ROCKVILLE, Md., Nov. 17 /PRNewswire-FirstCall/ -- Human Genome Sciences, Inc. announced today that the results of two ongoing Phase 1b clinical trials demonstrate that HGS-ETR1 in combination with chemotherapy was well tolerated and could be administered safely and repetitively at the doses and schedules evaluated in patients with advanced solid tumors. Partial response was observed in a number of patients in each of the studies. These results support further evaluation of HGS-ETR1 in combination with chemotherapy in Phase 2 trials. The results were presented at the AACR-NCI- EORTC International Conference on Molecular Therapeutics in Philadelphia.(1)
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A poster entitled “A Phase 1 and Pharmacological Study of HGS-ETR1, an Antibody Targeting TRAIL-R1, in Combination with Paclitaxel and Carboplatin in Patients with Advanced Solid Malignancies” presented data on 20 patients in an ongoing open-label, dose-escalation, two-center clinical trial, which is being conducted in the United States.(2) Patients participating in the Phase 1b/2a study previously received multiple cancer treatment regimens, including chemotherapy, radiotherapy and surgery. The patients are enrolled into one of three HGS-ETR1 dose cohorts (3.0, 10.0 or 20.0 mg/kg in combination with paclitaxel and carboplatin). Patients receive fixed intravenous (IV) doses of paclitaxel (200 mg/m2) and carboplatin (AUC 6) on Day 1 and every 21 days, and IV doses of HGS-ETR1 on Day 2 of Cycle 1 and on Day 1 of subsequent cycles every 21 days, with dose to progression of disease in the absence of dose- limiting toxicities. The primary objective of the study is to evaluate the safety and tolerability of escalating doses of HGS-ETR1 in combination with paclitaxel and carboplatin in patients for whom the combination of paclitaxel and carboplatin is considered appropriate treatment. Secondary objectives are to determine plasma concentrations of HGS-ETR1 for use in a population pharmacokinetic (PK) analysis, to assess the impact of HGS-ETR1 co- administration on plasma concentrations of gemcitabine and cisplatin, and to seek evidence of preliminary anti-tumor activity.
Results to date of the Phase 1b/2a study demonstrate that the combination of HGS-ETR1 with paclitaxel and carboplatin was safe and well tolerated and could be administered safely and repetitively at the doses and schedule evaluated. One dose-limiting hypersensitivity to HGS-ETR1 was observed. The 20 patients for whom data were presented have received a total of 87 cycles of therapy (median=4, range=1-11). HGS-ETR1 exposures were similar to those observed in single agent studies, implying that carboplatin and paclitaxel pretreatment does not affect HGS-ETR1 PK. Carboplatin and paclitaxel PK were not affected by co-administration of HGS-ETR1. Tumor tissue samples were collected from clinical trial participants and are being evaluated for TRAIL- R1 expression using immunohistochemical (IHC) techniques. Partial response, confirmed according to RECIST(3), was observed in 4 patients (3 with non-small cell lung cancer and 1 with adenocarcinoma of unknown primary origin). Stable disease was observed in 10 patients. Enrollment continues at the 20-mg/kg dose level.
A poster entitled “A Phase 1 Study of HGS-ETR1, a Fully Human Agonistic Monoclonal Antibody to TRAIL-R1, in Combination with Gemcitabine and Cisplatin in Subjects with Advanced Solid Malignancies” presented data on 16 patients in an ongoing open-label, dose-escalation, two-center clinical trial.(4) Seven of the patients treated to date in the Phase 1b study previously received other cancer treatment regimens, including chemotherapy, immunotherapy, surgery and/or radiotherapy. The patients are enrolled into 4 HGS-ETR1 dose cohorts (1.0, 3.0, 10.0 or 20.0 mg/kg), and receive 1250 mg/m2 of gemcitabine IV administered on Day 1 and Day 8 every 21 days, 80 mg/m2 of cisplatin IV on Day 1 every 21 days, and IV doses of HGS-ETR1 on Day 2 of Cycle 1 and on Day 1 of subsequent cycles every 21 days, for a maximum of 6 cycles. The primary objective of the study, which is being conducted in The Netherlands, is to evaluate the safety and tolerability of escalating doses of HGS-ETR1 in combination with gemcitabine and cisplatin in patients for whom the combination of gemcitabine and cisplatin is considered an appropriate treatment. Secondary objectives are to determine plasma concentrations of HGS-ETR1 for population PK analysis, to assess the possible influence of HGS- ETR1 co-administration on gemcitabine and cisplatin, and to evaluate disease response.
Results to date of the Phase 1b study demonstrate that the combination of HGS-ETR1 with gemcitabine and cisplatin was well tolerated and could be administered safely and repetitively at the doses evaluated. No allergic reactions were observed. The Maximum Tolerated Dose (MTD) was not reached. The pharmacokinetics of gemcitabine and cisplatin were not influenced by HGS- ETR1 co-administration or vice versa. Partial response was observed in 5 patients, 4 of which were confirmed according to RECIST(3) (1 with pancreatic cancer, 1 with head and neck carcinoma, 2 with a biliary tract carcinoma). The unconfirmed partial response was in a patient with an adenocarcinoma of unknown primary origin. Stable disease was observed in 9 patients. Enrollment of patients is currently ongoing at the 10-mg/kg dose.
Roger B. Cohen, M.D., Director, Phase 1 Clinical Trials Program, Fox Chase Cancer Center, Philadelphia, said, “The interim results of two clinical studies presented at the AACR-NCI-EORTC conference demonstrate that the combination of HGS-ETR1 with chemotherapeutic agents was well tolerated and showed signs of clinical activity. Both the combination of HGS-ETR1 with paclitaxel and carboplatin, and the combination of HGS-ETR1 with gemcitabine and carboplatin, were well tolerated and could be administered safely at the doses and schedules evaluated. Partial response was observed in a number of patients in each of these studies. The Maximum Tolerated Dose was not reached in either trial. Further Phase 2 studies of both combinations appear to be warranted.”
David C. Stump, M.D., Executive Vice President, Drug Development, said, “The interim results of the Phase 1b combination studies of HGS-ETR1 show that this novel drug was well tolerated and could be repetitively administered in combination with commonly used chemotherapeutic agents in patients with advanced solid malignancies. I am encouraged by the observation of partial response in a number of the patients in each of the combination studies. Earlier this year, we reported the results of Phase 2 trials of HGS-ETR1 as monotherapy in advanced colorectal cancer and advanced non-small cell lung cancer, as well as the interim results of a Phase 2 study of HGS-ETR1 as monotherapy in non-Hodgkin’s lymphoma.(5-10) Based on the clinical and preclinical results to date, we look forward to continuing the development of HGS-ETR1 in combination with chemotherapy in Phase 2 clinical studies.”
An additional poster entitled “HGS-ETR1, a Fully Human Monoclonal Antibody to the Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Receptor 1 (TRAIL-R1) in Patients with Advanced Solid Cancer: Results of a Phase 1 Trial” presented data on 41 patients treated in an open-label, dose-escalation clinical trial, which was conducted in Canada.(11) All patients admitted to the trial had relapsed or refractory disease, and 37 had received prior anti- cancer treatments (chemotherapy, radiotherapy, hormone therapy or immunotherapy). Patients were enrolled into 6 cohorts (0.01, 0.03, 0.3, 3.0, 10.0 or 20.0 mg/kg) and received HGS-ETR1 as monotherapy administered intravenously every 28 days. The primary objective of the trial was to evaluate the safety and tolerability of repeated doses of HGS-ETR1 in patients with advanced solid tumors or non-Hodgkin’s lymphomas. The secondary objectives were evaluation of immunogenicity, PK of repeated HGS-ETR1 doses, and tumor response. The 41 patients for whom data were presented have received a total of 135 doses to date. The results show that HGS-ETR1 was well tolerated with only two dose-limiting toxicities observed. The MTD has not been reached. No antibodies to HGS-ETR1 were detected. Stable disease was observed in 10 patients, with one patient continuing on treatment after 27 cycles of therapy. The observed mean terminal elimination half-life of HGS- ETR1 ranged from 12-18 days across dose groups.
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 human tumors. Human Genome Sciences took the approach of developing human monoclonal antibodies that would bind to the receptor and stimulate 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) does, but with the advantage of a longer serum 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.(2, 4-38)
HGS-ETR1 is a Human Genome Sciences drug that was generated through a collaboration between Human Genome Sciences and Cambridge Antibody Technology.(39) GlaxoSmithKline has exercised its option under a June 1996 agreement to develop and commercialize HGS-ETR1 jointly with Human Genome Sciences.(40) Under the terms of the agreement, GSK and Human Genome Sciences will share equally in Phase 3/4 development costs, and will share equally in sales and marketing expenses and profits of any product that is commercialized under the agreement, under a co-development and co-promotion agreement, the remaining terms of which are being negotiated by the parties.
Human Genome Sciences is a company with the mission to discover, develop, manufacture and market innovative drugs that serve patients with unmet medical needs, with a primary focus on protein and antibody drugs.
For more information about HGS-ETR1, see http://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, http://www.hgsi.com/products/request.html, or by calling (301) 610-5790, extension 3550.
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. The conference is jointly organized by the American Association for Cancer Research (AACR), National Cancer Institute (NCI) and European Organisation for Research and Treatment of Cancer (EORTC). 2. Hariharan S, Gore L, Eckhardt SG, Cohen RB, et al. A Phase 1 and pharmacological study of HGS-ETR1, an antibody targeting TRAIL-R1, in combination with paclitaxel and carboplatin in patients with advanced solid malignancies. 2005 AACR-NCI-EORTC International Conference on Molecular Therapeutics. 3. RECIST (Response Evaluation Criteria in Solid Tumors) is the methodology established in 2000 to provide objective means for evaluating changing disease status and the efficacy of drugs in the treatment of solid tumors. 4. Mom CH, Sleijfer S, Gietema JA, et al. A Phase 1 study of HGS-ETR1, a fully human monoclonal antibody to TRAIL-R1, in combination with gemcitabine and cisplatin in subjects with advanced solid malignancies. 2005 AACR-NCI-EORTC International Conference on Molecular Therapeutics. 5. Kanzler S, Trarbach T, Heinemann V, Kohne CH, Seeber S, et al. Results of a Phase 2 trial of HGS-ETR1 (agonistic human monoclonal antibody to TRAIL receptor 1) in subjects with relapsed or refractory colorectal cancer (CRC). ECCO 13 - the European Cancer Conference, 2005: Abstract #630. 6. (HGSI Press Release) Human Genome Sciences Reports Results of Phase 2 Clinical Trial of HGS-ETR1 in Patients with Advanced Colorectal Cancer. November 1, 2005. 7. Bonomi P, Greco FA, et al. Results of a Phase 2 trial of HGS-ETR1 (agonistic human monoclonal antibody to TRAIL receptor 1) in subjects with relapsed/recurrent non-small cell lung cancer. 11th World Conference on Lung Cancer. July 4, 2005. Abstract #1851. 8. (HGSI Press Release) Human Genome Sciences Reports Results of Phase 2 Clinical Trial of HGS-ETR1 in Patients with Non-Small Cell Lung Cancer. July 5, 2005. 9. Younes A, et al. Activity of selective agonistic monoclonal antibodies to TRAIL death receptors R1 and R2 in primary and cultured tumor cells of lymphoid origin. 9th International Conference on Malignant Lymphoma, 2005. Oral presentation. 10. (HGSI Press Release) Human Genome Sciences Reports Interim Results of Phase 2 Clinical Trial of HGS-ETR1 in Patients with Advanced Non- Hodgkin’s Lymphoma. June 13, 2005. 11. Hirte HW, Hotte SJ, Chen EX, Oza AM, et al. HGS-ETR1, a fully human monoclonal antibody to the tumor necrosis factor-related apoptosis- inducing ligand receptor 1 (TRAIL-R1) in patients with advanced solid cancer: results of a Phase 1 trial. 2005 AACR-NCI-EORTC International Conference on Molecular Therapeutics. 12. Pacey S, et al. Phase 1 and pharmacokinetic study of HGS-ETR2, a human monoclonal antibody to TRAIL-R2, in patients with advanced solid malignancies. 2005 Annual Meeting of the American Society of Clinical Oncology (ASCO), Orlando, Florida. Abstract #3055. 13. (HGSI Press Release) Human Genome Sciences Reports Results of Phase 1 Clinical Trials of HGS-ETR2 and HGS-ETR1 in Patients with Advanced Solid Tumors. May 17, 2005. 14. Mita M, et al. A Phase 1, pharmacokinetic (PK) study of HGS-ETR1, an agonistic monoclonal antibody to TRAIL-R1, in patients with advanced solid tumors. 96th Annual Meeting of the American Association for Cancer Research, Anaheim, California, 2005. Abstract #544. 15. Tolcher, et al. A Phase 1 clinical trial HGS-ETR2, a fully human monoclonal antibody to TRAIL-R2 in patients with advanced solid tumors. 96th Annual Meeting of the American Association for Cancer Research, Anaheim, California, 2005. Abstract #543. 16. (HGSI Press Release) Human Genome Sciences Reports Results of Phase 1 Clinical Trial of HGS-ETR1 in Patients with Advanced Solid Tumors. April 18, 2005. 17. Pukac L, Kanakaraj P, Humphreys R, et al. HGS-ETR1, a fully human TRAIL-receptor 1 monoclonal antibody, induces cell death in multiple tumour types in vitro and in vivo. British Journal of Cancer (April 2005): 92; 1430-1441. 18. 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. 19. 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. 20. (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. 21. 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. 22. 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. 23. (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. 24. 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. 25. 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. 26. 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. 27. 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. 28. 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. 29. 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. 30. 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. 31. 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. 32. Ashkenazi A. Targeting death and decoy receptors of the tumor necrosis factor superfamily. Nat Revs Cancer 2002; 2:420-430. 33. 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. 34. 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. 35. 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. 36. 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. 37. Ashkenazi A. Apo-2L/TRAIL in Cytokine Reference. Academic Press 2000. 38. Ashkenazi A. et al. Safety and anti-tumor activity of recombinant soluble APO2 ligand. J Clin Inv July 1999; 104(2): 155-162. 39. (HGSI Press Release) Cambridge Antibody Technology and Human Genome Sciences Announce Second Drug Partnership. January 8, 2002. 40. (HGSI Press Release) GlaxoSmithKline Exercises Option to Human Genome Sciences’ TRAIL Receptor Antibody. August 18, 2005.
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