Kaposi's Sarcoma (KS): Angiogenesis Inhibitors in Early Trials

Oncology Project of the Treatment Action Group (TAG), which
reports on treatments and research for various AIDS-related
malignancies, and for Kaposi's sarcoma (KS). He is also co-
authoring (with Marty Majchrowicz from AIDS Project Los
Angeles) a report on KS pathogenesis, treatments, and current
opinions of noted clinicians and researchers.]

Angiogenesis -- the formation of new blood vessels -- takes
place normally during wound healing. But abnormal
angiogenesis is an important contributor to certain diseases.
In cancer, for example, solid tumors must be able to
stimulate the growth of new blood vessels to nourish the
tumor cells, or they cannot grow beyond a small size. And
evidence now suggests that Kaposi's sarcoma may not be a true
cancer in most cases, but instead may be due to abnormal
blood-vessel growth caused by dysregulation of angiogenesis.

Since normal growth of blood vessels is not necessary at most
times during a person's life, researchers are developing
drugs which inhibit angiogenesis (both normal and abnormal),
in the hope of creating an entirely new class of treatments
for cancer and for KS. This article outlines the current
status of the research into three of these potential drugs,
and describes the clinical trials which are currently open.
(Note: For previous coverage of angiogenesis inhibitors, see
AIDS TREATMENT NEWS issues #188, #162, #135, and #122.)

Three anti-angiogenesis compounds currently in early clinical
trials as KS treatments are Tecogalan (SP-PG, also called DS-
4152), TNP 470 (formerly called AGM-1470), and recombinant
human platelet factor 4 (rPF4). They have only been tested in
a small number of patients with KS, and have mostly shown a
lessening of KS-associated swelling, and some minor activity
on existing lesions. Many researchers now feel that
angiogenesis inhibitors might be most effective in preventing
new lesions from occurring rather than affecting pre-existing
lesions.(1) If this is true, these drugs might work best as
maintenance therapy after systemic chemotherapy.


Tecogalan (SP-PG): Los Angeles, New York, San Antonio, San
Francisco

Tecogalan is an angiogenesis inhibitor which has been
isolated from the bacterium Arthrobacter. Tecogalan prevents
a protein (called fibroblast growth factor) from binding to
endothelial cells (the cells which line the insides of blood
vessels) and stimulating those cells to migrate and
reproduce. In animal tests conducted by Robert Gallo, M.D.,
and colleagues, "nude" mice (special immunodeficient mice)
were given a form of KS by injection of human KS cells;
Tecogalan "led to degeneration of newly formed vascular
lesions."(2)

Four sites are currently recruiting patients for a phase I
dose-escalating pharmacokinetic and safety trial of
intravenous Tecogalan. Preliminary results have shown some
activity on existing lesions, and a considerable lessening of
edema (swelling). So far, no serious toxicities have been
seen, except for prolonged APTT (activated partial
thromboplastin time, which can affect the time it takes for
blood to clot), which normalizes after the infusion.(3) Some
patients have also noted chills and fever.

Volunteers may have any T-helper count for this trial, but
they must have at least five cutaneous (skin) lesions, and no
evidence of systemic visceral involvement. During the first
dose, volunteers will be hospitalized for 24 hours for
monitoring; later doses will be given on an outpatient basis.

This trial is being conducted at the following four sites:

* Los Angeles: Kenneth Norris Jr. Cancer Hospital/USC.
Investigator: Parkash Gill, M.D. Contact: 213/224-6668.

* New York City: Memorial Sloan-Kettering Cancer Center.
Investigator: Susan Krown, M.D. Contact: 212/639-7426.

* San Antonio: Cancer Therapy Research Center. Investigator:
Gail Eckardt, M.D. Contact: 210/616-5798.

* San Francisco: San Francisco General Hospital.
Investigator: James Kahn, M.D. Contact: 415/476-9296x84104


TNP-470: Bethesda, Boston, Chicago, Los Angeles, St. Louis

TNP-470 is a synthetic chemical analog of fumagillin, which
is produced by a fungus. In 1990, researchers at Harvard
Medical School found that fumagillin and TNP-470 inhibited
angiogenesis in laboratory tests, and inhibited the growth of
solid tumors in mice; TNP-470 was found to be less toxic and
50 times as powerful as fumagillin.(4) Researchers at the
U.S. National Cancer Institute also found that TNP-470
inhibited abnormal spindle cells, which have a major role in
the development of KS.

Animal tests showed that very large doses, given all at once,
caused toxicity, most notably small hemorrhages in the brain,
lungs, heart, and retinas of dogs. The drug was better
tolerated when given as an infusion. Therefore, initial
clinical testing used a one-hour infusion, starting at low
doses.

In preliminary results from the phase I trial of TNP-470 in
persons with KS, researchers at the NCI reported that the
drug showed some activity on existing lesions (especially in
lessening edema, or swelling), and a decrease in the
development of new lesions. No dose-limiting toxicities were
found.(5)

This trial, as well as a four-site study by the AIDS Clinical
Trials Group (ACTG), is still ongoing; both are open for
volunteers. There is no T-helper count requirement for these
dose-escalating trials, but patients with pulmonary KS are
excluded from the NCI trial; the ACTG trial excludes all
potential volunteers with symptomatic visceral KS.

Note that the NCI trial, although conducted in Bethesda,
Maryland (near Washington, D.C.), is open to volunteers from
throughout the country. The NCI will pay travel expenses
(except for the first trip), and will pay a stipend toward
living expenses while volunteers are in Bethesda. The trial
lasts 24 weeks.

The first listing, below, is for the NCI trial. The other
four are locations of sites for the ACTG trial.

Bethesda, Maryland: U.S. National Cancer Institute.
Investigator: Robert Yarchoan, M.D. Contact: 301/496-8959.

Boston: Beth Israel Hospital. Investigator: Bruce Dezube,
M.D. Contact: Beryl Chapman, 617/735-4149.

Chicago: Northwestern University Medical Center.
Investigator: Jamie Von Roenn, M.D. Contact: 312/908-9412.

Los Angeles: Kenneth Norris Cancer Center Hospital/USC.
Investigator: Parkash Gill, M.D. Contact: 213/224-6668.

St. Louis: Washington University School of Medicine.
Investigator: Lee Ratner, M.D. Contact: Mary Gould, R.N.,
314/454-0058.


Recombinant Platelet Factor 4 (rPF4): Los Angeles,
Philadelphia, San Francisco

Recombinant platelet factor 4, a genetically engineered
version of a substance normally found in the body, has been
found to inhibit endothelial cells in laboratory tests.(6)
Another research group, following up this result, found that
rPF4 also inhibited KS cells in a dose-dependent manner.(7)

In the early phase I/II (safety and preliminary efficacy)
trial, rPF4 was injected into one lesion, while another
lesion on the same patient was given an inactive injection as
a control. An anti-KS effect was found in six of the 12
patients given rPF4. The only side effect was a mild rash
around the lesion in approximately 20 percent of the
patients.(8)

There are three phase I/II trials of rPF4 which are currently
open for volunteers in the U.S. They differ in how the drug
is administered; subcutaneously in Los Angeles,
intralesionally in Philadelphia, and intravenously in San
Francisco. There is no requirement for T-helper count. These
trials will last for a maximum of eight weeks.

Los Angeles: Kenneth Norris Cancer Center/USC. Investigator:
Parkash Gill, M.D. Contact: 213/224-6668.

Philadelphia: Graduate Hospital of Philadelphia.
Investigator: Arthur Staddon, M.D. Contact: 215/893-7520.

San Francisco: San Francisco General Hospital. Investigator:
James Kahn, M.D. Contact: 415/476-9296 x84104.

References

1. Pluda JM, Parkinson DR, Feigal E, and Yarchoan R.
Noncytotoxic approaches to the treatment of HIV-associated
Kaposi's sarcoma. ONCOLOGY. December 1993; volume 7, number
12, pages 25-33.

2. Nakamura S, Sakurada S, Salahuddin SZ, and others.
Inhibition of development of Kaposi's sarcoma-related lesions
by a bacterial cell wall complex. SCIENCE. 1992; volume 255,
pages 1437-1440.

3. Gill PS, PA-C Kidane S, Tulpule A, and others. A phase 1
study of DS-4152, a novel angiogenesis inhibitor in the
treatment of AIDS-related Kaposi's sarcoma. E.O.R.T.C.,
Amsterdam, March 15-18, 1994.

4. Ingber D, Fujita T, Kishimoto S, and others. Synthetic
analogues of fumagillin that inhibit angiogenesis and
suppress tumor growth. NATURE. December 6, 1990; volume 348,
pages 555-557.

5. Pluda JM, Wyvill K, Lietzau J, and others. A phase I trial
of TNP-470 (AGM-1470) administered to patients with HIV-
associated Kaposi's sarcoma (KS). The First National
Conference on Human Retroviruses and Related Infections,
Washington, D.C., December 1993 [abstract #31].

6. Maione TE, Gray GS, Petro J, and others. Inhibition of
angiogenesis by recombinant human platelet factor-4 and
related peptides. SCIENCE. January 5, 1990; volume 247, pages
77-79.

7. Miles S, Rezai A, Martinez-Maza O, and Maione TE.
Recombinant platelet factor 4 (rPF4) and a non-heparin
binding derivative inhibit AIDS-Kaposi sarcoma derived cell
lines. VII International Conference on AIDS, Florence, June
1991 [abstract # W.A.1066].

8. Kahn J, Ruiz R, Kerschmann R, and others. A phase I/II
study of recombinant platelet factor 4 (rPF4) in patients
with AIDS-related Kaposi's sarcoma (KS). Proceedings: Annual
Meeting of the American Society of Clinical ONCOLOGY. 1993;
volume 12:A4.