A Phase I Trial Of Pt-100 In Patients Receiving Myelosuppressive Chemotherapy.

2572 Background: PT-100 is a small molecule which competitively inhibits dipeptidyl peptidase activity of fibroblast activation protein (FAP) and dipeptidyl peptidase IV (DPP-IV). It rapidly increases cytokine (G-CSF, IL-8) production, accelerates neutrophil and erythrocyte regeneration, and causes tumor regression in mice via inhibition of FAP and DPP-IV. This dose-escalation study was conducted to evaluate the safety of PT-100 in patients receiving myelosuppressive chemotherapy (a doxorubicin or taxane based regimen) and to assess its effects on neutrophil recovery. Methods: Patients received 2 cycles of chemotherapy: the first cycle (C1) served as each patient's individual control. PT-100 was administered orally for 7 days in cycle 2 (C2) as a 200, 400, 800, and 1200mcg total daily dose (divided twice daily) to 6, 6, 13, and 4 patients, respectively. Most patients received PT-100 on Days 2–8 of chemotherapy in C2, except at 800mcg where one cohort was treated on a Day 5–11 schedule. Patients had to have Grade 3/4 neutropenia in C1 to receive PT-100 in C2. Results: Five of 13 patients receiving PT-100 800mcg experienced a ≥ 2-day improvement in ≥ Grade 3 neutropenia, and a 62% improvement in median AUC in C2 vs. C1 was observed in patients treated on the Day 2–8 schedule. A corresponding upregulation in G-CSF, IL-6, and IL-8 was observed in most patients. Overall, PT-100 was well-tolerated. Edema/peripheral swelling, hypotension, and hypovolemia were the most common non-hematologic AEs considered related to PT-100. Two Grade 3 AEs were considered related to PT-100: syncope (1200mcg) and orthostatic hypotension (800mcg). An MTD was not reached. Conclusions: Given the accelerated neutrophil recovery, strong preclinical evidence of antitumor activity, and tolerable toxicities of PT-100, studies using a longer PT-100 dosing schedule are warranted to investigate its antitumor and neutrostatic effects. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Point Therapeutics Point Therapeutics Point Therapeutics Cell Genesys; ONYX Pharmaceuticals Corixa