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 31^st 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 23^rd January 2013 to 12^th May 2016. Of these, 25 patients received CUDC-907 monotherapy and the remaining 12 were administered R-907. As of 7^th 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).