Phase I trial of PT-100 (PT-100), a cytokine-inducing small molecule, following chemotherapy for solid tumor malignancy.

Abstract

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.

• Authors: John Nemunaitis, Svetislava J Vukelja, Donald Richards, Casey Cunningham, Neil Senzer, John Nugent, Houston Duncan, Barry Jones, Eric Haltom, Margaret J Uprichard
• Journal: Cancer investigation (Cancer Invest) Vol. 24 Issue 6 Pg. 553-61 (Oct 2006) ISSN: 0735-7907 [Print] England
• PMID: 16982458 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study)

Chemical References

• Boronic Acids
• Cytokines
• Dipeptides
• PT-100 dipeptide
• Dipeptidyl-Peptidases and Tripeptidyl-Peptidases

Topics

• Administration, Oral
• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Boronic Acids (pharmacokinetics, therapeutic use)
• Cytokines (metabolism)
• Dipeptides (pharmacokinetics, therapeutic use)
• Dipeptidyl-Peptidases and Tripeptidyl-Peptidases (antagonists & inhibitors)
• Dose-Response Relationship, Drug
• Female
• Humans
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasms (drug therapy)
• Salvage Therapy
• Treatment Outcome