Trials of 9-amino-20(S)-camptothecin in Boston.
9-Amino-20(S)-camptothecin (9-AC) is an analog of camptothecin with limited water solubility which has shown significant preclinical activity in a variety of human solid tumor xenografts. A Phase I trial using a soluble formulation of 9-AC, given as a 72-hour continuous infusion, has been completed. Thirty-one patients with resistant cancers received 5-60 micrograms/M2/h at three week intervals. The Maximum Tolerated Dose (MTD) was 45 micrograms/M2/hour. Neutropenia was the dose limiting toxicity, with few significant non-myelosuppressive toxicities. Minor responses were seen in 3/31 patients. Pharmacokinetic studies of 9-AC lactone (closed ring) showed substantial interpatient variability with a predicted half-life of 36 hours. A phase I/II trial of the same formulation of 9-AC is ongoing in refractory leukemia. Stomatitis and diarrhea are the non-myelosuppressive dose limiting toxicities. Evidence of antineoplastic activity has been seen in 3/15 patients. A Phase II trial in previously untreated metastatic breast cancer is also underway. A Phase I trial of a colloidal dispersion formulation, not yet completed, is better tolerated with a MTD > 45 micrograms/M2/h as a 72-hour continuous infusion. Evidence of antineoplastic activity has also been demonstrated.
Eder
J P
JP
Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Rubin
E
E
Stone
R
R
Bryant
M
M
Xu
G
G
Supko
J
J
Kinchla
N
N
Lynch
T
T
Hurwitz
S
S
Rodriguez
D
D
Shapiro
C
C
Toppmeyer
D
D
Grossbard
M
M
Vosburg
E
E
Huberman
M
M
Schnipper
L
L
Shulman
L
L
Kufe
D W
DW
D000328:Adult; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001900:Boston; D001943:Breast Neoplasms / Q000188:drug therapy*; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D004264:DNA Topoisomerases, Type I / Q000097:blood; D005260:Female; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*
D000970:Antineoplastic Agents; C080125:9-aminocamptothecin; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin