DOX-SL (Doxil) Kaposi's Sarcoma Treatment: Trials, Development Status

DOX-SL (formerly called Doxil -- the name has been changed to
avoid a trademark dispute in Europe) is an experimental
treatment, now being tested for Kaposi's sarcoma and for some
cancers, which has generated considerable interest in the
AIDS treatment community. This article outlines what DOX-SL
is, what trials are underway, and what needs to happen to
make the drug more widely available (provided that the
results of clinical trials confirm early impressions that it
may be useful).

DOX-SL is a liposomal form of doxorubicin (also called
Adriamycin), a cancer chemotherapy drug. Liposomes are
microscopic spheres of lipids (fats), which can contain
active drugs within them. The liposomes can be specially
prepared to give the drug desired pharmacological properties
-- especially to improve the targeting of the active
compound, so that it is more selective in reaching the
intended tissues in the body, to improve efficacy and reduce
side effects.

DOX-SL consists of very small liposomes, smaller than the
cells of the body. Each one contains about ten thousand
molecules of doxorubicin. These liposomes have two lipid
layers; the outer layer contains a chemical, polyethylene
glycol (PEG), which makes the liposomes less likely to be
destroyed by the immune system, a major problem in the early
development of liposomal drugs.

An early phase I (dosage and toxicity) trial of DOX-SL, in
volunteers with Kaposi's sarcoma, has found that it delivers
about four to ten times the concentration of doxorubicin to
the lesion as the conventional free form of the drug. Also,
DOX-SL has a half-life of about 48 hours in the bloodstream,
compared to 10 to 15 minutes for the free drug. No one knows
for sure why the liposomal drug is targeted selectively to
the KS lesions. One theory is that these lesions (and also
cancer tumors) stimulate abnormal blood-vessel growth,
producing leaky capillaries; the liposomes keep the drug in
the bloodstream long enough that it has time to leak out into
the abnormal tissue, while the free drug tends to be
deposited indiscriminately.

DOX-SL is being developed by Liposome Technology, Inc. (LTI),
of Menlo Park, California. About 500 people have now used the
drug as a KS treatment in trials.

Published Experience

The AIDSLINE database, the most complete listing of AIDS-
related journal articles, conference presentations, and
letters to journals, currently includes 12 citations on the
use of DOX-SL to treat AIDS-related KS. Most of these reports
are from Germany. Six of the twelve were presented at the IX
International Conference on AIDS, June 6-11, 1993, in Berlin.
Only one of the 12 was published before 1993.

Most of these reports are favorable, suggesting that
liposomal doxorubicin was effective for the large majority of
patients, sometimes producing dramatic benefits. But these
results are not from controlled studies comparing the drug to
a different treatment regimen. Therefore, we will need data
from ongoing trials (see below) to evaluate the benefits and
risks of DOX-SL compared to the available alternatives. The
FDA usually requires two controlled trials before approving a
drug.

The main toxicities have been hematologic; these have been
manageable, sometimes with the help of G-CSF. On the positive
side, cardiac toxicity (which can occur with ordinary
doxorubicin) has not been a problem so far; however, this
effect is cumulative, related to the total lifetime use of
doxorubicin, so it might appear later after the liposomal
drug has been used longer.

There are published reports of two deaths from liver failure
among AIDS patients using DOX-SL; these may have been drug
related, but that is not known (see Hengge and others --
second reference -- and Simpson and others, in References
section, below). In the only case published in any detail,
the patient had a history of hepatitis and a T-helper count
of 17, and had been taking rifampicin, cycloserine,
clofazimine, fluconazole, and itraconazole, in addition to
DOX-SL. LTI has not seen any abnormal elevation of liver
enzymes in its trials, and does not know any other way to
screen or test for this possible problem.

Most of the reports suggest that liposomal doxorubicin was
well tolerated, often with no serious side effects, or none
at all. But clearly there are risks, as with any
chemotherapy, so the drug will have to be used carefully. The
phase III protocol includes special testing for cardiac
toxicity, but no special warning to physicians about the
possibility of liver problems.

DOX-SL Clinical Trials

Besides the early phase I trial mentioned above, a larger
phase II (early efficacy) trial of DOX-SL has now been
completed. The results are not yet available, however,
because the data is still being analyzed.

Full approval of DOX-SL will also require completion of a
phase III trial, which began over a year ago and still needs
about 100 more volunteers; about 125 are already enrolled.
This trial, now being conducted at over 30 sites in the U.S.,
has been slow to recruit, apparently because lack of
information or misunderstandings about it.

The trial, which was designed with activist input, is for
patients with KS which is severe enough to require systemic
chemotherapy. They are randomly assigned to receive either
DOX-SL, or the conventional chemotherapy called ABV --
Adriamycin (another name for doxorubicin, the active
ingredient in DOX-SL) plus bleomycin, plus vincristine.
However, those randomly assigned to ABV will only receive six
courses of it, at two-week intervals; then they will be able
to switch to DOX-SL. Also, if the ABV has unacceptable side
effects, or does not seem to be working, they can switch to
DOX-SL immediately. (The most serious toxicities of ABV --
especially cardiac toxicity which can be caused by the
Adriamycin -- tend to be cumulative, and unlikely to occur
early in the use of the treatment.)

Volunteers with any T-helper count can enter this study. They
must have "progressing KS with at least 25 mucocutaneous
lesions and/or the development of 10 or more new lesions in
prior month, and/or documented visceral disease and at least
2 assessable cutaneous lesions, and/or 2 assessable cutaneous
lesions with edema." They must have hemoglobin greater than
8, neutrophil count over 1200, and platelet count over
75,000. They must not have "active opportunistic infection
with mycobacteria, cytomegalovirus, toxoplasma, P. carinii or
other microorganism if under treatment with myelotoxic
drugs." There are also other inclusion/exclusion criteria.

No placebo is used in this study. Patients are randomly
assigned to a therapy, but then they are told what they are
getting.

Why has this trial been slow to recruit? There seem to be
several reasons. A major one, we believe, is that information
about the trial has not been effectively communicated. For
example, we spent well over ten hours researching this
article before we learned how a patient who wanted to
volunteer could go about doing so. And as far as we know, the
list of cities where the trial is being run (see below) has
never been published before, although a major phase III trial
has been open for over a year in the U.S. For effective
recruiting, such how-to-plug-in information should be
everywhere.

Some volunteers are rejected by the study's entry criteria,
of course; others are too far from a city where the trial is
being run. Another problem is that DOX-SL has not been well
known in the activist community until recently. And many who
do know about it have wanted to receive it and not risk being
randomized to ABV -- even though ABV is known to be effective
in a large majority of cases, and the trial allows everyone
to get DOX-SL after no more than six courses of ABV.

Another reason why this trial has been slow to recruit is
that it does not pay all costs -- and some insurance
companies have denied reimbursement for the costs which are
not covered. All the study drugs are paid for -- including
the ABV, not only the DOX-SL, which of course is provided
free. And LTI now pays for the cardiograms, which are
required as a safety measure. But it does not pay the cost of
the infusions.

Insurance will usually cover this cost (which should not be
surprising, since the infusions are necessary in any case,
because patients are not eligible for this trial unless they
need systemic chemotherapy). In San Francisco, Kaiser San
Francisco is now preparing to conduct the trial; but it has
not paid the costs at non-Kaiser sites, so until now it has
been difficult, even in the San Francisco area, for Kaiser
patients to enter.

LTI reimburses its trial sites for each patient. Sometimes
the physician may be willing to give patients a break on the
infusion cost, if there is no other way to pay for it. If
financing remains a problem, physicians should call LTI, to
see if some way that these costs can be paid for.

Expanded Access

In addition to the comparative trials, LTI has made DOX-SL
available to patients who cannot use ABV successfully and
have no other option. This expanded-access protocol now has
about 300 patients enrolled.

Earlier this year LTI closed the expanded access to new
"refractory" patients -- those for whom ABV does not work --
but re-opened it after furious protests from physicians and
activists. It might be closed in the future, however, as it
is a serious financial burden on the company, since this
particular protocol requires major paperwork for each
patient. Also, this expanded access (which will not
contribute much toward approval of the drug) appears to have
reduced recruitment in the all-important phase III trial --
as some patients, for example, would get their physician to
give them ABV just so they could say it didn't work and
become eligible. The company hopes to replace the current
expanded access system with a "treatment IND," -- a different
procedure which would provide the same treatment, but with
much less documentation overhead. The treatment IND requires
FDA approval, however, and that is not assured.

Approval Strategy

LTI intends to apply to the FDA for two different marketing
approvals for DOX-SL. First, it will ask for approval as a
salvage therapy, for patients who cannot benefit from ABV.
This kind of application can be considered quickly, based on
the data that already exists, without waiting for the phase
III trial to be finished.

LTI will apply for full approval later, after the phase III
trial is complete.

Pending approval for marketing, LTI hopes to replace its
current expanded access with a treatment IND, as explained
above. However, any approval for DOX-SL must go through the
oncology staff and advisory committee of the FDA -- not the
same people that usually judge AIDS treatments. The FDA's
oncologists have little personal experience in treating KS;
they are experts in cancer, not in AIDS. They may not be
entirely aware of the need for new treatment options, unless
oncologists and other physicians let them know what their
needs are.

Other Trials

In addition to the U.S. trial, a major European trial is
comparing DOX-SL to a conventional treatment called BV
(bleomycin plus vincristine) -- a treatment commonly used in
Europe, apparently to avoid the side effects of the
Adriamycin. (Although mainly a European study, this trial
also has three U.S. sites, Boston, Houston, and Seattle;
however, we do not know at press time if all three are still
open.)

One future possibility is to combine DOX-SL with BV. This
would appear to offer the advantage of the three-way
combination which is the accepted therapy in the U.S., but
with the presumably better efficacy and lower toxicity of the
Adriamycin (doxorubicin) component. The AIDS Clinical Trials
Group (ACTG) of the U.S. National Institute of Allergy and
Infectious Diseases (NIAID) is now planning a trial, in
collaboration with LTI, to compare DOX-SL plus BV to DOX-SL
alone; it could begin as early as summer 1994.

How to Volunteer

DOX-SL trials are currently being conducted in the cities
listed below (alphabetically, by state); this list only
includes U.S. sites. Not all trials are available at all
sites. If more than one physician or medical center is
conducting DOX-SL trials in a city listed, the total number
of sites appears after the city name.

Patients interested in more information should have their
physician call a physician conducting DOX-SL trials in a city
convenient to them, if their physician knows who that is.
Otherwise, their physician should call George Tidmarsh, M.D.,
staff oncologist at LTI, 415/323-9011.

California: Berkeley, Encino, Greenbrae, Los Angeles (2), San
Diego, San Francisco (5)

District of Columbia: Washington
Florida: Miami, Tampa
Georgia: Atlanta (2)
Illinois: Chicago (2)
Massachusetts: Boston, Cambridge
Michigan: Detroit
Missouri: St. Louis
New York: Buffalo (2), New York City (4)
Pennsylvania: Philadelphia
Texas: Dallas, Houston (3)
Washington: Seattle

References

The following are all of the published articles and
conference presentations we could find on liposomal
doxorubicin for treating AIDS-related KS. All but one were
published in 1993. They are in alphabetical order by lead
author.

Bogner JR, Zietz C, Held M, and others. Ultrasound as a tool
to evaluate remission of cutaneous Kaposi's sarcoma. AIDS.
August 1993; volume 7, number 8, pages 1081-1085.

Boyle MJ, Marshall NE, Dolan GM, and others. A phase II study
of stealth liposomal doxorubicin HCL (S-DXR) in HIV-
associated Kaposi's sarcoma (KS). IX International Conference
on AIDS, Berlin, June 6-11, 1993 [abstract #1570].

Goebel FD, Bogner JR, Spathling S, and others. Quantitative
ultrasound volume measurement serves as noninvasive method to
follow response of cutaneous Kaposi's sarcoma lesions to
Doxil therapy. PROCEEDINGS: ANNUAL MEETING OF THE AMERICAN
SOCIETY OF CLINICAL ONCOLOGY. 1993; 12:A7.

Goebel FD, Bogner JR, Spathling S, Held M, Sandor P, and
Rolinski B. Efficacy and toxicity of liposomal doxorubicin in
advanced AIDS-related Kaposi sarcoma (KS). An open study. IX
International Conference on AIDS, Berlin, June 6-11, 1993
[abstract #WS-B15-6].

Goebel FD, Liebschwager M, Held M, and others. Successful
treatment of advanced Kaposi sarcoma (KS) with liposomal
doxorubicin -- short term observations. VIII International
Conference on AIDS, Amsterdam, July 19-24, 1992 [abstract
#3108].

Hengge UR, Brockmeyer NH, Baumann M, Reimann G, and Goos M.
Liposomal doxorubicin in AIDS-related Kaposi's sarcoma
[letter]. LANCET. August 21, 1993; volume 342, page 497.

Hengge UR, Brockmeyer NH, Rasshofer R, and Goos M. Fatal
hepatic failure with liposomal doxorubicin [letter; see
comments]. LANCET. February 6, 1993; volume 341, pages 383-
384.

Jablonowski H, Szelenyi H, Armbrecht C, Mauss S, Niederau C,
and Strohmeyer G. Liposomal doxorubicin -- a new formulation
for the treatment of Kaposi's sarcoma: a study on safety and
efficacy in AIDS patients. IX International Conference on
AIDS, Berlin, June 6-11, 1993 [abstract #1573].

Northfelt DW, Martin FJ, Kaplan LD, and others.
Pharmacokinetics (PK), tumor localization (TL), and safety of
Doxil (liposomal doxorubicin) in AIDS patients with Kaposi's
sarcoma (AIDS-KS). PROCEEDINGS: ANNUAL MEETING OF THE
AMERICAN SOCIETY OF CLINICAL ONCOLOGY. 1993; 12:A8.

Sandor P, Bogner JR, Held M, Spathling S, Rolinski B, and
Goebel FD. Use of G-CSF in the management of chemotherapy-
induced neutropenia in patients with advanced-stage Kaposi-
sarcoma. IX International Conference on AIDS, Berlin, June 6-
11, 1993 [abstract #1890].

Simpson JK, Cottrill CP, Miller RF, and Spittle MF. Liposomal
doxorubicin: initial experience in a major London centre. IX
International Conference on AIDS, Berlin, June 6-11, 1993
[abstract #1603].

Szelenyi H, Jablonowski H, Armbrecht C, Mauss S, Niederau C,
and Strohmeyer G. Long term treatment with liposomal
doxorubicin in patients with AIDS-related Kaposi's sarcoma.
IX International Conference on AIDS, Berlin, June 6-11, 1993
[abstract #1574].