Abstract CT091: Phase I study of intraperitoneal TRX-E-002-1 in patients with persistent or recurrent ovarian cancer, fallopian tube cancer or primary peritoneal cancer: Results of dose-escalation phase
Authors: Coward Jermaine , Dizon Don , Kichenadasse Ganessan , Harnett Paul , Moore Kathleen , Barve Minal , Berg Daniel , Garner James 
Published: August 2019

Abstract
Introduction: Women with advanced epithelial ovarian cancer (EOC) are at a high risk of recurrence after standard therapy. TRX-E-002-1 (Kazia Therapeutics, Australia) is a novel, third generation benzopyran molecule that induces caspase-dependent and -independent apoptosis in CD44 positive ovarian cancer stem-like cells and CD44 negative ovarian somatic cancer cells. An ongoing trial aims to evaluate the safety, tolerability, pharmacokinetics and activity of intraperitoneal (IP) administered TRX-E-002-1 monotherapy and in combination with standard of care for recurrent EOC (NCT02903771). The dose escalation phase of this open-label, 2-part clinical trial has been completed.
Methods: Women with platinum resistant, persistent or recurrent EOC were enrolled in a dose escalation study (Part A) to determine the maximum tolerated dose (MTD) of TRX-E-002-1 monotherapy (0.24-20 mg/kg). Patients were dosed weekly with single agent TRX-E-002-1 IP for the first 2 cycles after which add-on standard intravenous chemotherapy was allowed (cycles 3-8). Assessments included disease response, based on CA-125 and Response Evaluation Criteria in Solid Tumours, circulating epithelial tumour cells and stem cell markers.
Results: Fourteen subjects were recruited to Part A of which 11 were evaluable. All 11 subjects completed ≥1 infusions of monotherapy with 3 completing 8 cycles; 1 subject is currently on active treatment. The MTD was established at 5 mg/kg based on the limiting toxicity of ileus syndrome (n=2) and safety signals of bowel obstruction (n=3) and abdominal pain (n=2). The pharmacokinetics of TRX-E-002-1 were characterised by a rapid increase in systemic concentrations with peak concentrations ranging from 9.81 to 6,100 ng/mL over ~0.4 to 4.6 hours after a single dose administration. Plasma concentrations in all subjects progressively declined to &lt;10% of maximal concentrations by 24 hours. The terminal half-life of TRX-E-002-1 ranged from 2.47 to 5.65 hours. Subject #03-002, who received 2 cycles TRX-E-002-1 2.5 mg/kg monotherapy and 6 cycles TRX-E-002-1 and paclitaxel 80 mg/m2, showed a CA-125 decline to 16 (baseline: 38), target lesion size decrease to 5 mm (baseline: 22 mm) and stable disease after 12-weeks follow up. Fifteen AEs were reported for the subject, none of which were considered serious, due to study drug, or unacceptable.
Conclusion: IP administered TRX-E-002-1 has clinical potential for the treatment of platinum resistant, recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal cancer. Additional subjects are being recruited to an expansion cohort study (Part B) to determine preliminary evidence of disease activity of this agent alone or when combined with standard of care (cycles 3-8). Enrolment to Part B commenced in Oct 2018 with 25% of the cohort being recruited to date.
Citation Format: Jermaine Coward, Don Dizon, Ganessan Kichenadasse, Paul Harnett, Kathleen Moore, Minal Barve, Daniel Berg, James Garner. Phase I study of intraperitoneal TRX-E-002-1 in patients with persistent or recurrent ovarian cancer, fallopian tube cancer or primary peritoneal cancer: Results of dose-escalation phase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT091.