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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.
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).
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).
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