CyberKnife Treatment Planning Capabilities in Precision Radiation Delivery for Lung Cancer

Accuray Incorporated, a global leader in the field of radiosurgery, announced today that it wil showcase the treatment planning capabilities of the CyberKnife Robotic Radiosurgery System at the 10th Biennial European Society for Therapeutic Radiology and Oncology (ESTRO) Conference on Physics and Radiation Technology for Clinical Radiotherapy in Maastricht, The Netherlands.

The CyberKnife Robotic Radiosurgery System is the world's only robotic radiosurgery system designed to treat tumors anywhere in the body non-invasively. Using continual image guidance technology and computer controlled robotic mobility, the CyberKnife System automatically tracks, detects and corrects for tumor and patient movement in real-time throughout the treatment. This enables the CyberKnife System to deliver high-dose radiation with pinpoint precision, which minimizes damage to surrounding healthy tissue and eliminates the need for invasive head or body stabilization frames.

The latest generation of the MultiPlan Treatment Planning System provides the most comprehensive set of tools available for high-precision radiosurgery treatment planning. The CyberKnife System's planning capabilities also include Monte Carlo Dose Calculation, which produces results in minutes compared to what commonly requires hours or days with other systems.

"We strongly believe that these new capabilities will transform the treatment planning practice, specifically for the treatment of lung tumors," said Frederic Sottilini, Senior Director, Marketing, Accuray EMEA.

Clinical findings will be presented during the conference, including the results of a study presented by Erasmus MC-Daniel den Hoed Cancer Center (Rotterdam, The Netherlands) that demonstrates the benefits of the dose calculations performed using the CyberKnife System's Monte Carlo Dose Calculation in the treatment of Non-Small Cell Lung Cancer.

"Medical physicists from renowned academic centers will contribute to the scientific quality of this symposium, which should gather physicists from all over Europe who are interested in learning more about the highly-sophisticated treatment planning techniques that are available," said Sottilini.

Erlotinib Improves Overall Survival After Initial Chemotherapy in Patients with Advanced Lung Cancer

Results from SATURN, a pivotal Phase III study, met a key secondary endpoint of extending overall survival in patients with advanced non-small cell lung cancer (NSCLC) who received erlotinib (Tarceva®, Genentech/Roche; OSI) immediately after their initial chemotherapy. A statistically significant improvement in overall survival was seen in the pre-planned final analysis of the total patient population in the study. The new data will be presented during the 13th World Conference on Lung Cancer to be held July 31 – August 4, 2009 in San Francisco.

Lung cancer is the most common cancer worldwide with 1.5 million new cases annually and NSCLC accounts for 85 – 90% of all lung cancers. Non-small cell lung cancer (NSCLC) progresses rapidly and survival rates are generally very poor. Most people are diagnosed with advanced stage disease and less than 5% of these advanced NSCLC patients survive for five years. Extending the time patients live and managing side effects are key treatment goals.

According to the American Cancer Society, lung cancer is the leading cause of cancer death in the United States. In 2009, approximately 159,000 Americans will die from the disease.
Treating patients immediately following first-line chemotherapy versus waiting for the cancer to grow or spread before giving additional treatment represents a new approach in advanced NSCLC.

A new approach
Erlotinib is, as a Human Epidermal Growth Factor Receptor Type 1/Epidermal Growth Factor Receptor (HER1/EGFR) tyrosine kinase inhibitor, different from conventional chemotherapies.
Over-expression of EGFR is common in several solid tumors, such as colorectal cancer, lung carcinomas, and cancers of the head and neck. It correlates with increased metastasis, decreased survival and a poor prognosis. EGFR protects malignant tumors cells from the cytotoxic effects of chemotherapy and radiotherapy, making these treatments less effective.

HER1 and EGFR receptors are directly involved in inter-cellular signaling in systems governing cell division and proliferation. By interfering with the function of these receptors, which are highly active and often over-expressed in rapidly dividing tumor cells, erlotinib inhibits EGFR-receptor tyrosine kinase activity, and may help to initiate pathways of apoptotic cell death. The interference with the cell signaling pathways involved in cell proliferation represents a novel approach to the treatment of solid tumors.

Today, erlotinib is the first and only EGFR oral targeted agent in second line with a proven and significant survival and symptom benefit in a broad range of patients with advanced lung cancer without the side effects associated with chemotherapy. The drug has been approved in the EU since September 2005 and in the US since November 2004 for the treatment of patients with locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen.

Patient benefit
In the landmark registration study BR.21, a randomised controlled phase III clinical trial comparing erlotinib with placebo/best supportive care in patients with locally advanced or metastatic non-small lung cancer which took place in 17 countries around the world, erlotinib delivered effectiveness comparable to chemotherapy and significantly improves overall quality of life.

The registration study underlined that more patients on erlotinib had improvement in cough, pain, shortness of breath and overall physical function versus patients on placebo. In addition erlotinib did not induce the distressing side-effects associated with chemotherapy, such as nausea and vomiting. An added benefit, improving adherence, is that erlotinib is convenient as patients can take a tablet once a day at home rather than receive intravenous treatments in a hospital.

Global trial
SATURN, a global multicentre, double blind, randomized, prospective phase III study was designed to evaluate the efficacy of erlotinib vs. placebo in patients with advanced, recurrent or metastatic NSCLC who had not progressed following first line platinum-based chemotherapy. The study involved more than 880 patients from approximately 160 centers; 438 received erlotinib and 451 placebo.

The study met its primary endpoint demonstrating a statistically significant extension of the time patients live without their disease worsening; there was a 41% increase compared with placebo (hazard ratio= 0.71, p-value <0.0001).>

“This study has now not only confirmed that immediate treatment with Tarceva after initial chemotherapy delayed the progression of disease, but also importantly helped patients in the study live longer,” said Professor Federico Cappuzzo, M.D., Istituto Clinico Humanitas IRCCS, Milan and principal investigator of the SATURN study. “This is good news for doctors and their patients since advanced lung cancer is one of the most challenging cancers to treat and is often associated with a very short life-expectancy.”

Commenting on the study, William M. Burns, CEO Division Roche Pharmaceuticals said, “This is the second set of data from large studies that has shown Tarceva helps patients with advanced lung cancer to live longer. These results confirm that Tarceva has an important role to play in improving the lives of patients earlier in the management of this devastating disease.”

Erlotinib is already a well established treatment in second-line management of advanced NSCLC after the failure of chemotherapy and is proven to extend survival for a broad range of patients in this setting. Most recently, presentation of the SATURN primary endpoint data analysis at ASCO 2009 showed that patients who received treatment with erlotinib immediately after initial chemotherapy if their cancer had not progressed had a 41% improvement in the length of time they lived without their disease getting worse compared to placebo.

Outcome confirmed
During the Annual Society of Clinical Oncology (ASCO) Vincent A. Miller, MD., a medical oncologist from the Memorial Sloan-Kettering Cancer Center, presented results from the phase III ATLAS study supported findings in the SATURN study.

The ATLAS study, a global multicentre, randomised, double blind, placebo controlled study that enrolled 1,160 patients with locally advanced, recurrent or metastatic NSCLC, was designed to evaluate bevacizumab (Avastin®, Genentech/Roche) in combination with erlotinib (150 mg daily) versus bevacizumab alone, following bevacizumab in combination with a platin-containing doublet chemotherapy, in patients with stage IIIb/IV NSCLC.

The study showed that combined treatment with bevacizumab and erlotinib, immediately following initial therapy with bevacizumab plus chemotherapy was highly effective and significantly delayed disease progression for patients with advanced NSCLC, without the need for chemotherapy.

The positive results from these trials were encouraging because previous Phase III studies in which erlotinib was used as first-line therapy in combination with cytotoxic drugs (the TRIBUTE and TALENT studies) failed to demonstrate a survival advantage when erlotinib was added to conventional treatment regimens.

The overall survival data fron SATURN will be used to support the European and US applications for use of erlotinib as a first-line maintenance treatment for patients with advanced NSCLC. These applications were made to the European Medicines Agency (EMEA) and US Food and Drug Administration (FDA) in March 2009 and are based on the pivotal Phase III SATURN trial. The FDA Prescription Drug User Fee Act (PDUFA) review date will be on or about January 18, 2010.

Commenting on the overal product development, Colin Goddard, Ph.D., Chief Executive Officer of OSI Pharmaceuticals, Roche's US partner, said:"We are pleased with the launch of Tarceva in the U.S. to date and we continue to believe that Tarceva will emerge as a fundamentally important new agent in changing the paradigm for the treatment of cancer patients around the world. With our partners, Genentech and Roche, we are committed to executing a post-approval development plan, studying Tarceva in earlier stage lung cancer patients, in patients with other tumor types and combinations with other targeted therapies."

For more information:

• Gatzemeier U, Pluzanska A, Szczesna A, Kaukel E, Roubec J, et al. Phase III Study of Erlotinib in Combination With Cisplatin and Gemcitabine in Advanced Non–Small-Cell Lung Cancer: The Tarceva Lung Cancer Investigation Trial. Journal of Clinical Oncology, Vol 25, No 12 (April 20), 2007: pp. 1545-1552.
• Herbst RS, Prager D, Hermann R, Fehrenbacher L, Johnson BE, et al. TRIBUTE: A Phase III Trial of Erlotinib Hydrochloride (OSI-774) Combined With Carboplatin and Paclitaxel Chemotherapy in Advanced Non–Small-Cell Lung Cancer. Journal of Clinical Oncology, Vol 23, No 25 (September 1), 2005: pp. 5892-5899.
• National Cancer Institute: Erlotinib (Tarceva®) Extends Survival in Advanced Lung Cancer
• Tarceva (erlotinib) USA website for healthcare professionals
• Tarceva (erlotinib) Global website for healthcare professionals
• Garcia M et al. Global Cancer Facts & Figures. Atlanta, GA: American Cancer Society, 2007.
• Highlights of Prescribing Information (USA)

ASCO 2009 Annual meeting:

• Cappuzzo F, Ciuleanu T, Stelmakh L, Cicenas S, Szczesna A, et al. SATURN: A double-blind, randomized, phase III study of maintenance erlotinib versus placebo following nonprogression with first-line platinum-based chemotherapy in patients with advanced NSCLC. J Clin Oncol 27:15s, 2009 (suppl; abstr 8001). Abstract presented at ASCO 2009 Annual Meeting, Orlando.
• Miller VA, O'Connor P, Soh C, Kabbinavar F. A randomized, double-blind, placebo-controlled, phase IIIb trial (ATLAS) comparing bevacizumab (B) therapy with or without erlotinib (E) after completion of chemotherapy with B for first-line treatment of locally advanced, recurrent, or metastatic non-small cell lung cancer (NSCLC). J Clin Oncol 27:18s, 2009 (suppl; abstr LBA8002). Abstract presented at ASCO 2009 Annual Meeting, Orlando.

Also read these PubMed abstracts:

• Allen J, Jahanzeb M. Neoadjuvant chemotherapy in stage III NSCLC. J Natl Compr Canc Netw. 2008 Mar;6(3):285-93.
• Brown ER, Shepherd FA. Erlotinib in the treatment of non-small cell lung cancer. Expert Rev Anticancer Ther. 2005 Oct;5(5):767-75. Review.
• Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, et al. Erlotinib in Previously Treated Non–Small-Cell Lung Cancer. N Engl J Med 2005; 353:123-132. (See also Full Text Article)
• Tsao MS, Sakurada A, Cutz JC, Zhu CQ, Kamel-Reid S, et al. Erlotinib in Lung Cancer — Molecular and Clinical Predictors of Outcome. N Engl J Med. 2005 Jul 14;353(2):133-44 (See also Full Text Article).
• Sandler A. Clinical experience with the HER1/EGFR tyrosine kinase inhibitor erlotinib. Oncology (Williston Park). 2003 Nov;17(11 Suppl 12):17-22

Information for your patient:

• Tarceva (erlotinib) USA patient website.
• Tarceva (erlotinib) Global patient website.

Images courtesy American Society of Clinical oncology (ASCO)

Pemetrexed First Agent Approved in Europe as Maintenance Therapy for Advanced, Nonsquamous Non-Small Cell Lung Cancer

The European Medicines Agency’s (EMEA) Committee for Medicinal Products for Human Use (CHMP) has granted approval for the use of pemetrexed for injection (Alimta ®, Eli Lilly and Company) as monotherapy for maintenance treatment of patients with other than predominantly squamous cell histology in locally-advanced or metastatic non-small cell lung cancer (NSCLC), whose disease has not progressed immediately following platinum-based chemotherapy. This approval is based on data that showed pemetrexed improved overall survival in other than predominantly squamous NSCLC patients in the maintenance setting.

Globally, lung cancer is the most common form of cancer and the biggest killer, causing 1.3 million cancer deaths annually. This is more than breast, colon and prostate cancer taken together. About 85 - 90 percent of all lung cancers are non-small cell lung cancer (NSCLC). Survival rates are very poor.

Major disease forms
Non-small cell lung cancer (NSCLC) is defined as a group of histologies, that is, tumor types differentiated by cellular structure. The most predominant is squamous cell carcinoma (also known as epidermoid carcinoma) which accounts for 30 - 40% of all NSCLC cases. Formed from round cells that replace damaged cells along the epithelium of the main, lobar or segmental bronchi, this disease is a relatively slow growing carcinoma with a relatively good prognosis. Recurrence rates for resected squamous cell carcinoma are relatively low compared top other types of NSCLC, with distant metastases less common given the same treatment at the same stage.

Also referred to as nonsquamous histology, adenocarcinoma, which account for more than half of all NSCLC diagnoses, usually arises from mucus-producing cells of the lung. Aproximately two-thirds of adenocarcinomas develop in the outer regions of the lung, while the remaining one-third develop centrally. The majority of adenocarcinomas are asymptomatic until they have progressed to an advanced stage. As a consequence, the prognosis is generally worse compared to that of squamous cell carcinoma. On the other hand, once diagnosed, adenocarcinomas generally respond better to treatment than other NSCLC histologies.

Squamous cell carcinoma tends to metastasize in the bone, adrenal glands, liver, small intestines and brain. Because this disease is almost always caused by smoking, occurrence has decreased over the past 30 - 35 years.

Other types of NSCLC include bronchoalveolar carcinoma (BAC), a subclassification of adenocarcinoma with distinct clinical and pathologic properties and large cell carcinoma.

The majority of patients with NSCLC eventually develop metastatic disease or disease that is not a candidate for surgical interventions. this makes them potential candidates for systemic therapies. However, the decision on whether a patient receives therapy, greatly depends upon a number of factors, including the disease stage. In general, the more advanced the disease is, the more likely that a physician will prescribe a drug therapy.

Staging of Lung Cancer
Lung Cancer is often classified according to the American Joint Commitee on Cancer (AJCC) TNM staging system, and has five-tier staging, starting at 0 and rising to the severity of stage IV.

The primary T1 tumor, generally smaller than 3 centimeter, is usually easy to define on computed tomography (CT) and fluorodeoxyglucose positron emission tomography (FDG-PET).

TNM stage T3 tumors include tumors of any size with direct extension into the chest wall, diaphragm, mediastinal pleura or pericardium. Stage T4 tumors invade the mediastinum, great vessels, trachea, oesophagus and vertebral bodies.

Lung cancer in metastatic stage becomes aggressive. In this stage a therapy to shrink tumour size, stabilize the disease and relieve debilitating symptoms, with minimal toxic effects of the drug is required. Pemetrexed is the most promising molecule in that aspect. The drug provides better survival, progression free time and response and has superior tolerability than other cytotoxic drugs used for the same condition.

Mechanism of action
Pemetrexed is a multitargeted antifolate currently approved for first-line treatment of advanced, other than predominantly squamous NSCLC in combination with a platinum-based chemotherapy, and as a single agent in the second-line setting for advanced, other than predominantly squamous NSCLC patients with recurrent disease. Pemetrexed is chemically similar to folic acid and is in the class ofchenotheray drugs called folate antimetabolites. It works by inhibiting three enzymes used in purine and pyrimidine synthesis—thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyl transferase (GARFT).

Improve Overall Survival in a Maintenance Setting
The concept of maintenance therapy represents a paradigm shift in the treatment of advanced, other than predominantly squamous NSCLC.

Traditionally, patients who respond to first-line chemotherapy are monitored until the disease recurs and are then treated with a second-line regimen. In maintenance therapy, rather than halting further treatment until disease progression, patients who respond to a first-line therapy are treated immediately with a maintenance regimen.

"The idea behind ALIMTA as maintenance therapy for nonsquamous, non-small cell lung cancer is to treat patients immediately following their initial course of therapy, in an effort to prolong survival," said Richard Gaynor, M.D., vice president, cancer research and global oncology platform leader at Lilly. "The study that led to this approval was the first that showed improved overall survival in the maintenance setting for NSCLC. This was also the third trial to show the benefit of tailoring ALIMTA treatment to the nonsquamous NSCLC patient population."

Overall survival data for pemetrexed as a maintenance therapy for NSCLC was presented on May 31, 2009, at the 45th Annual Meeting of the American Society of Clinical Oncology (ASCO) by Chandra P Belani M.D.

The trial compared efficacy with respect to overall survival of pemetrexed plus best supportive care versus placebo plus best supportive care in 663 patients with stage IIIB/IV NSCLC whose disease had not progressed after four cycles of platinum-based induction chemotherapy. Pemetrexed was not included among the induction regimens studied in the maintenance trial. The trial supported two previous studies looking at the use of histology to tailor treatment for patients with advanced, other than predominantly squamous NSCLC.

Patients in the trial were treated with pemetrexed (500 mg/m2 on day one of each 21-day cycle) plus best supportive care or placebo plus best supportive care. All patients were supplemented with vitamin B12, folic acid and dexamethasone.

Pemetrexed was initially approved by the FDA in 2004 for the treatment of mesothelioma, with subsequent approval for second-line treatment of NSCLC.

This latest approval for pemetrexed - the fourth in Europe - follows an initial positive opinion issued by the European Medicines Agency's (EMEA) Committee for Medicinal Products for Human Use (CHMP) on May 29, 2009, and the recent approval by the U.S. Food and Drug Administration (FDA) of pemetrexed for maintenance therapy in advanced, nonsquamous NSCLC patients whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.

Apart from the existing approvals in the EU and U.S. for the use of pemetrexed in the treatment of patients with locally-advanced or metastatic other than predominantly squamous NSCLC, pemetrexed is also approved, in combination with cisplatin, in both the EU and U.S. for the treatment of chemotherapy naive patients with unresectable malignant pleural mesothelioma.

For more information:

• Official Lilly Physician Resource for pemetrexemed
• Commitee for Medicinal Products for Human Use Post-Authorisation Summary of Positive Opinion for Alimta (EMEA)
• American Cancer Society: Lung Cancer - Non-Small Cell
• C. P. Belani, T. Brodowicz, et al. Maintenance pemetrexed (Pem) plus best supportive care (BSC) versus placebo (Plac) plus BSC: A randomized phase III study in advanced non-small cell lung cancer (NSCLC). Abstract #CRA8000. 2009 American Society of Clinical Oncology (ASCO) Annual Meeting. J Clin Oncol 27:18s, 2009 (suppl; abstr CRA8000).
• C.P. Belani. Maintenance Pemetrexed Plus Best Supportive Care (BSC) Versus Placebo Plus BSC: A Phase III Study in NSCLC. ASCO 2009 Annual Meeting. Oral presentation (Oral Presentation Chair(s): Jyoti D. Patel, MD; Karen L. Reckamp, MD)
• National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (Version 2.2006). Non-Small Cell Lung Cancer.
• Staging of non-small cell lung cancer (NSCLC)
• About the TNM System (Blog)
• American Joint Committee on Cancer: PowerPoint Presentation; Staging Lung Cancer.
• Mayo Clinic: Lung Cancer
• Lung Cancer Alliance

Also read these PubMed abstracts:

• Rossi A, Ricciardi S, Maione P, de Marinis F, Gridelli C. Pemetrexed in the treatment of advanced non-squamous lung cancer. Lung Cancer. 2009 Jul 3. [Epub ahead of print]
• Bobin-Dubigeon C, Amiand MB, Herrenknecht C, Bard JM. Development and validation of an improved liquid chromatography-mass spectrometry method for the determination of pemetrexed in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci. 2009 Jun 21. [Epub ahead of print].
• Belli C, Fennell D, Giovannini M, Gaudino G, Mutti L. Malignant pleural mesothelioma: current treatments and emerging drugs. E xpert Opin Emerg Drugs. 2009 Jun 24. [Epub ahead of print]
• Racanelli AC, Rothbart SB, Heyer CL, Moran RG. Therapeutics by cytotoxic metabolite accumulation: pemetrexed causes ZMP accumulation, AMPK activation, and mammalian target of rapamycin inhibition. Cancer Res. 2009 Jul 1;69(13):5467-74. Epub 2009 Jun 23.
• Vlastos F, Hillas G, Vidal P, Lacomme S, Galateau-Sallé F, et al. Survey and Biological Insights of Pemetrexed-Related Therapeutic Improvement in Mesothelioma: The Nancy Centre of Biological Resources' Mesothelioma Cohort. J Thorac Oncol. 2009 Jun 19. [Epub ahead of print]
• Comella P, Chiuri VE, De Cataldis G, Filippelli G, Maiorino L, et al. Gemcitabine combined with either pemetrexed or paclitaxel in the treatment of advanced non-small cell lung cancer A randomized phase II SICOG trial. Lung Cancer. 2009 Jun 20. [Epub ahead of print]
• Scagliotti GV, Ceppi P, Capelletto E, Novello S. Updated clinical information on multitargeted antifolates in lung cancer. Clin Lung Cancer. 2009 Mar;10 Suppl 1:S35-40. Review.

How to help your patients:

• Encourage your patients to have an open, honest talk with you. Tell them that they should feel free to ask any question that’s on their mind, no matter how small it might seem. Also, encourage your patients to talk to other healthcare professionals, including nurses, social workers, and other members of the healthcare team.

Patient resources:

• ASCO’s Guideline on Adjuvant Treatment for Lung Cancer

Images courtesy American Society of Clinical oncology (ASCO)

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.