title: Phase I and pharmacokinetic study of docetaxel combined with melphalan and carboplatin, with autologous hematopoietic progenitor cell support, in patients with advanced refractory malignancies.
abstract: The purpose of this study was to define the maximal tolerated dose (MTD), extramedullary toxicities, and pharmacokinetics of docetaxel combined with high-dose melphalan and carboplatin with autologous hematopoietic progenitor cell support. Fifty-nine patients with advanced refractory malignancy (32 breast cancer, 10 non-Hodgkin lymphoma, 6 germ cell tumors, 4 Hodgkin disease, 4 ovarian cancer, 2 sarcoma, and 1 unknown primary adenocarcinoma) with a median of 3 prior chemotherapy regimens and a median of 3 organs involved were enrolled. Treatment included docetaxel (150-550 mg/m2 infused over 2 hours on day -6), melphalan (150-165 mg/m2 infused over 15 minutes from day -5 to -3), and carboplatin (1000-1300 mg/m2 as a 72-hour continuous infusion from day -5). Five patients died from direct regimen-related organ toxicity (2 capillary leak syndrome, 2 enterocolitis, and 1 hepatic toxicity), and 1 additional patient died from pulmonary aspergillosis. The docetaxel MTD was defined as 400 mg/m 2 , combined with melphalan (150 mg/m2 ) and carboplatin (1000 mg/m2 ). The MTD cohort was expanded to enroll a total of 26 patients, 1 of whom died from toxic enterocolitis. The remaining 25 patients presented the following extramedullary toxicity profile, which was manageable and largely reversible: stomatitis, myoarthralgias, peripheral neuropathy, gastrointestinal and cutaneous toxicities, and syndrome of inappropriate antidiuretic hormone secretion. Docetaxel exhibited linear pharmacokinetics in the dose range tested (150-550 mg/m2 ). Pharmacodynamic correlations were noted between the docetaxel area under the curve and peripheral neuropathy or stomatitis. The response rate among 38 patients with measurable disease was 95%, with 47% complete responses. At a median follow-up of 26 months (range, 7-72 months), the 3-year event-free survival and overall survival were 26% and 36%, respectively. In conclusion, a 4-fold dose escalation of docetaxel, combined with melphalan and carboplatin, is feasible with autologous hematopoietic progenitor cell support. The notable activity of this regimen in treatment-refractory patients warrants its further evaluation.
authors.affiliation: University of Colorado Bone Marrow Transplant Program, Denver, Colorado, USA. ynieto@unav.es
authors.forename: Yago
authors.initials: Y
authors.lastname: Nieto
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Shpall
authors.forename: Scott I
authors.initials: SI
authors.lastname: Bearman
authors.forename: Peter A
authors.initials: PA
authors.lastname: McSweeney
authors.forename: Pablo J
authors.initials: PJ
authors.lastname: Cagnoni
authors.forename: Steve
authors.initials: S
authors.lastname: Matthes
authors.forename: Dan
authors.initials: D
authors.lastname: Gustafson
authors.forename: Michael
authors.initials: M
authors.lastname: Long
authors.forename: Anna E
authors.initials: AE
authors.lastname: Barón
authors.forename: Roy B
authors.initials: RB
authors.lastname: Jones
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D016190:Carboplatin / Q000008:administration & dosage / Q000493:pharmacokinetics; D002648:Child; D000077143:Docetaxel; D005260:Female; D006801:Humans; D008297:Male; D008558:Melphalan / Q000008:administration & dosage / Q000493:pharmacokinetics; D008875:Middle Aged; D043823:Taxoids / Q000008:administration & dosage / Q000493:pharmacokinetics
chemical_list: D043823:Taxoids; D000077143:Docetaxel; D016190:Carboplatin; D008558:Melphalan