Phase I and pharmacokinetic study of sequences of the rebeccamycin analogue NSC 655649 and cisplatin in patients with advanced solid tumors.
OBJECTIVE
To evaluate the feasibility of administering NSC 655649, a water-soluble rebeccamycin analogue that inhibits both topoisomerases I and II, in combination with cisplatin (CDDP) in adults with solid malignancies. Major toxicologic and pharmacologic differences between the two sequences of drug administration were also assessed.


METHODS
NSC 655649 was administered as a 60-minute i.v. infusion; CDDP was given i.v. before or after NSC 655649 on day 1. Each patient was treated with alternating drug sequences every 3 weeks; doses of each drug were escalated in separate cohorts of new patients. Sequential dose escalation of NSC 655649 or CDDP resulted in three dosage permutations of NSC 655649/CDDP: 440/50, 550/50, and 440/75 mg/m2. After the maximum tolerated dose level was determined, the feasibility of using granulocyte colony-stimulating factor to permit further dose escalation was explored.


RESULTS
Twenty patients were treated with 70 courses of NSC 655649/CDDP. Myelosuppression was the principal toxicity. The incidence of severe neutropenia, often associated with severe thrombocytopenia, was unacceptably high in minimally pretreated patients at the NSC 655649/CDDP dose level of 550/50 mg/m2 without and with granulocyte colony-stimulating factor. Major pharmacokinetic interactions between NSC 655649 and CDDP were not apparent. No relevant sequence-dependent differences in toxicity or pharmacokinetic variables occurred. Three patients had partial responses.


CONCLUSIONS
NSC 655649 and CDDP were well tolerated by minimally pretreated subjects at 440 and 50 mg/m2, respectively. Neither pharmacokinetic interactions between the agents nor sequence-dependent toxicologic or pharmacokinetic effects were apparent. The tolerance and preliminary activity observed with this combination suggest that disease-directed evaluations of the regimen are warranted.
Ricart
Alejandro D
AD
Institute for Drug Development, Cancer Therapy and Research Center, and Department of Pharmacology, University of Texas Health Science Center at San Antonio 78229, USA. aricart@idd.org
Hammond
Lisa A
LA
Kuhn
John G
JG
Takimoto
Chris H
CH
Goetz
Andrew
A
Forouzesh
Bahram
B
Forero
Leonardo
L
Ochoa-Bayona
Jose L
JL
Berg
Kristin
K
Tolcher
Anthony W
AW
Rowinsky
Eric K
EK
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000617:Aminoglycosides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D002227:Carbazoles; D002945:Cisplatin / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D004347:Drug Interactions; D005260:Female; D005960:Glucosides; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000000981:diagnostic imaging / Q000188:drug therapy*; D009503:Neutropenia / Q000139:chemically induced; D013921:Thrombocytopenia / Q000139:chemically induced; D014057:Tomography, X-Ray Computed
D000617:Aminoglycosides; D002227:Carbazoles; D005960:Glucosides; C093269:becatecarin; D002945:Cisplatin