Pharmacokinetic and Dose Response Relationships Observed in the Study “a Phase 1, Open- Label Dose Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of PTX-100 in Patients with Advanced and Relapsed/Refractory T Cell Lymphoma”

PTX-100 is a small molecule inhibitor of GGT-1 that disrupts the oncogenic activity of RAS pathways by inhibiting post-translational modification of RHO, RAL, and RAC. The objective of this trial (NCT03900442) is to evaluate the safety, PK and PD of PTX-100 administered as monotherapy in patients with advanced malignancies, with an expansion cohort in T-cell lymphomas. PTX-100 was given by IV infusion in escalating doses of 500 to 2000 mg/m² over days 1 to 5 in a 14-day cycle.

In order, to determine the optimal efficacious dose for PTX-100 and to further evaluate the clinical safety margin when administrated in multiple dose regime, a non-compartmental analysis (NCA) for PK and PD was performed, evaluating PTX-100 plasma pharmacokinetic parameters.

PTX-100 T_max occurred in all patients within 1.3hr in each dose group. At Day1 and Day 5 of Cycle1, Plasma PTX-100 C_max and AUC increased with increasing dose and appeared to be dose proportional over the range of 500 to 2000 mg/m². Complete clearance of PTX-100 between doses/days has been found, with half-life of about 9hr.

To further evaluate and optimize PTX-100 dose regimens for Phase 2 efficacy, an exploration of efficacy correlation was investigated using a dose proportionality, modeling and simulation by Phoenix WinNonLin /NLME.

No PTX-100 accumulation was observed after five consecutive days of daily dosing. Simulation analysis revealed no correlation between total dose and time of response and neither between Cmax and time of response. Increase in total dose of PTX-100 dose levels beyond 2000mg/m2 correlates with decrease in overall response rate (ORR) and increasing PTX-100 dose does not reduce time to achieve ORR. However, it appears that 1500mg/m2 (i.e. total dose of 2500mg) is predicted to be the optimal dose achieving the optimum distribution of PTX-100 response.

In conclusion, PK and dose response analysis of Phase 1 study revealed that drug exposure is correlated with response to PTX-100. In contrast, no correlation is noted with dose or exposure, using hematology, RBC, WBC, Neutrophils, and Platelets. This evaluation provides information regarding the selection of the doses used in the clinic.

Chew:Prescient Therapeutics, Ltd: Consultancy, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Mansour:Prescient Therapeutics Ltd: Current Employment, Current holder of stock options in a privately-held company. Fernando MALAVER ORTEGA:Prescient Therapeutics, Ltd: Current Employment, Current holder of stock options in a privately-held company. Bahadure:Prescient Therapeutics, Ltd: Current Employment, Current holder of stock options in a privately-held company. Yatomi-Clarke:Prescient Therapeutics Ltd: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company. Prince:Johnson and Johnson: Honoraria; Amgen: Honoraria; GSK: Honoraria; Bristol Myers Squibb: Honoraria; Takeda: Honoraria; Mallinckrodt: Honoraria; Kyowa Kirin: Honoraria; AbbVie: Research Funding.