http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=retrieve&db=pubmed&list_uids=15756027&dopt=Abstract

Clin Cancer Res. 2005 Mar 1;11(5):2008-17.

http://clincancerres.aacrjournals.org/cgi/content/abstract/11/5/2008

Herceptin Down-Regulates HER-2/neu and Vascular Endothelial Growth
Factor Expression and Enhances Taxol-Induced Cytotoxicity of Human
Ewing's Sarcoma Cells In vitro and In vivo.

Guan H, Jia SF, Zhou Z, Stewart J, Kleinerman ES.

Eugenie S. Kleinerman, Division of Pediatrics, Unit 87, University of
Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX
77030. Phone: 713-792-8110; Fax: 713-794-5042; E-mail:
ekleiner@mail.mdanderson.org

Division of Pediatrics and Department of Pathology, University of Texas
M.D. Anderson Cancer Center, Houston, Texas.

We have previously shown that high levels of HER-2/neu protein were
overexpressed in human Ewing's sarcoma cells (TC71, SK-ES1) relative to
normal human osteoblasts. The purpose of this study was to determine
whether herceptin alone or in combination with chemotherapeutic agents
could inhibit the growth of Ewing's sarcoma in vitro and in vivo.
Western blot analysis showed that the protein levels of HER-2/neu were
decreased following herceptin treatment. Cell growth was also inhibited
by herceptin in a dose-dependent manner with an IC(50) of 4 mg/mL in
TC71 and SK-ES1 cell line, whereas human immunoglobin had no effect.
Northern blot and ELISA showed the RNA expression and protein levels of
vascular endothelial growth factor were also inhibited by herceptin
treatment with no alteration in HIF-1alpha protein and topoisomerase
IIalpha expression. Furthermore, Ewing's sarcoma tumor growth was
significantly delayed by 100 mg/kg herceptin treatment in our Ewing's
sarcoma xenograft mouse model. Combining taxol with herceptin resulted
in additive cytotoxicity, whereas herceptin-etoposide, doxorubicin, and
9-nitrocamptothecin combinations did not. Taxol-herceptin enhanced
growth inhibition in TC71 cells in vitro compared with either agent
alone. Ewing's sarcoma growth was also delayed in vivo and mean tumor
size was significantly lower in mice treated with herceptin plus taxol
than in those receiving taxol or herceptin alone. These data suggest
that herceptin in combination with taxol may be a therapeutic option in
the treatment of Ewing's sarcoma.

PMID: 15756027 [PubMed – in process]

FOR IMMEDIATE RELEASE
CONTACT:
Jerry Parrott
Vice President, Corporate Communications
301/315-2777
Kate de Santis
Director, Investor Relations
301/251-6003

HUMAN GENOME SCIENCES COMPLETES PATIENT ENROLLMENT
IN A PHASE 2 CLINICAL TRIAL OF HGS-ETR1 FOR THE TREATMENT OF
COLORECTAL CANCER

– One in a series of Phase 2 trials of the agonistic
human monoclonal
antibody to TRAIL receptor 1 –

ROCKVILLE, Maryland – February 23, 2005 – Human Genome Sciences,
Inc. (Nasdaq: HGSI) announced today that it has completed the
enrollment and initial dosing of patients in a Phase 2 clinical trial
of HGS-ETR1 (mapatumumab) in patients with advanced colorectal cancer.

The Phase 2 clinical trial is an open-label study to evaluate the
efficacy, safety and tolerability of HGS-ETR1 in patients with relapsed
or refractory colorectal cancer. ¹ The Phase 2 study is
being conducted in Germany. Patients enrolled in the trial are
receiving up to six cycles of treatment in the absence of disease
progression, with HGS-ETR1 administered as an intravenous infusion once
every fourteen days. The primary objective of the study is to evaluate
tumor response. The secondary objectives are to evaluate the safety and
tolerability of HGS-ETR1, to determine plasma concentrations of
HGS-ETR1 for use in a population pharmacokinetic analysis, and to
evaluate other indicators of disease activity, including time to
response, duration of response, and progression-free survival.

Professor Dr. Siegfried Seeber, principal investigator and
Director, University Clinic for Internal Medicine and Policlinic (Tumor
Research), West German Tumor Center, University of Essen, Germany,
said, “Combinations of chemotherapeutic agents and, more recently,
monoclonal antibodies, have demonstrated clinical benefit for patients
with advanced colorectal cancer, but the prognosis for these patients
continues to be poor. ^2-16 Less than ten percent of the
patients who develop metastatic disease survive for five years. ^17-20
There is a significant medical need for effective new therapeutic
agents. We look forward to continuing the evaluation of HGS-ETR1
throughout the treatment phase of the current study.”

Florian Bieber, M.D., Vice President, Drug Development – Europe,
said, “The rapid enrollment of the Phase 2 trial of HGS-ETR1 reflects
the strong interest within the European oncology community in the
ability of our TRAIL receptor antibodies to inhibit or reduce tumor
growth in xenograft models of colorectal cancer, to induce significant
tumor regression in some models of the disease, and to trigger
apoptosis in numerous cancer cell lines, including colorectal cancer.”

David C. Stump, M.D., Executive Vice President, Drug Development,
said, “We
are pleased to have completed the enrollment of our Phase 2 clinical
trial of
HGS-ETR1 in patients with colorectal cancer. We also have completed the
enrollment
of our Phase 2 trial of HGS-ETR1 in non-small cell lung cancer, and we
continue
to enroll patients in our Phase 2 trial in non-Hodgkin’s lymphoma. ^21-23
We expect to have the results of the three ongoing Phase 2 studies of
HGS-ETR1
available in 2005. Phase 1b studies of HGS-ETR1 in combination
with chemotherapy also are ongoing. The results of these trials
will inform our decisions regarding further single agent and
chemotherapy combination
development of HGS-ETR1 as a treatment for cancer. ”

Interim results of two ongoing Phase 1 multi-center, open-label,
dose-escalation clinical trials of HGS-ETR1 were presented in September
2004 at the 16^th EORTC-NCI-AACR Symposium on Molecular
Targets and Cancer Therapeutics in Geneva, Switzerland. ^24-26
The data presented demonstrate the safety and tolerability of HGS-ETR1
in patients with advanced solid tumors or non-Hodgkin’s lymphoma, and
support further evaluation of HGS-ETR1 in Phase 2 clinical trials, both
as a single agent and in combination with chemotherapy. Data were
presented on 39 patients treated to date in a Phase 1 study conducted
in patients with advanced solid tumors. Interim results of the ongoing
study demonstrate that HGS-ETR1 can be administered safely and
repetitively to patients with advanced solid malignancies at doses up
to and including 10 mg/kg intravenously every 28 days. Some preliminary
evidence of biological activity has been observed. Durable stable
disease for greater than eight months was observed in one patient with
metastatic sarcoma. Durable stable disease was observed for four months
in one patient with head-and-neck cancer and in one patient with
Ewing’s sarcoma; both patients continue on treatment. Data also were
presented on 24 patients treated to date in an additional Phase 1 study
conducted in patients with advanced solid tumors or non-Hodgkin’s
lymphoma. Results presented from the ongoing clinical trial demonstrate
that HGS-ETR1 is well tolerated with no clearly attributable toxicities
to date and that the Maximum Tolerated Dose has not been reached.
Stable disease has been observed in eight patients for greater than two
cycles. The trial continues to enroll patients.

Human Genome Sciences, using genomic techniques, originally
identified the TRAIL receptor-1 protein as a member of the tumor
necrosis factor receptor super-family. The company’s own studies, as
well as those conducted by others, show that TRAIL receptor 1 plays a
key role in triggering apoptosis, or programmed cell death, in tumors.
Human Genome Sciences took the approach of developing human monoclonal
antibodies that would bind the receptor and stimulate the TRAIL
receptor-1 protein to trigger apoptosis in cancer cells, in much the
same way that the native TRAIL ligand (tumor necrosis factor-related
apoptosis-inducing ligand) triggers it, but with the advantage of a
longer half-life and an exclusive specificity for TRAIL receptor 1.
Human Genome Sciences’ own clinical and preclinical studies, along with
published results in the scientific literature, demonstrate that
agonistic antibodies to the death domain-containing TRAIL receptors
have significant potential to provide novel therapeutic options to
patients with a variety of cancer types. ^27-43

The TRAIL receptor 1 agonistic human monoclonal antibody, HGS-ETR1,
was made in a collaboration between Human Genome Sciences and Cambridge
Antibody Technology. ⁴⁴ The drug will be produced in the
Human Genome Sciences clinical manufacturing facilities located in
Rockville, Maryland. Human Genome Sciences holds the commercial rights
to the drug.

Colorectal cancer is the second-leading cause of cancer-related
deaths in Western Europe and the United States (after lung cancer). The
overall five-year survival of patients with colorectal cancer is
approximately fifty percent.

For more information about HGS-ETR1, see www.hgsi.com/products/ETR1.html.
Health professionals interested in more information about trials
involving Human Genome Sciences products are encouraged to inquire via
the Contact Us section of the company’s web site, www.hgsi.com/products/request.html,
or by calling (301) 610-5790, extension 3550.

Human Genome Sciences is a company with the mission to treat and
cure disease by bringing new gene-based protein and antibody drugs to
patients.

HGS and Human Genome Sciences are trademarks of Human Genome
Sciences, Inc.

This announcement contains forward-looking statements within the
meaning of Section 27A of the Securities Act of 1933, as amended, and
Section 21E of the Securities Exchange Act of 1934, as amended. The
forward-looking statements are based on Human Genome Sciences’ current
intent, belief and expectations. These statements are not guarantees of
future performance and are subject to certain risks and uncertainties
that are difficult to predict. Actual results may differ materially
from these forward-looking statements because of the Company’s unproven
business model, its dependence on new technologies, the uncertainty and
timing of clinical trials, the Company’s ability to develop and
commercialize products, its dependence on collaborators for services
and revenue, its substantial indebtedness and lease obligations, its
changing requirements and costs associated with planned facilities,
intense competition, the uncertainty of patent and intellectual
property protection, the Company’s dependence on key management and key
suppliers, the uncertainty of regulation of products, the impact of
future alliances or transactions and other risks described in the
Company’s filings with the Securities and Exchange Commission. Existing
and prospective investors are cautioned not to place undue reliance on
these forward-looking statements, which speak only as of today’s date.
Human Genome Sciences undertakes no obligation to update or revise the
information contained in this announcement whether as a result of new
information, future events or circumstances or otherwise.

Footnotes:

1. (HGSI
   Press Release) Human Genome Sciences Initiates a Phase 2 Clinical
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4. Tournigand C, Andre T, Achille E, et al. FOLFIRI followed by
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6. Erbitux, summary of product characteristics, EMEA, Committee for
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8. Plate S. ESMO minimum clinical recommendations for diagnosis,
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10. Holen KD, Saltz LB. New therapies, new directions: Advances in
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    treatment of colorectal cancer: Clinical overview. J Clin Oncol
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12. Douillard JY, Cunningham D, Roth AD, et al. Irinotecan combined
    with fluorouracil compared with fluorouracil alone as first-line
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    continuous infusion of fluorouracil compared with bolus administration
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14. University of York NHS Centre for Reviews and Dissemination. The
    management of colorectal cancer. Effective Health Care 1997;3:76.
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16. Lokich JJ, Ahlgren JD, Gullo JJ, et al. A prospective randomized
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    Oncology Program Study. J Clin Oncol 1989;7:425-432.
17. Ferlay J, Bray F, Pisani P, Parkin DM. GLOBOCAN 2000: Cancer
    incidence, mortality and prevalence worldwide. IARC Cancer Base No. 5.
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18. Parkin DM, Pisani P, Ferlay J. Global cancer statistics. CA: A
    cancer journal for clinicians, 1999;49:33-64.
19. Black RJ, Bray F, Ferlay J, Parkin DM. Cancer incidence and
    mortality in the European Union: cancer registry data and estimates of
    national incidence for 1990. Eur J Cancer 1997;33:1075-1107.
20. Jemal A, Tiwari RC, Murray T, et al. Cancer Statistics, 2004.
    Cancer 2004; 54(1):8-29.
21. (HGSI Press
    Release) Human Genome Sciences Advances Anti-Cancer Drug to Phase 2
    Clinical Development. September 8, 2004.
22. (HGSI Press
    Release) Human Genome Sciences Completes Enrollment in a Phase 2
    Clinical Trial of HGS-ETR1 for the Treatment of Non-Small Cell Lung
    Cancer. November 30, 2004.
23. (HGSI Press
    Release) Human Genome Sciences Begins Dosing of Patients in a Phase
    2 Clinical Trial of HGS-ETR1 in Non-Hodgkin’s Lymphoma. October 13,
    2004.
24. Cohen RB, et al. A Phase 1 clinical trial of HGS-ETR1, an
    agonistic monoclonal antibody to TRAIL-R1, in patients with advanced
    solid tumors. 16 th EORTC-NCI-AACR Symposium on Molecular Targets and
    Cancer Therapeutics, 2004: Oral Presentation.
25. Hotte SJ, et al. Phase 1 study of a fully human monoclonal
    antibody to the tumor necrosis factor-related apoptosis-inducing ligand
    receptor 1 (TRAIL-R1) in subjects with advanced solid malignancies or
    non-Hodgkin’s lymphoma (NHL). 16 th EORTC-NCI-AACR Symposium on
    Molecular Targets and Cancer Therapeutics, 2004: Abstract #208.
26. (HGSI
    Press Release) Human Genome Sciences Reports Results of Ongoing
    Phase 1 Clinical Trials of HGS-ETR1 in Patients with Advanced Cancers.
    September 29, 2004.
27. Tolcher AW, et al. A phase 1 and pharmacokinetic study of
    HGS-ETR1, a fully human monoclonal antibody to TRAIL-R1 (TRM-1), in
    patients with advanced solid tumors. American Society of Clinical
    Oncology Annual Meeting, 2004: Abstract #3060.
28. Le LH, et al. Phase 1 study of a fully human monoclonal antibody
    to the tumor necrosis factor-related apoptosis-inducting ligand death
    receptor 4 (TRAIL-R1) in subjects with advanced solid malignancies or
    non-Hodgkin’s lymphoma. American Society of Clinical Oncology Annual
    Meeting, 2004: Abstract #2533.
29. Halpern W, et al. Variable distribution of TRAIL receptor 1 in
    primary human tumor and normal tissues. 16 th EORTC-NCI-AACR Symposium
    on Molecular Targets and Cancer Therapeutics, 2004: Abstract #225.
30. Georgakis GV, et al. Selective agonistic monoclonal antibodies
    to the TRAIL receptors R1 and R2 induce cell death and potentiate the
    effect of chemotherapy and bortezomib in primary and cultured lymphoma
    cells. American Society of Clinical Oncology Annual Meeting, 2004:
    Abstract #6595.
31. Gillotte D, Zhang Y, Poortman C, et al. Human agonistic
    anti-TRAIL receptor antibodies, HGS-ETR1 and HGS-ETR2, induce apoptosis
    in ovarian tumor lines and their activity is enhanced by taxol and
    carboplatin. Proceedings from the AACR 2004; 73:3579.
32. Younes A, Kadin ME. Emerging applications for the tumor necrosis
    factor family of ligands and receptors in cancer therapy. J Clin Oncol
    2003;21:3526-3534.
33. Humphreys RC, et al. TRAIL R2-mAb, a human agonistic monoclonal
    antibody to tumor necrosis factor-related apoptosis inducing ligand
    receptor 2, affects tumor growth and induces apoptosis in human tumor
    xenograft models in vivo. 94th AACR Annual Meeting. Abstract 642.
34. Alderson RF, et al. TRAIL-R2 mAb, a human agonistic monoclonal
    antibody to tumor necrosis factor-related apoptosis inducing ligand
    receptor 2, induces apoptosis in human tumor cells. 94th AACR Annual
    Meeting. Abstract 963.
35. Buchsbaum DJ, Zhou T, Grizzle WE, et al. Antitumor efficacy of
    TRA-8 anti-DR5 monoclonal antibody alone or in combination with
    chemotherapy and/or radiation therapy in a human breast cancer model.
    Clin Cancer Research 2003; 9:3731-3741.
36. Pukac, Kanakaraj, Alderson, et al. TRAIL-R1 mAb, a human
    agonistic monoclonal antibody to tumor necrosis factor-related
    apoptosis-inducing ligand receptor 1, induces apoptosis in human tumor
    cells in vitro and in vivo. American Association
    for Cancer Research 94th Annual Meeting. July 2003, Abstract 6429.
37. Ashkenazi A. Targeting death and decoy receptors of the tumor
    necrosis factor superfamily. Nat Revs Cancer 2002; 2:420-430.
38. Salcedo, Alderson, Basu, et al. TRM-1, a fully human TRAIL-R1
    agonistic monoclonal antibody, displays in vitro and in vivo anti-tumor
    activity. American Association for Cancer Research 93rd Annual Meeting.
    April 2002, Abstract 4240.
39. Humphreys R, et al. TRAIL-R1 and TRAIL-R2 human agonistic
    monoclonal antibodies display in vitro and in vivo activity on human
    cancer cells. Society for Biological Therapy 2002; oral presentation.
40. Chuntharapai A, Dodge K, Grimmer K, et al. Isotype-dependent
    inhibition of tumor growth in vivo by monoclonal antibodies to death
    receptor 4. J Immunol 2001; 166:4891-4898.
41. Ichikawa K, Liu W, Zhao L, et al. Tumoricidal activity of a
    novel anti-human DR5 monoclonal antibody without hepatocyte
    cytotoxicity. Nat Med 2001; 7:954-960.
42. Ashkenazi A. Apo-2L/TRAIL in Cytokine Reference. Academic Press
    2000.
43. Ashkenazi A. et al. Safety and anti-tumor activity of
    recombinant soluble APO2 ligand. J Clin Inv July 1999; 104(2): 155-162.
44. (HGSI
    Press Release) Cambridge Antibody Technology and Human Genome
    Sciences Announce Second Drug Partnership. January 8, 2002.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15701855

http://clincancerres.aacrjournals.org/cgi/content/abstract/11/2/672

Clin Cancer Res. 2005 Jan 15;11(2 Pt 1):672-7.

    A Phase I and Pharmacokinetic Study of Ecteinascidin-743 (Yondelis)
in Children with Refractory Solid Tumors. A Children's Oncology Group
Study.

    Lau L, Supko JG, Blaney S, Hershon L, Seibel N, Krailo M, Qu W,
Malkin D, Jimeno J, Bernstein M, Baruchel S.

    The Hospital for Sick Children, Toronto, Ontario, Canada.

    PURPOSE: To determine the dose-limiting toxicity (DLT) and the
maximum tolerated dose of ecteinascidin-743 (ET-743, Yondelis) in
children with refractory solid tumors, to establish the recommended
dose for pediatric phase II trials, and to characterize the
pharmacokinetics of ET-743 in children.EXPERIMENTAL DESIGN: ET-743 was
administered as a 3-hour i.v. infusion every 21 days. The starting dose
was 1,100 mug/m(2) with planned dose escalation of 200 mug/m(2)
increments. Pharmacokinetic sampling was done during the first
treatment course.RESULTS: Twelve evaluable patients received a total of
29 courses. One grade 4 DLT (prolonged grade 4 neutropenia) was noted
at the first dose level. At the second dose level (1,300 mug/m(2)),
there were two DLTs (reversible grade 4 elevations of hepatic
transaminase); hence the maximum tolerated dose was defined as 1,100
mug/m(2). Overall, reversible hepatic toxicity, manifested as grade 3
or 4 elevations in hepatic transaminase, occurred in more than 50% of
the patients. No grade 3 or 4 thrombocytopenia was reported at either
dose level and only one episode of isolated creatine phosphokinase
grade 4 elevation was observed. One complete response was
documented after six courses in a patient with metastatic Ewing sarcoma.
The pharmacokinetics of ET-743 in 8 children was characterized by a
terminal disposition phase with a mean half-life of 43.8 +/- 18.4
hours, a total body clearance of 28.2 +/- 10.5 L/h/m(2), and a 959 +/-
807 L/m(2) steady-state apparent volume of distribution.CONCLUSION:
ET-743 is safe. The phase II recommended dose of ET-743 administered as
a 3-hour i.v. infusion following premedication with dexamethasone is
1,100 mug/m(2).

PMID: 15701855 [PubMed – in process]

http://www.jco.org/cgi/content/full/23/1/242

Journal of Clinical Oncology, Vol 23, No 1 (January 1), 2005: pp.
242-244
© 2005 American Society of Clinical Oncology
DOI: 10.1200/JCO.2005.05.940
 

http://jco.highwire.org

CORRESPONDENCE
Graft-Versus–Ewing Sarcoma Effect and Long-Term Remission Induced by
Haploidentical Stem-Cell Transplantation in a Patient With Relapse of
Metastatic Disease

Ewa Koscielniak, Ute Gross-Wieltsch, Joern Treuner, Peter Winkler
Olgahospital, Stuttgart, Germany

Thomas Klingebiel
Children's University Hospital, Frankfurt, Germany

Peter Lang, Peter Bader, Dietrich Niethammer
Children's University Hospital, Tübingen, Germany

Rupert Handgretinger
St Jude Children's Research Hospital, Memphis, TN

To the Editor:

The chance of cure is very low for patients with primary metastatic or
relapsed rhabdomyosarcoma or Ewing tumors.1-3 In the German multicenter
studies CWS-81, -86, -91, and -96, patients older than 10 years at
diagnosis with bone or bone marrow metastases had a 5-year event-free
survival of 2%.4 This poor outcome is due mainly to the high relapse
rate after initial chemotherapy, and patients in remission after double
high-dose chemotherapy (HDC) had a median time to relapse of 5.7 months
(range, 3 to 9 months). Unfortunately, there is no single survivor
registered after relapse.4 Allogeneic transplantation might provide a
possible graft-versus-tumor effect, and regression of metastatic
lesions has been documented in patients with solid tumors.5-8 To exert
a graft-versus-tumor effect, we have performed allogeneic
transplantation using a haploidentical donor in a patient with
metastatic Ewing sarcoma who relapsed after double HDC.

A previously healthy 15-year-old girl was diagnosed in April 1998 with
a disseminated Ewing sarcoma. Magnetic resonance imaging (MRI) scans
showed a 10 x 11-cm tumor originating from the thorax wall, with
erosion and destruction of the 11th rib, with penetration into the
retropleural thoracic and retrocrural space. It extended caudally to
the upper left kidney pole and spleen, and laterally into the foramina
intervertebralia between Th7 and Th11. Skeletal imaging showed
metastatic lesions in the eighth rib and in vertebrae C7, Th1, Th5,
Th6, Th7, and L5. A chemotherapy scan showed four lung nodules. Bone
marrow aspirated from the right and left posterior iliac spines showed
massive tumor cell infiltration at both sites.

After initial chemotherapy, an almost complete remission was achieved
(only residual tumor was seen in the primary site in the 11th rib), and
she received consolidation with double HDC and autologous hematopoietic
stem-cell rescue. MRI after the second HDC showed residual tumor in the
11th rib, which was locally irradiated. The patient remained well for 8
months when routine imaging showed a large new lytic lesion in the
right parietal bone (Fig 1A), with a component occupying the extradural
space (Fig 1B). A bone scan revealed many other lesions in the C7, L4,
and S1 vertebrae and the right iliac bone. After two 8-day courses of
low-dose oral trophosphamide and idarubicin, the soft part of the
cranial lesion was slightly reduced in size (Fig 1C), but all other
lesions remained unchanged. She was then considered a candidate for
experimental allogeneic stem-cell transplantation (SCT) to induce a
graft-versus-tumor effect. The patient's mother, mismatched at two
human leukocyte antigen loci, was chosen as the donor. The graft
consisted of isolated mobilized peripheral CD34+ stem cells.9 After
conditioning with busulfan, thiotepa, fludarabine, cyclophosphamide,
and anti-CD3 antibody (Muronomab), a total of 19.1 x 106/kg CD34+ cells
and 104/kg CD3+ donor cells were infused without any further
post-transplantation immunosuppressive therapy. Her
post-transplantation course was uncomplicated, with only grade 1 skin
graft-versus-host disease (GvHD). Since the patient still had
disseminated persisting tumor lesions, we started, at day +73
post-transplantation, an immunoaugmenting therapy with low-dose
interleukin-2. After two weeks of therapy with interleukin-2, she
developed grade 3 skin and gut GvHD. On day +123, grade 4 GvHD of the
gut and chronic skin GvHD developed. MRI 6 weeks after allogeneic SCT
showed reduction of the cranial tumor (Fig 1D). Bone scans showed the
skull and S1 lesions to be unchanged, lesions in L4 and the iliac bone
regressing, and no lesion in C7. Eight months after SCT, MRI and bone
scans showed a slowly regressing abnormal contrast enhancement in the
cranium (Fig 1E), lesions in S1 and the iliac bone, but no L4 and C7
lesions. The residual lesion in the 11th rib remained unchanged. Eleven
months after SCT, MRI scan of the cranium was completely normal (Fig
1F), and the skeletal lesions had almost completely resolved. At a
follow-up in July 2003 (3.5 years after SCT), the patient was in good
clinical condition with no evidence of active disease. Unfortunately,
the patient presented with a local relapse in the vertebrae C7 1 month
later. The patient's response and the unusually long progression-free
survival after allogeneic transplantation is highly suggestive of a
graft-versus–Ewing sarcoma effect and has prompted us to study this
treatment approach in patients with metastatic pediatric soft tissue
sarcoma in a prospective clinical trial.

      Fig 1. Magnetic resonance imaging scans of the scull at relapse
after high-dose chemotherapy demonstrate a metastasis at the parietal
bone (A, rectangle) with a contrast-enhancing soft tissue component
adjacent to the external table (B, arrow). Magnetic resonance imaging
after oral chemotherapy shows reduction of size (C). Scans at 6 weeks
(D), 8 months (E), and 11 months (F) postallotransplantation show a
slowly regressing abnormal contrast enhancement with a final complete
regression.

 
Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

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breast cancer. J Clin Oncol 16:986-993, 1998[Abstract]
   6. Childs R, Chernoff A, Contentin N, et al: Regression of
metastatic renal-cell carcinoma after nonmyeloablative allogeneic
peripheral-blood stem-cell transplantation. N Engl J Med 343:750-758,
2000[Abstract/Free Full Text]
   7. Childs RW, Clave E, Tisdale J, et al: Successful treatment of
metastatic renal cell carcinoma with a nonmyeloablative allogeneic
peripheral-blood progenitor-cell transplant: Evidence for a
graft-versus-tumor effect. J Clin Oncol 17:2044-2049,
1999[Abstract/Free Full Text]
   8. Eibl B, Schwaighofer H, Nachbaur D, et al: Evidence for a
graft-versus-tumor effect in a patient treated with marrow ablative
chemotherapy and allogeneic bone marrow transplantation for breast
cancer. Blood 88:1501-1508, 1996[Abstract/Free Full Text]
   9. Handgretinger R, Klingebiel T, Lang P, et al: Megadose
transplantation of purified peripheral blood CD34(+) progenitor cells
from HLA-mismatched parental donors in children. Bone Marrow Transplant
27:777-783, 2001[CrossRef][Medline]

http://www.clinicaltrials.gov/show/NCT00061191

hase I Trial of G3139 Plus Chemotherapy to Treat Relapsed Childhood
Tumors

This study is currently recruiting patients.
Sponsored by:     National
Cancer Institute (NCI)
Information provided by:     Warren G Magnuson Clinical Center
(CC)

Purpose

This study will examine the use of the experimental drug G3139 (also
called BCL-2 antisense, or Genasense), in combination with the
anti-cancer drugs doxorubicin (Adriamycin) and cyclophosphamide
(Cytoxan), on tumors in children. G3139 blocks the action of Bcl-2, a
protein produced by the body that works to prevent cell death. Some
cancer cells may have elevated Bcl-2, which protects them from dying
normally, and therefore makes them more resistant to cancer treatments.
G3139 blocks Bcl-2 production. Lowering Bcl-2 levels with G3139 may
enhance the effectiveness of anti-cancer drugs or radiation therapy.
This study will determine the following:

– The highest dose of G3139 that can be given safely to children and
adolescents with cancer;

– The side effects of G3139 given together with doxorubicin and
cyclophosphamide;

– The pharmacology of G3139; that is, how the body handles the drug;

– The effects of G3139 on blood levels of Bcl-2;

– The level of Bcl-2 in the child's tumor and the effects of G3139 on
the Bcl-2 in the tumor;

– Whether G3139, together with doxorubicin and cyclophosphamide can
inhibit the growth of the cancer.

Children with solid tumors, except central nervous system tumors and
lymphomas, whose cancer no longer responds to standard treatment or for
whom standard therapy is not available may be eligible for this study.

Participants will receive a continuous infusion of G3139 into a vein
for 7 days. On days 5 and 6, they will also receive doxorubicin,
cyclophosphamide and dexrazoxane. (The latter drug protects the heart
from possible damage from doxorubicin.) After 14 days off drugs, the
children will begin a second 21-day treatment cycle. Treatment will
continue for up to 18 cycles (about 1 year) as long as the tumor does
not worsen and there are no serious side effects. The children will be
hospitalized for the first 8 or 9 days of the first cycle to monitor
treatment side effects. For the infusions, children will need a central
venous catheter – a plastic tube placed into a major vein in the chest.
This line can stay in the body and be used for the entire treatment
period to give chemotherapy or other medications and to draw blood
samples. The line is usually placed under local anesthesia in the
radiology department or the operating room. In addition to drug
treatment, patients will have the following tests and procedures:

– Examinations by a doctor at least once a week and routine blood tests
twice a week during the first 21-day treatment cycle.

– Physical examinations, routine blood tests, and imaging tests (e.g.,
x-rays, CT scans, MRI scans) periodically throughout the course of
treatment after the first cycle to evaluate the response to treatment
and treatment side effects.

– Blood samples for a pharmacology study during the first treatment
cycle (optional). This requires taking 12 separate blood samples of 1/2
teaspoon each-one each on days 1, 5, and 6 of the infusion; 7 samples
on day 8, when the infusion ends (every 1/2-hour for 8 hours); and two
samples on day 9.

– Blood samples to test white blood cells to examine the effect of
G3139 on normal cells (optional). This requires taking blood samples on
days 1, 5, 6, and 8 of the first treatment cycle.

– Tumor tissue tests to determine if cancer cells have increased Bcl-2
levels (optional). These tests are performed on frozen tissue samples
obtained during surgery or biopsy, if these procedures are required for
the child's care during the time of this study.
Condition     Treatment or Intervention     Phase
Tumors     Drug: G3139    Phase
I

MedlinePlus
related topics:  Cancer;   Cancer
Alternative Therapy

Study Type: Interventional
Study Design: Treatment, Safety

Official Title: A Phase I Trial of G3139 (Bcl-2 Antisense) Combined
with Cytotoxic Chemotherapy in Relapsed Childhood Solid Tumors

Further Study Details:

Expected Total Enrollment:  6

Study start: May 19, 2003

Chemotherapy-induced apoptosis is regulated by the expression of the
Bcl-2 family of proteins. Overexpression of Bcl-2 in tumors has been
associated with poor clinical response to therapy or shorter survival
in patients. Dysregulation of Bcl-2 expression has been described in
leukemia, lymphoma, and solid tumors, including prostate carcinoma,
melanoma, and neuroblastoma. Bcl-2 overexpression has been shown in
pediatric tumor cell lines, including Ewing's sarcoma, Wilms' tumor,
and synovial cell sarcoma.

G3139 (Bcl-2 antisense, GenasenseTM) is an 18-base-pair
phosphorothioate oligonucleotide (5'-TCTCCCAGCGTGCGCCAT-3') designed to
bind the first six codons of human Bcl-2 mRNA. Down regulation of Bcl-2
in tumor cells by G3139 (Bcl-2 antisense, GenasenseTM) has increased
chemotherapy-induced apoptosis in vitro and in human tumor xenograft
models. G3139 (Bcl-2 antisense, GenasenseTM) alone and in combination
with chemotherapy has completed Phase I and Phase II testing in adults.
Dose-limiting toxicities have been thrombocytopenia, fever,
hypotension, and fatigue. Target plasma G3139 (Bcl-2 antisense,
GenasenseTM) concentrations have been achieved with continuous
subcutaneous or intravenous infusions of greater than or equal to 5
mg/kg/day. A 40% decrease in tumor Bcl-2 was observed in adults with
lymphoma treated with 1.7 mg/kg/day of G3139 (Bcl-2 antisense,
GenasenseTM) in combination with dacarbazine.

In this Phase I trial of G3139 (Bcl-2 antisense, GenasenseTM) in
pediatric patients with relapsed solid tumors, G3139 (Bcl-2 antisense,
GenasenseTM) will be administered as a continuous infusion for seven
days. Doxorubicin and cyclophosphamide will be administered on days 5
and 6 of each cycle. Dexrazoxane cardioprotectant will be administered
prior to each dose of doxorubicin. Filgrastim (G-CSF) will be
administered daily beginning on day 8 and continuing until the post
nadir ANC is greater than 5000/mm(3). If the patient does not
experience dose-limiting toxicity or progressive disease, cycles can be
repeated every 21 days for a maximum of 18 cycles. Lifetime cumulative
anthracycline dose will not exceed 750 mg/m2 on this trial. Three dose
levels of G3139 (Bcl-2 antisense, GenasenseTM) will be studied. The
spectrum of toxicity and maximum tolerated dose of G3139 (Bcl-2
antisense, GenasenseTM) in combination with doxorubicin and
cyclophosphamide will be defined. The pharmacokinetics of G3139 (Bcl-2
antisense, GenasenseTM) in the pediatric population will be studied,
and the biological activity of G3139 (Bcl-2 antisense, GenasenseTM)
will be evaluated by studying Bcl-2 protein expression in peripheral
blood mononuclear cells and, when available, tumor specimens.

Eligibility

Genders Eligible for Study:  Both

Criteria
INCLUSION CRITERIA
Patients' age at the time of study entry must be older than 12 months
and younger than or equal to 21.
Patients must have had histologic verification of the malignancy at
original diagnosis. All solid tumors are eligible with the exclusion of
lymphomas and CNS tumors.
Disease must have failed standard therapy (therapies) or be a disease
for which no standard therapy exists. Patient must have a disease for
which there is no known curative potential.
Karnofsky greater than or equal to 50% for patients greater than 10
years.
Lansky greater than or equal to 50 for children less than or equal to
10 years of age.
Life Expectancy: Must be greater than or equal to 8 weeks.
It is recommended, but not required, for enrolled patients to have a
central venous line.
Patients must have fully recovered from the acute toxic effects of all
prior chemotherapy, immunotherapy, or radiotherapy prior to entering
this study.
Myelosuppressive chemotherapy: Patients must not have received within 2
weeks of entry onto this study (6 weeks if prior nitrosourea).
Biologic (anti-neoplastic agent): At least 7 days since the completion
of therapy with a biologic agent.
XRT: – Greater than 2 weeks for local palliative XRT (small port).
– Greater than 6 months must have elapsed for other substantial BM
radiation. (Cranio-spinal XRT, TBI, greater than or equal to
hemi-pelvic XRT).
Stem Cell Transplant (SCT): For autologous SCT, 6 months or more must
have elapsed.
Allogeneic Transplant: For allogeneic BMT, 6 months or more must have
elapsed. There must be full organ recovery and no evidence of graft
versus host disease at the time of enrollment.
Concomitant Therapy:
Growth Factor(s): Must not have received within 1 week of entry onto
this study. Growth factors may not be administered during the course of
this study.
Study Specific: Patients may not receive any other chemotherapy,
radiation therapy, or immunomodulating agents, while enrolled on study.
Chronic Medications: Patients may be on chronic medications (e.g.:
steroids, narcotics, anti-epileptics) at the time of enrollment.
Investigators should avoid, when possible, increasing or decreasing the
doses of these medications while the patient is on study.
Adequate Bone Marrow Function Defined as:
For patients with solid tumors including status post SCT (Stratum 1):
– Peripheral absolute neutrophil count (ANC) of 1000 microliters or
greater.
– Platelet count of 100,000 microliters or greater (transfusion
independent).
– Hemoglobin of 8.0 gm/dL or greater (may receive RBC transfusions).
For patients with tumor metastatic to bone marrow who have
granulocytopenia, anemia, and/or thrombocytopenia (Stratum 2):
– Peripheral absolute neutrophil count (ANC) of 750/microliters or
greater.
– Platelet count greater than or equal to 100,000/microliters
(transfusion independent).
-Hemoglobin greater than or equal to 8.0 gm/dL (may receive RBC
transfusions).
Adequate Renal Function Defined as:
– Creatinine clearance or radioisotope GFR of 70 ml/min/m(2) OR
– A serum creatinine based on age as follows:
5 years of age or less – Maximum Serum Creatinine (mg/dL) of 0.8.
Between 5 and 10 years of age – Maximum Serum Creatinine (mg/dL) of 1.0.
Between 10 and 15 years of age – Maximum Serum Creatinine (mg/dL) of 1.2
Greater than 15 years of age – Maximum Serum Creatinine (mg/dL) of 1.5.
Adequate Liver Function Defined as:
– Total bilirubin less than or equal to 1.5 times the upper limit of
normal for age, and
– SGPT (ALT) less than or equal to 3 times the upper limit of normal
for age.
Adequate Cardiac Function Defined as:
– Shortening fraction of 28% or greater by echocardiogram, or
– Ejection fraction of 45% or greater by MUGA.
EXCLUSION CRITERIA
Total lifetime cumulative anthracycline dose must be less than or equal
to 450 mg/m(2) doxorubicin or equivalent at the time of enrollment.
(Conversions: 1mg/m(2) of daunorubicin &eq; 1 mg/m(2) of
doxorubicin; and 1 mg/m(2) of idarubicin &eq; 3 mg/m(2) of
doxorubicin.)
Any patient with known metastases of a non-CNS tumor to the brain or
spinal cord will not be eligible. CNS tumors are not eligible.
Patients with lymphomas are not eligible.
Pregnancy tests must be obtained in females of childbearing potential.
Pregnant patients are ineligible for this study due to the known
teratogenic effects of the cytotoxic agents and the unknown human fetal
or teratogenic toxicities of G3139. Lactating women must agree not to
breast-feed. Males or females of reproductive age may not participate
unless they have agreed to use an effective contraceptive method.
Patients will not be eligible for enrollment until all infections are
under control.
Patients with serious infections or significant pulmonary, hepatic,
renal, or other end-organ dysfunction which in the judgment of the
Principal or Associate Investigator would compromise the patient's
ability to tolerate G3139 or are likely to interfere with the study
procedures or results will not be eligible.

Location and Contact Information

Maryland
      National Cancer Institute (NCI), 9000 Rockville Pike,  Bethesda, 
Maryland,  20892,  United States; Recruiting
Patient Recruitment and Public Liaison Office  1-800-411-1222    prpl@mail.cc.nih.gov

TTY  1-866-411-1010

More Information

Detailed
Web Page

Publications

Reed
JC, Stein C, Subasinghe C, Haldar S, Croce CM, Yum S, Cohen J.
Antisense-mediated inhibition of BCL2 protooncogene expression and
leukemic cell growth and survival: comparisons of phosphodiester and
phosphorothioate oligodeoxynucleotides. Cancer Res. 1990 Oct
15;50(20):6565-70.

Smith
MR, Abubakr Y, Mohammad R, Xie T, Hamdan M, al-Katib A. Antisense
oligodeoxyribonucleotide down-regulation of bcl-2 gene expression
inhibits growth of the low-grade non-Hodgkin's lymphoma cell line
WSU-FSCCL. Cancer Gene Ther. 1995 Sep;2(3):207-12.

Reed
JC. Bcl-2: prevention of apoptosis as a mechanism of drug resistance.
Hematol Oncol Clin North Am. 1995 Apr;9(2):451-73. Review.

Study ID Numbers:  030202; 03-C-0202
Record last reviewed:  April 21, 2004
Last Updated:  April 21, 2004
Record first received:  May 21, 2003
ClinicalTrials.gov Identifier:  NCT00061191
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2004-11-19

http://clinicalstudies.info.nih.gov/cgi/detail.cgi?A_2004-C-0001.html

NIH Clinical Research Studies

Protocol Number: 04-C-0001
Active Accrual, Protocols Recruiting New Patients

Title:
Phase II Study of Sequential Gemcitabine Followed by Docetaxel for
Recurrent Ewing's Sarcoma, Osteosarcoma, and Unresectable Sarcoma

Number:
04-C-0001

Summary:
This study will examine the side effects and possible benefits of the
anti-cancer drugs gemcitabine (Gemzar ) and docetaxel (Taxere ) in
patients with bone or soft tissue cancer (sarcoma); determine how the
body absorbs and eliminates the drugs; and perform genetic studies on
the tumor and try to grow the tumor in the laboratory or in animals.

Patients 10 years of age and older with recurrent osteosarcoma, Ewing's
sarcoma, and inoperable or recurrent inoperable chondrosarcoma may be
eligible for this study. Candidates will be screened with a medical
history and physical examination, blood tests, and CT or MRI scans, or
both.

Participants receive gemcitabine and docetaxel in 21-day cycles as
follows:

– Gemcitabine is given as a 90-minute infusion on days 1 and 8 of each
cycle through a catheter (thin plastic tube) placed in an arm vein.

– Docetaxel is given as a 60-minute infusion following the gemcitabine
infusion on day 8 of each cycle.

– Filgrastim is given as an injection under the skin either: 1) daily,
beginning the day after each docetaxel infusion and continuing until
the bone marrow is recovered from chemotherapy (usually 7 to 10 days);
or 2) in a long-acting form on the day after the docetaxel infusion.
Filgrastim boosts production of blood cells that have been depleted as
a result of chemotherapy. Patients are taught to self-administer the
injections.

Treatment will continue for a total of 14 cycles or until the patient's
tumor gets larger, side effects are unacceptable, the patient decides
to stop treatment, or further treatment would not be in the patient's
best interest.

In addition to taking the study drugs, patients undergo the following
tests and procedures:

– Placement of temporary (IV line) or semi-permanent (Hickman, Broviac,
or Port-a-Cath) catheters for giving chemotherapy and other drugs and
for drawing blood samples.

– History and physical examination before each dose of chemotherapy to
assess health status and drug side effects.

– Blood tests to measure blood counts, liver and kidney function, and
electrolyte levels.

– Blood sampling for pharmacology studies on days 1 and 8 of treatment
cycle 1 (6 samples on day 1; 11 samples on day 8) to study how the body
handles gemcitabine and docetaxel.

– Imaging studies that may include x-rays, CT scans, MRI scans, nuclear
medicine scans, and bone scans

– Tumor genetic studies. Tumor samples from patients who require
surgery to remove a tumor will be grown in a test tube or in animals to
define what genes are expressed (turned on) in the tumor.

At the end of chemotherapy, patients will be monitored for treatment
side effects and disease progress, initially every 3 months and then
every 6 months until 2 years from finishing treatment

Sponsoring Institute:
    National Cancer Institute (NCI)

Recruitment Detail
    Type: Active Accrual Of New Subjects
    Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): None

Eligibility Criteria:

    INCLUSION CRITERIA:

    A. Patients with recurrent high grade osteosarcoma, Ewing's
sarcoma, unresectable or locally recurrent unresectable chondrosarcoma.
Histological diagnosis from initial diagnosis is acceptable for local
recurrences, however, biopsy confirmation is strongly recommended. For
isolated pulmonary recurrences, biopsy is required. Histological
diagnosis will be determined at the treating institution, central
review is not required. For patients with chondrosarcoma, determination
of unresectable will be made by the treating oncologist and surgeon at
the treating institution.

    B. Age greater than or equal to 4 years.

    C. Measurable Disease-defined as lesions that can be measured in at
least one dimension by medical imaging techniques. Ascites, pleural
effusions, and bone marrow disease will not be considered measurable
disease.

    D. Performance Status: Patients greater than or equal to 18 years
must have an ECOG performance status of less than or equal to 2.
Patients less than 18 years and greater than 10 years must have a
Karnofsky Score greater than or equal to 50 percent. Patients less than
or equal to 10 years must have Lansky score greater than or equal to 50.

    E. Osteosarcoma and Ewing's sarcoma: Patients must have progressed
after standard therapy, and may have received no more than 2 additional
salvage regimens. Chondrosarcoma: must be unresectable or locally
recurrent and unable to be completely resected.

    F. Patients must have recovered (defined as toxicity less than
grade 2) from toxic effects of all prior therapy before entering onto
study.

    G. A treatment free interval of at least 2 weeks since the last
dose of myelosuppressive therapy is required.

    H. At least 6 month interval since last dose of myeloablative
therapy or total body irradiation is required.

    I. A minimum of 6 weeks since local radiation and 4 months from
extensive radiation (greater than 50% of pelvis or cranial spinal
radiation) is required.

    J. Patients who received filgrastim on a previous cycle of
chemotherapy must be off filgrastim for at least 72 hours prior to
entry onto study.

    K. Adequate bone marrow function with an ANC greater than or equal
to 1500/mm3, platelet count greater than or equal to 100,000 mm3
(transfusion independent) and hemoglobin greater than or equal to 8.0
g/dl (transfusions permitted).

    L. Adequate renal function with serum normal age adjusted serum
creatinine (see table below) or creatinine clearance or radioisotope
GFR greater than 70 ml/min/1.73 m2. For patients over 18 years of age,
creatinine must be less than or equal to upper limit of normal range.

    Less than 5 years of age with Maximum Serum Creatinine (mg/dl) of
0.8.

    Greater than or equal to 5 and less than or equal to 10 years of
age with Maximum Serum Creatinine (mg/dl) of 1.0.

    Greater than 10 and less than or equal to 15 years of age with
Maximum Serum Creatinine (mg/dl) of 1.2

    Greater than 15 and less than or equal to 18 years of age with
Maximum Serum Creatinine (mg/dl) of 1.5

    M. Patients must have adequate liver function, defined as bilirubin
within normal limits, SGPT (ALT) less than or equal to 2.5 x the upper
limit of normal. For patients with documented Gilbert Syndrome, total
bilirubin greater than ULN may be acceptable if the Principal
Investigator in consultation with Medical Affairs, Aventis Oncology
approves a special exemption for treatment on this protocol.

    N. Neuropathy (Sensory or Motor) due to prior chemotherapy, if
present, must be less than or equal to grade 1. Neuropathy (Sensory or
Motor) due to prior surgery or tumor involvement must be less than or
equal to grade 2 and stable or improving.

    O. Subjects of childbearing or child-fathering potential must be
willing to use a medically acceptable form of birth control, which may
include abstinence, while being treated on this study and for 3 months
afterwards.

    P. Informed consent: All patients or their legal guardians (if the
patient is less than 18 years of age) must sign a document of informed
consent indicating their awareness of the investigational nature and
the risks of the study. When appropriate the patient will be included
in all discussions in order to obtain assent.

    EXCLUSION CRITERIA:

    A. Pregnant or breast feeding females

    B. Prior treatment with gemcitabine or taxanes

    C. Active or uncontrolled infection

    D. History of known hypersensitivity reaction to docetaxel or other
agents formulated in polysorbate 80.

    E. Recipient of prior allogeneic transplants.

Special Instructions: Currently Not Provided

Keywords:
    Antineoplastic Drugs
    Refractory Sarcomas
    Ewing Sarcoma
    Osteosarcoma
    Chondrosarcoma

Recruitment Keyword(s):
    None

Condition(s):
    Osteosarcoma
    Sarcoma, Ewing's
    Chondrosarcoma

Investigational Drug(s):
    None

Investigational Device(s):
    None

Intervention(s):
    None

Supporting Site:
    N/A

Contact(s):
    Patient Recruitment and Public Liaison Office
    Building 61
    10 Cloister Court
    Bethesda, Maryland 20892-4754
    Toll Free: 1-800-411-1222
    TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
    Fax: 301-480-9793

    Electronic Mail:prpl@mail.cc.nih.gov

Citation(s):
    Hensley
ML, Maki R, Venkatraman E, Geller G, Lovegren M, Aghajanian C,
Sabbatini P, Tong W, Barakat R, Spriggs DR.

    Gemcitabine
and docetaxel in patients with unresectable leiomyosarcoma: results of
a phase II trial. J Clin Oncol. 2002 Jun 15;20(12):2824-31.

    Saylors
RL 3rd, Stine KC, Sullivan J, Kepner JL, Wall DA, Bernstein ML, Harris
MB, Hayashi R, Vietti TJ; Pediatric Oncology Group. Cyclophosphamide
plus topotecan in children with recurrent or refractory solid tumors: a
Pediatric Oncology Group phase II study. J Clin Oncol. 2001 Aug
1;19(15):3463-9.

    Rischin
D, Boyer M, Smith J, Millward M, Michael M, Bishop J, Zalcberg J,
Davison J, Emmett E, McClure B. A phase I trial of docetaxel and
gemcitabine in patients with advanced cancer.

    Ann
Oncol. 2000 Apr;11(4):421-6.

Active Accrual, Protocols Recruiting New Patients

If you have:

    * Questions about participating in a study, please contact the
Patient Recruitment and Public Liaison Office, CC.
    * Technical questions regarding the Clinical Center web site,
please contact the Department of Networks and Applications, CC.

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Clinical Center LogoWarren Grant Magnuson Clinical Center (CC)
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Bethesda, Maryland 20892. Last update: 11/09/2004

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10847460

Ann Oncol. 2000 Apr;11(4):421-6.     Related Articles, Links

    A phase I trial of docetaxel and gemcitabine in patients with
advanced cancer.

    Rischin D, Boyer M, Smith J, Millward M, Michael M, Bishop J,
Zalcberg J, Davison J, Emmett E, McClure B.

    Division of Haematology and Medical Oncology, Peter MacCallum
Cancer Institute, Melbourne, Australia. drischin@petermac.unimelb.edu.au

    BACKGROUND: Docetaxel and gemcitabine are active in a broad range
of malignancies. The objective of this phase I trial was to determine
the maximally tolerated doses of the combination of docetaxel and
gemcitabine. PATIENTS AND METHODS: Patients with advanced cancer, WHO
performance status 0-2, who had received up to one prior chemotherapy
regimen were treated with gemcitabine on days 1 and 8 and docetaxel on
day 8 repeated every 21 days. Prophylactic ciprofloxacin was commenced
on day 11 of each cycle and continued until the neutrophil count
reached 1.0 x 10(9)/l. G-CSF was not administered. Dose levels studied
were docetaxel/gemcitabine: 60/800, 60/1000, 75/1000, 75/1200, 85/1200
and 100/1200 mg/m2. RESULTS: Thirty-nine patients were entered and all
were assessable for toxicity. The highest administered dose level was
100 mg/m2 docetaxel and 1200 mg/m2 gemcitabine with dose limiting
toxicities of febrile neutropenia, grade 4 neutropenia > or = 7
days, grade 4 thrombocytopenia, grade 3 stomatitis and/or grade 3
fatigue in three out of six patients. Treatment was well tolerated (40
cycles) in the 10 patients treated at the recommended dose level
(85/1200) with only a single episode of febrile neutropenia and grade 3
or 4 non-hematologic toxicity was infrequent. There was no significant
pulmonary toxicity. Responses were seen in a range of malignancies
including non-small-cell lung cancer. CONCLUSIONS: The recommended dose
level of 85 mg/m2 docetaxel and 1200 mg/m2 gemcitabine has a favourable
toxicity profile and is suitable for further investigation in phase II
trials. This non-platinum containing regimen warrants further
investigation as a potential alternative to platinum containing
regimens in non-small-cell lung cancer and other malignancies.

    Publication Types:

        * Clinical Trial
        * Clinical Trial, Phase I

    PMID: 10847460 [PubMed – indexed for MEDLINE]

HUMAN GENOME SCIENCES BEGINS DOSING OF PATIENTS IN A PHASE 2 CLINICAL
TRIAL OF HGS-ETR1 IN NON-HODGKIN’S LYMPHOMA

– Clinical trial of novel genomics-derived anticancer drug is the third
Phase 2 study of the drug to be initiated in 2004 –

ROCKVILLE, Maryland – October 13, 2004 – Human Genome Sciences, Inc.
(Nasdaq: HGSI) announced today that it has begun dosing patients in a
Phase 2 clinical trial of HGS-ETR1 (agonistic human monoclonal antibody
to TRAIL Receptor 1) in patients with advanced non-Hodgkin’s lymphoma.

The Phase 2 clinical trial is a multi-center, open-label study to
evaluate the efficacy, safety and tolerability of HGS-ETR1 in patients
with relapsed or refractory non-Hodgkin’s lymphoma. The Phase 2 study
will enroll a maximum of thirty patients. Each patient will receive up
to six cycles of treatment in the absence of disease progression, with
HGS-ETR1 administered as an intravenous infusion once every twenty-one
days. The objectives of the study are to evaluate disease activity and
tumor response to HGS-ETR1 in patients with advanced non-Hodgkin’s
lymphoma, to evaluate the safety and tolerability of HGS-ETR1, and to
determine plasma concentrations of HGS-ETR1 for use in a population
pharmacokinetic analysis. Disease response will be assessed using the
International Working Group Recommendations for Non-Hodgkin’s Lymphoma,
which were established in 1999 to provide an objective means for
evaluating changing disease status and the efficacy of drugs in the
treatment of non-Hodgkin’s lymphoma.1

In a separate press release distributed earlier today, Human Genome
Sciences announced that it has begin dosing patients in a Phase 2
clinical trial of HGS-ETR1 in patients with advanced colorectal cancer.2
On September 8, 2004, the company announced the initiation of a Phase 2
study of HGS-ETR1 in patients with advanced non-small cell lung cancer.3
The three Phase 2 studies of HGS-ETR1 initiated to date fit into a
global clinical development program through which Human Genome Sciences
plans to evaluate the novel, genomics-derived anticancer drug’s
potential for use in the treatment of specific cancers.

Anas Younes, M.D., Professor, Lymphoma/Myeloma, University of Texas M.D.
Anderson Cancer Center, Houston, said, “Non-Hodgkin’s lymphoma is the
seventh most common cancer in the United States, with approximately
56,000 new cases diagnosed each year. 4 The current standard of care
calls for treating most patients with a combination of chemotherapy and,
in recent years, monoclonal antibodies. This therapeutic approach
produces cures in approximately fifty percent of patients with
aggressive lymphoma. Those who relapse or do not respond are treated
with additional chemotherapeutic and other therapeutic modalities, but
cures are difficult to achieve. New therapies that can improve response
rates, extend the duration of response, extend survival, minimize
toxicity, and provide patients with improved quality of life represent a
significant need. We look forward to evaluating HGS-ETR1 to determine
whether it may play a role in the treatment of non-Hodgkin’s lymphoma.” 5-13

David C. Stump, M.D., Executive Vice President, Drug Development, said,
“The interim results from our ongoing Phase 1 clinical trials of
HGS-ETR1 demonstrate that it is well tolerated and can be safely and
repetitively administered to patients with non-Hodgkin’s lymphoma or
advanced solid tumors.14-19 Based on the clinical evidence to date,
along with strong preclinical support, we are pleased to initiate a
Phase 2 study of HGS-ETR1 in patients with non-Hodgkin’s lymphoma. We
look forward to continuing to elucidate the potential of HGS-ETR1 as a
treatment for solid tumor and other malignancies.”

Craig A. Rosen, Ph.D., President and Chief Operating Officer, said, “The
advancement of HGS-ETR1 to Phase 2 clinical trials is one of the key
milestones that we set for Human Genome Sciences at the beginning of
2004. We are now moving forward with a broad Phase 2 program of clinical
study to investigate the use of HGS-ETR1 in the treatment of specific
cancers, including colorectal cancer, non-small cell lung cancer, and
non-Hodgkin’s lymphoma. The results of our own in vitro and in vivo
preclinical studies, as well as studies conducted by others, demonstrate
that agonistic antibodies to TRAIL Receptors 1 and 2 have significant
potential to provide novel therapeutic options to patients with a
variety of cancer types, including non-Hodgkin’s lymphoma. 20-45 Our
preclinical studies also show that the activity of HGS-ETR1 may be
increased by co-treatment with chemotherapeutic agents.”46-52

Interim results of two ongoing Phase 1 multi-center, open-label,
dose-escalation clinical trials of HGS-ETR1 were presented in September
2004 at the 16th EORTC-NCI-AACR Symposium on Molecular Targets and
Cancer Therapeutics in Geneva, Switzerland. 14-16 The data presented
demonstrate the safety and tolerability of HGS-ETR1 in patients with
advanced solid tumors or non-Hodgkin’s lymphoma, and support further
evaluation of HGS-ETR1 in Phase 2 clinical trials, both as a single
agent and in combination with chemotherapy. Data were presented on
thirty-nine patients treated to date in a Phase 1 study conducted in
patients with advanced solid tumors.14, 16 Interim results of the
ongoing study demonstrate that HGS-ETR1 can be administered safely and
repetitively to patients with advanced solid malignancies at doses up to
and including 10 mg/kg intravenously every 28 days. No evidence of
drug-related hematologic or hepatic toxicity has been observed at the
doses administered to date. The Maximum Tolerated Dose (MTD) has not
been reached, and accrual in the trial continues at a dose of 10 mg/kg
every 14 days. Some preliminary evidence of biological activity has been
observed. Durable stable disease for greater than eight months was
observed in one patient with metastatic sarcoma. Durable stable disease
was observed for four months in one patient with head-and-neck cancer
and in one patient with Ewing’s sarcoma; both patients continue on
treatment. Data also were presented on twenty-four patients treated to
date in an additional Phase 1 study conducted in patients with advanced
solid tumors or non-Hodgkin’s lymphoma. Results presented from the
ongoing clinical trial demonstrate that HGS-ETR1 is well tolerated with
no clearly attributable toxicities to date and that the MTD has not been
reached. Stable disease has been observed in eight patients for greater
than two cycles. The trial continues to enroll patients.15-16

Human Genome Sciences, using genomic techniques, originally identified
the TRAIL Receptor-1 protein as a member of the tumor necrosis factor
receptor super-family. The company’s own studies, as well as those
conducted by others, show that TRAIL Receptor 1 plays a key role in
triggering apoptosis, or programmed cell death, in tumors. Human Genome
Sciences took the approach of developing human monoclonal antibodies
that would bind the receptor and stimulate the TRAIL Receptor-1 protein
to trigger apoptosis in cancer cells, in much the same way that the
native TRAIL ligand (tumor necrosis factor-related apoptosis-inducing
ligand) triggers it, but with the advantage of a longer half-life and an
exclusive specificity for TRAIL Receptor 1. The TRAIL Receptor 1
agonistic human monoclonal antibody, HGS-ETR1, was made in a
collaboration between Human Genome Sciences and Cambridge Antibody
Technology.53 The drug will be produced in the Human Genome Sciences
clinical manufacturing facilities located in Rockville, Maryland. Human
Genome Sciences holds the commercial rights to the drug.

For more information about HGS-ETR1, see

www.hgsi.com/products/ETR1.html. Health professionals interested in more
information about trials involving HGSI products are encouraged to
inquire via the Contact Us section of the Human Genome Sciences web
site, www.hgsi.com/products/request.html, or by calling (301) 610-5790,
extension 3550.

Human Genome Sciences is a company with the mission to treat and cure
disease by bringing new gene-based protein and antibody drugs to patients.

HGS and Human Genome Sciences are trademarks of Human Genome Sciences, Inc.

This announcement contains forward-looking statements within the meaning
of Section 27A of the Securities Act of 1933, as amended, and Section
21E of the Securities Exchange Act of 1934, as amended. The
forward-looking statements are based on Human Genome Sciences’ current
intent, belief and expectations. These statements are not guarantees of
future performance and are subject to certain risks and uncertainties
that are difficult to predict. Actual results may differ materially from
these forward-looking statements because of the Company’s unproven
business model, its dependence on new technologies, the uncertainty and
timing of clinical trials, the Company’s ability to develop and
commercialize products, its dependence on collaborators for services and
revenue, its substantial indebtedness and lease obligations, its
changing requirements and costs associated with planned facilities,
intense competition, the uncertainty of patent and intellectual property
protection, the Company’s dependence on key management and key
suppliers, the uncertainty of regulation of products, the impact of
future alliances or transactions and other risks described in the
Company’s filings with the Securities and Exchange Commission. Existing
and prospective investors are cautioned not to place undue reliance on
these forward-looking statements, which speak only as of today’s date.
Human Genome Sciences undertakes no obligation to update or revise the
information contained in this announcement whether as a result of new
information, future events or circumstances or otherwise.

###

Footnotes:

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workshop to standardize response criteria for non-Hodgkin’s lymphomas. J
Clin Oncol 1999;4:1244-1253.
2. (HGSI Press Release) Human Genome Sciences Initiates a Phase 2
Clinical Trial of HGS-ETR1 in Patients with Colorectal Cancer. October
13, 2004.
3. (HGSI Press Release) Human Genome Sciences Advances Anti-Cancer Drug
to Phase 2 Clinical Development. September 8, 2004.
4. Jemal A, Murray T, Samuels A, et al. Cancer statistics, 2003. CA
Cancer J Clin. 2003;53:5-26.
5. Coiffier B. Immunotherapy: The new standard in aggressive
non-Hodgkin’s lymphoma in elderly. Semin Oncol 2003;30:21-27.
6. Coiffier B, Pfreundschuh M, Stahel R, et al. Aggressive lymphoma:
Improving treatment outcome with rituximab. Anticancer Drugs 2002;13
(Suppl2):43-50.
7. Vose JM, Link BK, Grossbard ML, et al. Phase II study of rituximab in
combination with CHOP chemotherapy in patients with previously untreated
aggressive non-Hodgkin’s lymphoma. J Clin Oncol 2001;19:389-397.
8. Horning SJ, Cascoyne RD, Fischer RI. Large cell lymphoma; let’s chop
down barriers to progress. ASCO Educational Book, Spring 1999;319-331.
9. McLaughlin P, Grillo-Lopez AJ, Link BK, et al. Rituximab chimeric
anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma;
half of patients respond to a four-dose treatment program. J Clin Oncol
1998;16:2825-2833.
10. Johnson PWM, Roahtimer AZS, Whelan JS, et al. Patterns of survival
in patients with recurrent follicular lymphoma: A 20-year study from a
single center. J Clin Oncol 1995;13:140-147.
11. Kimby E, Bjorkholm M, Gahrton G, et al. Clorambucil/prednisone vs.
CHOP in symptomatic low-grade non-Hodgkin’s lymphomas; a randomized
trial from Lymphoma Group of Central Sweden. Ann Oncol 1994;5(suppl):67-71.
12. Armitage JO. Treatment of non-Hodgkin’s lymphomas. N Engl J Med
1993;328:1023-1030.
13. Dana BW, Dahlberg S, Nathwanmi BN, et al. Long-term follow-up of
patients with low-grade malignant lymphomas treated with
doxorubicin-based chemotherapy or chemoimmunotherapy. J Clin Oncol
1993;11:644-651.
14. Cohen RB, et al. A Phase 1 clinical trial of HGS-ETR1, an agonistic
monoclonal antibody to TRAIL-R1, in patients with advanced solid
tumors.” 16th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer
Therapeutics, 2004: Oral Presentation.
15. Hotte SJ, et al. Phase 1 study of a fully human monoclonal antibody
to the tumor necrosis factor-related apoptosis-inducing ligand receptor
1 (TRAIL-R1) in subjects with advanced solid malignancies or
non-Hodgkin’s lymphoma (NHL). 16th EORTC-NCI-AACR Symposium on Molecular
Targets and Cancer Therapeutics, 2004: Abstract #208.
16. (HGSI Press Release) Human Genome Sciences Reports Results of
Ongoing Phase 1 Clinical Trials of HGS-ETR1 in Patients with Advanced
Cancers. September 29, 2004.
17. Tolcher AW, et al. A Phase 1 and pharmacokinetic study of HGS-ETR1,
a fully human monoclonal antibody to TRAIL-R1 (TRM-1), in patients with
advanced solid tumors. American Society of Clinical Oncology Annual
Meeting, 2004: Abstract #3060.
18. Le LH, et al. Phase 1 study of a fully human monoclonal antibody to
the tumor necrosis factor-related apoptosis-inducting ligand Death
Receptor 4 (TRAIL-R1) in subjects with advanced solid malignancies or
non-Hodgkin’s lymphoma. American Society of Clinical Oncology Annual
Meeting, 2004: Abstract #2533.
19. (HGSI Press Release) Human Genome Sciences Reports Results of Phase
1 Clinical Trials of HGS-ETR1 (TRAIL-R1 mAb) in Patients with Advanced
Cancers. June 7, 2004.
20. Halpern W, et al. Variable distribution of TRAIL Receptor 1 in
primary human tumor and normal tissues. 16th EORTC-NCI-AACR Symposium on
Molecular Targets and Cancer Therapeutics, 2004: Abstract #225.
21. Humphreys R, et al. HGS-TR2J, a human, agonistic, TRAIL Receptor-2
monoclonal antibody, induces apoptosis, tumor regression and growth
inhibition as a single agent in diverse human solid tumor cell lines.
16th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer
Therapeutics, 2004: Abstract #204.
22. (HGSI Press Release) Human Genome Sciences Reports Results of
Preclinical Studies of TRAIL-R1 and TRAIL-R2 Agonistic Human Monoclonal
Antibodies at EORTC-NCI-AACR Symposium. October 1, 2004.
23. Younes A, Kadin ME. Emerging applications for the tumor necrosis
factor family of ligands and receptors in cancer therapy. J Clin Oncol
2003;21:3526-3534.
24. Georgakis GV, Li Y, Humphreys R, et al. Activity of selective
agonistic antibodies to TRAIL death receptors R1 and R2 in primary and
cultured tumor cells of hematologic origin. Blood 2003;102:228a
(abstract #799).
25. Johnson RL, Huang X, Fiscella M. Human agonistic anti-TRAIL
antibodies, HGS-ETR1 and HGS-ETR2, induce apoptosis in diverse
hematological tumor lines. Blood 2003;102:981a (abstract #3316).
26. Pukac L, Kanakaraj P, Alderson R, et al. TRAIL-R1 mAb, a human
agonistic monoclonal antibody to tumor necrosis factor-related
apoptosis-inducing ligand receptor 1, induces apoptosis in human tumor
cells in vitro and in vivo. American Association for Cancer Research
94th Annual Meeting. July 2003, Abstract 6429.
27. Salcedo, Alderson R, Basu, et al. TRM-1, a fully human TRAIL-R1
agonistic monoclonal antibody, displays in vitro and in vivo anti-tumor
activity. American Association for Cancer Research 93rd Annual Meeting.
April 2002, Abstract #4240.
28. Humphreys R, et al. TRAIL-R1 and TRAIL-R2 human agonistic monoclonal
antibodies display in vitro and in vivo activity on human cancer cells.
Society for Biological Therapy 2002; oral presentation.
29. Ashkenazi A. Targeting death and decoy receptors of the tumor
necrosis factor superfamily. Nat Revs Cancer 2002; 2:420-430.
30. Choi C, Kutsch O, Park J, et al. Tumor necrosis factor-related
apoptosis-inducing ligand induces caspase-dependent interleukin-8
expression and apoptosis in human astroglioma cells. Mol Cell Biol
2002;22(3):724-736.
31. Chuntharapai A, Dodge K, Grimmer K, et al. Isotype-dependent
inhibition of tumor growth in vivo by monoclonal antibodies to death
receptor 4. J Immunol 2001; 166:4891-4898.
32. Ichikawa K, Liu W, Zhao L, et al. Tumoricidal activity of a novel
anti-human DR5 monoclonal antibody without hepatocyte cytotoxicity. Nat
Med 2001;7:954-960.
33. Gores GJ, Kaufmann SH. Is TRAIL hepatoxic? Hepatology 2001;34:3-6.
34. Jo M, Kim TH, Seol DW, et al. Apoptosis induced in normal human
hepatocytes by tumor necrosis factor-related apoptosis-inducing ligand.
Nat Med 2000;6:564-567.
35. Kelley SK, Harris LA, Xie D, et al. Preclinical studies to predict
the disposition of Apo2L/tumor necrosis factor-related
apoptosis-inducing ligand in humans: Characterization of in vivo
efficacy, pharmacokinetics, and safety. J Pharmacol Exp Ther 2001;299:31-38.
36. Lawrence D, Shahrokh Z, Marsters S, et al. Differential hepatocyte
toxicity of recombinant ApoL/TRAIL versions. Nat Med 2001;7:383-385.
37. Mitsiades CS, Treon SP, Mitsiades N, et al. TRAIL/Apo2L ligand
selectively induces apoptosis and overcomes drug resistance in multiple
myeloma: Therapeutic applications. Blood 2001; 98:795-804.
38. Ashkenazi A. Apo-2L/TRAIL in cytokine reference. Academic Press 2000.
39. Tanaka S, Sugimachi K, Shirabe K, et al. Expression and antitumor
effects of TRAIL in human cholangiocarcinoma. Hepatology 2000;32:523-527.
40. Ashkenazi A, Pai RC, Fong S, et al. Safety and anti-tumor activity
of recombinant soluble Apo2 ligand. J Clin Invest 1999;104:155-162.
41. Walczak H, Miller RE, Ariail K, et al. Tumoricidal activity of tumor
necrosis factor-related apoptosis-inducing ligand in vivo. Nat. Med.
1999; 5:157-163.
42. Snell V, Clodi K, Zhao S, et al. Activity of TNF-related
apoptosis-inducing ligand (TRAIL) in haematological malignancies. Br J
Haematol 1997;99:618-624.
43. Pitti RM, Marsters SA, Ruppert S, et al. Induction of apoptosis by
Apo-2 ligand, a new member of the tumor necrosis factor receptor family.
J Biol Chem. 1996; 271:12690-12697.
44. Wiley SR, Schooley K, Smolak PJ, et al. Identification and
characterization of a new member of the TNF family that induces
apoptosis. Immunity 1995;3:673-682.
45. Anderson KC, Bates MP, Slaughenhhoupt BL, et al. Expression of human
B-cell associated antigens on leukemias and lymphomas: a model of human
B-cell differentiation. Blood 1984;63:1424-1433.
46. Krishnan B, Ormerod MG, Kaye SB, Jackman AL. Effective combinations
of carboplatin with low doses of TRAIL, HGS-ETR1 and HGS-ETR2 in the
TRAIL-sensitive HX62 human ovarian tumour cell line. 16th EORTC-NCI-AACR
Symposium on Molecular Targets and Cancer Therapeutics, 2004: Abstract #637.
47. Georgakis GV, et al. Selective agonistic monoclonal antibodies to
the TRAIL Receptors R1 and R2 induce cell death and potentiate the
effect of chemotherapy and bortezomib in primary and cultured lymphoma
cells. American Society of Clinical Oncology Annual Meeting, 2004:
Abstract #6595.
48. Gillotte D, Zhang Y, Poortman C, et al. Human agonistic anti-TRAIL
receptor antibodies, HGS-ETR1 and HGS-ETR2, induce apoptosis in ovarian
tumor lines and their activity is enhanced by taxol and carboplatin.
Proceedings from the AACR 2004; 73:3579.
49. Humphreys R, Shepard L, Zhang Y, et al. Novel, agonistic, human
anti-TRAIL receptor monoclonal antibodies, HGS-ETR1 and HGS-ETR2, are
capable of potently inducing tumor regression and growth inhibition as
single agents and in combination with chemotherapeutic agents in models
of human NSCLC. Proceedings of the AACR-NCI-EORTC International
Conference on Molecular Targets and Cancer Therapeutics, Boston,
November 2003.
50. Buchsbaum DJ, Zhou T, Grizzle WE, et al. Antitumor efficacy of TRA-8
anti-DR5 monoclonal antibody alone or in combination with chemotherapy
and/or radiation therapy in a human breast cancer model. Clin Cancer
Research 2003; 9:3731-3741.
51. Nagane M, Pan G, Weddle JJ, et al. Increased death receptor 5
expression by chemotherapeutic agents in human gliomas causes
synergistic cytotoxicity with tumor necrosis factor-related
apoptosis-inducing ligand in vitro and in vivo. Cancer Research. 2000;
60:847-853.
52. Gliniak B, Le T. Tumor necrosis factor-related apoptosis-inducing
ligand’s antitumor activity in vivo is enhanced by the chemotherapeutic
agent CPT-11. Cancer Research 1999; 59:6153-6158.
53. (HGSI Press Release) Cambridge Antibody Technology and Human Genome
Sciences Announce Second Drug Partnership. January 8, 2002.

FOR IMMEDIATE RELEASE
CONTACTS:
David C. Stump, M.D.
Executive Vice President, Drug Development
240/314-4400
Jerry Parrott
Vice President, Corporate Communications
301/315-2777
Kate de Santis
Director, Investor Relations
301/251-6003

ARIAD INITIATES PHASE 2 CLINICAL TRIAL OF AP23573 IN PATIENTS WITH RELAPSED AND/OR REFRACTORY SARCOMAS

First global multicenter Phase 2 clinical trial of AP23573 in solid tumors

Cambridge, MA, September 30, 2004 – ARIAD Pharmaceuticals, Inc.
(Nasdaq: ARIA) today announced initiation of enrollment of patients
with bone and soft tissue sarcomas in the first multicenter Phase 2
clinical trial of its novel mTOR inhibitor, AP23573, as a single agent
in solid tumors.

This non-randomized study will evaluate the clinical benefit of AP23573
in four well-defined groups of sarcoma patients, characterized by tumor
type. Up to approximately 175 patients
will be enrolled in the trial at approximately 15 centers in the United
States and Europe.AP23573 will be administered using a daily dosing
regimen of drug.

“In our nearly completed Phase 1 clinical trials reported today at
the EORTC international cancer symposium, all evaluable patients with
relapsed and/or refractory sarcoma had evidence of anti-tumor activity
– a promising result that supports our decision to further evaluate
AP23573 in this patient population in Phase 2,”� said Harvey J. Berger,
M.D., chairman and chief executive officer of ARIAD. “Despite
advancements in anti-cancer therapy, currently available treatment
options for such patients are extremely limited due the highly
resistant
nature of this cancer. Sarcoma remains a disease with high unmet medical need.”

The study will also include use of pharmacodynamic and pharmacogenomic
biomarkers,including functional imaging, to assess the effects of
AP23573 on the mTOR pathway and to
help identify patients who are likely to benefit most from treatment with AP23573.

About Sarcoma

Sarcomas are cancers of the connective tissue, including bones,
muscles, fat, cartilage, and joints. Sarcomas can arise anywhere in the
body and are divided into two main groups – bone tumors and soft tissue
sarcomas. They are further sub-classified based on the type of cell
found in the tumor. All sarcomas share certain pathologic
characteristics. There are approximately 10,000 new cases of sarcoma
diagnosed each year in the United States and close to 40,000 sarcoma
patients being treated in the United States and Europe. More
information about sarcomas is available on the web at http://www.sarcoma.net/facts.htm and at  http://www.sarcomafoundation.com/master.html?Articleld=90.

About AP23573

The small-molecule drug, AP23573, starves cancer cells and shrinks
tumors by inhibiting the critical cell-signaling protein, mTOR, which
regulates the response of tumor cells to nutrients and growth factors,
and controls tumor blood supply and angiogenesis through effects on
Vascular Endothelial Growth Factor (VEGF).

About ARIAD

ARIAD is engaged in the discovery and development of breakthrough
medicines to treat cancer by regulating cell signaling with small
molecules. The Company is developing a comprehensive approach to
patients with cancer that addresses the greatest medical need –
aggressive and advanced-stage cancers for which current treatments are
inadequate. ARIAD also has an exclusive license to pioneering
technology and patents related to certain NF-kB treatment methods, and
the
discovery and development of drugs to regulate NF-kB cell-signaling
activity, which may be useful in treating certain diseases. Additional
information about ARIAD can be found on the web at http://www.ariad.com.

Some of the matters discussed herein are “forward-looking statements”
within the meaning of the Private Securities Litigation Reform Act of
1995. Such statements are identified by the use of words such as
“anticipate,”  “estimate,”� “expect,”  “project,” “intend,”
“plan,” “believe, ” and other words and terms of similar meaning in
connection with any discussion of future operating or financial
performance. Such statements are based on management's current
expectations and are subject to certain factors, risks and
uncertainties that may cause actual results, outcome of events, timing
and performance to differ
materially from those expressed or implied by such forward-looking
statements. These risks include, but are not limited to, risks and
uncertainties regarding the Company's ability to accurately estimate
the actual research and development expenses and other costs associated
with
the preclinical and clinical development of our product candidates, the
adequacy of our capital resources and the availability of additional
funding, risks and uncertainties regarding the Company's ability to
successfully conduct preclinical and clinical studies of its product
candidates, including those clinical trials noted in this press
release,
risks and uncertainties that clinical trial results at any phase of
development may be adverse or may not be predictive of future result or
lead to regulatory approval of any of the Company's product candidates,
and risks and uncertainties relating to regulatory oversight,
intellectual property claims, the timing, scope, cost and outcome of
legal proceedings, future capital needs, key employees, dependence on
the Company's collaborators and manufacturers, markets, economic
conditions, products, services, prices, reimbursement rates,
competition and other risks detailed in the Company's public filings
with the Securities and Exchange Commission, including ARIAD's Annual
Report on Form 10-K for the fiscal year ended December 31, 2003. The
information contained in this document is believed to be current as of
the date of original issue. The Company does not intend to update any
of the
forward-looking statements after the date of this document to conform
these statements to actual results or to changes in the Company's
expectations, except as required by law.
###
CONTACT: Tom Pearson
(610) 407-9260
Kelly Lindenboom
(617) 621-2345

HUMAN GENOME SCIENCES REPORTS RESULTS OF ONGOING PHASE 1
CLINICAL TRIALS OF HGS-ETR1 IN PATIENTS WITH ADVANCED CANCERS

– Results of Phase 1 clinical studies support
further evaluation of HGS-ETR1 in Phase 2 clinical trials both as a
single agent and in combination with chemotherapy –

– Data presented at 16 th EORTC-NCI-AACR
Symposium on Molecular Targets and Cancer Therapeutics –

ROCKVILLE, Maryland – September 29, 2004 – Human Genome Sciences,
Inc. (Nasdaq: HGSI) announced today that the results of ongoing Phase 1
clinical trials demonstrate the safety and tolerability of HGS-ETR1
(agonistic human monoclonal antibody to TRAIL Receptor 1) in patients
with advanced solid tumors or non-Hodgkin’s lymphoma, and support
further evaluation of HGS-ETR1 in Phase 2 clinical trials, both as a
single agent and in combination with chemotherapy.

Safety, pharmacokinetic and biological activity data from two Phase
1 studies of HGS-ETR1 were presented today at the 16^th
EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics
in Geneva, Switzerland. The conference is jointly organized by the
European Organisation for Research and Treatment of Cancer (EORTC),
National Cancer Institute (NCI) and American Association for Cancer
Research (AACR).

In an oral presentation at the EORTC-NCI-AACR Symposium’s plenary
session, entitled “A
Phase 1 Clinical Trial of HGS-ETR1, an Agonistic Monoclonal Antibody to
TRAIL-R1, in Patients with Advanced Solid Tumors,” data were
presented on thirty-nine patients treated to date in an ongoing
open-label, dose-escalation clinical trial.¹ The median
number of chemotherapeutic treatment regimens previously received was
two, and ranged as high as nine. The patients were enrolled into seven
cohorts (0.01, 0.03, 0.1, 0.3, 1.0, 3.0, or 10.0 mg/kg) and received
HGS-ETR1 administered intravenously on a 28-day or 14-day schedule. The
primary purpose of the study is to determine the safety, maximum
tolerated dose (MTD), dose-limiting toxicities, and pharmacokinetics of
HGS-ETR1 in patients with relapsed or refractory advanced tumors.
Disease response also is being evaluated. Available tumor tissue
samples from patients participating in the trial will be evaluated for
expression of the TRAIL Receptor-1 protein using immunohistochemical
(IHC) techniques.

Results to date of the ongoing Phase 1 clinical trial demonstrate
that HGS-ETR1 can be administered safely and repetitively to patients
with advanced solid malignancies at doses up to and including 10 mg/kg
intravenously every 28 days. No evidence of drug-related hematologic or
hepatic toxicity has been observed at doses up to and including 10
mg/kg. The MTD has not been reached, and accrual in the trial continues
at a dose of 10 mg/kg every 14 days. Dose-proportional pharmacokinetics
were observed up to a dose of 1.0 mg/kg, with a terminal elimination
half-life of 15 days. In seven patients treated at the 10 mg/kg dose
level, the terminal elimination half-life of HGS-ETR1 was longer,
averaging about 18 days. Some preliminary evidence of biological
activity has been observed. Durable stable disease for greater than
eight months was observed in one patient with metastatic sarcoma.
Durable stable disease was observed for four months in one patient with
head-and-neck cancer and in one patient with Ewing’s sarcoma; both
patients continue on treatment.

A poster entitled “Phase
1 Study of a Fully Human Monoclonal Antibody to the Tumor Necrosis
Factor-Related Apoptosis-Inducing Ligand Receptor 1 (TRAIL-R1) in
Subjects with Advanced Solid Malignancies or Non-Hodgkin’s Lymphoma”
(Abstract #208) presented data on twenty-four patients treated to date
in an open-label, dose-escalation clinical trial currently ongoing at
two centers in Canada.² All patients admitted to the trial
have relapsed or refractory disease and had received prior anti-cancer
treatments (chemotherapy, radiotherapy, or hormone therapy). To date,
twenty-four patients have been enrolled into five cohorts (0.01, 0.03,
0.3, 3.0, or 10.0 mg/kg) and received HGS-ETR1 administered
intravenously every 28 days. Patients continue to be enrolled into the
10 mg/kg dose cohort. The study design calls for enrollment of an
additional cohort at a dose of 20 mg/kg. Patients are treated every 28
days in the absence of disease progression or dose-limiting toxicities.
The primary objective of the trial is to evaluate the safety and
tolerability of repeated doses of HGS-ETR1 administered intravenously
in patients with advanced solid tumors or non-Hodgkin’s lymphoma. The
secondary objectives are to evaluate the pharmacokinetics of repeated
doses of HGS-ETR1 and to assess tumor response.

Results to date of the ongoing clinical trial demonstrate that
HGS-ETR1 is well tolerated with no clearly attributable toxicities to
date and that the MTD has not been reached. The median number of
treatment cycles delivered is two (1-12). Stable disease has been
observed in eight patients for greater than two cycles. Preliminary
data indicate that the pharmacokinetics of HGS-ETR1 are
dose-proportional up to 0.3 mg/kg. The trial continues to enroll
patients.

An additional poster presented at the EORTC-NCI-AACR Symposium, “Variable
Distribution of TRAIL Receptor 1 in Primary Human Tumor and Normal
Tissues” (Abstract #225), described the results of a preclinical
study designed to identify specific malignancies that are most likely
to express TRAIL Receptor 1.³ Such malignancies could be
strong candidate indications for HGS-ETR1. The study, conducted by
scientists at Human Genome Sciences in collaboration with scientists
from DakoCytomation ⁴ and Fox Chase Cancer Center, used a
highly specific immunohistochemical assay to evaluate TRAIL-R1 in human
tumor and normal tissue. Of the first 134 malignancies evaluated, a
total of 87 tumors (65 percent) showed some degree of TRAIL-R1 specific
staining. TRAIL-R1 specific staining was consistently weak or absent in
all 17 normal tissues assayed. Tumors of the pancreas, colon and lung
were the most likely to have substantial staining for TRAIL-R1.
Prostatic carcinomas were least likely to demonstrate TRAIL-R1
staining. The level of TRAIL-R1 protein in the colon was explored
further in 26 additional samples representative of typical neoplastic
progression. TRAIL-R1 staining distribution and intensity were
increased in malignancies of the colon as compared to benign lesions or
focal carcinomas in situ.

Roger B. Cohen, M.D., Director, Phase 1 Clinical Trials Program,
Fox Chase Cancer Center, Philadelphia, said, “The Phase 1 clinical
results we presented today demonstrate that HGS-ETR1 is well tolerated
and can be safely and repetitively administered to patients with
advanced malignancies. We have seen no evidence of drug-related
hematological or hepatic toxicity at the dose levels administered to
date. We have not reached a maximum tolerated dose, and we have seen
preliminary evidence of biological activity. Patient accrual continues
in the ongoing Phase 1 trials. Further evaluation of HGS-ETR1 is
appropriate in Phase 2 clinical trials, both as a single agent and in
combination with chemotherapy.”

David C. Stump, M.D., Executive Vice President, Drug Development,
said, “We continue to be encouraged by the results emerging from our
ongoing Phase 1 clinical trials of HGS-ETR1. The data show that
HGS-ETR1 is well tolerated in patients with advanced solid tumors or
non-Hodgkin’s lymphoma. Stable disease has been observed in a number of
patients in these studies as well. Based on the encouraging interim
clinical results from our Phase 1 studies, along with the strongly
supportive preclinical evidence^{1-3, 6-11}, we announced at
the beginning of September that we have advanced HGS-ETR1 to a Phase 2
clinical trial in patients with relapsed or refractory non-small cell
lung cancer.⁵ We plan to initiate additional Phase 2
clinical trials of HGS-ETR1 in the weeks and months to come.”

Human Genome Sciences, using genomic techniques, originally
identified the TRAIL Receptor-1 protein as a member of the tumor
necrosis factor receptor super-family. The company’s own studies, as
well as those conducted by others, show that TRAIL Receptor 1 plays a
key role in triggering apoptosis, or programmed cell death, in tumors.
Human Genome Sciences took the approach of developing human monoclonal
antibodies that would bind the receptor and stimulate the TRAIL
Receptor-1 protein to trigger apoptosis in cancer cells, in much the
same way that the native TRAIL ligand (tumor necrosis factor-related
apoptosis-inducing ligand) triggers it, but with the advantage of a
longer half-life and an exclusive specificity for TRAIL Receptor 1. The
TRAIL Receptor-1 agonistic human monoclonal antibody, HGS-ETR1, was
made in a collaboration between Human Genome Sciences and Cambridge
Antibody Technology.¹² The drug will be produced in the
Human Genome Sciences clinical manufacturing facilities located in
Rockville, Maryland. Human Genome Sciences holds the commercial rights
to the drug.

For more information about HGS-ETR1, see www.hgsi.com/products/ETR1.html.
Health professionals interested in more information about trials
involving HGSI products are encouraged to inquire via the Contact Us
section of the Human Genome Sciences web site, www.hgsi.com/products/request.html,
or by calling (240) 314-4400, extension 3550.

Human Genome Sciences is a company with the mission to treat and
cure disease by bringing new gene-based protein and antibody drugs to
patients.

HGS and Human Genome Sciences are trademarks of Human Genome
Sciences, Inc.

This announcement contains forward-looking statements within the
meaning of Section 27A of the Securities Act of 1933, as amended, and
Section 21E of the Securities Exchange Act of 1934, as amended. The
forward-looking statements are based on Human Genome Sciences’ current
intent, belief and expectations. These statements are not guarantees of
future performance and are subject to certain risks and uncertainties
that are difficult to predict. Actual results may differ materially
from these forward-looking statements because of the Company’s unproven
business model, its dependence on new technologies, the uncertainty and
timing of clinical trials, the Company’s ability to develop and
commercialize products, its dependence on collaborators for services
and revenue, its substantial indebtedness and lease obligations, its
changing requirements and costs associated with planned facilities,
intense competition, the uncertainty of patent and intellectual
property protection, the Company’s dependence on key management and key
suppliers, the uncertainty of regulation of products, the impact of
future alliances or transactions and other risks described in the
Company’s filings with the Securities and Exchange Commission. Existing
and prospective investors are cautioned not to place undue reliance on
these forward-looking statements, which speak only as of today’s date.
Human Genome Sciences undertakes no obligation to update or revise the
information contained in this announcement whether as a result of new
information, future events or circumstances or otherwise.

###

Footnotes:

1. R.B.
Cohen, et al. “A Phase 1 Clinical Trial of HGS-ETR1, an Agonistic
Monoclonal Antibody to TRAIL-R1, in Patients with Advanced Solid Tumors.”
16th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer
Therapeutics, 2004: Oral Presentation.
2. S.J.
Hotte, et al. Phase 1 Study of a Fully Human Monoclonal Antibody to the
Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Receptor 1
(TRAIL-R1) in Subjects with Advanced Solid Malignancies or
Non-Hodgkin’s Lymphoma (NHL). 16th EORTC-NCI-AACR Symposium on
Molecular Targets and Cancer Therapeutics, 2004: Abstract #208.
3. W.
Halpern, et al. Variable Distribution of TRAIL Receptor 1 in Primary
Human Tumor and Normal Tissues. 16th EORTC-NCI-AACR Symposium on
Molecular Targets and Cancer Therapeutics, 2004: Abstract #225.
4. (HGSI Press Release) Human Genome Sciences Announces License
Agreement with DakoCytomation for Development of Pharmacogenomic
Diagnostic Assays. March 31, 2004.
5. (HGSI Press Release) Human Genome Sciences Advances Anti-Cancer Drug
to Phase 2 Clinical Development. September 8, 2004.
6. A.W. Tolcher, et al. A Phase 1 and Pharmacokinetic Study of
HGS-ETR1, A Fully Human Monoclonal Antibody to TRAIL-R1 (TRM-1), in
Patients with Advanced Solid Tumors. American Society of Clinical
Oncology Annual Meeting, 2004: Abstract #3060.
7. L.H. Le, et al. Phase 1 Study of a Fully Human Monoclonal Antibody
to the Tumor Necrosis Factor-Related Apoptosis-Inducting Ligand Death
Receptor 4 (TRAIL-R1) in Subjects with Advanced Solid Malignancies or
Non-Hodgkin’s Lymphoma. American Society of Clinical Oncology Annual
Meeting, 2004: Abstract #2533.
8. G.V. Georgakis, et al. Selective Agonistic Monoclonal Antibodies to
the TRAIL Receptors R1 and R2 Induce Cell Death and Potentiate the
Effect of Chemotherapy and Bortezomib in Primary and Cultured Lymphoma
Cells. American Society of Clinical Oncology Annual Meeting, 2004:
Abstract #6595.
9. TRAIL R2-mAb, a human agonistic monoclonal antibody to tumor
necrosis factor-related apoptosis inducing ligand receptor 2, affects
tumor growth and induces apoptosis in human tumor xenograft models in
vivo. Robin C. Humphreys, Ralph F. Alderson, Eliel Bayever, Kevin
Connolly, Gil H. Choi, Norma Lynn Fox, Gilles Gallant, Krzystof J.
Grzegorzewski, Viktor Roschke, Theodora W. Salcedo, Jing Zhang, Junli
Zhang, Vivian R. Albert. 94th AACR Annual Meeting. Abstract 642.
10. TRAIL-R2 mAb, a human agonistic monoclonal antibody to tumor
necrosis factor-related apoptosis inducing ligand receptor 2, induces
apoptosis in human tumor cells. Ralph F. Alderson, Charles E. Birse,
Kevin Connolly, Gil H. Choi, Norma Lynn Fox, Gilles Gallant, Ina Han,
Robin C. Humphreys, Ron Johnson, Palanisamy Kanakaraj, Vikram Patel,
Oxana Pickeral, Laurie Pukac, Viktor Roschke, Theodora Salcedo, Tara
Shah, Junli Zhang, Vivian R. Albert. 94th AACR Annual Meeting. Abstract
963.
11. Ashkenazi A. et al. Safety and anti-tumor activity of recombinant
soluble APO2 ligand. J Clin Inv July 1999; 104(2): 155-162.
12. (HGSI Press Release) Cambridge Antibody Technology and Human Genome
Sciences Announce Second Drug Partnership. January 8, 2002.

FOR IMMEDIATE RELEASE
CONTACTS:
David C. Stump, M.D.
Executive Vice President, Drug Development
240/314-4400
Jerry Parrott
Vice President, Corporate Communications
301/315-2777
Kate de Santis
Director, Investor Relations
301/251-6003