High-dose paclitaxel, cyclophosphamide, and cisplatin with autologous hematopoietic progenitor-cell support: a phase I trial.
OBJECTIVE
To determine the maximal-tolerated dose (MTD) of paclitaxel in combination with high-dose cyclophosphamide (CPA) and cisplatin (cDDP) followed by autologous hematopoietic progenitor-cell support (AHPCS).


METHODS
Forty-nine patients with poor-prognosis breast cancer, non-Hodgkin's lymphoma (NHL), or ovarian cancer were treated with escalating doses of paclitaxel infused over 24 hours, followed by CPA (5,625 mg/m2 intravenously over 1 hour in three divided doses) and cDDP (165 mg/m2 intravenously as a continuous infusion over 72 hours) and AHPCS. Pharmacokinetic measurements for each drug were performed.


RESULTS
Dose-limiting toxicities were encountered in two patients at 825 mg/m2 of paclitaxel; one patient died of multiorgan failure that involved the lung, CNS, and kidneys, and the other developed grade 3 respiratory, CNS, and renal toxicity, which resolved. The MTD of this combination was determined to be paclitaxel 775 mg/m2, CPA 5,625 mg/m2, and cDDP 165 mg/m2 followed by AHPCS. Sensory polyneuropathy and mucositis were prominent toxicities, but both were reversible and tolerable. The pharmacokinetics of paclitaxel correlated significantly with the severity of mucositis (P < .001) and peripheral neuropathy (P < .00004). Eighteen of 33 patients (54%) with measurable, heavily pretreated metastatic breast cancer achieved a partial response (PR). Responses were also observed in patients with NHL (four of five patients) and ovarian cancer (two of two).


CONCLUSIONS
It is possible to escalate the dose of paclitaxel to 775 mg/m2 in combination with 5,625 mg/m2 of CPA, 165 mg/m2 of cDDP, and AHPCS. An encouraging response rate in poor-prognosis patients with breast cancer, NHL, and ovarian cancer warrants further study.
Stemmer
S M
SM
University of Colorado Bone Marrow Transplant Program, University of Colorado Cancer Center, Denver, USA.
Cagnoni
P J
PJ
Shpall
E J
EJ
Bearman
S I
SI
Matthes
S
S
Dufton
C
C
Day
T
T
Taffs
S
S
Hami
L
L
Martinez
C
C
Purdy
M H
MH
Arron
J
J
Jones
R B
RB
D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000628:therapy*; D002945:Cisplatin / Q000008:administration & dosage / Q000493:pharmacokinetics; D015331:Cohort Studies; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000628:therapy*; D017239:Paclitaxel / Q000008:administration & dosage / Q000493:pharmacokinetics; D011379:Prognosis
D003520:Cyclophosphamide; D017239:Paclitaxel; D002945:Cisplatin