Onco’Zine reports about current research and development in hematology and oncology and includes comments on peer-reviewed reports and congress reports from international medical meetings.
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.
The U.S. Food and Drug Administration, in late December 2008, approved imatinib mesylate (Glivec®, Novartis AG, Lichtstrasse 35, 4056 Basel, Switzerland and Gleevec®, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, NJ) forthe post-surgery treatment of adult patients following complete surgical removal of KIT (CD117)-positive gastrointestinal stromal tumors (GIST).
The tyrosine kinase inhibitorimatinib mesylate is now the only post-surgery treatment indicated to delay the return of this highly aggressive cancer, filling a major need for GIST patients in the United States. The filing received FDA priority review status in August 2008, with regulatory reviews currently underway in other regions, including the European Union (EMEA) and Switzerland.
Soft Tissue Sarcoma While most cancers are carcinomas, gastrointestinal stromal tumors (GIST) belong to a group of cancers known as soft tissue sarcomas. These cancers grow from cells of the body’s connective or supportive tissues such as bone, cartilage, tendons, nerves, fat, muscle, synovial tissue, or blood vessels.
A life-threatening disease GIST is a life-threatening cancer of the GI tract affecting the digestive tract or nearby structures within the abdomen. It is the most common mesenchymal tumor of the gastrointestinal tract originating from cells found in the stomach and small intestine, Interstitial Cells of Cajal (ICCs) or from less differentiated stem cells or precursor cells, known as mesenchymal precurser cells, in the gut wall, which can develop into ICCs.
These Interstitial Cells of Cajal or ICCs are part of the autonomic nervous system , and generally found in the myenteric plexus and nearby areas between the circular and longitudinal layers of the gastrointestinal tract. Their function is to regulate gastrointestinal motility, or peristalsis, which is the autonomic movement of the GI tract to propel food and liquid through the digestive tract through the stomach and intestines.
Incidence Data concerning the worldwide prevalence of GIST is lacking. But some population based studies estimate the annual incidence to be 4,500 - 6,000 new cases per year in the United Sates (15-20 cases per million population), of which more than 90% are KIT-positive.
Genetics KIT - also known as CD117 - is a protein that, when mutated, has been identified as one of the major causes of GIST. These mutations result in spontaneous activation of tyrosine kinase domains, providing a constant growth stimulus to the tumor cells.
Many GIST contain mutations in exon 11 and, to a lesser degree, in exons 9, 13 or 16, of the c-kit (KIT) protooncogene coding for C-KIT (CD117). Imatinib mesylate inhibits the activity of several proteins such as KIT.
Some GISTs have a mutation of the platelet-derived growth factor receptor-alpha (PDGFRA) gene. Furthermore, a snall number of GISTs, aproximately 5-15%, have no detectable KIT or gene mutation. This includes most pediatric GISTs and GISTs arising in patients with an inactivation of the neurofibromatosis gene (NF1).
Like most cancers, GIST affects older people. The average age at presentation is 50 to 60 years of age. Children are rarely affected, while familial GIST develops in younger or middle-aged adults.
Difficult to diagnose Most patients, especially those with smaller tumors, are asymptomatic. Asymptomatic GISTs can be discovered incidentally during endoscopy or laparoscopy as well as during computed tomography (CT). Biopsy and endoscopic ultrasound are generally used for staging. However, because tumors are slow growing and symptoms of GIST are generally not different than other GI complaints such as nausea, vomiting, bleeding, dyspepsia and obstruction, earely detection of the cancer is rather dificult.
Approximately 60% of these tumors occur in the muscular wall of the stomach. However tumors may also develop in the small intestine, colon, rectum, esophagus and other intra-abdominal locations. The likelihood of malignant behavior is dependent on the size of the tumor and its rate of growth. Metastases usually occur within the abdominal cavity and/or the liver.
Treatment options Early gastrointestinal stromal tumors, or GIST that has not yet metastasized, is often treated initially with surgery to remove the cancer. Unfortunately, the risk of recurrence is high, and GIST remains relatively resistant to chemotherapy and/or radiation therapy. Targeted drugs that inhibit the KIT, such as imatinib mesylate, offer an important approach to treating these cancers. These drug are intended to be given to patients following surgery to help prevent recurrence.
However, in some cases patients with gastrointestinal stromal tumors (GIST) whose disease has progressed or who are unable to tolerate treatment with imatinib mesylate require alternative treatment. Researchers found that sunitinib malate (Sutent®, Pfizer Oncology, Pfizer Inc, 235 East 42nd Street, New York, NY 10017), an orally-available small-molecule multiple receptor tyrosine kinase inhibitor, delayed the time it takes for tumors or new lesions to grow in patients with this tare type of cancer. Specifically, the median time-to-tumor progression (TTP) for patients treated with sunitinib malate was 27 weeks compared to 6 weeks for patients who were not treated.
Established efficacy The efficacy of imatinib mesylate was established in a clinical trial in which patients received either imatinib mesylate or a placebo for one year after surgical removal of the tumor. The optimal treatment duration is not known.
There were significantly fewer recurrences of GIST in patients receiving imatinib mesylate than in patients who did not. The most frequently reported adverse reactions were diarrhea, fatigue, nausea, swelling of the feet, decreased red blood cell counts, rash, vomiting and abdominal pain.
Recurrence After initial removal, GIST tumors can return in as many as one of two patients. Recurrent GISTs are often more aggressive than primary tumors, with relapses associated with lower survival rates.
'After surgery, my doctor told me there was a high likelihood that my gastrointestinal tumors would come back. I immediately searched for a possible solution and found the Glivec clinical trial, which aimed to help patients like me,' said Roslyn Fuller, a GIST patient. 'This FDA approval is good news for me and other GIST patients who will now have the option to start treatment with Glivec earlier to help prevent recurrence.'
Phase II study The approval for this new indication is based on data from an international Phase III trial sponsored by the National Cancer Institute. The study showed a dramatic reduction in the return of GIST after surgery in patients treated for about one year with imatinib mesylate versus placebo.
The FDA regulatory filing for the adjuvant GIST indication was based on data from a Phase III, double-blind, randomized, multicenter, international study of more than 700 GIST patients who had undergone surgery to remove their tumors. The efficacy endpoint of the study was recurrence-free survival (RFS), defined as the time from the date of randomization to the date of recurrence or death from any cause. Participants were randomized to receive either imatinib mesylate 400 mg/day or a matching placebo for one year.
Based on a 14-month median follow up, 91.6% of patients receiving imatinib mesylate remained cancer-free compared with 80.2% of those taking placebo. (30 RFS events out of 359 patients in the imatinib mesylate arm (8.4%) compared to 70 RFS events out of 354 patients in the placebo arm (19.8%) (hazard ratio=0.398 [95% CI: 0.259, 0.610], p<0.0001).'Approval of Gleevec offers health care professionals and patients an important new therapeutic option for patients with this uncommon gastrointestinal disease,' said Richard Pazdur, M.D., director, Office of Oncology Drug Products, Center for Drug Evaluation and Research, FDA. 'It illustrates how the continued study of a once novel drug throughout its product lifecycle can yield new and important uses.'
Revolution in the making Imatinib mesylate was first approved by the FDA in 2001. It is one of the first drugs in a class of agents that block cellular communications that result in tumor growth. Soon after the introduction of effective molecularly targeted therapies such as imatinib mesylate and sunitinib malate the standard of practice for GIST rapidly changed.
'When Glivec was first approved for the treatment of inoperable and/or metastasized KIT-positive GIST six years ago, it revolutionized the treatment of this life-threatening cancer,' said David Epstein, President and CEO, Novartis Oncology. 'This atest FDA approval means patients can benefit from Glivec earlier in the course of their disease.'
Multiple indications The drug is now approved for nine indications, including the treatment of Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML), Kit (CD117)-positive gastrointestinal stromal tumors which cannot be surgically removed and/or have already spread to other parts of the body (metastasized) and five other rare diseases.
Mode of Action The effectiveness of imatinib mesylate is based on overall hematological and cytogenetic response rates and progression-free survival in CML, on hematological and cytogenetic response rates in Ph+ ALL, MDS/MPD, on hematological response rates in SM, HES/CEL, on objective response rates and progression-free survival in unresectable and/or metastatic GIST, on recurrence free survival in adjuvant GIST, and on objective response rates in DFSP. Increased survival in controlled trials has been demonstrated only in newly diagnosed chronic phase CML and GIST.
Z9001: A Phase III Randomized Double-blind Study of Adjuvant STI571 (Glivec®) Versus Placebo in Patients Following the Resection of Primary Gastrointestinal Stromal Tumor (GIST). Accessed January 2009.
American Cancer Society. Cancer Reference Information. Detailed Guide for Gastrointestinal Stromal Tumors. Key Statistics. Accessed January 2009.
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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. 
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