Introduction
Several inhibitors of histone deacetylase have been shown to enhance chemotherapy induced apoptosis and reduce sarcoma tumor volume in preclinical models. We sought to determine the MTD, PK/PD, safety and toxicity of the histone deacetylase inhibitor (HDACi) abexinostat (PCI-24781) when administered with doxorubicin in patients with metastatic sarcomas.
Methods
Participants were enrolled in a standard 3+3 dose escalation phase I study design. Abexinostat was administered on days 1–5 with 75 mg/m2 of doxorubicin administered on day 4 of every 21 day cycle until disease progression, drug intolerance, or a cumulative lifetime dose of 450 mg/m2 of doxorubicin was reached. G-CSF support was provided at physician discretion on Arm A or provided to all participants in Arm B. 3–6 participants were initially administered abexinostat at 30 mg/m2 BID, and then subsequent cohorts were administered doses of 15, 45, or 60 mg/m2 BID. All patients without progressive disease after receiving a cumulative lifetime dose of 450 mg/m2 of doxorubicin were given the option to continue with abexinostat as a single agent until disease progression.
Results
22 participants (10 with prior tumor growth after doxorubicin therapy) were enrolled (6 in Arm A, 14 in Arm B), 20 were evaluable for DLT, and 17 were evaluable for radiologic response. In Arm A, participants were administered abexinostat at 15 or 30 mg/m2 BID. DLTs of grade 3 and 4 ANC were observed in two out of three participants dosed at 30 mg/m2 BID. Neither of these patients received G-CSF prophylaxis. In Arm B, participants were administered abexinostat at 30, 45, or 60 mg/m2 BID, all with mandated G-CSF support. Two DLTs were observed on the 60 mg/m2 BID dose (grade 3 infection and grade 4 thrombocytopenia). The pharmacokinetics of abexinostat was not affected by doxorubicin. HDAC activity, as measured by histone acetylation in PBMC, was maximally inhibited at 30 mg/m2 BID. In the 17 participants evaluable for radiologic response there was 1 PR, 9 SD, and 7 PD as best response, with 8 participants completing 5 cycles or more. 3 of those participants remain in SD as their last disease status when this abstract was submitted. 4 participants who continued on monotherapy remained in SD for a median of 9.8 weeks after completing doxorubicin. The most common toxicities were fatigue, thrombocytopenia, and anemia. No study related deaths were observed.
Conclusion
The MTD for abexinostat is 45 mg/m2 BID when administered on days 1–5 when doxorubicin is given at 75 mg/m2 on day 4 of a 3-week cycle and G-CSF support is mandated. Toxicities were manageable and tumor responses were seen. Additional studies are needed to further define the specific contributions of HDAC inhibition for patients receiving doxorubicin to treat metastatic sarcoma.