Significant Activity of the mTOR Inhibitor Sirolimus and HDAC Inhibitor Vorinostat in Heavily Pretreated Refractory Hodgkin Lymphoma Patients

Background: Preclinical models have suggested that HDAC and mTOR inhibitors have synergistic antineoplastic activity in Hodgkin lymphoma and other cancers by reducing the activity of AKT, mTOR and HDAC.

Methods: We designed a phase I study to determine the safety of the mTOR inhibitor sirolimus (1 mg – 5 mg PO daily q 28 days) and HDAC inhibitor vorinostat (100 mg – 400 mg PO daily q 28 days) in advanced cancers with an expansion cohort at the recommended phase 2 dose (RP2D) of sirolimus 4 mg and vorinostat 300 mg for patients with refractory classical Hodgkin lymphoma. The expansion cohort included optional pre- and post-treatment tumor biopsies, peripheral blood mononuclear cells (PBMCs), plasma/serum collections for pharmacodynamic (PD) and pharmacokinetic (PK) endpoints.

Results: A total of 19 patients (men, n = 9; women, n = 10), median age 34 years, median of 5 prior therapies (including autologous SCT [n = 16], autologous and allogeneic SCT [n = 4]) were enrolled in dose escalation (n = 1) or RP2D (n = 18) cohorts. At the median follow-up of 5.7 months, 18 (95%) patients demonstrated decreased FDG uptake including 4 CRs (21%) and 4 PRs (21%) using Cheson criteria, with a total CR+PR rate of 42%. The median reduction of tumor was -51% (-100% to +50%). The median time-to-treatment failure was 4.5 months and 9 (47%) of the patients either continued on therapy (7, 37%) or were sent for allogeneic SCT (2, 11%). Major grade 3 – 4 treatment-related toxicities included grade 3 thrombocytopenia (6 patients, 32%), grade 4 thrombocytopenia (6, 32%), grade 3 anemia (1, 5%), febrile neutropenia (1, 5%), grade 3 neuropathy (1, 5%) and led to treatment interruptions and/or dose modifications in 12 (63%) patients. Five (26%) patients had archival tissue available for targeted next-generation sequencing and one patient had a loss of TSC2, an abnormality that putatively activates mTOR. This patient has had a continuing response to therapy (-56%) for 12+ months. PD studies in pre- and post-treatment tumor biopsies, PBMCs and plasma as well as PK analysis continue.

Conclusion: The combination of sirolimus and vorinostat is well tolerated with encouraging activity in very heavily pretreated patients with Hodgkin lymphoma refractory to standard therapies. Enrollment continues.