Phase I and pharmacokinetic study of an oral platinum complex given daily for 5 days in patients with cancer.
OBJECTIVE
We aimed to determine the maximum-tolerated dose (MTD) clinical toxicities, pharmacokinetics, and pharmacodynamics of oral JM216 given once daily for 5 days to cancer patients.


METHODS
Patients who fulfilled standard phase I trial criteria were enrolled. Oral JM216 was given at doses based on patient body-surface area, on an empty stomach, once daily for 5 consecutive days, as 10-, 50-, and 200-mg hard gelatin capsules and with oral antiemetics. The pharmacokinetics of platinum were studied on days 1 and 5 of the first treatment course using atomic absorption spectrophotometry (AAS).


RESULTS
Thirty-two patients received 94 courses of oral JM216 at doses that ranged from 30 to 140 mg/m2 body-surface area for 5 consecutive days. The MTD was 140 mg/m2/d. The dose-limiting toxicities were thrombocytopenia and neutropenia. Hematotoxicity was reversible (nadir, 17 to 21 days; recovery, 28 days), noncumulative, and dependent on the dose and history of previous therapy. There were two instances of neutropenic sepsis. Two-thirds of patients experienced mild nausea, vomiting, or diarrhea. There was no ototoxicity, neurotoxicity, nephrotoxicity, or objective tumor responses. There was a significant correlation between JM216 dose and the day 1 and 5 plasma ultrafiltrate area under the concentration-time curve (AUC; r = .78), which indicates linear pharmacokinetics. There was considerable intersubject pharmacokinetic and pharmacodynamic variability, but a significant sigmoidal relationship between the plasma ultrafiltrate AUC and severity of thrombocytopenia (R2 = .83).


CONCLUSIONS
We recommend JM216 doses of 100 and 120 mg/m2/d x 5 for previously treated and untreated patients, respectively, for phase II trials.
McKeage
M J
MJ
Cancer Research Campaign Centre of Cancer Therapeutics, Institute of Cancer Research and Royal Marsden Hospital, Sutton, Surrey, United Kingdom.
Raynaud
F
F
Ward
J
J
Berry
C
C
O'Dell
D
D
Kelland
L R
LR
Murrer
B
B
Santabárabara
P
P
Harrap
K R
KR
Judson
I R
IR
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D004334:Drug Administration Schedule; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy; D009944:Organoplatinum Compounds; D012720:Severity of Illness Index; D014462:Ultrafiltration
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; C081294:satraplatin