AIDS Treatment News No. 195 - March 18, 1994
John S. James

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].

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