Phase I and pharmacokinetic study of docetaxel combined with melphalan and carboplatin, with autologous hematopoietic progenitor cell support, in patients with advanced refractory malignancies.
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.
Nieto
Yago
Y
University of Colorado Bone Marrow Transplant Program, Denver, Colorado, USA. ynieto@unav.es
Shpall
Elizabeth J
EJ
Bearman
Scott I
SI
McSweeney
Peter A
PA
Cagnoni
Pablo J
PJ
Matthes
Steve
S
Gustafson
Dan
D
Long
Michael
M
Barón
Anna E
AE
Jones
Roy B
RB
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
D043823:Taxoids; D000077143:Docetaxel; D016190:Carboplatin; D008558:Melphalan