Phase I Study of Vorinostat Combined with Isotretinoin and Temozolomide in Adults with Recurrent Malignant Gliomas.

2039 Background: Vorinostat (Vor), a histone deacetylase inhibitor, has shown preliminary activity in recurrent GBM. Preclinical studies demonstrated that Vor can overcome resistance to isotretinoin (cRA) and temozolomide (TMZ). We hypothesized that Vor could overcome resistance to cRA and cytotoxic chemotherapy in the treatment of recurrent gliomas. Carboplatin (CBP) was originally selected as the cytotoxic drug since eligible patients would have failed prior standard TMZ therapy. Methods: We conducted a Phase I study of combinations of these agents preceding a proposed adaptive randomized 3-arm Phase II study. Adults with recurrent malignant glioma were enrolled into one of 3 arms. Arm 1: Vor + cRA, Arm 2: CBP + cRA, or Arm 3: Vor + cRA + CBP. Dose escalation was by a 3 + 3 design to define the maximum tolerated dose (MTD). Due to excessive toxicity in arms containing CBP, this drug was replaced by dose-dense TMZ due to preliminary evidence of activity in recurrent gliomas. Results: A total of 55 patients (8 anaplastic gliomas, 47 GBM) were enrolled from 11/2007 to 03/2012. Among 52 evaluable patients, a total of 11 DLTs were seen, but none after introduction of TMZ to Arm 3. MTDs are summarized in Table. Toxicities included: Arm 1 – neutropenia, thrombocytopenia, pulmonary embolism, elevated AST (DLT), and hypertriglyceridemia (DLT); Arm 2/CBP – neutropenia, thrombocytopenia (DLT), and hypertriglyceridemia; Arm 3A/CBP - thrombocytopenia (DLT) and hypokalemia (DLT); Arm 3B/TMZ – thrombocytopenia, hypertriglyceridemia, fatigue. Best response was stable disease in 26 patients, for ≥ 4 months in 15 patients; 10 patients achieved 6-month progression-free survival; 7 of whom had GBM. Conclusions: Two and 3 drug combinations of Vor, cRA, and dose-dense TMZ were well tolerated with MTD that will be used in a multicenter adaptive randomized Phase II study in the near future. Clinical trial information: NCT00555399. MTD Arm 1 (n=14) Vor 400 mg/day, D 1-14 cRA 100 mg/m2/day, D 1-21 Arm 2/CBP (n=12)* CBP AUC 5, D 1 cRA 100 mg/m2/day, D 1-21 Arm 3A/CBP (n=19)* De-escalation to dose level -3 (Vor 300 mg/day x 14 days; cRA 100 mg/m2/day x 21 days; CBP AUC 4) Arm 3B/TMZ (n =10) Vor 500 mg/day, D 1-7 & 15-21 cRA 100 mg/m2/day, D 1-21 TMZ 150 mg/m2/day, D 1-7 &15-21 *Not going to Phase II