Phase I clinical and pharmacological study of intraperitoneal cis-bis-neodecanoato( trans- R, R-1, 2-diaminocyclohexane)-platinum II entrapped in multilamellar liposome vesicles.
OBJECTIVE
To perform a phase I study of intraperitoneal cis-bis-neodecanoato ( trans- R, R-1, 2-diaminocyclohexane)-platinum II entrapped in multilamellar vesicles (L-NDDP) for peritoneal carcinomatosis or sarcomatosis.


METHODS
Eligible patients had normal renal, hematologic, and liver functions. Laparoscopy was performed on the first two courses for evaluation, adhesiolysis, and chemotherapy administration. Afterwards, chemotherapy was administered through a peritoneal catheter. Up to six courses were allowed. Peritoneal imaging with technetium-labeled sulfur colloid was used to determine adequate distribution prior to each course. Volunteering patients underwent pharmacokinetics studies during the second course.


RESULTS
Fifteen of 16 registered patients, seven women and eight men (median age 53 years (range 26-76) and median performance status of 1) were assessable. Diagnoses were: malignant mesothelioma (six patients), signet ring cell (three), colon adenocarcinoma, pseudomyxoma peritonei, gastrointestinal stromal tumor (two each), and ovarian carcinoma (one). Median number of courses was two (range, one to six) Dose-limiting toxicity symptoms were fatigue and abdominal pain. Hematologic toxicities were minimal. Peri-operative complications included one colonic perforation requiring primary closure, a peritoneal catheter malfunction, a port site hematoma, and an ascites leak requiring re-suture. Five patients survived at least 3 years. Pharmacokinetics studies indicated a rapid but low absorption of drug into the systemic circulation, with a prolonged retention of platinum in the plasma compartment. Peritoneal L-NDDP exposure was 17 to 49-times greater than in the plasma compartment.


CONCLUSIONS
Peritoneal cavity exposure to L-NDDP is prolonged, and systemic absorption is limited, yielding a high peritoneal/plasmatic ratio. The recommended dose for phase II studies is 400 mg/m2 every 28 days.
D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001201:Ascites / Q000378:metabolism; D018279:Carcinoma, Signet Ring Cell / Q000188:drug therapy / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism; D036821:Endometrial Stromal Tumors / Q000188:drug therapy / Q000378:metabolism; D005260:Female; D006801:Humans; D007274:Injections, Intraperitoneal; D008081:Liposomes; D008297:Male; D008654:Mesothelioma / Q000188:drug therapy / Q000378:metabolism; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism; D010534:Peritoneal Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D010537:Peritoneum / Q000000981:diagnostic imaging / Q000378:metabolism; D011877:Radionuclide Imaging; D013667:Technetium; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D008081:Liposomes; D009944:Organoplatinum Compounds; C054367:bis-neodecanoato-1,2-diaminocyclohexaneplatinum(II); D013667:Technetium