DLBCL|FL

Mocetinostat has limited single-agent activity and acceptable toxicity profile in patients with relapsed/refractory Diffuse Large B-Cell and Follicular Lymphoma

On 25th April 2017, Connie L. Batlevi from the Memorial Sloan-Kettering Cancer Center, New York, NY, USA, and colleagues published in the British Journal of Haematology the results of their phase II, open-label, non-randomized, multicenter trial of mocetinostat in patients with R/R DLBCL and FL (NCT00359086).

In total, 72 patients were treated with the HDAC inhibitor mocetinostat; the median age of the 41 DLBCL patients was 60 years (range, 31–80 years) and for the 31 FL patients was 64 years (range, 36–76 years).

Oral mocetinostat was administered 3 times a week in 4-week cycles (i.e. 12 doses per 28-day cycle) until disease progression, unacceptable toxicity, or discontinuation for any other reason. The initial starting dose was 110mg; however, in subsequent protocol amendments, starting dose was reduced to 85mg and then to 70mg. The median number of cycles per patient was 3 (range, 1–23).

Key Highlights:
Efficacy
  • Evaluable pts = 37 DLBCL, 26 FL
  • ORR:
    • DLBCL = 18.9% (95% CI, 7.2–32.2%) with 1 CR, 6 PRs, and 13 SDs
    • FL = 11.5% (95% CI, 1.7–20.7%) with 1 CR, 2 PRs, and 16 SDs
  • DoR:
    • DLBCL = 1.8+ to 7.4 months with a median of 90 days
    • FL = 4.4 to 22.7 months
  • Time to response:
    • DLBCL = 1.6–19.9 months
    • FL = 3.7–7.9 months
  • Median duration of SD:
    • DLBCL = 3.5 months (95% CI, 1.6–8.4 months)
    • FL = 4.0 months (95% CI, 3.5 months–not estimable)
  • Overall, 54.1% of DLBCL pts and 73.1% of FL pts derived clinical benefit from therapy (response or SD)
  • Median PFS:
    • DLBCL = 2.1 months (95% CI, 1.6–3.6 months); 14 pts (37.8%) remained progression free for ≥90 days
    • FL = 3.7 months (95% CI, 2.1 months–not estimable); 13 pts (50.0%) remained progression free for ≥90 days
  • PFS among pts with objective responses:
    • DLBCL = 1.8–22.8 months and was ongoing at last evaluation in 5 pts
    • FL = 11.8–26.3 months and was ongoing at last evaluation in 3 pts
  • Median OS:
    • DLBCL = 12.3 months (95% CI, 5.8–17.8 months)
    • FL = Not reached, 76.9% of pts alive at last evaluation
Safety
  • 68 pts discontinued mocetinostat; the most common reasons included PD/relapse (DBLCL, n=27 [67.5%]; FL, n=11 [39.3%]) and treatment-related AEs (DLBCL, n=12 [30.0%]; FL, n=7 [25.0%])
  • 6% of pts experienced ≥1 AE; overall incidence of drug-related AEs was similar between DLBCL and FL pts
  • Treatment-related hematological AEs included anemia (23.6%), neutropenia (19.4%), and thrombocytopenia (19.4%)
  • ≥Grade 3 treatment-related AEs reported in 56.9% of pts (41 pts), the most frequent were fatigue (23.6%), neutropenia (15.3%), and thrombocytopenia (12.5%)
  • Treatment-related AEs resulting in dose reduction/interruption reported in 36 pts (50.0%)
  • Treatment-related AEs resulting in discontinuation occurred in 7 (21.9%) and 9 (24.3%) pts in the 110mg and 85mg dose groups, respectively
  • SAEs occurred in 26 pts (36.1%); included = hypotension (8.3%), and pyrexia, pleural effusion, and pericardial effusion (4.2% each)
  • No deaths occurred on treatment
  • Nine pericardial AEs resulting in discontinuation were experienced by 6 pts (8.3%); 4 pts experienced 5 events considered related to mocetinostat: pericardial effusion (n=3), pericarditis (n=1), and cardiac tamponade (n=1)

The group concluded that their study shows that oral mocetinostat administered 3 times a week and dosed at 70–110mg “has limited single-agent activity in patients with R/R DLBCL and FL” and has an “acceptable and manageable” toxicity profile. Furthermore, the group suggest that mocetinostat should be investigated in combination with other agents in the future.

Abstract:

Deregulation of histone deacetylase (HDAC) is important in the pathogenesis of follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). Mocetinostat, an isotype-selective HDAC inhibitor, induces accumulation of acetylated histones, cell cycle arrest and apoptosis in several cancers. This phase 2 study evaluated mocetinostat in patients with relapsed/refractory (R/R) DLBCL and FL. Seventy-two patients received mocetinostat (starting doses: 70-110 mg TIW, 4-week cycles). The best overall response rate (95% CI) was 18·9% (7·2, 32·2) for the DLBCL cohort (n = 41), and 11·5% (1·7, 20·7) for the FL cohort (n = 31). Responses were durable (≥90 days in 7 of 10 responses). Overall, 54·1% and 73·1% of patients derived clinical benefit (response or stable disease) from mocetinostat in the DLBCL and FL cohorts, respectively. Progression-free survival ranged from 1·8 to 22·8 months and 11·8 to 26·3 months in responders with DLBCL and FL, respectively. The most frequent treatment-related adverse events were fatigue (75·0%), nausea (69·4%) and diarrhoea (61·1%). Although mocetinostat had limited single-agent activity in R/R DLBCL and FL, patients with clinical benefit had long-term disease control. The safety profile was acceptable. This drug class warrants further investigation, including identifying patients more likely to respond to this agent, or in combination with other agents.

Reference:
  1. Batlevi C.L. et al. A phase 2 study of mocetinostat, a histone deacetylase inhibitor, in relapsed or refractory lymphoma. British Journal of Haematology. 2017 Apr 25. DOI: 10.1111/bjh.14698. [Epub ahead of print].