Phase 1 study of oral abexinostat, a histone deacetylase inhibitor, in combination with doxorubicin in patients with metastatic sarcoma

Abstract

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.

Therapeutic applications of histone deacetylase inhibitors in sarcoma

“…More importantly, the maximum tolerated dose of abexinostat and doxorubicin exceeded doses for maximal histone acetylation, so that the effectiveness of this combination would not be limited by inadequate dosing. Clinical benefit of this combination resulted in 7 out of 17 evaluable participants maintained stable disease for at least 5 cycles of chemotherapy 113 . Another study evaluated the response rate of belinostat in combination with doxorubicin for patients with soft tissue sarcoma.…”

Why Hydroxamates May Not Be the Best Histone Deacetylase Inhibitors—What Some May Have Forgotten or Would Rather Forget?

“…[3] In the meantime, more than ten hydroxamate-based pan-HDACIs are under clinical investigation for the treatment of various cancers (Figure 1). [4] Outside oncology, the targeting of specific HDAC isoforms is being pursued as a promising therapeutic strategy for neurological disorders, [5] based on the finding that several selective HDACIs bearing hydroxamate groups exhibit neuroprotective properties and improve cognition and motor activity, as well as other behaviors in animal models of depression, [6] Alzheimer’s disease (AD), [7] Huntington’s disease (HD), [8] Charcot– Marie–Tooth disease (CMT), etc. [9] The potential utility of HDAC inhibitors appears to be tremendous, but further translation of these ideas to the clinic will ultimately require the design of potent, isozyme-selective, and drug-like molecules that have minimal side effects.…”

Targeted therapy for soft tissue sarcomas in adolescents and young adults

“…The majority of patients had Ewing’s sarcoma, but the drug appeared to be well tolerated 123. Another Phase I study again showed tolerability of abexinostat in combination with doxorubicin 124. The combination of vorinostat with bortezomib (a proteasome inhibitor) was tested in a Phase I study of patients with advanced solid tumors and appeared to have a favorable side effect profile, with some clinical responses 125.…”