CUDC-907 in relapsed/refractory diffuse large B-cell lymphoma, including patients with MYC-alterations: results from an expanded phase I trial

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 pre-clinical models, including MYC-driven ones. In this report, we present the safety and preliminary activity results of CUDC-907, with and without rituximab, in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), with a particular focus on those with MYC-altered disease. Thirty-seven DLBCL 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 out of 30) in evaluable patients [30% (11 out of 37) including all patients]. The objective response rate in evaluable MYC-altered DLBCL patients was 64% (7 out of 11; 4 complete responses and 3 partial responses), while it was 29% (2 out of 7) in MYC unaltered, and 17% (2 out of 12) in those with unknown MYC status. 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. (clinicaltrials.gov identifier: 01742988).

CUDC‐907 blocks multiple pro‐survival signals and abrogates microenvironment protection in CLL

“…Of note, the sensitivity of CLL cells to BCL‐2 inhibitors shown in these figures is consistent with previous reports . These data suggest that CLL cells are highly sensitive to CUDC‐907 at concentrations that are within the expected therapeutic levels that can be achieved in vivo, which range from 27 to 70 ng/mL …”

“…The simultaneous inhibition of HDAC and PI3K signalling has been previously shown to promote the inhibition on tumour cell growth and induction of apoptosis in different cancers, including hematopoietic malignancies . Indeed, CUDC‐907 has recently been shown to be safe and effective in patients with relapsed/refractory DLBCL . In hematopoietic cells, PI3K signalling activation is normally mediated by the p110δ isoform of PI3K, and it has been suggested that its inhibition has therapeutic value for CLL patients .…”

“…CUDC‐907 is a dual inhibitor targeting class I PI3Ks as well as class I and II HDACs, and has been reported to induce apoptosis in various cancer cells in vitro . Recent clinical trials showed the safety, tolerability, and a promising activity of CUDC‐907 in patients with relapsed or refractory lymphoma or multiple myeloma, or DLBCL, particularly in MYC mutant malignancies . In this study, we investigated the efficacy of CUDC‐907 in CLL cells and found that it effectively disrupted multiple pro‐survival signalling pathways to overcome the microenvironment protection and induce apoptosis.…”

Epigenetic polypharmacology: A new frontier for epi‐drug discovery

“…In particular, treatment with CUDC‐907 52 gave a reduction in MYC gene expression in MYC‐driven tumor model, whose overexpression has been reported to be among the worst prognostic factors in relapsed refractory diffuse large B‐cell lymphoma (DLBCL) . Dose escalation and expansion of CUDC‐907 52 in DLBCL and MYC‐altered disease, with and without the monoclonal antibody rituximab (25 patients received monotherapy treatment while 12 received the combination) (NCT 01742988) showed a median duration of the overall response of 11.2 months (of 13.6 months in MYC‐altered patients, 7.8 months in those with unknown MYC status, and 6.0 months in MYC unaltered patient), a durable antitumor activity (in particular in MYC‐altered patients) as well as a safety and tolerable profile . CUDC‐907 52 has been reported to downregulate FLT3 expression in AML cells.…”

Frontline treatment of diffuse large B‐cell lymphoma: Beyond R‐CHOP

“…69 These data support further exploration of Ven + R-CHOP in a high-risk population of BCL2+ and DHL patients. Epigenetics-based treatments using BET bromodomain inhibition (BAY1238097 [NCT02369029], CPI-0610 [NCT01949883], OTX015[NCT01713582], and JQ1) and histone deacetylase inhibition (HDACi) are other avenues for these subtypes 20,70. Recently, the interim analysis of a phase II trial (NCT02753647) evaluating the efficacy and safety of the HDAC inhibitor chidamide in combination with R-CHOP in elderly, newly diagnosed DLBCL, showed ORR of 90.3% (CR 85.4%), 1-year PFS was 92.1%, and 1-year OS was 94.7%.…”