No MTD of hydralazine was observed in this trial, but as the maximum recommended dose of hydralazine for the treatment of hypertension or congestive heart failure is 300 mg per day,

the phase II dose of hydralazine in combination with valproic acid at therapeutic doses was defined as 300 mg per day; six additional patients were enrolled at this dose level (total of nine) to better define any potential toxicities, without any DLTs observed. A median number of two treatment cycles were administered on this protocol (range = 1 -29). There were no complete responses. One partial response by Response Evaluation Criteria In Solid Tumors (RECIST) criteria was observed in a patient who had metastatic mutant B-RAF V600E-positive melanoma (before the availability of vemurafenib). They received this regimen as a second-line systemic therapy after a combination of temozolomide, paclitaxel, Neratinib purchase and carboplatin and remained on therapy for 29 months. They initially

had stable disease for 4 months, which slowly evolved into a partial response. They developed vitiligo on this experimental combination. On disease progression, they received ipilimumab without response. Five additional subjects experienced stable disease for 3 to 6 months: two with soft-tissue sarcoma (3 and 4 months), ovarian cancer (3 months), squamous cell cancer of the head and neck (4 months), and breast cancer (6 months). At the time of this report, 24 of the 27 subjects have died, with a median overall survival of 3 months (range = 1-18 months); the three survivors are alive at 16, 18, and 18 months.

Although CYTH4 the primary selleck screening library objective of this phase I study was to identify the MTD of the combination of escalating doses of hydralazine with a fixed, steady-state concentration of valproic acid, the significance of the study was to design and test a tolerable combination of agents that may subsequently be evaluated as a regimen for the chemoprevention of lung cancer. Chromatin-modifying agents have demonstrated activity in vitro and in vivo against non–small cell lung cancer. However, the adverse event profiles of current FDA-approved chromatin-modifying agents are not justifiable for chronic delivery in healthy patients at risk for lung cancer. In our trial, the recommended dose for further study is hydralazine at 300 mg per day and valproic acid with a target serum concentration of 0.4 to 0.7 μg/ml. Although the dose of 400 mg per day of hydralazine did not exceed DLT as defined, the rates of mild, symptomatic hypotension and edema were considered unacceptable for the purpose of prolonged administration. This study demonstrates that pharmacological doses of hydralazine and valproic acid may be delivered to patients with heavily pretreated malignancies, with evidence of potential clinical activity in melanoma, soft-tissue sarcoma, and carcinomas of the breast, ovary, and head and neck.