Phase 1 pharmacokinetic (PK) and pharmacodynamic(PD) evaluation of SF1126 a vascular targeted pan phosphoinositide 3- kinase (PI3K) inhibitor in patients with solid tumors

Abstract

14532 Background: SF1126 is a conjugate of the well known pan PI3K inhibitor LY294002 with an RGD containing peptide designed for increased solubility and binding to specific integrins within the tumor compartment. This prodrug approach has been demonstrated to enhance delivery of the active inhibitor to the tumor resulting in increased antitumor efficacy coupled with improved tolerability in a number of preclinical studies including PC-3, DU-145, U87MG, U251MG, LN229, 786-O, MDA-MB-468 xenograft/orthotopic cancer models (Cancer Research, 2008;68(1)pp206–15). Methods: Patients are being dosed twice/ week by IV infusion over 1.5 hours in treatment cycles of 4 weeks. This is a dose escalation study with patients being entered onto a 3+3 modified Fibonacci schema. Activity of SF1126 is assessed by standard RECIST criteria, PD effects by 18F-deoxygluose PET scans 4 - 8 hours after dosing and at the end of cycle 1 and by enumeration of tumor cells. Results: To date 10 patients have been treated with SF1126 twice/ week for up to six months, the average treatment duration was 2 months (2 cycles). The dose escalation has progressed from 90 mg/m2 to 140 mg/m2 and to 180 mg/m2. One dose limiting toxicity (DLT) was seen at the 180 mg/m2 dose and consisted of a hypersensitivity reaction manifested by hypotension and also diarrhea. In general the drug was well tolerated, 1 patient discontinued study because of an SAE, the remainder of the patients discontinued study for disease progression. The analysis of blood samples for parent drug (SF1126) and the hydrolysis product SF1101 (LY294002) showed a clearance and T1/2 values of CL: 178 ± 68 L/hr and T1/2 of 1.21 ± 0.58 hr respectively. Parent drug was measurable in some subjects at 5 and 15 min post-infusion, but not at any of the later sampling times. Intrapatient variability was low and subgroup of slow metabolizers is likely. Conclusions: SF1126 is well tolerated and converted in plasma rapidly to SF1101, which has a T1/2 of 1.2 ± 0.58 hrs. Dose escalation continues at 180 mg/m2. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Semafore Pharmaceuticals Inc. Semafore Pharmaceuticals Inc. Semafore Pharmaceuticals Inc. Semafore Pharmaceuticals Semafore Pharmaceuticals