Phase 1 Study of Weekly Polyethylene Glycol-Camptothecin in Patients with Advanced Solid Tumors and Lymphomas

Abstract

Purpose:To determine the maximal tolerated dose and dose-limiting toxicities (DLT) of pegamotecan (polyethylene glycol-camptothecin) in patients with advanced malignancies when administered in cycles of once weekly for 3 of 4 weeks. Experimental Design: Eligible patients had advanced solid tumors that failed to respond to standard therapy or for which no standard therapy was available, including also the following criteria: measurable disease, Eastern Cooperative Oncology Group performance status of V2, and acceptable organ function. Pegamotecan was administered as a 60-minute infusion, with successive patient cohorts receiving escalating doses from 800 to 4,300 mg/m 2 . The primary end point was to determine the maximal tolerated dose. Other end points were toxicity, pharmacokinetics, pharmacodynamics, and efficacy. Pharmacokinetic analysis measured free camptothecin. Pharmacodynamic analysis correlated drug effects with pegamotecan dose and pharmacokinetic variables. Results: Twenty-seven patients were enrolled. The maximal tolerated dose was 3,240 mg/m 2 . Grade 4 neutropenia, the DLT, was noted in two of four patients treated at 4,300 mg/m 2 . Other grade 3 and 4 toxicities were anemia, thrombocytopenia, fatigue, prolonged partial thromboplastin time, hemorrhagic cystitis, dysuria, and urinary frequency. Pharmacokinetic analysis showed the apparent terminal elimination half-life to be 46 F 12.8 hours. Pharmacodynamic analysis showed that hematuria occurred in 8 of 15 patients with an area under the curve extrapolated to infinity (AUC 0-1 ) > 20 ng h/mL and 0 of10 patients with an AUC 0-1 V 20 ng h/mL. Unconfirmed partial responses were observed in two patients, one with metastatic small bowel adenocarcinoma and the other with metastatic esophageal cancer. Conclusions: The maximal tolerated dose of pegamotecan when administered weekly for 3 of 4 weeks is 3,240 mg/m 2 . The DLT was neutropenia. Among nonhematologic toxicities, the incidence of gastrointestinal toxicity was low, but genitourinary toxicity seems to occur in the same effective dose range as noted with native camptothecin in earlier trials (27-43 mg/m 2 ). The observed antitumor activity suggests that pegamotecan has single-agent activity and merits further investigation in phase 2 studies.

Correlating preclinical animal studies and human clinical trials of a multifunctional, polymeric nanoparticle

“…This high binding to human albumin is not observed with the active metabolic of irinotecan, SN-38 (30,31). When CPT was conjugated to linear PEG, the PK profiles of the released CPT in animals (32) and humans (33,34) showed the same form of the dynamics as observed for CRLX101. Likewise, the MAG-CPT gave released CPT dynamics of the same type (35,36).…”

Polymer-drug conjugates: Recent development in clinical oncology

“…The 20-OH of CPT in Pegamotecan, is blocked by the alaninate linker, which stabilizes the CPT molecule into its active lactone conformation [57]. The MTD of Pegamotecan when administered weekly for 3 of 4 weeks was 3,240 mg/m 2 , with neutropenia being its DLT [58]. Other grade 3 and 4 toxic effects were anemia, thrombocytopenia, fatigue, prolonged partial thromboplastin time, hemorrhagic cystitis, dysuria, and urinary frequency.…”

Molecular imaging with nanoparticles: giant roles for dwarf actors

“…Polyglutamic acid (PGA)-paclitaxel copolymer (CT-2103) (Xyotax) is entering the market as cancer treatment for non-small-cell lung cancer in women (Singer 2005). Polyethyleneglycol in conjugation with camptothecin (EZ-246, Pegamotecan) (Posey et al 2005) and cyclodextrin in conjugation with camptothecin (Schluep et al 2006a, b;Zamboni et al 2006) are entering clinical trials. Polymer-drug conjugates are being directed not only against tumour cells, but also against angiogenic blood vessels, for example, HPMA-fumagillol (TNP-470) caplostatin (Satchi-Fainaro et al 2004;Huang et al 2004;Inoue et al 2003;Bhujwalla et al 2003), the HPMA copolymer-RGD4C-Tc-99m conjugate, capable of targeting tumour angiogenic vessels and delivering adequate radiotherapy to arrest tumour growth (Mitra et al 2006) and PEGylated cyclic arginine-glycine-aspartic acid (RGD) radiotracers (64-Cu-DOTAPEG-RGD and 125 I-RGD-mPEG) targeted at integrins (Chen et al 2004a, b).…”