Phase I trial of poly-L-glutamate camptothecin (CT-2106) administered weekly in patients with advanced solid malignancies.
OBJECTIVE
CT-2106 is a 20(S)-camptothecin poly-L-glutamate conjugate. This linkage stabilizes the active lactone form of camptothecin and enhances aqueous solubility. In addition, poly-L-glutamate is postulated to increase tumor delivery of the active compound through enhanced permeability and retention effect in tumor. We studied a weekly schedule of CT-2106 in patients with refractory solid tumor malignancies.


METHODS
CT-2106 was infused (10 min i.v. infusion) on days 1, 8, and 15 of each 28-day cycle. Plasma and urine were analyzed for total and unconjugated camptothecin by high-performance liquid chromatography equipped with a fluorescence detector. Toxicity and response assessments were done with Common Toxicity Criteria for Adverse Events version 3 and Response Evaluation Criteria in Solid Tumors, respectively.


RESULTS
Twenty-six patients were enrolled. Median age was 58 years (range, 36-83) and median number of doses was 6 (range, 1-9). The most frequent tumor type (50%) was melanoma. Dose limiting toxicities were thrombocytopenia and fatigue. A weekly dose of 25 mg/m2 given every 3 of 4 weeks was the maximum tolerated dose. The majority of grade 3 and 4 toxicities were hematologic. The pharmacokinetic profile of conjugated and unconjugated camptothecin showed a polyexponential decline with similar terminal half life (t1/2 range was 44-63 and 31-48 h for conjugated and unconjugated, respectively). Pharmacokinetics of conjugated and unconjugated camptothecin were dose and time independent in the tested dose range. Urinary excretion of conjugated and unconjugated camptothecin accounted for about 30% and 4% of the administered dose, respectively.


CONCLUSIONS
CT-2106 has a more manageable toxicity profile compared with unconjugated camptothecin. The maximum tolerated dose is 25 mg/m2 weekly given 3 of 4 weeks. This compound results in prolonged release of unconjugated camptothecin.
Homsi
Jade
J
H. Lee Moffitt Cancer Center, Tampa, Florida 33612-9497, USA.
Simon
George R
GR
Garrett
Chris R
CR
Springett
Gregory
G
De Conti
Ronald
R
Chiappori
Alberto A
AA
Munster
Pamela N
PN
Burton
Michelle K
MK
Stromatt
Scott
S
Allievi
Claudia
C
Angiuli
Patrizia
P
Eisenfeld
Amy
A
Sullivan
Daniel M
DM
Daud
Adil I
AI
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D002166:Camptothecin / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007783:Lactones / Q000737:chemistry; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011099:Polyglutamic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D012995:Solubility; D013997:Time Factors
D000970:Antineoplastic Agents; D007783:Lactones; C525022:polyglutamate camptothecin; D011099:Polyglutamic Acid; D002166:Camptothecin