ENGAGE- 501: Phase 2 Study Investigating the Role of Epigenetic Therapy with Entinostat (SNDX-275) In Relapsed and Refractory Hodgkin's Lymphoma (HL), Interim Results

Entinostat (ENT) is an oral, class 1 isoform selective HDACi. In vitro in HL cell lines, ENT decreases proliferation and induces cell death in a dose dependent manner with an IC50 of 0.4 uM. As an epigenetic agent, ENT modulates immune pathways from a TH2 to a TH1 cytokine/chemokine profile and can upregulate the expression of cancer testis antigens, thus acting as an immunomodulator. This phase 2 study was initiated to define ENT single agent antitumor activity and safety and tolerability.

The trial is a Simon 2-stage design that has completed enrollment in 2 dosing schedules with 24 evaluable patients at 6 sites, 6 patients remain active; enrollment is continuing in an alternate dosing schedule. ENT was administered at a dose of 10 mg every 14 days (d), in a 28 d cycle (C) for the first stage of the study, for the second stage the dose was escalated to 15 mg every 14 d beginning C1d15. Subjects ongoing from the first stage were also allowed to escalate. CT/PET scans are conducted every 2 cycles. Blood samples for correlative study analysis are obtained pre-treatment, C1D8, C1D15, and C3D15.

As of August 6, 2010, demographic data are available on 23 evaluable subjects, median age is 28 years (19-53), median prior regimens is 3 (2-10), 13 (56%) had prior autologous transplant, 3 (13%) had prior allogeneic and 3 (13%) had prior autologous and allogeneic transplant. 23 patients have >1 post baseline result available, 65% have disease control (CR+PR+SD), 35% had PD and 2 patients with SD discontinued due to AE (Pericarditis and thrombocytopenia). Two (9%) responses (PR) are reported with time on study 14.7 months and one >6 months. An additional 4 (17%) patients have tumor reduction (25-49%) for at least 4 cycles. Six (26%) patients completed ≥ 6 cycles. Common G1/2 AEs including all causalities were gastrointestinal, fatigue, and pyrexia. Of the 32 patients evaluated for safety, G 3/4 thrombocytopenia occurred in 19 (59.4%) patients, G 3/4 neutropenia in 9 (28.1%) patients, and G 3/4 anemia in 11 (34.4%) patients, including all causalities. Profiling of cytokine, chemokine and growth factor levels in patient serum samples provides support for the biological activity of entinostat as an immunomodulatory agent with ongoing evaluation demonstrating a reduction of IL-13 and TNFα levels within one week of therapy.

ENT as a single agent in HL was well tolerated and demonstrated encouraging activity in this heavily pretreated patient population. Further dose intensity is currently being tested; updated results on the immunomodulatory effects will be presented.

Off Label Use: Given the CD20 positivity of nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) rituximab has been evaluated previously for relapsed NLPHL and was shown to be efficacious. Rituximab however is not FDA approved for NLPHL. This is a retrospective study that evaluates the use of R-CHOP and other therapies for NLPHL. Current NCCN guidelines support consideration of R-CHOP for NLPHL treatment, and given the rarity of the disease there is no one defined preferred chemotherapy regimen. This information will be disclosed to the audience.