Phase I clinical and pharmacokinetic study of 3'-deamino-3'-(2-methoxy-4-morpholinyl)doxorubicin (FCE 23762).
Methoxymorpholinyldoxorubicin (FCE 23762) is a novel, highly lipophilic doxorubicin analogue. It possesses potent in vitro and in vivo antitumor activity including efficacy in multidrug-resistant tumor cell lines. It is also metabolically activated in vivo resulting in an 80-fold increase in potency over the parent drug. In this phase I study the drug was administered by i.v. bolus injection at 3-week intervals. Fifty-three patients with refractory solid tumors were treated; 133 courses of FCE 23762 were administered at doses ranging from 30 to 2250 micrograms/m2. The dose limiting toxicity was reversible myelo-suppression (granulocytopenia and thrombocytopenia), demonstrating a delayed nadir and recovery in comparison to doxorubicin. Other toxicities included transient elevation of hepatic transaminases, delayed and prolonged nausea and vomiting, mucositis, anorexia, fatigue, and diarrhea. Heavily pretreated patients demonstrated more myelosuppression than previously untreated patients at 1250 micrograms/m2. No cardiotoxicity was observed. Four objective tumor responses were seen: one complete response in a patient with pelvic recurrence of cervical cancer; one partial response in a patient with cutaneous and lymph gland metastases from head and neck cancer; and two minor responses in patients with liver metastases from colorectal cancer. Plasma concentrations of FCE 23762 and its 13-dihydro metabolite, FCE 26176, were measured in 20 patients at doses > or = 675 micrograms/m2, using HPLC with fluorescence detection. The area under the plasma concentration-time curve ranged from 30 to 80 ng/h/ml; plasma data suggested linear kinetics in the range of tested doses (although there was considerable interpatient variability). The maximum tolerated dose defined in this study using this schedule is 1500 micrograms/m2. A safe phase II dose for previously untreated patients using this schedule is 1250 micrograms/m2; however, this may actually be below the optimal dose for this patient population.
Vasey
P A
PA
Beatson Oncology Centre, Western Infirmary, Glasgow, United Kingdom.
Bissett
D
D
Strolin-Benedetti
M
M
Poggesi
I
I
Breda
M
M
Adams
L
L
Wilson
P
P
Pacciarini
M A
MA
Kaye
S B
SB
Cassidy
J
J
D000328:Adult; D000368:Aged; D004317:Doxorubicin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008099:Liver / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D009503:Neutropenia / Q000139:chemically induced; D013921:Thrombocytopenia / Q000139:chemically induced
C066998:methoxy-morpholinyl-doxorubicin; D004317:Doxorubicin