The HDAC Inhibitor Entinostat (SNDX-275) Induces Clinical Responses in Patients with Relapsed and Refractory Hodgkin's Lymphoma: Results of ENGAGE-501 Multicenter Phase 2 Study

Entinostat (ENT) is an oral, class 1 isoform selective HDACi that preclinically has been shown to induce apoptosis in HL cells, block production of tumor growth promoting factors found in the HL microenvironment and up-regulate T cell co-activators important in inducing anti-tumor immune responses. Based on these data and promising activity observed with this class of agents, this phase 2 study was designed to define ENT single agent activity and safety profile in relapsed and refractory HL.

A total of 49 patients (pts) were enrolled on two dosing schemes designed to establish single agent ENT activity for HL. 33 pts received either 10 mg or 15 mg every other week (wk) and 16 pts received 15 mg on days 1, 8, and 15 every 28 days. Primary endpoint was objective response rate (CR+PR), CT/PET scans were conducted every 2 cycles. Blood was obtained at baseline, D1, D8, and D15 of cycle 1 of both schedules for biomarker analysis to determine ENT effects on a panel of immunomodulatory cytokines, chemokines and growth factors.

The median age was 33 years (19–73), median prior regimens was 3 (1–10); 30 (61%) pts relapsed after autologous SCT, 4 (8%) after allogeneic SCT and 5 (10%) following both; 17 pts progressed after one or more investigational therapies, 30 (79%) pts had bulky disease (1 or more baseline lesions > 5cm).

For the efficacy analysis, 38 pts were evaluable for response. Tumor reductions were observed in 61% of pts (23 (6 PR+17 SD) with preliminary PFS of 3.8 months (mths). Four pts with PR remain on treatment with time on study from 4.4–17 mths and 1 PR went on to SCT. One SD pt became PET negative and remains on ENT in mth 7; an additional SD pt was PET negative and went on to SCT. The majority of pts had some tumor reduction at wk 8, however maximum response often occurred after 4 cycles (wk 16). A similar percentage of patients completed > 2 cycles with both dosing schedules with 15/27 (56%) on the every other wk dosing and 5/11 (45%) on weekly dosing. 9 pts (5 pts on weekly dosing) remain alive without disease progression, and 7 began a new anticancer therapy prior to PD; median PFS is not yet reached for pts on the weekly dosing schedule. The median OS is 22.1 mths for the first 33 pts (not reached for 16 pts dosed weekly). Common G 1/2 AEs regardless of treatment relationship were gastrointestinal, fatigue, and edema. The most common ENT-related events were G 3/4 thrombocytopenia in 27 (55%) patients, G 3/4 neutropenia in 20 (41%) patients, and G 3/4 anemia in 21 (43%) patients. These events were reversible with dose reduction or delay.

Single agent ENT was well tolerated and demonstrated antitumor activity in HL pts progressing after SCT with bulky disease in about a third of patients within 2 cycles of therapy. The ORR is consistent with activity demonstrated with other HDACi in HL. Durable responses in bulky disease pts can be achieved with this single agent with tolerable toxicity. ENT provides a non-cross resistant mechanism of action with cytotoxic therapy and study in combination with other agents earlier in the disease course is warranted.

Younes:Genentech: Research Funding; SBIO: Research Funding; Syndax: Research Funding; Novartis: Honoraria, Research Funding; Seattle Genetics: Honoraria, Research Funding; Sanofi-Aventis: Honoraria, Research Funding. Hernandez:Celgene: Consultancy, Honoraria, Research Funding; Millenium Pharmaceuticals: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding. Kasamon:Genentech: Research Funding; Seattle Genetics: Research Funding.