Phase I and pharmacokinetic study of pemetrexed plus cisplatin in chemonaive patients with locally advanced or metastatic malignant pleural mesothelioma or non-small cell lung cancer.
OBJECTIVE
Pemetrexed is approved as monotherapy and in combination with cisplatin. The established combination dose was identified before the addition of folic acid and vitamin B(12) to the treatment regimen. We evaluated the toxicity and pharmacokinetics (PK) of higher pemetrexed doses with cisplatin and vitamin supplementation.


METHODS
Patients with malignant pleural mesothelioma or non-small cell lung cancer received pemetrexed doses from 500 to 900 mg/m(2) + 75 mg/m(2) cisplatin once every 21 days. Folic acid and vitamin B(12) were administered per label recommendations.


RESULTS
Twenty-one patients received a combined total of 84 cycles. The maximum tolerated dose was 900 mg/m(2) pemetrexed + 75 mg/m(2) cisplatin. Dose-limiting toxicities at this dose included grade 3 anemia, bronchopneumonia, and neutropenia, and 1 death from sepsis secondary to grade 4 febrile neutropenia, considered possibly related to study drugs. The recommended dose was 800 mg/m(2) pemetrexed + 75 mg/m(2) cisplatin. Pemetrexed PK were consistent across doses; pemetrexed did not seem to affect total or free platinum PK.


CONCLUSIONS
Pemetrexed with vitamin supplementation was safe and well tolerated at higher doses than the currently established 500 mg/m(2) + 75 mg/m(2) cisplatin. Based on this study, the recommended dose would be 800 mg/m(2) pemetrexed + 75 mg/m(2) cisplatin. However, recent studies showed a lack of improved efficacy for 900 or 1,000 mg/m(2) single-agent pemetrexed versus 500 mg/m(2) and a lack of PK/pharmacodynamic exposure-response relationship for the pemetrexed/cisplatin combination across pemetrexed exposures corresponding to this dose range. Based on currently available evidence, we recommend retaining the established dose.
Dickgreber
Nicolas J
NJ
Hannover Medical School, Hannover, Germany. nicolas.dickgreber@gmx.de
Fink
Thomas H
TH
Latz
Jane E
JE
Hossain
Anwar M
AM
Musib
Luna C
LC
Thomas
Michael
M
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000556:secondary; D002945:Cisplatin / Q000008:administration & dosage*; D019587:Dietary Supplements; D004334:Drug Administration Schedule; D005260:Female; D005971:Glutamates / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D006147:Guanine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D008297:Male; D020714:Maximum Tolerated Dose; D008654:Mesothelioma / Q000188:drug therapy* / Q000556:secondary; D008875:Middle Aged; D000068437:Pemetrexed; D010984:Platinum / Q000097:blood; D010997:Pleural Neoplasms / Q000188:drug therapy*; D014815:Vitamins / Q000008:administration & dosage
D005971:Glutamates; D014815:Vitamins; D000068437:Pemetrexed; D010984:Platinum; D006147:Guanine; D002945:Cisplatin