Phase I clinical and pharmacokinetic study of high-dose mitoxantrone combined with carboplatin, cyclophosphamide, and autologous bone marrow rescue: high response rate for refractory ovarian carcinoma.
OBJECTIVE
To develop an active high-dose chemotherapy regimen for the treatment of ovarian carcinoma. Due to the rapid development a drug resistance, conventional chemotherapy cures only 20% of patients with advanced disease. However, in vitro data demonstrate a steep dose-response curve to a variety of agents, most notably mitoxantrone.


METHODS
A phase I study of escalated bolus mitoxantrone (10 to 25 mg/m2 x 3) and cyclophosphamide (30 to 50 mg/kg x 3) with a 5-day infusion of carboplatin (1,500 mg/m2) and an autologous bone marrow transplant (ABMT) was performed. Mitoxantrone pharmacokinetics were performed to document levels required to kill platinum-resistant ovarian carcinoma in vitro.


RESULTS
We treated 25 patients; the maximum-tolerated total doses (MTD) were 75 mg/m2 for mitoxantrone, 120 mg/kg for cyclophosphamide, and 1,500 mg/m2 for carboplatin. The dose-limiting toxicity was gastrointestinal, with severe diarrhea, ileus, and resulting sepsis. Transient partial deafness was seen in four patients, and acute renal failure (ARF) occurred in one patient at the first dose level, but was eliminated in subsequent patients with aggressive hydration. There were four early deaths due to ARF (n = 1), Legionella pneumonia (n = 1), and sepsis (n = 2). Peak mitoxantrone levels at the MTD were 623 to 2,810 ng/mL, and the area under the curve (AUC) values of the concentration versus time measurements were 560 to 1,700 ng/mL/h. Of 20 assessable patients, 65% responded, with a 45% complete remission (CR) rate. All six of the assessable patients with ovarian cancer responded: CR in five (83%) and partial remission (PR) in one (17%); the CRs have lasted 7 to 30+ months. Responses were also seen in testicular and breast carcinoma.


CONCLUSIONS
This regimen was well tolerated at the MTD and appears promising for relapsed/refractory ovarian carcinoma, with mitoxantrone levels achieved that are active in vitro against platinum-resistant ovarian carcinoma cells.
Stiff
P J
PJ
Department of Medicine, Loyola University Medical Center, Maywood, IL 60153.
McKenzie
R S
RS
Alberts
D S
DS
Sosman
J A
JA
Dolan
J R
JR
Rad
N
N
McCloskey
T
T
D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects*; D001855:Bone Marrow Diseases / Q000139:chemically induced / Q000517:prevention & control*; D016026:Bone Marrow Transplantation; D016190:Carboplatin / Q000009:adverse effects; D003520:Cyclophosphamide / Q000009:adverse effects; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone / Q000009:adverse effects / Q000493:pharmacokinetics; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D016896:Treatment Outcome
D003520:Cyclophosphamide; D016190:Carboplatin; D008942:Mitoxantrone