Biomedical Engineering Reference
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activity without apparent toxicity at doses in which serious toxic
eff ects of the free drug occurs (Lopez-Berestein et al., 1985). A
similar study with another (sonicated) liposomal amphotericin-B
formulation was performed later in cancer patients with fungal
infections by Sculier and coworkers (1988). A pilot human study with
the water-insoluble cytotoxic drug NSC 251635 was also performed
(Sculier et al., 1986).
One early clinical “first in man” study was performed with a
liposomal doxorubicin formulation by Kumai et al. (1985). They
reported on a treatment of liver cancer by local (hepatic intra-
arterial) injection of small doses of liposomal doxorubicin, up to
15 mg/m 2 , in 10 cancer patients with liver metastasis. The main
side eff ect found was fever, which could be explained by a small
contamination of the liposomal formulation with endotoxin. Our
main take-home lesson from all the above “first in man” trials was
that the preparation of liposomal formulations for clinical use is
feasible. These early experiments were very helpful in convincing
the ethical committee and Israel MOH to grant permission for our
“first in man” and phase I clinical trials of OLV-DOX.
12.3.2
Phase I Clinical Trials of Liposomal Doxorubicin
(OLV-DOX)
EPC/EPG/Cholesterol/TCS 7:3:4:0.2 OLV-DOX having a doxorubicin
(membrane associated) to phospholipid mole ratio of 0.056 and a
size distribution of 300-500 nm were used in our clinical trials.
In our first study (Gabizon et al., 1989a, 1989b), 32 patients,
most of them with primary or metastatic liver cancer refractory to
conventional therapy, were treated. A total of 69 courses of therapy
was administered by intravenous infusion of a suspension of OLV-
DOX (0.5-2.0 mg DOX/mL) in physiologic saline containing 200 mM
Desferal (pH 6.2) at an approximate infusion rate of 2 mL/min given
on a 3-week intermittent schedule.
OLV-DOX and phospholipid doses were escalated from 20 mg/m 2
and 0.3 g/m 2 to 120 mg/m 2 and 3.2 g/m 2 for DOX and phospholipids,
respectively. Treatment was generally well tolerated, and acute toxic
eff ects such as nausea and vomiting were mild and infrequent. Chills
and fever (>38 ° C) were observed on infusion. Median WBC nadir
counts were 2700, 2300, and 700/ml at 85, 100, and 120 mg/m 2 ,
respectively. All three patients receiving 120 mg/m 2 developed grade
 
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