkin lymphoma or chronic lymphocytic leukemia received oral abexinostat at 80 mg BID for 14 days of a 21-day cycle and continued until progressive disease or unacceptable toxicity. A total of 100 patients with B-cell malignancies and T-cell lymphomas were enrolled between Oct 2011 and Jul 2014. All patients received at least 1 dose of study drug; primary reasons for discontinuation included progressive disease (56%) and adverse events (25%). Grade ≥3 adverse events and any serious adverse events were reported in 88% and 73% of patients, respectively. The most frequently reported grade ≥3 treatment-emergent related adverse events were thrombocytopenia (80%), neutropenia (27%), and anemia (12%). Among the 87 patients evaluable for efficacy, overall response rate was 28% (complete response, 5%), with highest responses observed in patients with follicular lymphoma (overall response rate, 56%), T-cell lymphoma (overall response rate, 40%), and diffuse large B-cell lymphoma (ORR, 31%). Further investigation of the safety and efficacy of abexinostat in follicular lymphoma, T-cell lymphoma, and diffuse large B-cell lymphoma implementing a less dose-intense week-on-week-off schedule is warranted. Trial registration identifier: EudraCT-2009-013691-47.