DLBCL

The dual HDAC-PI3K inhibitor CUDC-907 as monotherapy and in combination with rituximab achieves responses and is tolerable in heavily pre-treated R/R DLBCL patients

On 31st August, in Haematologica, Yasuhiro Oki from the University of Texas MD Anderson Cancer Center, Houston, TX, USA, and colleagues reported results from their expanded phase I, open-label, multi-center, dose-escalation study (NCT01742988) to evaluate the safety, tolerability, and pharmacokinetics of CUDC-907 in patients with Relapsed/Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL). Patients with DLBCL from Transformed Follicular Lymphoma (t-FL) was permitted.

CUDC-907 is a first-in-class, oral, small molecular inhibitor of HDAC (class I and II) and PI3K (class Iα, β, and δ). A Recommended Phase II Dose (RP2D) of 60mg for 5 days on and 2 days off as monotherapy and in combination with rituximab at 375mg/m2 on day 1 of every cycle for six cycles (R-907) was further assessed.

Overall, 37 R/R DLBCL patients with a median age of 60.6 years (range, 20–85) were included from across 6 US cancer centers from 23rd January 2013 to 12th May 2016. Of these, 25 patients received CUDC-907 monotherapy and the remaining 12 were administered R-907. As of 7th July 2017, three patients (all MYC-altered) remained on active treatment, with RP2D and R-907 being administered to one and two patients, respectively.

Key Highlights:

Patients and treatment:

  • Median duration of treatment:
    • For all pts = 1.3 months (range, 0.1–35.4)
    • For monotherapy pts = 1.4 months (range, 0.2–35.4)
    • For R-907 pts = 1.2 months (range, 0.5–21.9+)
    • For responding pts = 15.5 months (range, 1.0–20.8+)
  • Pts on treatment beyond cycle 2 (42 days) = 15 pts (41%)
  • COO available for 11 pts (32%): GCB = 7 pts; non-GCB = 3 pts; ABC = 1 patient

Efficacy:

  • Thirty pts evaluable for response
  • ORR in evaluable pts = 37%; ORR in all pts = 30%
  • Objective responses achieved in 9/19 pts (47%) with monotherapy and 2/11 pts (18%) with R-907
  • Three responses with monotherapy and both R-907 responses were CRs (ongoing at 10.2 and 20.8 months)
  • Median DoR for:
    • All 11 responding pts = 11.1 months (range, 1.0–20.8+)
    • Monotherapy pts = 6.0 months (range, 1.0–16.4)
  • Median time to response = 2.4 months (range, 1.2–15.3)
  • Median PFS for:
    • All pts on study = 2.9 months (range, 0.2–35.5)
    • Monotherapy pts = 5.7 months (range, 0.5–35.5)
    • R-907 pts = 1.3 months (range, 0.5–21.9+)

Efficacy in MYC-altered patients:

  • MYC-altered pts in: monotherapy group = 7/19; R-907 group = 4/11
  • ORR in all MYC-altered pts = 64% (7/11)
  • Objective responses seen in 5/7 (71%) of monotherapy pts and 2/4 (50%) of R-907 pts
  • Two of three CRs in the monotherapy group and both CRs in the R-907 group were in MYC-altered pts
  • Response rate in: MYC non-altered pts = 29% (2/7); unknown MYC status pts = 17% (2/12)
  • Median DoR in:
    • All MYC-altered pts = 13.6 months (range, 1.0–20.8+)
    • Monotherapy MYC-altered pts = 7.5 months (range, 1.0–16.4)
    • R-907 MYC-altered pts = not reached
    • MYC negative pts = 6.0 months (3.4–8.7)
    • MYC status unknown pts = 7.7 months (range, 1.4–14.0)
  • Median PFS in:
    • All MYC-altered pts = 21.8 months (range, 1.0+–25.4+)
    • Monotherapy MYC-altered pts = 21.8 months (range, 1.0–16.4)
    • R-907 MYC-altered pts = not reached
    • MYC negative pts = 1.3 months (range, 0.4–15.5)
    • MYC status unknown pts = 1.3 months (range, 0.2–35.3)

Safety:

  • Most AEs in both the monotherapy and R-907 groups were grade 1–2 in severity and reversible with standard medication or dose holds/reductions
  • The most common AEs reported: diarrhea (57%), thrombocytopenia (54%), fatigue (41%), nausea (38%), constipation (24%), vomiting (24%), and neutropenia (22%)
  • Grade ≥3 AEs reported in 16 pts (43%); grade ≥3 treatment-related AEs reported in 15 pts (40%)
  • The most common grade ≥3 treatment-related AEs: thrombocytopenia (32%), neutropenia (16%), anemia (5%), diarrhea (5%), and fatigue (5%)
  • SAEs reported in 4 pts (28%), none considered treatment-related
  • AEs resulting in: dose hold = 16 pts (43%); dose reductions = 10 occasions in 5 pts (13.5%)

The authors stated that CUDC-907 as monotherapy, or in combination with rituximab, is able to achieve responses with tolerable safety profiles in heavily pre-treated R/R DLBCL patients. Generally, AEs were mild to moderate, reversible, and manageable. Furthermore, CUDC-907 achieved promising ORRs with durable response, particularly in patients harboring MYC alterations. The authors concluded that CUDC-907 as a monotherapy achieved a greater response than in combination with rituximab; however, the group note that this comparison is limited by the small sample size of the R-907 arm (11 patients).

Abstract:

CUDC-907 is a first-in-class, oral small molecule inhibitor of both HDAC (class I and II) and PI3K (class Iα, β, and δ) enzymes, with demonstrated anti-tumor activity in multiple preclinical models, including MYC-driven ones. In this report the safety and preliminary activity results of CUDC-907, with and without rituximab, in patients with relapsed/refractory diffuse large B-cell lymphoma are presented, with a particular focus on those with MYC-altered disease. Thirty-seven diffuse large B-cell lymphoma patients were enrolled, 14 with confirmed MYC-altered disease. Twenty-five patients received monotherapy treatment and 12 received the combination of CUDC-907 with rituximab. CUDC-907 monotherapy and combination demonstrated similar safety profiles consisting primarily of Grade 1/2 hematologic and gastrointestinal events. The most frequently reported Grade ≥3 treatment-related events were thrombocytopenia, neutropenia, diarrhea, fatigue, and anemia. Eleven responses (5 complete responses and 6 partial responses) were reported, for a response rate of 37% (11/30) in evaluable patients (30% [11/37] including all patients). The objective response rate in evaluable MYC-altered diffuse large B-cell lymphoma patients was 64% (7/11; 4 complete responses and 3 partial responses), while it was 29% (2/7) in MYC unaltered, and 17% (2/12) in those with unknown MYC status. The median duration of response was 11.2 months overall; 13.6 months in MYC-altered patients, 6.0 months in MYC unaltered, and 7.8 months in those with MYC status unknown. The tolerable safety profile and encouraging evidence of durable anti-tumor activity, particularly in MYC-altered patients, support the continued development of CUDC-907 in these populations of high unmet need. The trial is registered at ClinicalTrials.gov (NCT01742988).

References
  1. Oki Y. et al. CUDC-907 in relapsed/refractory diffuse Large B-cell lymphoma, including patients with MYC-alterations: results from an expanded phase 1 trial. Haematologica. 2017 Aug 31. pii: haematol.2017.172882. DOI: 10.3324/haematol.2017.172882. [Epub ahead of print].