A phase I and pharmacokinetic study of SAM486A, a novel polyamine biosynthesis inhibitor, administered on a daily-times-five every-three-week schedule in patients with Advanced solid malignancies.
OBJECTIVE
SAM486A is a novel inhibitor of the polyamine biosynthetic enzyme S-adenosylmethionine decarboxylase (SAMDC). This study was performed to characterize the toxicity profile and the pharmacological behavior and to determine the maximum tolerated dose (MTD) of SAM486A administered by a 1-h i.v. infusion daily for 5 days every 3 weeks in patients with advanced cancer.


METHODS
Twenty-three patients received 46 cycles of SAM486A at dose levels ranging from 3.6 to 202.8 mg/m(2)/day. SAM486A plasma concentrations were measured during the first cycle for pharmacokinetic and pharmacodynamic evaluations. Paired tumor biopsy specimens pre- and posttreatment were obtained in 1 patient to assess the impact of SAM486A on intratumoral enzymes and metabolites involved in the polyamine biosynthetic pathway.


RESULTS
The dose-limiting toxicity of SAM486A on this schedule was myelosuppression. Nonhematological toxicities, including nausea, vomiting, anorexia, and fatigue, were mild to moderate in severity. The MTD of SAM486A was 102.4 mg/m(2)/day. Pharmacokinetic analyses demonstrated a rapid initial decrease in plasma drug concentrations at the end of infusion, followed by a long terminal elimination phase with a mean (+/- SD) terminal elimination half-life of 65.4 +/- 55.6 h. Dose and area under the concentration-time curve correlated with the appearance of grade 4 neutropenia with correlation coefficients of 0.70 and 0.69, respectively. Analysis of paired tumor biopsy specimens taken before and after SAM486A treatment in 1 patient with metastatic melanoma revealed decreased SAMDC activity, increased ornithine decarboxylase activity, increased levels of putrescine, and depleted levels of decarboxylated S-adenosylmethionine and spermine, all of which are consistent with the proposed mode of action of SAM486A.


CONCLUSIONS
SAM486A was well tolerated on this schedule of administration with the MTD established at 102.4 mg/m(2)/day. Neutropenia was dose-limiting and correlated with dose and area under the concentration-time curve. Pharmacodynamic assessment of tumoral tissues in 1 study patient demonstrated changes in the levels of polyamines and their biosynthetic enzymes consistent with SAMDC inhibition.
Siu
Lillian L
LL
Cancer Therapy and Research Center, Institute for Drug Development, San Antonio, Texas 78229, USA.
Rowinsky
Eric K
EK
Hammond
Lisa A
LA
Weiss
Geoffrey R
GR
Hidalgo
Manuel
M
Clark
Gary M
GM
Moczygemba
Judy
J
Choi
Les
L
Linnartz
Ron
R
Barbet
Nicholas C
NC
Sklenar
Ivo T
IT
Capdeville
Renaud
R
Gan
Gregory
G
Porter
Carl W
CW
Von Hoff
Daniel D
DD
Eckhardt
S Gail
SG
D012437:Adenosylmethionine Decarboxylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000328:Adult; D000368:Aged; D000578:Amidines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D007189:Indans / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D011073:Polyamines / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000578:Amidines; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007189:Indans; D011073:Polyamines; C082408:4-amidinoindan-1-one 2'-amidinohydrazone; D012437:Adenosylmethionine Decarboxylase