Phase I dose-escalating study of biweekly fixed-dose rate gemcitabine plus pemetrexed in patients with advanced solid tumors.
OBJECTIVE
To determine the maximum tolerated dose (MTD) and the recommended phase II dose and to identify the dose-limiting toxicities (DLTs) of gemcitabine, administered by fixed-dose rate (FDR) infusion, combined with the antifolate agent pemetrexed in patients with advanced solid tumors.


METHODS
Eligible patients were entered into this open label, phase I trial. Using a 3 + 3 dose escalation design, patients received intravenous pemetrexed 300-800 mg/m(2) followed by FDR gemcitabine 900-1,500 mg/m(2) at 10 mg/m(2)/min on Day 1 every 2 weeks. All patients received folic acid and vitamin B(12) supplementation. Patients continued until DLT or disease progression.


RESULTS
A total of 33 patients were treated at 7 dose levels with a total of 230 cycles (median: 4 cycles; mean: 7 cycles; range: 1-35 cycles). The MTD of the combination was pemetrexed 800 mg/m(2) and gemcitabine 1,500 mg/m(2) over 150 min. DLTs were febrile neutropenia and grade 3 renal failure. Of the 28 patients evaluable for response, 3 patients experienced a partial response (10.7%) and 13 patients had stable disease (46.4%); the disease control rate was 57.1%.


CONCLUSIONS
The recommended phase II dose for biweekly pemetrexed with FDR gemcitabine is 800 mg/m(2) and 1,200 mg/m(2) × 120 min, respectively. This regimen allows good dose intensity of both drugs to be administered on a simple schedule with an excellent tolerability profile. This regimen showed moderate activity in a diverse phase I population, possibly greater than either single agent. Further assessment of the combination in a phase II setting is suggested.
Yuan
Yuan
Y
Loma Linda University Cancer Center, Loma Linda, CA 92354, USA.
Cohen
Deirdre J
DJ
Love
Erica
E
Yaw
Michelle
M
Levinson
Benjamin
B
Nicol
Steven J
SJ
Hochster
Howard S
HS
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects* / Q000627:therapeutic use; D015331:Cohort Studies; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018450:Disease Progression; D005260:Female; D005334:Fever / Q000139:chemically induced; D005493:Folic Acid Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D005971:Glutamates / Q000008:administration & dosage* / Q000009:adverse effects* / Q000627:therapeutic use; D006147:Guanine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy*; D009503:Neutropenia / Q000139:chemically induced; D010352:Patient Dropouts; D000068437:Pemetrexed; D011743:Pyrimidines / Q000037:antagonists & inhibitors; D051437:Renal Insufficiency / Q000139:chemically induced; D012720:Severity of Illness Index; D055815:Young Adult; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D005493:Folic Acid Antagonists; D005971:Glutamates; D011743:Pyrimidines; D000068437:Pemetrexed; D003841:Deoxycytidine; D006147:Guanine; D000093542:Gemcitabine