CHEMOTHERAPY

In general, chemotherapy agents are relatively ineffectiveagainst adenoid cystic
carcinoma. However, a Cisplatin/5-FU regimen appears to produce a low rate of
objective response but useful palliative benefits in advanced symptomatic
adenoid cystic carcinoma. A higher objective response rate may be possible
with a platinum/anthracycline/fluorouracil combination.[1] Virtually all the
oncologists and researchers we contacted advised that there were no
chemotherapy protocols that were effective against adenoid cystic carcinoma.

ELECTROPORATION

Electroporation (EPT) uses a series of brief, carefully controlled electrical
impulses to the site of the tumor in combination with a direct injection of a
chemotherapy agent. The advantages of EPT are the reduction of side effects
of standard IV chemotherapy since only alow dose of agent is given. Phase II
trials are underway at Rush-Presbyterian-St. Luke's Medical Center.

RADIOIMMUNOTHERAPY

Radioimmunotherapy (RIT) is a promising therapeutic modality for the treatment
of a wide variety of malignancies. RIT utilizes antibodies to carry radioactivity to
disease sites. Antibodies are immunoglobulin molecules that bind to specific
targeted antigens. Monoclonal antibodies (MAB) are produced by a single clone
of antibody producing cells, and are highly specific for a given antigen.
Radionuclides can be chemically linked to MAB, resulting in stable
radioimmunoconjugates for therapy. Various trials are underway.[2]
Unfortunately, none are applicable to ACC.

Simple ions and small molecules which follow physiological pathways as either
the substrates or analogues form the best examples of biological targeting.
Current clinical studies in targeted radiotherapy focus on the integration of
radionuclide treatment with conventional treatments and the optimization of such
combined approaches.[3]

Radionuclides which decay by the emission of alpha particles are attractive for
certain radioimmunotherapeutic applications. Preliminary results obtained in a
variety of in vitro systems and in vivo models have documented the
effectivetoxicity of alpha-particles and have established a basis for initiating
radiotherapy trials in humans with monoclonal antibodies labeled with alpha-
emitting radionuclides.[4]

Challenges that currently face radioimmunotherapy include circulating free
antigen, binding of antibodies to nonspecific Fc receptors, insufficient tumor
penetration, antigenic heterogeneity and insufficient antigen expression,
antigenic modulation, and development of human antimouse antibodies.
Potential solutions to these challenges, including high-dose radioimmunotherapy
and chemotherapy followed by autologous bone marrow transplantation, the use
of radionuclides such as yttrium 90 (90Y) and copper 67 (67Cu), and the
development of humanized and bifunctional antibodies are under
investigation.[5]

Preliminary data from recent clinical radioimmunoscintigraphy studies indicate
that 99mTc-labelled murine monoclonal antibodies (MABs) E48 and U36 have a
similar ability to target squamous cell carcinoma of the head and neck
selectively. [6]

ANTIANGIOGENIC, ANTI-HYPOXIC AND VIRAL
AGENTS24

ONYX-015
Interferons
Retinoic Acid
N-Acetyl-Dinacine
Shark Cartilage
Whey Protein (Immunocal)
Thalidomide
Vitaxin
Carboxyamidotriazole (CAI)
TNP-470
AG-3340
INGN-201
FLK-1
SU-5416
2-ME
Anti-VEGF
Tetrahydracortizol
Angiostatin
Endostatin
Marimastat
Interleukin
Photodynamic Therapy
Doxycycline
Neovastat
Vitamin E
Pentosan Polysulfate
CAI
Combrestatin
Squalamine

DISCUSSION

RETINOIC ACID

Interferons (IFNs) and retinoic acid (RA) are known to possess antiproliferative
effects in various human cancer cell lines. When combining IFN-gamma and 9-
cis-RA, synergism could be observed. These results suggest that a regimen of
IFN, RA, and radiotherapy might be a promising combination in the therapy
ofsolid tumors where radiotherapy is part of the treatment.[7]

Clinical investigations have shown that significant regions of hypoxia exist in
solid tumors in patients. Of the various strategies developed for reducing or
eliminating hypoxia in tumors, the intravenous administration of nontoxic oxygen-
carrying materials is probably the most generally applicable in a clinical
setting.[8]

MITOXANTRONE

In a Phase II clinical trial, Mitoxantrone had modest activity in adenoid cystic
carcinomas.[9]

WHEY PROTEIN

Glutathione (GSH) concentration is high in most tumor cells. This may be an
important factor in resistance to chemotherapy. In a clinical trial, patients were
fed 30 grams of whey protein concentrate daily for six months. Results indicate
that whey protein might deplete tumor cells of GSH and render them more
vulnerable to chemotherapy (and radiotherapy).[10]

ENDOSTATIN AND ANGIOSTATIN

Endostatin and Angiostatin specifically inhibit endothelial proliferation and
potently inhibits angiogenesis in tumor growth. A method of sustained release
has been developed using E. coli-derived endostatin.[11] However, endostatin
and angiostatin have not progressed beyond murine trials. This is due, in large
part, to difficulties experienced in synthesizing adequate amounts of the
compounds.

TIRPAZAMINE

Hypoxic cytotoxins, such as tirpazamine, represent a novel approach in
overcoming radioresistant hypoxic cells. Tirpazamine is a bioreductive agent
which, by undergoing one electron reduction in hypoxic conditions, forms cytoxic
free radicals that produce DNA strand breaks causing cell death. Phase I
studies indicated that tirpazamine can be given safely. A Phase II trial using
tirpazamine with concurrent RT for head and neck cancer is now in progress at
Johns Hopkins University.

ONYX-015

ONYX-015 is an antiangiogenic compound that is in Phase I trials in several
locations, one of which is CTRC in San Antonio, TX. Although the recurrent
cancer this patient has is not excludable from the protocol entry parameters, its
location is. Entry to the trial is predicated upon the tumor existing in an
"injectable" location. There is concern about the potential side effects of ONYX-
015 in areas other than those affected by the tumor. Accordingly, for the current
trials, the compound must be injected directly into the tumor. this patentient's tumor is
not injectable.

ONYX-015 was well tolerated with no dose-limiting toxicities observed. A Phase
II trial is underway with patients with recurrent and refractory head and neck
cancers. Twenty seven percent of patients who received a single injection of
ONYX-015 experienced significant necrosis of the injected tumor masses. Of 19
patients whose follow-up is complete, 3 experienced more than 50% reduction in
tumor size with 1 patient experiencing more than 70% reduction. Three other
patients had significant necrosis of their tumors. Five patients had stable, non-
progressive tumors after treatment. A second Phase II trial of ONYX-015, in
conjunction with Cisplatin and 5FU, has been started to include head and neck
cancer patients who have not received previous chemotherapy.

Onyx is planning to conduct multiple Phase II trials in patients with tumors of the
head and neck. ONYX-015 will be administered along with Cisplatin and 5FU
daily over a five day period.

NEOVASTAT and SHARK CARTILAGE

Shark Cartilage preparations have been used to treat cancer and chronic
inflammatory disorders for many years. Proposed mechanisms of antitumor
action include direct inhibition of angiogenesis or indirect immunomodulation
with elaboration of antiangiogenic factors. However, supporting preclinical
studies and reports of trials in humans are often anecdotal. A trial was
conducted including fifty eight patients with advanced cancers (breast, colon,
lung, prostate, brain). The dose of shark cartilage was 1gm/kg/day p.o., t.i.d. for
six weeks. This study concluded that shark cartilage was ineffective in patients
with advanced cancers.[12]

Neovastat is a shark cartilage liquid extract manufactured under patents granted
to AEterna. The active fraction of Neovastat is AE-941. It is in Phase I/II clinical
trials in the U.S. for lung, prostate and breast cancer, and Phase III trial in
Canadawhere the drug has been dispensed to 150 patients on a compassionate
basis. Results from the former trials indicate that Neovastat was well tolerated
and reduced the number of metasteses up to 70% with no signs of toxicity at an
oral daily dose of 500 mg/kg. Trials did not evidence any adverse events
attributable to Neovastat and biological analyses (blood and urine) did not detect
any abnormality attributable to its administration. Some patients have been
dosed for up to 18 months indicating a well established safety profile.

THALIDOMIDE

There are several Phase II trials at NCI of Thalidomide in refractory
adenocarcinoma of the prostate. There are also Phase II trials in glioblastoma
multiforma and anaplastic gliomas and Kaposi's sarcoma. The results form the
trial on glioblastoma and anaplastic gliomas indicate a 50% biological response
rate and the trial on Kaposi's sarcoma indicate a 60% response rate to
treatment. Although the particular circumstances of this patient's recurrence do not
qualify her for entry into one of the trials, there is sufficient evidence of the
efficacy of Thalidomide to warrant its inclusion in a long-term, low risk protocol.
The long-term dosages have been well established in treating leprosy patients in
Europe. Arkansas Cancer Research Center has used Thalidomide sparingly in a
number of protocols, but has no organized trials. Also being used by Dr.
Michael Gruber in NYU.

CARBOXYAMIDOTRIAZOLE (CAI)

Orally administered in a Phase I trial with patients with refractory solid tumors. .
Patients received a test dose followed 1 week later by daily administration of CAI
in the encapsulated micronized formulation at doses of 100 to 350 mg/m2. Dose
limiting toxicity was observed at 350 mg/m2/d. Disease stabilization was
achieved in 47% of the patients. A dose of 300 mg/m2/d is proposed for Phase
II investigations. [13]

VITAMIN E

In pre-clinical experimentation, Vitamin E inhibited carcinogenesis, tumor
angiogenesis and tumor growth factor alpha (TGF alpha).[14]

PENTOSAN SULFATE

In a Phase I trial of patients with advanced stage metastatic cancer, pentosan
sulfate was well tolerated, but there was no objective tumor response in 12 of 13
cases. [15]

SQUALAMINE

Squalamine is an aminosterol, an angiogenic inhibitor developed from the body
tissues of the dogfish shark. Squalamine blocks the normal action of growth
factors in stimulating endothelial cells to assemble into capillaries by inhibiting
salt and acid regulating pumps on the endothelial cell required for capillary
formation.

INGN 201 (Adenoviral p53)

Phase I trials were successfully completed with INGN 201 in patients with non-
small cell lung cancer and, head and neck cancer. Phase II trials are scheduled
for approximately 80 patients with advanced recurrent squamous carcinoma of
the head and neck who have failed standard therapy.

Adenoviral (Ad-p53)

A Phase I clinical trial was conducted of primarily squamous cell cancers of the
oral cavity, pharynx and larynx. Patients with non-resectable tumors received
Ad-p53 every other day for two weeks (6 injections) were observed fortwo
weeks, and then repeated the treatment cycle. Of 17 patients, 5 were stable, 2
had partial remissions, defined as at least a 50% reduction in injected tumor at
the end of the trial.

Flk-1 Angiogenesis Inhibitors

Several small molecule inhibitors of the Flk-1 receptor have been developed that
will be placed in clinical trials. Research focuses on members of the tyrosine,
tyrosine phosphase and serine-threonine kinase families of signal transduction
molecules andtheir signaling pathways.

SU101

This PDGF receptor inhibitor is in Phase II clinical trials for the treatment of
gliomas and other cancers.

SU5416

The target of SU5416 inhibitor is Flk-1/KDR, a molecular driver of blood vessel
formation. Phase I trials have begun recruiting patients with advanced
malignancies who have failed previous drug therapy.

AG3340

AG3340 is a synthetic molecule designed to inhibit matrix metalloprotesaes
required for tumor progression. A Phase I trial of AG3340 was conducted in
Scotland on patients with advanced cancers. The agent was well tolerated and
rapidly absorbed following oral administration. A further trial will be conducted
at the University of Wisconsin Comprehensive Care Center and at the Vanderbilt
Clinic at Vanderbilt University in Nashville, TN.

SURAMIN

A Phase II trial of Suramin in recurrent brain tumors is currently underway at
Emory University. A Phase II trial of Suramin in refractory myelomas is also
underway at Northwestern University.

CARBOGEN/NICOTINAMIDE

Improving tumor oxygenation and perfusion by carbogen inhalation and
nicotinamide or vasoactive agents (flunarizine, verapamil, nicotinamide)
enhances the effects of radiotherapy and improves delivery of chemotherapeutic
agents to the tumor. [16] A clinical trial of RT with carbogen inhalation and
nicotinamide in tumors of head and neck, bladder, bronchi and brain is
underway at Ziekenhuis Canisius-Wilhelmina, afd. Neurologie, Nijmegen.

Pre-Clinical Antiangiogenesis Candidates

2-Methoxyestradiol (2ME) - 2ME is a natural, orally active estrogen metabolite
believed to be an inhibitor of angiogenesis and also an anti-tumor agent.
Nortriterpinoid (Tz-93)
Omega-3

PRELIMINARY CONCLUSIONS

LIMITED ACCESS TO TRIALS

As can be seen from the above literature search results, there are a very limited
number of clinical trials of antiangiogenic agents that allow ACC patients to
participate. In this patient's case, her particular expression of ACC precludes her from
participation in any of these tests.

TUMOR INSPECIFICITY

Much of the literatureon antiangiogenesis as a mechanism for containing tumors
supports the contention that antiangiogenic agents appear to be relatively
inspecific with respect to the tumors they act upon. The fact that the target of
antiangiogenesis agents is the ability of the tumor to develop a blood supply to
support further growth, and not the tumor itself, would seem to support the
hypothesis that antiangiogenic agents would have broad applicability.

CHRONIC DOSING

Angiogenesis inhibitors might be used as a long-termtreatment against cancer.
If the cancer has metastesized, antiangiogenic treatment might be needed
indefinitely. In other situations, antiangiogenic treatment might be administered
intermittently, for a period of months or years, to maintain a tumor's dormancy.
The general lack of drug resistance developed against these compounds as well
as their low toxicity makes them amenable to extended use. [17]

PROPOSAL:
LONG-TERM, LOW-RISK, ANTIANGIOGENIC
MAINTENANCE PROTOCOL

We propose for the patient that, given the absence of any effective standard protocol
or clinical trial for which she would qualify, we should devise a long-term, low-
risk antiangiogenic maintenance protocol. We propose to assemble a suite of
compounds, the goal of which is to decrease the long-term ability of the
recurrent tumor to acquire and maintain an adequate blood supply. Our intent is
not necessarily to eradicate the tumor, though that would be a highly desirable
outcome. Rather, our intent is to halt the progression of the recurrenceand
maintain the patient's current status indefinitely, if need be. Our hope is that this
maintenance program will be effective in stabilizing the patient's condition until one or
more of the second-generation antiangiogenic agents currently in trials prove to
be effective against ACC. We have focused on compounds that are currently
readily available, only one of which is controlled. We have also focused on
compounds that have little or no side effects to limit the potential side effects of
combining compounds into a protocol. The following were our parameters for
inclusion:

verifiable antiangiogenic activity in clinical trials
active against analogous tumors
limited side effects
well understood dosage tolerance
track record of chronic dosing

The compounds we have identified that appear to fit the above parameters are:

Thalidomide
Doxycycline
Whey Protein
Neovastat
Retinoic Acid
Vitamin E

Compounds and Sources

TNP-470, Tap Holdings, Deerfield, Ill. Early Phase II trials, currently closed
AG-3340, Aguron Pharmaceuticals, La Jolla, CA.
RhuMad VEGF, Anti-VEGF - Genetech, South San Francisco. Phase II trials
underway.
Combrestatin - Oxigene, Boston, NA. Phase I trials starting.
Marimastat - British Biotech, Annapolis, MD. Phase III tests underway.
Expects FDA approval in FY99.
Squalamine - Magainin Pharmaceuticals, Plymouth Meeting, PA. Phase I trials
in CTRC and Georgetown.
Neovastat - Aeterna Laboratories, Inc. Dr. John Blasecki (R&D)
Jacques Labrie (Communications).
Col-3 (Metastat) - CollaGenex Pharmaceuticals, Newtown, PA, Phase I trials of
unresponsive metastatic cancer, Kaposi's Sarcoma, AIDS related cancer, solid
tumors and brain tumors.
Thalidomide - EntreMed, Susan J. Lewis.
Adenoviral (Ad-p53) - Introgen Therapeutics, C. Channing Burke, and M.D.
Anderson Cancer Center, Michael Courtney.
CARBOXYAMIDOTRIAZOLE (CAI) - NCI, Laboratory of Pathology, WD Figg.
SU5416 - Sugen, Inc., and Lee Rosen, Johnsson Cancer Center Cancer
Therapy Development Program University of California School of Medicine, Los
Angeles, CA.
SU201 - Sugen, Inc.
INGN 201 - Introgen Therapeutics, Inc, C. Channing Burke, and Rhone-Poulenc
Rorer, Bob Pearson.
ONYX-015 - Onyx Pharmaceuticals, Jana Cuiper CTRC, San Antonio, Daniel
Von Hoff.

REFERENCES

1. 0Hill ME, Constenla DO, A'Hern RP, Henk JM, Rhys-Evans P, Breach N,
Archer D, Gore ME: Cisplatin and 5-fluorouracil for symptom control in
advanced salivary adenoid cystic carcinoma, Oral Oncol 1997 Jul;33(4):
275-278.

2. 0Knox SJ, Department of Radiation Oncology, Stanford Medical Center.

3. 0Gaze MN, The current status of targeted radiotherapy in clinical practice,
Phys Med Biol, 1996 Oct, 41:10, 895-903.

4. 0Zalutsky MR, Bigner DD, Radioimmunotherapy with alpha particle emitting
immunoconjugates, Acta Oncol, 1996, 35:3, 373-379.

5. 0Wilder RB, DeNardo GL, DeNardo SJ, Radioimmunotherapy: recent results
and future directions, J Clin Oncol, 1996 Apr, 14:4, 1383-1400.

6. 0de Bree R, Roos JC, Plazier MA, Quak JJ, van Kamp GJ, den Hollander W,
Snow GB, van Dongen GA, Selection of monoclonal antibody E48 IgG or
U36 IgG for adjuvant radioimmunotherapy in head and neck cancer patients,
Br J Cancer, 1997, 75:7, 1049-1060.

7. 0Windbichler GH, Hensler E, Widschwendter M, Posch A, Daxenbichler G,
Fritsch E, Marth C, Increased radiosensitivity by a combination of 9-cis-
retinoic acid and interferon-y in breast cancer cells, Gynecol Oncol, 1996
Jun, 61:3, 387-94.

8. 0Teicher BA, Physiologic mechanisms of therapeutic resistance. Blood flow
and hypoxia, Hematol Oncol Clin North Am, 1995 Apr, 9:2, 475-506.

9. 0Verweij J, de Mulder PH, de Graeff A, Vermorken JB, Wildiers J, Kerger J,
Schornagel J, Cognetti F, Kirkpatrick A, Sahmoud T, Lefebvre JL, Phase II
study on mitoxantrone in adenoid cystic carcinomas of the head and neck,
Ann Oncol, 1996 Oct, 7:8, 867-869.

. b0Kennedy RS, Konok GP, Bounous G, Baruchel S, Lee TD, The use of whey
protein concentrate in the treatment of patients with metastatic carcinoma - a
Phase I-II clinical study, Anticancer Res, 1995 Nov-Dec, 15:6B, 2643-2649.

. b0O'Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, Flynn WS,
Birkhead JR, Olsen BR, Folkman J: Endostatin: an endogenous inhibitor of
angiogenesis and tumor growth. Cell, 1997 Jan 24, 88:2, 277-285.

. b0Miller DR, Granick JL, Stark JJ, Anderson GT: Phase I/II trial of the safety
and efficacy of shark cartilage in the treatment of advanced cancers, Proc.
Annu Meet Am Soc Clin Oncol 1997;16:A173.

13. Kohn EC, Figg WD, Sarosy GA, Bauer KS, Davis PA, Soltis MJ, Thompkins
A, Liotta LA, Reed E, Phase I trial of micronized formulation
carboxyamidotriazole in patients with refractory solid tumors:
pharmokinetics, clinical outcome, and comparison of formulations, J Clin
Oncol; 15(5): 1985-93 1997.

14. Shklar G, Schwartz JL, Vitamin E inhibits experimental carcinogenesis and
tumor angiogenesis, Eur J Cancer B Oral Oncol; 32B: 114-9-1996.

15. Lush RM, Figg WD, Pluda JM, Bitton R, Headlee D, Kohler D, Reed E,
Sartor O, Cooper MR, A Phase I study of pentosan sulfate sodium in patients
with advanced malignancies, Ann Oncol; 7(9):939-44 1996.

16. Bernsen HJ, van der Kogel AJ, van Daal WA, Rijken PF: Vascularization and
perfusion of tumors as a target in cancer therapy. Ned Tijdschr Geneskd,
1997 Feb 22, 141:8, 364-368.

17. Folkman J, Fighting Cancer by Attacking its Blood Supply, Scientific
American, 9/96.

CONTACT REPORTS

Contact: Dr. Bruce Davidson
Georgetown University Hospital
Department of Otolaryngology

Dr. Davidson examined the patient to determine her potential as a surgical candidate.
He had the following recommendations:

1. The patient's case will be difficult due thecomplicating factors of radiation and the
need to minimize the blood flow to the area of the recurrence.

2. Patient's double vision at the extreme end of her lateral vision is likely not due
to the invasion of the optic nerve, but rather due to radiation induced fibrosis
of the muscles controlling the eye.

3. Dr. Davidson reviewed the most recent films but his review was inconclusive.
Swelling in the area of the radiation field makes determination of the level of
progression difficult.

4. Dr. Davidson suggested that we see Drs. Posnick and Attinger next.

Contacts: Dr. Jeffrey Posnick
Dr. Chris Attinger
Georgetown University Hospital
Department of Craniofacial Surgery

Dr. Attinger suggested that it would be impossible to release the scar band
unless a free flap were interposed. He suggested that a radial forearm free flap
could be used to accomplish the surgery. He also suggested that musculature
not be used becauseof the vastly increased resultant blood flow which could aid
tumor development. Instead, the radial forearm flap would bring in some blood
flow, but far less than a muscle flap would.

Dr. Attinger also suggested that the process of releasing the scar band would
also release the tension on the upper left lip and may allow it to return to a more
normal position.

He suggested that he (or I) contact Dr. Judah Folkman to determine how long
antiangiogenic compounds remain in the body to determine how long patient
would need to be off these compounds to promote surgical healing.

Dr. Attinger noted that Jan appeared to have good pulse to the area where the
flap would be attached. He felt that the operation wouldn't be particularly
difficult, but he cautioned that we should not consider filling the fistula for the
foreseeable future. Generallyhe recommends two years after a recurrence
before filling the defect. He felt that this could only be accomplished with
interposed muscle tissue and this would be unwise due to the increase in local
profusion.

Our second meeting was with Dr. Posnick. Dr. Posnick was less encouraging
than Dr. Attinger. Dr. Posnick felt that there were a series of challenges,
peculiar to this patient's case that might make the surgery problematic. These were:

1. Any interposed tissue into the area of the scar band might increase profusion
to the area which could be problematic, even if muscle tissue wasn't used.

2. Patient's extremely limited range of motion may make intubation difficult.

3. Patient might have healing problems in the area that received radiation
treatment.

4. Dr. Posnick also felt that he might not be able to sufficiently contour the flap
inside the cheek and that it might protrude into her mouth, getting in the
way of chewing motion.

5. In general, there is no scientific evidence to justify a surgical expectation -
positive or negative.

6. Patient would need to be on an NG tube during her recovery period.

7. Patient might have ankylosed TMJ's and may need further surgical
intervention. In addition, she may not be able to maintain opening, if
attained.

Rather, Dr. Posnick suggested that Dr. Razavi explore the possibility of
decreasing the size of the obturator, thereby making it easier to remove and
replace.

Note: We had already visited Dr. Ramin Razavi, the prosthedontist following
patient's case, who had determined that further modifications to her obturator
would significantly compromise its function.

Contact: Prof. Mike Retsky

Date: Jan 11,1998

Prof. Retsky posted a note on the ACC newsgroup about a new therapy for ACC
cancers that had metastasized in the lungs. He also noted that he was a visiting
professor with Prof. Judah Folkman at Mass. General. I posted an e-mail to
Mike to which he returned his phone number. I called him afterward. The
following summarizes our conversation.

Mike started out by saying that he is a visiting professor with Folkman. Mike
claims that 5FU, though it is an older compound (about 40 yrs. old) that is
moderately effective as a toxin, also has antiangiogenic properties. In this
regard, 5FU is like most other antiangiogenic compounds in that it is wide
spectrum in its application and has relatively few side effects in the dosages
necessary (2.6 g/week (though this depends upon body weight)). Mike
mentioned that overdosing with 5FU can be problematic to the extremities. For
the first year of treatment, patients typically are on 6 hrs. infusion/day, every day.
For the second year, they are on infusion 6 hrs./day, 1 week per month. For the
third year, they are on infusion 6 hrs./day, several days per month. Dosages
were worked out by Bill Hruschefskyat the Albany VA Hospital. Mike claims that
in these dosages, 5FU has virtually no side effects.

In talking about this 5FU protocol, he claims that to obtain its antiangiogenic
benefits, it must be infused since it has a half life in the body of 10 to 20 minutes.
Like other antiangiogenic compounds, 5FU does not appear to have problems
with acquired drug resistance. Mike recommended two papers in the Journal of
Cancer Investigation, Vol. 13:

1. Review of infusional cancer therapies: Lokich, Anderson
2. Use of 72-4 in management of carcinoma

Mike also suggested that I contact Entre-med in Rockville, MD. He claims that
they have several protocols to use Thalidomide as an antiangiogenic agent.
Mike claims that they have the dosages well worked out and are always
interested in finding new patients. (Note - I'm not sure if these are controlled
trials or not.) Mike mentioned that Entre-med is a financial supporter of
Folkman's lab and research.

Mike stated that, in animal trials, Thalidomide appears to be relatively effective
at shrinking tumors to 50% of the original size. However, the current crop of
angiostatin and endostatin are effective in shrinking animal tumors to 1% of their
original size. An interesting point is that Bristol Meyers and Entre-med, the firms
that are cooperatively developing angiostatin and endostatin with Folkman are
apparently having difficulty in synthesizing the compounds. In fact, their current
animal trials are awaiting a sufficient supply of the compounds to continue.

In general, Mike stated that NCI is putting a lot of energy and money into
antiangiogenesis trials. However, he felt that we are at least two years away
from Phase II trials for the most effective compounds. These are collagen-18
based compounds.

In passing, Mike mentioned that we probably should be using monthly marker
scanning instead of CT and MRI scans. He claimed that using markers such as
CEA, 19-9 and 72-4 covers 90% of the cancer spectrum and is two to three
times more effective at identifying growth than CTs and MRIs. Though he
admitted that the markers can be affected by second hand smoke and diet items,
over time, a statistical analysis can be used to identify true anomalies.

Contact: Prof. Mike Retsky

Date: May 12, 1998

I called Mike to see if anything was new in the area of antiangiogenic
compounds and if there were any status changes in the development and
production path of angiostatin and endostatin.

According to Mike, the production problems (inability to synthesize bulk amounts
of angiostatin/endostatin) persist. There will not be sufficient amounts of the
compounds to support more than limited trials for the foreseeable future.
Clinical trials are supposed to start next year.

Mike stated that his suspicion is that these compounds will not be nearly as
successful in human trials as they were in murine trials. TNP-470, an
antiangiogenic compound also developed by Dr. Folkman's group, was very
successful in mouse trials and has been not nearly as successful in human
trials. Mike feels that the new compounds may turn out to be weapons in an
arsenal, but will not likely be the magic bullet.

Mike agreed with my suggestion to anchor a protocol on thalidomide. He feels
that this is one of the best of the current antiangiogenic compounds available
and there is a lot of experiencewith developing tolerable, chronic dosages for
leprosy patients. He gave me two contact points for developing a protocol.

Dr. Bob D'Amato, Children's Hospital in Boston, has experience in chronic
dosing of thalidomide and would be a good resource. His number is (617) 355-
6234. Maureen Pelosi, in FDA, is the contact point to obtaining compassionate
release of a compound.

Contact: Dr. Kevin Cullen
Georgetown University
Department of Hematology/Oncology

Date: May 12, 1998

Dr. Cullen called to report on the findings of the tumor board case presentation
for the patient last week. Dr. Cullen had the following findings/recommendations to
report:

It is difficult to tell from the CT and MRI scans whether the abnormalities
evidenced result from necrotic tissue (resulting from the radiation treatment),
additional scar tissue (also resulting from the radiation treatment), or remaining
tumor.

The safest assumption at this point would be to expect that there is at least some
remaining tumor and proceed accordingly. Dr. Cullen reiterated that standard
chemotherapy is relatively ineffective against adenoid cystic carcinoma (ACC)
and should not be pursued.

Dr. Cullen suggested that we pursue a Phase I antiangiogenesis trial next.
There are several such trials underway at Georgetown University and Dr. Cullen
suggested that we contact the Developmental Therapeutics Department to
discuss trials with them.

Regarding the critical need to release Jan's scar tissue to impove the range of
motion of her jaw, Dr. Bruce Davidson (ENT), was cautious and advised against
attempting a surgical solution unless absolutely necessary. There were several
factors which could negatively impact the success of a free flap transfer. These
are:

The flap might not survive. This could leave Jan worse off than when
she started.
The flap might improve the vascularization locally to the tumor which
could, in turn, prompt it to grow.

In cases such as this, often the ENT team will put the patient under general
anesthesia and attempt to physically break or stretch the scar band in the
operating room. Although this might be a possibility for the patient, Dr. Davidson was
concerned that the severity of scarring and the potential weakness of the
surrounding bone due to repeated radiation treatment might result in a
mandibular fracture.

Our next steps are: 1) to contact Dr. Davidson to see if there is a more
experienced specialist to address the surgical intervention, and 2) make contact
with the Developmental Therapeutics Department.

Contact: Dr. Waung Hong
Chairman, Head and Neck Surgery
M.D. Anderson Cancer Center

Dr. Waung Hong in M.D. Anderson suggested the use of Retinoic Acid as a
chemopreventative agent. He has also used accutane, a vitamin A derivative.
He suggested that we contact Dr. Cullen for an evaluation and have Dr. Cullen
contact him to determine applicability and dosage for Retinoic Acid.

Contact: Dr. Eddie Reed
NCI

Dr. Reed was not aware of any data, that could be used to guide our
decision making process. NCI has "Phase I" types of clinical trials with
antiangionenesis and non-antiangiogenesis agents. However, Dr. Reed
reiterated that Phase I trials are not focused on clinical benefit.

The agents I listed for Dr. Reed (thalidomide, retinoic acid, doxycycline, vitamin
E, neovastat, whey protein) are among those that MIGHT have
anti-angiogenic properties against ACC, but these agents have not been tested
against ACC specifically.

Contact: Dr. Ed Oldfield
NCI

Dr. Oldfield indicated that he had no experience with adenoid cystic carcinoma
whatsoever. A neurosurgical colleague of Dr. Oldfield's, and whom he holds in
high regard, Donald Wright (George Washington University Hospital, Dept. of
Neurosurgery), has significant experience with treatment of skull base tumors
and has very good clinical judgment. Dr. Oldfield felt he would more likely be
able to help.

Contact: Susan Beardslee5, CTRC
Sherry Tony, ONYX

Trial: Phase I Study of ONYX-015 in patients with Head & Neck
Tumors

Organization: CTRC

Sherry stated that the current compound being tested in clinical trials by ONYX
is called ONYX-015 and is an antiangiogenic compound that is being tested in
Phase I trials in CTRC, San Antonio. Phase II trials are planned in 14 sites
nationwide. However, the current trials are limited to "injectable" tumors. The
research staff at ONYX is concerned about the potential antiangiogenic side
effects in unintended areas. Since patient's tumor is not injectable, she is not a
candidate for the current trials.

ONYX-015 is an antiangiogenic compound that is in Phase I trials in several
locations, one of which is CTRC in San Antonio, TX. Although the recurrent
cancer patient has is not excludable from the protocol entry parameters, its
location is. Entry to the trial is predicated upon the tumor existing in an
"injectable" location. There is concern about the potential side effects of ONYX-
015 in areas other than those affected by the tumor. Accordingly, for the current
trials, the compound must be injected directly into the tumor. patient's tumor is
not injectable.

Contact: Dr. Sadeghi
Rush-Presbyterian-St. Luke's Hospital

I called for Dr. William Panje, the Director of Head and Neck Reconstruction and
Skull Base Surgery, to discuss a recent article about electoporation. I reached
one of his associates, Dr. Sadeghi who gave me the following information.

Rush has a trial underway using electroporation on head and neck cancers
(though, predominantly squamous cell cancers) using electroporation in
conjunction with direct dosed chemotherapy. The theory is that a minimal dose
of chemotherapeutic agent is injected into the tumor which is subsequently given
a small electrical shock. Administering the shock ensures that the agent enters
the tumor cells and can impact them. Typically, a treatment takes about a half
hour and a follow up CT/MRI determines if more treatments are needed.

Dr. Sadeghi agreed to review the case to see if she could be included, either
in the trial, or on a compassionate basis. He asked to be sent the most recent
pathology report, the operation report and any scans that would be relevant.

Note: He specifically recommended that we get a PET scan to determine the
extent of remaining tumor. He claimed that a PET scan could differentiate
between remaining tumor and chronic swelling resultant from the most recent
radiotherapy.

Contact: Dr. Fidler
M.D. Anderson

MD Anderson is conducting some limited antiangiogenesis research some work
using alpha interferon, but no structured trials are underway.

Contact: WD Figg
NCI
Pharmokinetics Section

NCI has a limited number of antiangiogenesis clinical trials at (CAI, CAI + Taxol,
COL-3, Thalidomide). Although, none of the clinical trials at NCI are directly
applicable for patients with recurrent adenoid cystic carcinoma, the action of
Thalidomide in NCI trials appears relevant to ACC.

Contact: Joel Bernstein
Scripps

No clinical trials are underway at Scripps that are applicable to patients with
recurrent adenoid cystic carcinoma.

Contact: Jim Stewart
Univ. of Wisconsin

No clinical trials are underway at Wisconsin that are applicable to patients with
recurrent adenoid cystic carcinoma. Dr. Stewart suggested contacting Mike
Hawkins at Georgetown.

Contact: Arlene Forestierre
Johns Hopkins
Member of Eastern Cooperative Oncology Group (ECOG)
Head and Neck Group

The only organized ECOG trial that's close to relevant is a Phase II study of
taxol on salivary gland tumors that has been cancelled for ineffectiveness.

Contact: Gerald Soff
Bill Gradisher
Northwestern

No clinical trials are underway at Northwestern that are applicable to patients
with recurrent adenoid cystic carcinoma.

Contact: Clinial Trials Hotline
Dana Farber Institute

No clinical trials are underway at the Dana Farber Institute that are applicable to
patients with recurrent adenoid cystic carcinoma.

RESEARCH PROGRAM AND INDIVIDUAL
CONTACT LISTINGS

OTHER ORGANIZATIONS AND TRIALS

1. Madhav Dhodapkar, Arkansas Cancer Research Center
2. Bakesh Singh, Cell Biology, M.D. Anderson - Only does lab work
3. Fidler, M.D. Anderson - some work using alpha interferon, but no structured
trial
4. WD Figg, NCI, Pharmokinetics Section - some trials at NCI (CAI, CAI + taxol,
COL-3) but none for which patient qualifies
5. Joel Bernstein, Scripps - No clinical trials applicable
6. Jim Stewart, Univ. of Wisconsin - Nothing at Wisconsin. Suggested
contacting Mike Hawkins at Georgetown
7. Arlene Forestierre, Johns Hopkins - only organized ECOG trial that's close is
a Phase II study of taxol on salivary gland tumors that has been cancelled for
ineffectiveness
8. Gerald Soff, Northwestern - suggested contacting Bill Gradisher @
Northwestern
9. Bill Gradisher, Northwestern - Is aware of no A/C trials. Drug companies are
not active in this area
10. Dana Farber Institute, Clinical Trials Hotline. Marlene polled contacts @
Dana Farber and concluded that they have no trials available
11. Baidas, Ephraim, Sloan Kettering, TNP 470 trial on pancreatic cancer
12. Baidas, Said, Georgetown, Phase II trial of Suramin on gliomas
13. Benson, Al, Northwestern, TNP 470 trial on pancreatic cancer
14. Calabresi, Paul, Rhode Island Hosp., Phase II trial of Suramin on gliomas
15. Craig, John, Schumpert Med. Ctr., TNP 470 trial on pancreatic cancer
16. Delmore, James, Univ. of Kansas, Ph. II trial of TNP 470 on cervical
squamous
17. Ervin, Tom, Maine Med. Ctr., TNP 470 trial on pancreatic cancer
18. Garewal, Harinder, VA Tucson, TNP 470 trial on pancreatic cancer
19. Goldberg, Richard, Mayo Clinic, TNP 470 trial on pancreatic cancer
20. Guarino, Michael, Delaware Clinic, TNP 470 trial on pancreatic cancer
21. Hochberg, Fred, Mass. General, Phase II trial of Suramin on gliomas
22. Hurteau, Jean, Indiana Cancer Pavillion, Ph. II trial of TNP 470 on cervical
squamous
23. Madajewicz, Stefan, SUNY Stony Brook, Ph. II trial of TNP 470 on cervical
squamous
24. Mani, Sridar, Univ. of Chicago, TNP 470 trial on pancreatic cancer
25. Marshall, John, Georgetown, TNP 470 trial on pancreatic cancer
26. McCachen, Samuel, Thompson Cancer Ctr., TNP 470 trial on pancreatic
cancer
27. Mikkelsen, Tom, Henry Ford Hospital, Phase II trial of Suramin on gliomas
28. Nguyen, Mai, UCLA, TNP 470 trial on pancreatic cancer
29. Potkul, Keith, Loyola, Ph. II trial of TNP 470 on cervical squamous
30. Ritch, Paul, Med. Coll. Of Wisconsin, TNP 470 trial on pancreatic cancer
31. Venook, Alan, UCSF, TNP 470 trial on pancreatic cancer
32. Shepherd, Frances, Toronto General, Ph. II trial of TNP 470 on cervical
squamous
33. Wajsman, Zev, Univ. of Florida, Ph. II trial of TNP 470 on cervical squamous
34. Krook, James, Duluth Clinic, Ph. II trial of TNP 470 on cervical squamous
35. Malkin, Mark, Sloan Kettering, Ph. II trial of TNP 470 on cervical squamous

Phone Numbers

Agarwala, Sanjiv (412) 648-6576
Arkansas Cancer Research Center Clinical Trials Hotline (501) 686-8274
Baidas, Said (202) 687-2198
Bakesh Singh (713) 792-8219
Benson, Al (312) 908-9412
Bernstein, Joel (619) 453-9200
Boston Children's Hospital (main) (617) 355-6000
Boston Children's Hospital, Department of Surgery (617) 355-7641
Calabresi, Paul (401) 444-8977
Casper, Ephraim (201) 983-7346
Craig, John (318) 681-4139
D'Amato, Robert, (617) 355-6234
Dahut, William, Dept. of Dev. Therapeutics, Georgetown, (202) 687-2223
Dana Farber, main (617) 632-3000
Davidson, Bruce, Georgetown, Dept of Otolaryngology, (202) 687-8186
Delmore, James (316) 681-0251
Emory University, Crawford Long Hospital (main) (404) 686-4411
Ervin, Tom (207) 885-7600
Fetell, Michael (212) 305-5571
Fidler (713) 792-8577
Figg, WD (301) 402-3630
Folkman, Judah (617) 355-7661
Forestierre, Arlene (410) 955-9818
Garewal, Harinder (520) 626-6374
Georgetown University Developmental Therapeutics (202) 687-5718
Georgetown University Lombardi Help Link (Laura Williams) (202) 784-4000
Goldberg, Richard (507) 284-2511
Gradisher, Bill (312) 908-8697
Guarino, Michael (302) 733-6229
Harvard Medical School (main) (617) 432-1000
Harvard Medical School (surgery) (617) 432-2001
Hawkins, Michael, Dir. Dept. of Dev. Therapeutics, Georgetown, (202) 687-2223
Herman, Terry, Dir. Of Radiation Oncology @ CTRC, (210) 616-5648
Hochberg, Fred (617) 726-8657
Hong, Chair of Head and Neck Cancer, M.D. Anderson (713) 792-6363
Krook, James (218) 722-8364
Lee, D.J. (410) 955-8062
M.D. Anderson Clinical Trials Hotline (800) 632-2221, (800) 392-1611
Madajewicz, Stefan (516) 444-1727
Madhav Dhodapkar (501) 686-5222
Malkin, Art (212) 639-6688
Mani, Sridar (773) 702-0360
Marshall, John (202) 687-2198
Mary Ellen @ Northwestern (312) 908-8143
McCachen, Samuel (423) 541-1720
NCI (main) (301) 496-4000
Nguyen, Mai (310) 206-215
Olson, Jeff (404) 778-3091
Pelosi, Maureen, FDA (Compassionate Release Process) (301) 594-5768
Posnick, Jeffrey, Georgetown, Dept of Craniofacial Surgery, (202) 687-8565
Potkul, Keith (708) 327-3314
Princess Margaret Hospital (main) (416) 946-2000
Reed, Eddie, NCI (301) 402-1904
Ritch, Paul (414) 257-6868
Rosental, Jack, (312) 908-8177
Rothenberg, Mace, Vanderbilt, Dept. of Medical Oncology, (615) 322-4967
Sadeghi, Rush-Presbyterian-St. Luke's, (312) 664-6715
Shepherd, Frances (416) 340-3833
Tom Mikkelsen (313) 876-8688
UCLA Clinical Trials Hotline (888) 294-2808
University of Texas, Southwestern Medical Center (214) 648-3111
Venook, Alan (415) 476-1421
Wajsman, Zev (904) 392-5348
Wisconsin University Clinical Trials Hotline (608) 263-6400
Zwelling, Leonard (713) 792-2933

Feedback on Proposal

Contact: Dr. James Pluda
NCI

Date: 7/1/98

Dr. Pluda stated that there were several criteria that we should look for in any
potential compound that we were trying to obtain on a compassionate basis.
These are: 1) demonstratedactivity on analogous tumors, 2) understood
dosages, 3) availability, and 4) a lack of other options. All of the compounds we
had identified fulfilled these parameters. He thought that the protocol we had
identified was reasonable. He claimed that there was no particular reason to
expect that the protocol would work or would not work. However, he had some
information about three potential trials of antiangiogenic agents that were
proceeding into Phase III trials and, therefore, would be available on a
compassionate basis. These compounds were: 1) Marimastst from British
Biotech, 2) AG3340 from Agouron Pharmaceuticals, and 3) BAY 1266 from
Bayer. Dr. Pluda suggested we call Dr. Rachel Humphrey at Bayer at (203)
812-5085.

We had become aware of Dr. Pluda when he was quoted in a recent JAMA
article about an ASCO convention. Dr. Pluda had suggested that antiangiogenic
treatments for cancer might be effective in long term maintenance programs,
similar to current treatments for diabetes. Diabetes is not curable, but it is
manageable. Stabilizing tumors so that patients can live with them for extended
periods would be a reasonable goal. This, coincidentally, is the same
conclusion we have reached and is the central reasoning behind the protocol we
have proposed.

Dr. Pluda had some additional information that was of interest. First, he stated
that antiangiogenic compounds do not appear to inhibit wound healing. This
information supported prior information we had received from Mike Retsky on
Judah Folkmanes staff. Second, he stated that, for the protocol we had outlined,
only several days would be necessary for the compounds to clear patient's
system before surgical intervention.

Dr. Pluda also had some insights to offer on the progress to date in synthesizing
angiostatin and endostatin. Currently, NCI and Bristol Meyers are taking
different routes to recombinant protein synthesis and are in a loose form of
competition. Whoevergets done first will supply the first round of human trials.

Contact: Kathy Rugg
British Biotech

Date: 7/6/98

Based upon a suggestion from Dr. Pluda, I contacted Kathy Rugg to determine
the potential for receiving compassionate release of Marimastat for the patient. Kathy
was quick to point out three important barriers. First, the trials for Marimastat
are rather narrow and specifically exclude the patient from their Phase II trials.
Second, preliminary results are not releasable from their current trials.
Accordingly, we cannot ascertain whether this protocol could be logically
extended to ACC. Third, British Biotech is a small firm and is not able to
manufacture sufficient amounts of Marimastat to support compassionate release.

Contact: Dr. Mary Collier
Project Director
Agouron Pharmaceuticals

Date: 7/6/98

I asked Dr. Collier about the potential effectiveness of AG3340 (Agouron's
proprietary matrix metalloprotienase inhibitor) on solid tumors (like adenoid
cystic carcinoma (ACC) and the possibility of obtaining it on a compassionate
basis. Dr. Collier confirmed that AG3340 is entering Phase III trials, though the
entrance criteria would preclude ACC. She also stated that Agouron was too
small a company to support the compassionate release of AG3340. Dr. Collier
went on to state thatin the trial cases where responses from AG3340 were
evidenced, there was only minimal tumor shrinkage.That is why they have
decided to start a new Phase I trial of AG3340, carboplatinum and taxol to test
pharmokinetics. Entrance criteria will include unspecified tumors that have not
been treated with chemotherapy agents. The patient would qualify for this trial.

Note: This is a common approach that is currently being used with a variety of
antiangiogenic and chemotherapy agent combinations. Current thinking
appears to be that there is a synergistic effect hoped for between the two
families of agents.

Dr. Collier claimed that it is expected that AG3340 will have a significantly
increased response rate in combination with the two chemotherapy agents. Dr.
Collier also stated that AG3340 would be dosed orally at 10 mg. twice daily and
increase gradually to 100 mg. twice daily as long as it is tolerated by the patient.
Expected side effects include joint soreness.

This Phase I trial will be a small one and will be held at Vanderbilt University and
North Shore University Hospital.

Contact: Dr. Terry Herman
CTRC @ San Antonio

Date: 7/08/98

I called Terry to outline the AG3340 trial and get his opinion on this protocol for
the patient. Compared to the maintenance program we identified, Terry felt that the
agents we would get access to in the trial would likely be more powerful than the
agents included in our design. Accordingly, he recommended that we opt for the
AG3340 trial. In his opinion, this should be a first choice. If this trial didn't work
out, for any reason, he suggested that we get on the protocol we developed as
soon as possible. He felt that we had identified a reasonable grouping of agents
that fit our protocol goals - demonstrated clinical benefit with lease concomitant
risk.

Contact: Dr. Mace Rothenberg
Vanderbilt University

Date: 7/8/98

I contacted Dr. Rothenberg after e-mailing him our proposal and to get his views
on the new Phase I trial of AG3340. First, Dr. Rothenberg stated that our report
represented a reasonable approach for patient's current condition. He confirmed
that, other than the new Phase I AG3340 trial which will be started at Vanderbilt,
we has aware of no antiangiogenic trials for which the patient would qualify. Given
tthis fact, he felt that we really only had two choices (assuming doing nothing is
not an option for us): our protocol or the AG3340 trial.

Dr. Rothenberg suggested that we might want to seriously consider the AG3340
trial for several reasons. First, since patient's tumor is relatively small, it doesn't
need many blood vessels to exist. Second, the upcoming AG3340 trial is unique
in that all patients will be given doses up to their tolerance level to test the
pharmokinetics. In this respect it is more like a Phase III trial. Third, Dr.
Rothenberg stated that the combination of angiogenic agents with more classical
chemotherapy agents is a popular current approach.

Although Dr. Rothenberg stated that AG3340 rarely has csued tumor shrinkage,
a more reasonable expectation is to induce tumor stability. This, coincidentally,
is the same goal we were trying to achieve in the protocol we developed. In
closing, he mentioned that this will bea very small trial and that we should
hasten to get in.

Contact: Dr. Robert D'Amato
Harvard University

Date: 7/6/98

Based upon a suggestion from Mike Retsky, I contacted Dr. D'Amato to get his
opinion of our proposed protocol. Mike claimed that Dr. D'Amato was one of the
most knowledgeable researchers on the activity and dosing of Thalidomide.
According to Dr. D'Amato, Thalidomide has shown effect against Glioblastomas
and Kaposi's Sarcoma. It also is in current trials against breast and prostate
cancers. These trials are still recruiting. Pharmokinetics from these trials
indicate that the threapeutic range is 400mg./day to 800 mg./day. Doses were
given up to 1,200 mg./day, but saturation levels were typically reached at 800
mg./day. Doses are typically given at night time. Should we go ahead with our
protocol, Dr. D'Amato recommends that we begin at 200 mg./day and increase to
800 mg./day in 200 mg. increments every two weeks.

Dr. D'Amato also stated that obtaining FDA approval for release of Thalidomide
should only take one to two weeks.

Contact: Barbara Barile-Thiem
Clinical Trial Coordinator
North Shore University Hospital

Date: 7/09/98

Barbara is the clinical trial coordinator at the North Shore University Hospital
that is managing trial NSUH 9881: Phase I Pharmokinetic and Safety Study
of the Matrix Metalloproteinase Inhibitor AG3340 in Combination with
Paclitaxel and Carboplatin in Patients Having Advanced Solid Tumors.
Based upon the information provided by Barbara,patient appears to qualify for
NSUH 9881 clinical trial. According to Barbara, the Taxol and Carboplatin are
infused for approximately three hours every three weeks. AG3340 is taken
orally each day. Blood tests are done once a week. Barbara was unaware of a
specific end point for the trial. Dr. Jim D'Olimpio is the lead investigator on the
project. We made a tentative appointment to consult with Dr. D'Olimpio on July
28th to determine the appropriateness of this trial for the patient.

Phone Numbers

Agarwala, Sanjiv (412) 648-6576
Agouron Pharmaceuticals, (619) 622-3000
Rugg, Kathy, British Biotech, (800) 355-6957
Arkansas Cancer Research Center Clinical Trials Hotline (501) 686-8274
Baidas, Said (202) 687-2198
Bakesh Singh (713) 792-8219
Bayer Clinical Hotline, (888) 442-4950
Benson, Al (312) 908-9412
Bernstein, Joel (619) 453-9200
Boston Children's Hospital (main) (617) 355-6000
Boston Children's Hospital, Department of Surgery (617) 355-7641
British Biotech (410) 266-7909
Calabresi, Paul (401) 444-8977
Casper, Ephraim (201) 983-7346
Collier, Mary, Agouron Pharmaceuticals, (619) 622-8036
Craig, John (318) 681-4139
D'Amato, Robert, (617) 355-6234
D'Olimpio, James, North Shore University Hospital (516) 562-8906
Dahut, William, Dept. of Dev. Therapeutics, Georgetown, (202) 687-2223
Dana Farber, main (617) 632-3000
Davidson, Bruce, Georgetown, Dept of Otolaryngology, (202) 687-8186
Delmore, James (316) 681-0251
Emory University, Crawford Long Hospital (main) (404) 686-4411
Ervin, Tom (207) 885-7600
Fetell, Michael (212) 305-5571
Fidler (713) 792-8577
Figg, WD (301) 402-3630
Folkman, Judah (617) 355-7661
Forestierre, Arlene (410) 955-9818
Garewal, Harinder (520) 626-6374
Georgetown University Developmental Therapeutics (202) 687-5718
Georgetown University Lombardi Help Link (Laura Williams) (202) 784-4000
Goldberg, Richard (507) 284-2511
Gradisher, Bill (312) 908-8697
Guarino, Michael (302) 733-6229
Harvard Medical School (main) (617) 432-1000
Harvard Medical School (surgery) (617) 432-2001
Hawkins, Michael, Dir. Dept. of Dev. Therapeutics, Georgetown, (202) 687-2223
Herman, Terry, Dir. Of Radiation Oncology @ CTRC, (210) 616-5648
Hochberg, Fred (617) 726-8657
Hong, Chair of Head and Neck Cancer, M.D. Anderson (713) 792-6363
Humphrey, Rachel, Bayer (203) 812-5085
Krook, James (218) 722-8364
Lee, D.J. (410) 955-8062
M.D. Anderson Clinical Trials Hotline (800) 632-2221, (800) 392-1611
Madajewicz, Stefan (516) 444-1727
Madhav Dhodapkar (501) 686-5222
Malkin, Art (212) 639-6688
Mani, Sridar (773) 702-0360
Marshall, John (202) 687-2198
Mary Ellen @ Northwestern (312) 908-8143
McCachen, Samuel (423) 541-1720
NCI (main) (301) 496-4000
Nguyen, Mai (310) 206-215
North Shore trial coordinator (Barbara), (516) 562-8977
Olson, Jeff (404) 778-3091
Pelosi, Maureen, FDA (Compassionate Release Process) (301) 594-5768
Pelosi, Maureen, FDA compassionate release coordinator, (310) 594-5768
Posnick, Jeffrey, Georgetown, Dept of Craniofacial Surgery, (202) 687-8565
Potkul, Keith (708) 327-3314
Princess Margaret Hospital (main) (416) 946-2000
Reed, Eddie, NCI (301) 402-1904
Ritch, Paul (414) 257-6868
Rosental, Jack, (312) 908-8177
Rothenberg, Mace, Vanderbilt, Dept. of Medical Oncology, (615) 322-4967
Sadeghi, Rush-Presbyterian-St. Luke's, (312) 664-6715
Shepherd, Frances (416) 340-3833
Tom Mikkelsen (313) 876-8688
UCLA Clinical Trials Hotline (888) 294-2808
University of Texas, Southwestern Medical Center (214) 648-3111
Venook, Alan (415) 476-1421
Wajsman, Zev (904) 392-5348
Wisconsin University Clinical Trials Hotline (608) 263-6400
Zwelling, Leonard (713) 792-2933

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