Phase III DECISION trial Evaluates Sorafenib in Patients with Non-Responsive Thyroid Cancer

Earlier this month recruitment has begun to enroll patients in an international Phase III trial to evaluate sorafenib (Nexavar®) tablets for the treatment of patients with radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer (papillary, follicular and Hurthle cell). The study is scheduled to start later this month at sites in the United States, Europe, Asia, and Japan. The study is schedules to complete in November 2011.

Thyroid cancer, one of the few cancers that has increased in incidence over the past several years. According to the American Cancer Society, it is the sixth most common cancer and about three times as many women as men get thyroid cancer. Information from the World Health Organization (Globocan 2002 database) indicates that there are more than 140,000 new cases of thyroid cancer and more than 35,000 people die worldwide each year.

"Patients with thyroid cancer who failed to respond to surgical or radiotherapies, have limited treatment options to help them manage their disease," said Dimitris Voliotis, vice president, Nexavar clinical development, Bayer HealthCare Pharmaceuticals. "Recognizing this unmet need, we are evaluating Nexavar in this special patient population."

Phase III Trial Design
The DECISION (stuDy of sorafEnib in loCally advanced or metastatIc patientS with radioactive Iodine refractory thyrOid caNcer) trial is an international, multicenter, randomized, placebo-controlled study that will enroll approximately 400 patients with locally advanced or metastatic, radioactive iodine-refractory, differentiated thyroid cancer (papillary, follicular and Hurthle cell) who have received no prior systemic therapy.

Patients will be randomized to receive 400 mg of oral sorafenib twice daily or matching placebo. Patients will continue on treatment until disease progression, toxicity, non-compliance or withdrawal of consent. At the time of progression, patients receiving placebo will have an option to cross over to sorafenib at the discretion of the investigator, based on the patient's clinical status. The primary endpoint of the study is progression-free survival as defined by Response Evaluation Criteria in Solid Tumors (RECIST). Secondary endpoints include overall survival, time to progression and response rate. The safety and tolerability of the two treatment groups will also be compared.

Phase II Trial Results
This Phase III trial initiative was started based on the results from Phase II clinical trials evaluating sorafenib in patients with advanced thyroid cancer.

Updated results from a single institution, investigator sponsored Phase II open-label study in 55 patients with metastatic, iodine refractory, thyroid cancer treated with Sorafenib r 400 mg twice daily were presented at the American Society of Clinical Oncology (ASCO) Annual Meeting, May 29-June 3, 2009 Orlando, FL, by Marcia Brose, M.D., Ph.D., an assistant professor of Hematology/Oncology and Otorhinolaryngology in the Abramson Cancer Center at the University of Pennsylvania, Philadelphia, PA, U.S.A. In 50 evaluable patients, 18 (36%) had a partial response per RECIST criteria.

The survival results on the first 30 patients enrolled into the study demonstrated that across all histologies the median progression-free survival (PFS) was 63 weeks and the median overall survival was 140 weeks. The most common adverse events (AE) seen in the trial were hand-foot skin reaction, rash, fatigue, stomatitis/mucositis, weight loss, and musculoskeletal pain, and were predominantly grade 1 or 2. Dr. Brose and Martin J. Schlumberger, Institut Gustave-Roussy, Villejuif, France, are the lead investigators on the Phase III trial.

"Based on the positive signal generated in the Phase II trial, the initiation of this Phase III represents progress in exploring the full potential of Nexavar in a variety of treatment settings and tumor types," noted Todd Yancey, M.D., vice president of clinical development at Onyx. "Building on our successful foundation of treating unresectable liver cancer and advanced kidney cancer, we are hopeful that this Phase III trial will lead to a new treatment option for patients with non-responsive thyroid cancer."

A Differentiated Mechanism of Action
Sorafenib is one of the first of a new class of drugs. In preclinical studies, the drug has shown to block a variety of multiple kinases. Multiple kinase inhibition works at multiple levels of signaling pathways in tumor cells and tumor vasculature - important processes that enable cancer growth. These targets include Raf kinase, VEGFR-1, 2 and 3 (Vascular Endothelial Growth Factor Receptor), PDGFR-B (Platelet Derived Growth Factor Receptor), KIT, FLT-3 and RET.

Sorafenib is currently approved in more than 80 countries for the treatment of patients with hepatocellular carcinoma (HCC), or liver cancer, and in more than 90 countries for the treatment of patients with advanced renal cell carcinoma (RCC), or kidney cancer. Even though these indications are well established, the utility of sorafenib continues to be evaluated in these tumor types, with ongoing studies examining special patient populations and long-term use.

Data on these indications was presented at Europe’s largest cancer congress, the ECCO 15 – ESMO 34 meeting in Berlin (Germany) and included results from two Phase III studies evaluating sorafenib in HCC and six studies examining sorafenib in RCC. During the same meeting, phase II study data of single-agent sorafenib in patients with thyroid cancer was also presented (Late-breaking poster 51LBA, Poster 276, Tuesday, September 22, 9:00 a.m.-5:00 p.m. Hall 14.1)

Ongoing trials
In addition to its current indications, sorafenib continues to be evaluated as a single agent or combination treatment in a wide range of cancers, including breast cancer and as an adjuvant therapy for kidney cancer and liver cancer.

Data from a recently unblinded Phase II trial evaluating the safety and efficacy of Nexavar as a potential treatment for breast cancer will be presented during an oral session at ECCO-ESMO. This trial examined sorafenib compared to placebo in combination with the oral chemotherapeutic agent, capecitabine, in patients with locally advanced or metastatic breast cancer. (Late-breaking presentation 3LBA, Presidential Session III, Wednesday, September 23, 1:30 p.m., Hall 1)

Sorafenib is also being evaluated as a single agent or combination treatment in a wide range of cancers, including breast cancer, colorectal cancer, lung cancer, ovarian cancer, and as an adjuvant therapy for liver cancer.

Sorafenib (Nexavar®) is being co-developed by Bayer HealthCare AG and Onyx Pharmaceuticals, Inc.

For more information:

• Nexavar® Versus Placebo in Locally Advance RAI-Refractory Differentiated Thyroid Cancer

New cancer drug may offer broad potential in the treatment of solid tumors

TGen Clinical Research Services (TCRS) is testing a new drug that may offer broad potential to treat solid tumors. Clinical trials of the drug TH-302, an anticancer agent in clinical development by Threshold Pharmaceuticals (1300 Seaport Blvd, Suite 500, Redwood City, CA 94063), are being conducted at the Mayo Clinic in Arizona by TGen Clinical Research Services, a partnership of Translational Genomics Research Institute (TGen) and Scottsdale Healthcare Corp.

Dr. Glen Weiss, Director of Thoracic Oncology at TGen Clinical Research Services TCRS at Scottsdale Healthcare, said the new drug appears promising and may be more effective and less toxic to healthy tissues than conventional drugs.

‘TH-302 is a new, novel, small molecule that is activated under a metabolic condition characteristic of cancer cells — hypoxia. The drug candidate may provide an opportunity to treat slowly dividing tumor cells within hypoxic regions that generally evade traditional chemotherapeutic agents and ultimately contribute to relapse,’ Dr. Weiss explained.

Phase I and Phase I/II trials are underway to investigate the safety and activity of TH-302 in patients with advanced solid tumors. After evidence of tumor activity was observed in the Phase I trial in patients with advanced melanoma – both non-small cell lung cancer and small cell lung cancer – the study was expanded to further investigate TH-302 anti-tumor activity in these tumors. Both Phase I and I/II trials continue to enroll patients with other solid tumors. If successful, Phase II and III clinical trials will confirm the drug's effectiveness on solid tumors.

Tumor hypoxia
Hypoxia is a condition in which there is a decrease in the oxygen concentration in tissue. In cancer, as a tumor grows, it rapidly outgrows its blood supply, leaving portions of the tumor with regions where the oxygen concentration is significantly lower than in healthy tissues. This condition is called tumor hypoxia. Several studies have shown that higher levels of tumor hypoxia correlate with poor treatment outcomes for a variety of solid tumors. It is believed that hypoxia may severely limit the curability of tumors.

This lack of oxygen in cancer cells compared to normal cells is exploited by Threshold’s Hypoxia-Activated Prodrug (HAP) platform. In time, this breakthrough technology platform may provide an opportunity to treat slowly dividing tumor cells within hypoxic regions that generally evade traditional chemotherapeutic agents and ultimately contribute to relapse.

A New Class of Drug
TH-302 is converted selectively in the presence of hypoxia to the drug’s active form, bromo-isophosphoramide mustard, a potent DNA alkylator. TH-302 targets levels of hypoxia that are common in tumors but are rare in normal tissues – this is how selective targeting of the tumor occurs. After conversion to the active form of the drug, the more resistant hypoxic cells are exposed to high concentrations of released cytotoxic agent, which can also diffuse into the oxygenated regions of a tumor cell. The Phase I/II trials are investigating the safety and activity of TH-302 in combination with a number of conventional chemotherapies that are believed to be effective in the non-hypoxic regions of solid tumors.

The clinical trial at TCRS at Scottsdale Healthcare will investigate the safety and pharmacology of multiple doses of TH-302 in patients with late-stage cancer.

The initial phase I clinical trial of TH-302 started in July 2007. In July 2008, interim results were presented. This trial was designed with an initial accelerated titration design followed by a standard dose escalation schema. The trial completed the accelerated titration design component and has enrolled the eighth dosing cohort. The weekly dose had been escalated from the initial dose of 7.5 mg/m2 to 670 mg/m2. None of the 20 patients enrolled at the time of the presentation has experienced any dose limiting toxicities (DLTs). One patient with refractory small cell lung cancer metastatic to the liver had a partial response at their initial response assessment with a greater than 45% reduction in target lesion diameters. The patient, who had received two cycles of TH-302, was being followed by RECIST (Response Evaluation Criteria In Solid Tumors) criteria. Other anti-tumor activity observed include one patient with non-small cell lung cancer with tumor shrinkage lasting over 6 months.

In August 2008, an additional clinical trial of TH-302 was initiated. The design of this trial included three separate treatment arms that will each examine TH-302 in combination with either gemcitabine, docetaxel or pemetrexed.

Approximately 50 patients with advanced solid tumors are planned to enroll in the Phase I/II, open-label, dose-escalation portion of the clinical trial. Up to six patients per dose level will participate in the dose escalation phase of the trial. Once the maximum tolerated dose (MTD) has been reached, the Phase II portion of the trial will enroll an additional 12 patients at the MTD within each treatment arm including gemcitabine in advanced pancreatic cancer patients, docetaxel in patients with castrate-resistant prostate cancer (CRPC) and pemetrexed in patients with non-small cell lung cancer.

Researchers expect that within the next several years a number of development candidates will arise from the hypoxia-activate prodrug platform.

For more information:

• Curd J, Sun J, Liu Q, et al, Targeting Tumor Hypoxia with TH-302 and Complementary Chemotherapy; 2nd American Association for Cancer Research (AACR) Conference on Translational Medicine, July 20-23, 2008; Monterey, CA. Drug Development/New Technologies: Poster Presentations - Proffered Abstracts, Abstract A5.
• Duan JX, Jiao H, Kaizerman J, et al. Potent and Highly Selective Hypoxia-Activated Achiral Phosphoramidate Mustards as Anticancer Drugs. Journal of Medicinal Chemistry, 51: 2412-2420, 2008.
• Hart C, Meng F, Banica M, et al., In vitro activity profile of the novel hypoxia-activated cytotoxic prodrug, TH-302. 99th American Association for Cancer Research (AACR) Annual Meeting, April 12-16, 2008; San Diego, CA, mTOR/Akt/PI3K Inhibitors and Vascular/Hypoxia Targeting Agents: Poster Presentations - Proffered Abstracts; Abstract 1441
• Jung D, Lin L, Plasma pharmacokinetics, oral bioavailability, and interspecies scaling of the hypoxically activated prodrug, TH-302, in mice, rats, dogs and monkeys. 99th American Association for Cancer Research (AACR) Annual Meeting- April 12-16, 2008; San Diego, CA, mTOR/Akt/PI3K Inhibitors and Vascular/Hypoxia Targeting Agents: Poster Presentations - Proffered Abstracts; Abstract #1447
• Hart C, et al., Discovery of TH-302: an achiral hypoxia-activated cytotoxic prodrug, American Society of Clinical Oncology (ASCO) Annual Meeting, June 2007.
• Wang J. Liu Q, Rosario G, et al., In vivo anti-cancer activity of a hypoxia activated prodrug, TH-302. American Association for Cancer Research (AACR) 98th AACR Annual Meeting, April 2007, 14-18, 2007; Los Angeles, CA. Meeting Abstracts, Apr 2007; 2007: 3988. Abstract # 3988.
• Ammons W, Wang J, Ma H, et al. Anti-tumor activity of a hypoxia activated prodrug, TH-302, in pancreatic and prostate orthotopic models of cancer. American Association for Cancer Research (AACR) 98th AACR Annual Meeting, April 14-18, 2007; Los Angeles, CA. Meeting Abstracts, Apr 2007; 2007: 3985. Abstract #3985

Note:

• The new version of RECIST (version 1.1) has been presented at the 20th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Geneva, Switzerland (21-24 October 2008) and will be published in a special edition of the European Journal of Cancer in the first quarter of 2009.