Phase I study of CT2106 (polyglutamate camptothecin) in patients with advanced malignancies
Citation: European Journal of Cancer Supplements Volume 2, No.8, September 2004, page 154
C. Takimoto1, S. Syed1, M. McNamara2, J. Doroshow3, S. Pezzulli4, E. Eastham1, A. Bernareggi5, J. Dupont4
1Cancer Therapy and Research Center, San Antonio, USA
2City of Hope Medical Group, Pasadena, USA
3City of Hope Medical Center, Department of Medical Oncology, Duarte, USA
4Memorial Sloan-Kettering Cancer Center, Department of Medicine, New York, USA
5Cell Therapeutics, Inc., Department of Clinical Pharmacology, Seattle, USA
Background: CT-2106 is a novel camptothecin (CPT) conjugate in which CPT is bound to a biodegradable water-soluble poly-L-glutamic acid-glycine polymer. CPT-polymer conjugation allows for greater stability of CPT in circulation and enhanced permeability and retention in tumor tissue. CT-2106 has demonstrated anti-tumor activity in several human tumor cell lines in vivo.
Methods: To determine the maximum tolerated dose (MTD) and evaluate the pharmacokinetics (PK) of CT-2106, 31 pts were treated with a 10-minute IV infusion every 21 days. Toxicity was assessed according to NCI CTC v2. PK samples (cycles 1 and 2) were analyzed for conjugated and unconjugated CPT levels by validated HPLC/FD methods. Cohorts of pts received conjugated CPT doses of 12, 25, 50, 75, 90, or 105 mg/m2.
Results: Dose-limiting toxicities (DLTs) included: grade (g) 3/4 neutropenia, thrombocytopenia, and mucositis. One pt experienced a g4 cholinergic reaction and esophageal spasm; this pt had previously experienced a severe reaction to irinotecan. Other related toxicities were g3 increased ALT and £g2 anemia, anorexia, dysgeusia, peripheral sensory neuropathy, fatigue, nausea, diarrhea, vomiting, abdominal pain, alopecia, rash, decreased hemoglobin, and hematuria. No g3/4 hematuria or diarrhea was observed. Using standard response criteria, 1 pt with metastatic pancreatic cancer had a partial response, 2 pts with NSCLC had stable disease (SD) for >35 weeks, and 2 pts with colon cancer had SD for >9 weeks.
Preliminary PK parameters calculated from 18 pts treated at 25, 50, 75, or 105 mg/m2 demonstrated sustained levels of conjugated CPT in systemic circulation, with mean elimination half-life from 16.6 to 50.8 hrs. Cmax and AUC of conjugated CPT increased linearly with dose, suggesting PK linearity. Unconjugated CPT levels suggest that this active form of the compound is generated by a slow, progressive release from the polymer following the distribution of conjugated CPT to tissues. The PK profile of unconjugated CPT is dependent on the disposition profile of the conjugated drug; unconjugated CPT elimination is formation rate limited. Unconjugated CPT half-life ranged from 31.9 to 60.4 hours. Five days after the 1st administration, mean cumulative urinary excretion of conjugated and unconjugated CPT accounted for 27.9% and 5.1% of the administered dose, respectively. A major conjugated CPT species in urine was glu-gly-CPT (6.9% of dose). Accumulation of conjugated or unconjugated CPT was not observed with repeated dose administration. Plasma and urine PK parameters were nearly identical in cycles 1 and 2. The MTD has been established at 75 mg/m2.
Conclusion: CT-2106 has been well tolerated with easily manageable toxicities while generating prolonged systemic exposures to free CPT in plasma. Since clinical activity has been observed, phase I/II single-agent and combination trials are planned. |
