Phase I trial of PT-100 (PT-100), a cytokine-inducing small molecule, following chemotherapy for solid tumor malignancy.
PT-100 upregulates cytokine expression competitively inhibiting the dipeptidyl peptidase activity of fibroblast activation protein (FAP) and dipeptidyl peptidase IV (DPP-IV). This dose-escalation study was conducted to evaluate the safety of PT-100 in patients receiving myelosuppressive chemotherapy and to assess its effects on neutrophil recovery.PT-100 was administered orally for 7 days as a 200 microg, 400 microg, 800 microg, or 1,200 microg total daily dose (divided twice daily) to 6, 6, 17, and 5 patients, respectively. Patients received 2 cycles of chemotherapy: The first cycle served as each individual patient's control. Patients had to develop Grade 3+ neutropenia in Cycle 1 in order to receive PT-100 in Cycle 2. Most patients received PT-100 on Days 2-8 of chemotherapy in Cycle 2, except at 800 microg where an additional cohort (n = 8) was treated on a Days 5-11 schedule. Five of 7 patients receiving 800 microg on Days 2-8 experienced a >/=1-day improvement in Grade 3+ neutropenia in Cycle 2 versus Cycle 1. Overall, PT-100 was well tolerated. A reduction in chemotherapy-related nausea, vomiting, fatigue, alopecia, and diarrhea was noted in patients receiving PT-100. Edema/peripheral swelling, hypotension, hypovolemia, and dizziness were the most common nonhematologic adverse events considered related to PT-100. Two Grade 3 adverse events were considered related to PT-100: syncope (1,200 microg) and orthostatic hypotension (800 microg). A maximum tolerated dose was not reached. Given the accelerated neutrophil recovery, preclinical evidence of antitumor activity, and tolerable toxicities of PT-100, additional studies to optimize the PT-100 dosing schedule in patients receiving myelosuppressive chemotherapy are needed.
Nemunaitis
John
J
Mary Crowley Medical Research Center, Sammons Cancer Center, Baylor University Hospital, Dallas, Texas, USA. jnemunaitis@mcmrc.com
Vukelja
Svetislava J
SJ
Richards
Donald
D
Cunningham
Casey
C
Senzer
Neil
N
Nugent
John
J
Duncan
Houston
H
Jones
Barry
B
Haltom
Eric
E
Uprichard
Margaret J
MJ
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001897:Boronic Acids / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016207:Cytokines / Q000378:metabolism*; D004151:Dipeptides / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D016879:Salvage Therapy; D016896:Treatment Outcome
D001897:Boronic Acids; D016207:Cytokines; D004151:Dipeptides; C477478:PT-100 dipeptide; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases