The purpose of the present study was to determine the maximally tolerated dose of
thioTEPA given with fixed high-dose
cyclophosphamide (CPA) and
cisplatin (cDDP) followed by autologous bone marrow (ABM) with or without
granulocyte colony-stimulating factor (
G-CSF)-primed peripheral-blood progenitor cells (PBPCs) in patients with advanced
malignancies. Patients were required to have histologically documented
malignancies and adequate renal, hepatic, pulmonary, and cardiac function. CPA was given at 1,875 mg/m2 per day as a 1-h i.v. infusion for 3 consecutive days, and cDDP was given at 55 mg/m2 per day as a 24-h continuous i.v infusion over 3 days concurrently with CPA.
ThioTEPA was given once as a 1-h i.v. infusion (300-900 mg/m2) either following (the first 13 patients) or prior to CPA and cDDP. In all, 31 patients received PBPCs. A total of 46 patients were treated. There were 6 deaths among the 15 patients who did not receive PBPCs (13 received
thioTEPA following CPA and cDDP). Among the other 31 patients who received PBPCs (all of whom also received
thioTEPA prior to CPA and cDDP), there were 4 deaths, all involving patients with refractory ovarian
carcinoma. The main toxicities were
mucositis,
esophagitis, hepatotoxicity, and nephrotoxicity. The median time required to achieve an absolute neutrophil count of 500 microliter was 10 days (range, 9-12 days) for those who received PBPCs and 15 days (range, 15-34 days) for those who did not receive PBPCs. Altogether, 47% of the major organ toxicities (grades 3 and 4 renal, hepatic, and
cardiac toxicities) occurred among the 15 patients who did not receive PBPCs, although these patients received
thioTEPA at the lowest 2 dose levels. There were 3 complete responses and 22 partial responses among 35 evaluable patients (overall response rate, 71%), with the median duration of response being 3.5 months (range, 2-17 months). The maximally tolerated dose of
thioTEPA was 600 mg/m2 given as a 1-h i.v. infusion on the day prior to CPA and cDDP administration, The combination of high-dose CPA, cDDP, and
thioTEPA is a well-tolerated regimen when
thioTEPA is given prior to CPA and cDDP and when the combination also includes PBPCs in addition to ABM. This regimen is active in a variety of
malignancies.