A phase I trial of gemcitabine in combination with patupilone in patients with advanced solid tumors. Cancer Chemother Pharmacol 2008 Sep;62(4):727-33
Date
01/04/2008Pubmed ID
18172649DOI
10.1007/s00280-007-0656-8Scopus ID
2-s2.0-47549111409 (requires institutional sign-in at Scopus site) 10 CitationsAbstract
INTRODUCTION: Chemotherapy regimens including gemcitabine in combination with microtubule inhibitors such as docetaxel and paclitaxel have wide clinical application. Patupilone is a novel tubulin-polymerizing agent with activity against paclitaxel-resistant cell lines. We conducted a phase I trial to assess the maximum tolerated dose, dose limiting toxicity (DLT) and antitumor activity of gemcitabine and patupilone.
METHODS: Patients with refractory solid tumors enrolled in cohorts of three. Cohorts received fixed doses of gemcitabine (1,000 or 750 mg/m(2)) along with escalating doses of patupilone (1.5-3 mg/m(2)) on days 1 and 8 of a 21-day cycle.
RESULTS: Twenty-seven patients received a total of 99 courses of treatment on study. Hematologic toxicity in the first cohort required a modification of the protocol to decrease the gemcitabine dose. Subsequent patients received gemcitabine 750 mg/m(2) and escalating doses of patupilone from 1.5 to 3 mg/m(2). DLTs were grade 3 asthenia and grade 3 dehydration. There was also one treatment-related death due to neutropenic infection. Other clinically significant toxicities were persistent asthenia and persistent nausea. Four patients, one each with pancreatic cancer, esophageal carcinoma, cholangiocarcinoma and gallbladder carcinoma, experienced a partial response.
CONCLUSIONS: The dose-limiting toxicities of gemcitabine and patupilone were asthenia and dehydration. Dose reductions also occurred due to persistent fatigue that was not dose-limiting. However, patients with advanced malignancies were able to tolerate gemcitabine and patupilone at doses that resulted in clinical benefit. The recommended phase II dose for this schedule is gemcitabine 750 mg/m(2) and patupilone 1.5 mg/m(2) on days 1 and 8 of a 21-day cycle.
Author List
Schelman W, Morgan-Meadows S, Bailey H, Holen K, Thomas JP, Eickhoff J, Brandon H, Oliver K, Alberti D, Wilding GAuthor
James P. Thomas MD, PhD Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdultAged
Antineoplastic Combined Chemotherapy Protocols
Deoxycytidine
Dose-Response Relationship, Drug
Epothilones
Female
Humans
Male
Maximum Tolerated Dose
Middle Aged
Neoplasms
Treatment Outcome