XMT-1001, A Novel Biodegradable Polyacetal Polymer Conjugate of Camptothecin in Clinical Development

A.      V. Yurkovetskiy; R.      J. Fram

doi:10.2174/157340711795163839

Abstract

XMT-1001 is a conjugate of camptothecin (CPT) and Fleximer®, a biodegradable stealth polymer (poly [1- hydroxymethylethylene hydroxymethylformal], also called PHF). CPT is covalently linked to PHF via a hydrolizable linker. The conjugation of CPT with PHF increases the solubility of CPT. XMT-1001 releases CPT via intermediates camptothecin-20-O-(N-succinimidoglycinate) (CPT-SI) and camptothecin-20-O-(N-succinamidoyl-glycinate) (CPT-SA) over an extended time interval. XMT-1001 has an improved therapeutic window compared to CPT and irinotecan in human tumor xenograft models. XMT-1001 pharmacokinetics and biodistribution studies in rodents demonstrated extended plasma and tissue/tumor exposure for conjugated CPT and small molecule drug release products. An ongoing Phase 1 study of XMT-1001 in patients with advanced solid tumors demonstrates that XMT-1001 can be safely administered to patients. While neutropenia has been observed, no patients, to date, have experienced severe diarrhea or hemorrhagic cystitis. Early pharmacokinetic findings confirm the formation of the expected release products and a favorable PK profile. Evidence of a partial response in one patient as well as prolonged stable disease in numerous patients was observed. One patient had evidence of tumor shrinkage at a dose well below the maximum tolerated dose (MTD). Further clinical development is under consideration after completion of the Phase 1 study.

Keywords: Camptothecin conjugate, Fleximer®, biodegradable stealth polymer