A phase I/II study of the safety and anti-cancer activity of IV-administered belinostat (PXD101) plus carboplatin (C) or paclitaxel (P), or both in patients with advanced solid tumors
3574 Background: Belinostat (PXD101), a HDAC inhibitor of the hydroxamate class has shown anti-tumor preclinical activity in combination with other standard chemotherapeutic agents. In Ph. I and II clinical trials the MTD for belinostat has been established at 1,000 mg/m2/d. This Ph I/II study assesses safety, and anti-cancer activity of belinostat administered in combination with C and/or P. Methods: Sequential cohorts of 3–6 patients (pts) with advanced solid tumors and PS 0–2 were recruited to determine the MTD of standard dose C and/or P with escalating doses of belinostat administered as a 30-min IV infusion daily for 5 days (d) every 21 d. C and/or P were administered 2–3 hours following infusion of belinostat on d 3. Results: 23 pts have been treated with a mean of 5 cycles (range 1 - 15) at 5 dose levels: C and belinostat (600 mg/m2) (5 pts); P and belinostat (600 mg/m2) (5 pts); C and P and belinostat (600 mg/m2) (3 pts); C and P and belinostat (800 mg/m2) (4 pts); C and P and belinostat (1,000 mg/m2) (6 pts). Possibly drug-related grade 3 or 4 toxicities were thrombocytopenia (2), vomiting (1), sensory neuropathy (1), myalgia (1), and fatigue (1).No DLT was observed. One SAE (grade 1 T-wave morphology change) was graded as possibly drug-related. No QTcf greater than 500ms were reported. There are 2 confirmed PRs: 1 with heavily treated metastatic rectal cancer and 1 with gemcitabine pre-treated metastatic pancreatic cancer. An additional 11[E1] patients had SD for 2–15 cycles, with 4 being SD for >10 cycles. One pt with mixed mullerian cancer of ovarian origin with SD had an 81% reduction in CA-125 to normal levels after 6 cycles. [E1]If you include MMMT pt as SD on radio. Conclusions: Belinostat with standard dose C and/or P is well-tolerated and shows clinical activity in heavily pre-treated patients with advanced metastatic disease. Recruitment to a phase II expansion in pts with recurrent ovarian cancer is ongoing. No significant financial relationships to disclose.