Abstract LB-167: Phase I dose escalation study of abexinostat and doxorubicin in patients with metastatic sarcomas.
Authors: Choy Edwin , Balasubramanian Sriram , Butrynski James , Morgan Jeffrey , Sirisawad Mint , Mani Chitra , George Suzanne , Wagner Andrew , Harmon David , Rubinstein Yael , Duan Zhenfeng , Hornicek Francis , Demetri George 
Published: August 2014

Abstract
Intro/Objective: Several inhibitors of histone deacetylase have been shown to enhance chemotherapy induced apoptosis and reduce sarcoma tumor burden in preclinical models. We sought to determine the MTD, PK/PD, safety and toxicity of the histone deacetylase inhibitor (HDACi) abexinostat when administered with doxorubicin in patients with metastatic sarcomas.
Methods: Participants were enrolled in a standard 3x3 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. GCSF support was provided at physician discretion on Arm A or provided to all participants in Arm B. 3-6 subjects were administered abexinostat at doses of 15, 30, 45, and 60 mg/m2 BID. All patients without progressive disease after receiving a cumulative lifetime dose of 450 mg/m2 of doxorubicin continued with abexinostat as a single agent until disease progression. Results: 22 participants (10 with prior 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 30 or 15 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 GCSF prophylaxis. In Arm B, participants were administered abexinostat at 30, 45, or 60 mg/m2 BID, all with mandated GCSF 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 30mg/m2 BID. In the 17 participants evaluable for radiologic response there was 1 PR, 11 SD, and 5 PD as best response, with 7 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 (see Table 1). 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 GCSF support is provided. 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.
Grade Type 1 2 3 4 Totals Fatigue 13 6 0 0 19 Platelets 10 3 1 2 16 Hemoglobin 11 4 1 0 16 Nausea 13 1 0 0 14 Neutrophils 4 1 4 3 12 Leukocytes 6 3 3 0 12 Diarrhea w/o prior colostomy 7 3 1 0 11 Hyperglycemia 7 1 1 0 9 QTc interval 7 2 0 0 9 Alopecia 1 5 1 0 7 Hypophosphatemia 3 4 0 0 7 Constipation 5 2 0 0 7 Extremity/limb pain 6 1 0 0 7 Anorexia 7 0 0 0 7 Lymphopenia 0 2 4 0 6 Pain: other 5 1 0 0 6 Hypomagnesemia 4 1 0 0 5 Hyponatremia 5 0 0 0 5 Taste disturbance 5 0 0 0 5
Citation Format: Edwin Choy, Sriram Balasubramanian, James Butrynski, Jeffrey Morgan, Mint Sirisawad, Chitra Mani, Suzanne George, Andrew Wagner, David Harmon, Yael Rubinstein, Zhenfeng Duan, Francis Hornicek, George Demetri. Phase I dose escalation study of abexinostat and doxorubicin in patients with metastatic sarcomas. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-167. doi:10.1158/1538-7445.AM2013-LB-167