A phase I trial of amsalog (CI-921) administered by intravenous infusion using a 5-day schedule.
OBJECTIVE
Amsalog, a derivative of 9-aminoacridine, is an inhibitor of topoisomerase II. Early studies of intravenous amsalog administered either once weekly, or daily for 3 days repeated every 3 weeks, showed that myelosuppression is the dose-limiting toxicity (DLT). Phase II studies showed only limited activity in breast, head and neck, and non-small-cell lung cancer. The activity of other topoisomerase inhibitors is schedule-dependent. We therefore performed a phase I study to evaluate the use of amsalog on a more prolonged schedule.


METHODS
A group of 19 patients with refractory malignancies were treated in six cohorts using 2-h infusions of amsalog daily for 5 days, repeated every 3 weeks.


RESULTS
Myelosuppression was seen as DLT at 200 mg/m2 per day. Other toxicities included nausea and vomiting, fatigue, and, when administered via a peripheral venous line, severe phlebitis necessitating administration via an indwelling central venous catheter for doses greater than 100 mg/m2. Pharmacokinetic studies showed a linear relationship between Cmax and AUC, and dose. The terminal half-life was 2 h, consistent with previous studies.


CONCLUSIONS
We conclude that amsalog can be safely given on a 5-day schedule every 3 weeks at doses up to 200 mg/m2. The dose recommended for further studies is 180 mg/m2 per day for 5 days repeated every 3 weeks. However, in view of the phlebitis, which necessitated the use of central venous catheters for administration, other routes of administration, for example oral formulations, should be explored.
Fyfe
D
D
CRC Department of Clinical Oncology, City Hospital, Nottingham NG5 1PB, UK.
Price
C
C
Langley
R E
RE
Pagonis
C
C
Houghton
J
J
Osborne
L
L
Woll
P J
PJ
Gardner
C
C
Baguley
B C
BC
Carmichael
J
J
D000328:Adult; D000368:Aged; D000677:Amsacrine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D019540:Area Under Curve; D001855:Bone Marrow Diseases / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D059005:Topoisomerase II Inhibitors
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D059005:Topoisomerase II Inhibitors; D000677:Amsacrine; C042315:asulacrine