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Synta Announces First Patient Treated In Clinical Trial Of STA-9090 In Combination With Docetaxel In Solid Tumors

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Synta Pharmaceuticals Corp. (NASDAQ: SNTA), a biopharmaceutical company focused on discovering, developing, and commercializing small molecule drugs to treat severe medical conditions, announced that the first patient has been treated in its clinical trial of STA-9090 in combination with docetaxel for the treatment of advanced solid tumor malignancies. This is the first clinical trial of STA-9090, a potent second-generation, small-molecule Hsp90 inhibitor with a chemical structure unrelated to the first-generation, ansamycin family of Hsp90 inhibitors (e.g., 17-AAG or IPI-504), in combination with another anti-cancer agent. Recent studies support synergistic anti-cancer activity of taxanes and Hsp90 inhibitors[1-9].

“The scientific rationale for combining an Hsp90 inhibitor with taxanes is well established based on preclinical and prior clinical studies,” said Suresh Ramalingam, M.D., Associate Professor, Department of Hematology/Medical Oncology and Chief of Medical Oncology, Winship Cancer Institute of Emory University. “STA-9090 has demonstrated high potency, early signs of clinical activity, and a favorable safety profile that make it ideal for combinations with docetaxel and other cytotoxic agents.”

“The broad range of anti-cancer activity of docetaxel will make this combination an attractive option for several organ site malignancies including non-small cell lung, breast, prostate, head and neck, and gastric cancers,” said R. Donald Harvey, Pharm.D., Assistant Professor of Hematology and Medical Oncology and Director of the Phase I Clinical Trials Program at Emory University. “The combination of STA-9090 and docetaxel could possibly expand the therapeutic potential of both agents.” Docetaxel is also known to be active in ovarian, bladder, esophageal cancers, small cell lung cancer and sarcoma.

STA-9090 is currently being studied in 11 clinical trials including trials in non-small cell lung cancer (NSCLC), gastrointestinal stromal tumors (GIST), colorectal cancer, gastric cancer, small cell lung cancer (SCLC), acute myeloid leukemia (AML), and hepatocellular carcinoma. Additional trials will be initiated this year with a total of up to 15 trials expected by the end of 2010.

“We believe that STA-9090 is the leading Hsp90 inhibitor in clinical development today based on the encouraging safety profile and clinical activity seen to date, as well as the breadth of our clinical program,” said Vojo Vukovic, M.D., Ph.D., Senior Vice President and Chief Medical Officer, Synta Pharmaceuticals. “Combining STA-9090 with established anti-cancer drugs begins a second stage of exploring the ability of this compound to unlock the true potential of Hsp90 inhibition.”

Study Design

The Phase 1, open-label, dose escalation study is designed to determine the recommended doses for the combination of STA-9090 and docetaxel in subjects with solid tumor malignancies. Patients must have histologically confirmed malignancy (ECOG Performance Status ?2) that is metastatic or unresectable and evidence of disease progression prior to study entry. If patients have received prior treatment with docetaxel, there must be evidence of persistent or progressive disease. Secondary objectives will be to define the dose-limiting toxicities (DLT), pharmacokinetics, safety and tolerability as well as anti-tumor activity of the combination of STA-9090 and docetaxel. Dose escalation will continue until recommended doses are defined and then an additional cohort of 12-18 subjects will be enrolled to obtain additional safety and pharmacokinetic data. Subjects tolerating STA-9090 in combination with docetaxel can continue treatment until disease progression.

About STA-9090

STA-9090 is a potent second-generation, small-molecule Hsp90 inhibitor, with a chemical structure unrelated to the first-generation, ansamycin family of Hsp90 inhibitors (e.g., 17-AAG or IPI-504). In preclinical studies, STA-9090 has shown potency up to 100 times greater than the first-generation Hsp90 inhibitors as well as activity against a wider range of kinases. In in vitro and in vivo models, STA-9090 has shown potent activity against a wide range of cancer types, including lung, prostate, colon, breast, gastric, pancreatic, gastrointestinal stromal tumors (GIST), melanoma, AML, chronic myeloid leukemia, Burkitt’s lymphoma, diffuse large B-cell lymphoma, and multiple myeloma – as well as potent activity against cancers resistant to imatinib (Gleevec®), sunitinib (Sutent®), erlotinib (Tarceva®), and dasatinib (Sprycel®).

In addition to the docetaxel combination trial announced today, STA-9090 is currently being evaluated in 10 clinical trials: six Phase 2 trials in solid tumor cancers – non-small cell lung cancer, gastrointestinal stromal tumors, colon cancer, gastric cancer, hepatic cancer and small cell lung cancer; two trials in hematologic cancers; and two Phase 1 solid tumor trials. Trials in colon, gastric, hepatic, and small cell lung cancer are investigator-sponsored.

About Hsp90

Hsp90 is a chaperone protein required for the proper folding and activation of other cellular proteins, particularly kinases. Many of these “client proteins” of Hsp90 – such as AKT, BCR-ABL, BRAF, KIT, MET, EGFR, FLT3, HER2, PDGFRA, VEGFR – have been shown to be critical to cancer cell growth, proliferation, and survival and are the targets of clinically validated cancer drugs. In preclinical studies, inhibiting Hsp90 causes the degradation of multiple client proteins and leads to cancer cell death. Because mutated kinases which no longer respond to treatment with kinase inhibitors remain dependent on Hsp90 for their activity, inhibiting Hsp90 offers the potential for treating cancers that have become resistant to targeted therapies such as kinase inhibitors.

References

1. Blackman R, et al.: Hsp90 inhibitor STA-9090 enhances the activity of standard of care therapies in erlotinib-sensitive and -resistant NSCLC models, 101st AACR Annual Meeting, April 19, 2010.

2. Foley K, et al.: Synergy Between the Novel Hsp90 Inhibitor STA-9090 and Taxanes in Preclinical Models of NSCLC, AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer, January 12, 2010.

3. Ying W, et al.: In vitro and in vivo efficacy of the novel Hsp90 inhibitor STA-9090 and its synergy with paclitaxel, AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics, November 17, 2009.

4. Ramalingam SS, Egorin MJ, Ramanathan RK, Remick SC, Sikorski RP, Lagattuta TF, Chatta GS, Friedland DM, Stoller RG, Potter DM, Ivy SP, Belani CP: A phase I study of 17-allylamino-17-demethoxygeldanamycin combined with paclitaxel in patients with advanced solid malignancies. Clinical Cancer Research: an official journal of the American Association for Cancer Research. 2008 Jun 1;14(11):3456-61.

5. Solit DB, Egorin M, Valentin G, Delacruz A, Ye Q, Schwartz L, Larson S, Rosen N, Scher HI: Phase 1 pharmacokinetic and pharmacodynamic trial of docetaxel and 17aag (17-allylamino-17-demethoxygeldanamycin). J Clin Oncol (Meeting Abstracts) 2004;22:3032.

6. Murtagh J, Lu H, Schwartz EL: Taxotere-Induced Inhibition of Human Endothelial Cell Migration Is a Result of Heat Shock Protein 90 Degradation. 2006 Aug 15;66(16):8192-9.

7. Solit DB, Basso AD, Olshen AB, Scher HI, Rosen N: Inhibition of Heat Shock Protein 90 Function Down-Regulates Akt Kinase and Sensitizes Tumors to Taxol. Cancer Research 2003 May 1;63(9):2139-44.

8. Sain N, Krishnan B, Ormerod MG, De Rienzo A, Liu WM, Kaye SB, Workman P, Jackman AL: Potentiation of paclitaxel activity by the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin in human ovarian carcinoma cell lines with high levels of activated AKT. Mol Cancer Ther 2006 May;5(5):1197-208.

9.Sawai A, Chandarlapaty S, Greulich H, Gonen M, Ye Q, Arteaga CL, Sellers W, Rosen N, Solit DB: Inhibition of Hsp90 Down-regulates Mutant Epidermal Growth Factor Receptor (EGFR) Expression and Sensitizes EGFR Mutant Tumors to Paclitaxel. Cancer Res 2008 Jan 15;68(2):589-96.

Source:
Synta Pharmaceuticals


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