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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 Trial of HGS-ETR1 in Patients with Colorectal Cancer. October 13, 2004.
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4. Tournigand C, Andre T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: A randomized GERCOR study. J Clin Oncol 2004;22(2):229-237.
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6. Erbitux, summary of product characteristics, EMEA, Committee for Proprietary Medicinal Products summary of opinion for Erbitux. Mar 2004. CPMP/7618/04 corr.
7. Rothenberg ML, Oza AM, et al. Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: Interim results of a Phase III Trial. J Clin Oncol 2003;21:2059-2069.
8. Plate S. ESMO minimum clinical recommendations for diagnosis, adjuvant treatment and follow-up of colon cancer. Ann Oncol 2003;12:1053-1054.
9. Köhne CH, Van Cutsem E, Wils J, et al. Irinotecan improves the activity of the AIO regimen in metastatic colorectal cancer: Results of EORTC GI Group study 40986. Proc AmSocClinOncol 2003;22:Abstract 1018.
10. Holen KD, Saltz LB. New therapies, new directions: Advances in the systematic treatment of metastatic colorectal cancer. Lancet Oncol 2001;2:290-297.
11. Vanhoefer U, Harstrick A, Achterrath W, et al. Irinotecan in the treatment of colorectal cancer: Clinical overview. J Clin Oncol 2001;19:1501-1518.
12. Douillard JY, Cunningham D, Roth AD, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomized trial. Lancet 2000;355:1041-1047.
13. Meta-analysis Group in Cancer. Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. J Clin Oncol 1998;16:301-308.
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16. Lokich JJ, Ahlgren JD, Gullo JJ, et al. A prospective randomized comparison of continuous infusion fluorouracil with a conventional bolus schedule in metastatic colorectal carcinoma: A Mid-Atlantic 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. Lyon, IARC Press, 2001;1.
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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