Pharmaceutical Manufacturing Handbook: Production and

504 LIPOSOMES AND DRUG DELIVERY
cancer, vinorelbine has been used in combination with liposomes as a pallia -
tive second - line therapy for patients with refractory/resistant ovarian cancer to
platinum – paclitaxel [451] . The best MTD (mean therapeutic dose) was 25 mg/m 2
at days 1 and 8 for vinorelbine and 30 mg/m 2 at day 1 for liposomal DXR of every
21 days, which was well tolerated with moderate hematologic and mild nonhematologic
toxicities. A phase II study relevant to the clinical effi cacy, toxicity, and
pharmacokinetics of that combined therapeutic regimen was carried out by
Katsaros et al. in 30 patients with platinum – paclitaxel pretreated recurrent ovarian
cancer [452] . Caelyx (30 mg/m 2 ) and vinorelbine (30 mg/m 2 ) were administered every
3 weeks for six cycles. The regimen was proved of signifi cant activity for patients
pretreated with paclitaxel – platinum fi rst - line therapy. The overall response rate was
37% with 10% of patients demonstrating stable disease. Vinorelbine bioavailability
was higher under the current regimen. The overall survival was 9 months while the
toxicity was mild and reversible. There were no treatment - related deaths and there
were only 2 patients, one reported with grade 4 and the other with grade 3 hand – foot
syndrome. Also, the toxicity due to liposomal formulation was much lower compared
to that reported from a phase III study with the drug given as a single agent
[453] . In another phase II study, the combination of liposomal doxorubicin and
infused topotecan was studied in 27 patients with platinum - resistant ovarian cancer
in two cohorts [454] . Liposomal DXR (30 mg/m 2 at day 1) and topotecan (1 mg/m 2
for 5 days) were infused and the cycle was repeated every 21 days. The overall
response rate of the regimen was 28% and the median overall survival was 40 weeks.
However, neutropenia and thrombopenia were observed at 70 and 41% of the
patients. Therefore, the topotecan dose was reduced to 0.75 mg/m 2 and liposomal
DXR was increased to 40 mg/m 2 in order to reduce the toxicity. After that, the cytotoxic
effect due to liposomal doxorubicin increased and the bone marrow cytotoxicity
remained the same despite the effectiveness of the regimen.
Lurtotecan is a more advanced camptothecin analogue with probably greater
potency with regard to topotecan and therefore was encapsulated in liposomes to
investigate the toxicity and pharmacokinetics [455] . In a multi - institutional open -
label phase II study, 22 patients with topotecan - resistant ovarian cancer were administered
liposomal lurtotecan in a dose of 2.4 mg/m 2 on days 1 and 8 every 21 days.
Although the toxicity profi le of the drug was lower, no response was observed.
Others used a regimen of liposomal delivery at days 1 and 3 with more promising
therapeutic results, but higher toxicity, too [456] .
A variety of new molecules either in combination with liposomal doxorubicin or
not are in development at the moment [457] . For example, a phase III study will be
conducted to test the effi cacy and safety of pattupilone versus PEG – liposomal DXR
in taxane/platinum refractory/resistant patients with recurrent epithelial ovarian,
primary fallopian, or primary peritoneal cancer. A phase III randomized study of
Telcyta with Doxil/Caelyx versus Doxil/Caelyx has been planned in patients with
platinum - refractory or platinum - resistant ovarian cancer. A phase II study relevant
to side effects and best dose of ixabepilone combined with liposomal DXR will be
assessed in patients with advanced ovarian epithelial, peritoneal cavity, or fallopian
tube cancer or metastatic breast cancer.
Gemcitabine is a clinically active antineoplastic drug in platinum - refractory
ovarian cancer. The effi cacy and tolerability of the particular drug in combination
with liposomal DXR were investigated in athymic mice bearing cisplatin - resistant
human ovarian carcinoma [458] .