ROCKVILLE, MdDoxil (doxorubicin HCl liposome injection, ALZA
Corporation) has won accelerated FDA approval of its supplemental New
Drug Application for the treatment of metastatic ovarian cancer
refractory to both paclitaxel (Taxol)- and platinum-based
chemotherapy regimens. Accelerated approval requires the company to
conduct additional research to demonstrate that the drug is
associated with clinical benefit. Doxil, a liposomal formulation of
doxorubicin, is currently approved for use in AIDS-related
In its presentation to the Oncology Drugs Advisory Committee (ODAC)
only 3 weeks before approval was granted, ALZA provided data from
four studies in support of its applicationthree phase II
trials, two completed and one ongoing, and an ongoing phase III
According to the FDA, study 30-22 (involving 27 eligible patients
with refractory ovarian cancer, treated at two US sites) showed a
response rate of 22.2%. Study 30-47 (82 eligible patients treated at
18 US sites) produced a response rate of 17.1%. Study 30-47E, still
in progress with 52 patients at 14 centers in Europe, found no
responses among 36 patients.
Finally, an interim analysis of study 30-49, comparing Doxil with
topotecan (Hycamtin) in 237 patients at 90 sites in the United States
and Europe, showed a Doxil response rate of 13.6% (6 of 44 patients)
vs 8.1% (3 of 37) for topotecan.
The combined Doxil response rate for the four studies was 13.8% (26
of 189 patients), according to the FDA. This was slightly lower than
the 14.4% rate claimed by the company. Duration of response across
the trials was 39.4 weeks, and time to progression was 15.9 weeks,
according to ALZA.
At the ODAC meeting, several members expressed puzzlement about the
zero response rate in study 30-47E, the ongoing phase II European
trial. The company said several factors indicate that patients in
that trial may have been sicker, which could account for the
The sum total of major disease at baseline was somewhat larger,
and patients spent a shorter amount of time on trial, said
Edward Schnipper, MD, ALZAs vice president for Clinical
Research. It appears possible that patients on this trial
entered at a later state of their disease and were treated for
shorter periods of time than were patient on the other Doxil trials.
ALZAs data presentation did not satisfy patient representative
Martha Solonche of New York City. From a patients
perspective, were looking at survival, and I dont think
we have enough data at the moment to see this as a drug that is going
to advance treatment in a great way, Ms. Solonche said.
Two dosage schedules were used in the trials presented by ALZA: every
3 weeks in trial 30-22 and every 4 weeks in the other three. Due to
higher toxicity with the every-3-week regimen, ALZA requested that
the FDA consider only the every-4-week regimen.
Generally Well Tolerated
In its safety analysis, FDA staff limited its review to study 30-47,
which was the one completed study that used the every-4-week
schedule. It found the following: hand-foot syndrome, 42%/20% severe;
asthenia, 42%/9%; leukopenia, 39%/7%; anemia, 39%/14%; nausea,
38%/7%; neutropenia, 37%/16%; stomatitis, 35%/9%.
We would submit that Doxil is generally well tolerated,
Ken Cunningham, MD, vice president for European Clinical Research,
said in summing up ALZAs safety presentation. Hand-foot
syndrome is the most common adverse event, and it is manageable, as
evidenced by the relatively low number of patients who actually
withdrew as a result.
Stacy R. Nerenstone, MD, of the Gray Cancer Center, Hartford,
commended the sponsor for looking at this patient population,
which notoriously has been clinically underrepresented in clinical
trials in terms of drug development. I think, for this carefully
defined population, the 13% response rate is meaningful.