Dual HDAC, PI3K Inhibition Promising In Refractory Lymphoma, Multiple Myeloma

Preliminary findings support the further development of the histone deacetylase and phosphoinositide 3-kinase inhibitor CUDC-907 as monotherapy or combination therapy in the lymphoma and multiple myeloma settings

medwireNews: Phase I trial results indicate that CUDC-907, a first-in-class, dual inhibitor of histone deacetylase (HDAC) and phosphoinositide 3-kinase (PI3K), is well tolerated and shows promising efficacy in heavily pretreated patients with relapsed or refractory lymphoma or multiple myeloma.

The 3+3 dose-escalation phase of the trial included 44 patients, the majority of whom had lymphoma (91%), including diffuse large B-cell lymphoma (DLBCL) and Hodgkin’s lymphoma, while the remaining 9% had multiple myeloma.

Participants received oral CUDC-907 in 21-day cycles as per one of four dosing schedules: once daily, twice or thrice weekly, or daily for 5 days followed by a 2-day break (5/2 schedule). Dosing started at 30 mg for the once-daily schedule and at 60 mg for the other schedules, and increased by 30 mg increments, with a maximum dosage of 60 mg for patients in the once-daily and 5/2 groups, and 150 mg for those on the weekly schedules.

Four dose-limiting toxicities were observed in three of 40 evaluable patients – specifically, one patient in the 60 mg once-daily group experienced grade 4 hyperglycaemia and grade 3 diarrhoea, while one patient each in the 150 mg twice-weekly and 150 mg thrice-weekly groups had grade 3 hyperglycaemia and grade 3 diarrhoea, respectively.

None of the seven patients treated on the 5/2 schedule experienced any dose-limiting toxicities, say Anas Younes, from Memorial Sloan Kettering Cancer Center in New York, USA, and colleagues.

Toxicities of grade 3 or higher occurred in 43% of all enrolled participants, with thrombocytopenia (20%), neutropenia (7%) and hyperglycaemia (7%) the most common. Serious adverse events were observed in a quarter of participants, but only three were deemed related to treatment.

Dose reductions and treatment discontinuation as a result of adverse effects occurred in 14% and 16% of patients, respectively, the team reports in The Lancet Oncology.

Among 37 evaluable patients, objective responses – of which three were complete responses – were achieved by five patients with DLBCL, including three with transformed Follicular lymphoma DLBCL. And 21 participants, including those with Hodgkin’s lymphoma and multiple myeloma, attained stable disease as the best response.

On the basis of their findings, the researchers recommend that the 60 mg dose given on the 5/2 schedule be used in future phase II testing of CUDC-907, which they believe is warranted, especially in patients with DLBCL.

Commentator Paul Richardson, from Dana Farber Cancer Institute in Boston, Massachusetts, USA, agrees that “the primary emphasis for the future of CUDC-907 will be for the treatment of DLBCL”.

But in light of the responses observed in the heavily pretreated multiple myeloma patients, he thinks that “this particular oral agent in combination with other drugs might be of particular interest in relapsed or refractory myeloma.”

The commentary author concludes: “Thus the promise of this particular oral agent extends beyond the lymphomas, and given the attractive aspects of its biology, broader studies are warranted.”

References

Younes A, Berdeja JG, Patel MR, et al. Safety, tolerability, and preliminary activity of CUDC-907, a first-in-class, oral, dual inhibitor of HDAC and PI3K, in patients with relapsed or refractory lymphoma or multiple myeloma: an open-label, dose-escalation, phase 1 trial. Lancet Oncol 2016; Advance online publication 31 March. doi: http://dx.doi.org/10.1016/S1470-2045(15)00584-7

Richardson PG. Dual inhibition of oncogenic targets for B-cell malignancies. Lancet Oncol 2016; Advance online publication 31 March. doi: http://dx.doi.org/10.1016/S1470-2045(16)00109-1

medwireNews (www.medwireNews.com) is an independent medical news service provided by Springer Healthcare Limited. © Springer Healthcare Ltd; 2016