Purpose: Histone deacytylase inhibitors are promising targets for therapeutic interventions intended to reverse aberrant epigenetic states associated with cancer. Valproic acid (VPA) is a strong histone deacetylase inhibitor. Lenalidomide (CC-5013, Revlimid) is an immunomodulatory drug with an enhanced potency and pharmacological profile for the regulation of cellular immunity and cytokine response such as TNFa and IL-12. VPA can be additive or synergistic with lenalidomide in inducing cell apoptosis. Objectives of this Phase I study were to evaluate the tolerability and efficacy of VPA and lenalidomide.

Experimental Design: Patients in sequential cohorts ("3+3" design) received escalating doses of VPA with lenalidomide. Prophylactic anticoagulation was not required for this protocol. VPA was administered daily for 7 days with 7 days off; and lenalidomide was administered daily for 28 days. At MTD, 10 additional patients with adenocystic carcinoma were enrolled for efficacy.

Results: Twenty six patients with advanced cancer (14 M/12 F), median age = 56 (38-70), median number of prior therapies = 2 (0-12) were enrolled. MTD was reached at VPA 30 mg/ kg for 7 days on with 7 days off, and lenalidomide 25 mg daily. Most common toxicities included fatigue, rash, neutropenia and thrombocytopenia. One patient had deep venous thrombosis and two others had pulmonary embolism. DLTs included grade III confusion (n=3), grade III somnolence (n=1) and grade III gait disturbance (n=1). Even though 2/12 patients from dose expansion had DLT during the first cycle of VPA 30 mg /kg for 7 days on and 7 days off with lenalidomide 25 mg PO QD, majority of patients required dose reduction of VPA to 5- 20 mg /kg during the subsequent cycles due to fatigue and drowsiness. Seven patients with adenocystic carcinoma had stable disease over 4 cycles. Of non-adnocystic carcinoma patients, one patient with melanoma and another patient with parathyroid carcinoma had stable disease for 6 cycles and 8 cycles respectively.

Conclusions: Lenalidomide 25 mg PO QD combined with VPA (5 -20 mg /kg for 7 days on 7 days off) was well tolerated. No significant tumor reductions were noticed in patients with adenocystic carcinoma. Stable disease was noted in patients in adenocystic carcinoma, melanoma and parathyroid carcinoma.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C69.

Citation Format: Mehmet A. Bilen, Siqing Fu, David S. Hong, Jennifer J. Wheler, Maen Abdelrahim, Gerald S. Falchook, Apostlia M. Tsimberidou, Filip Janku, Sarina Piha-Paul, Ralph Zinner, Razelle Kurzrock, Aung Naing. Phase I trial of lenalidomide and valproic acid in patients with advanced cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C69.