Phase I Study of Topotecan, Ifosfamide, and Etoposide (TIME) with autologous stem cell transplant in refractory cancer: pharmacokinetic and pharmacodynamic correlates.
OBJECTIVE
To determine the maximum tolerated dose (MTD) of topotecan in combination with ifosfamide, mesna, and etoposide (TIME), followed by autologous hematopoietic cell transplant (HCT), in patients with chemotherapy-refractory malignancies.


METHODS
Patients were treated with (in mg/m(2)/d) ifosfamide 3,333, mesna 3,333, and topotecan 3.3 to 28.3 during days -8 through -6 and etoposide 500 (days -5 through -3) followed by HCT on day 0. Once MTD was defined, we expanded this dosing cohort to include patients with high-risk lymphoma due to activity seen during dose escalation. Topotecan pharmacokinetic analyses were carried out, and topoisomerase I levels and activity were measured.


RESULTS
The topotecan MTD in this regimen was 64 mg/m(2) (21.3 mg/m(2)/d). Mucositis was dose limiting and correlated with topotecan dose level and area under the curve (AUC). Dose level was also correlated with length of hospitalization, number of days of parenteral nutrition, and neutrophil and platelet engraftment. Topotecan AUC was significantly correlated with time to platelet recovery. The baseline peripheral blood mononuclear cell topoisomerase I level was found to be a significant positive predictor for overall and progression-free survival. Topotecan AUC was positively correlated with dose level, with a trend toward decreasing clearance with increasing dose.


CONCLUSIONS
Topotecan can be a useful drug in the high-dose setting given its activity in some malignancies when given in standard dose. Pharmacokinetic monitoring may be a valuable tool for optimizing the use of topotecan and to avoid toxicity seen with high-systemic exposures. Baseline topoisomerase I levels may have an important role in predicting topotecan efficacy.
Department of Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
Janelle B
JB
Perkins
Steven C
SC
Goldstein
Jana L
JL
Dawson
Jongphil
J
Kim
Teresa L
TL
Field
James S
JS
Partyka
Karen K
KK
Fields
Beth L
BL
Maddox
Christine E
CE
Simonelli
Anthony M
AM
Neuger
Richard M
RM
Lush
Daniel M
DM
Sullivan
D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D019540:Area Under Curve; D003131:Combined Modality Therapy / Q000706:statistics & numerical data; D004264:DNA Topoisomerases, Type I / Q000097:blood; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage / Q000009:adverse effects; D053208:Kaplan-Meier Estimate; D008297:Male; D015080:Mesna / Q000008:administration & dosage / Q000009:adverse effects; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D052016:Mucositis / Q000139:chemically induced; D015999:Multivariate Analysis; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D016016:Proportional Hazards Models; D019772:Topotecan / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D014182:Transplantation, Autologous; D016896:Treatment Outcome
D005047:Etoposide; D019772:Topotecan; D004264:DNA Topoisomerases, Type I; C528909:TOP1 protein, human; D015080:Mesna; D007069:Ifosfamide