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The Lancet Oncology

Monday, June 29, 2009

XL184 shows substantial activity in Patients with Previously Treated Glioblastoma Multiforme and Medullary Thyroid Cancer

Results from the ongoing phase II trial of XL184 demonstrates substantial activity in patients with previously treated progressive or recurrent glioblastoma multiforme (study XL184-201). Data of the ongoing trial was presented during the 45th annual meeting of the American Society of Clinical Oncology (ASCO). XL184 has exhibited dose-dependent tumor growth inhibition and tumor regression in a variety of tumor models, including breast cancer, colon cancer, medullary thyroid cancer , non-small cell lung cancer, and glioblastoma. Additional research now shows that treatment with XL184 at a dose of 175 mg PO qd results in potent inhibition of glioblastoma multiforme (GBM).

XL184 (BMS-907351) is a potent, orally administered, small molecule inhibitor of receptor tyrosine kinases. The compound also inhibits MET, a receptor tyrosine kinase that plays a key role in cellular proliferation, migration, and angiogenesis. MET is mutationally activated in some tumor types, such as hereditary and sporadic papillary renal cell carcinoma and some head and neck cancers. More frequently, MET is either over-expressed or activated in the absence of mutation in glioblastomas, breast carcinomas, some gastric cancers, and other solid tumors. MET amplification has been demonstrated in some NSCLCs.

Overexpression of MET and vascular endothelial growth factor receptor-2 (VEGFR2), as well as the ligands which activate these receptors, has been shown to correlate with poor prognosis in glioblastoma multiforme, which is the most common and most aggressive form of brain tumor in humans, accounting for 52% of all primary brain tumor cases and 20% of all intracranial tumors, and occurs in only 2–3 cases per 100,000 people in Europe and North America.

In addition, phosphorylated RET has been described in some cases of glioblastoma multiforme. Expression of VEGF has been observed in a variety of cancers and has been associated with prognostic significance. Targeting the VEGF receptor has been recognized as a potential anti-cancer strategy in multiple tumors. Dual targeting of MET and VEGFR2 blocks two of the major mechanisms tumors use to overcome hypoxia. Activated RET is involved in cell signaling cascades that regulate cell proliferation, migration, differentiation, and survival. RET is mutationally activated in papillary thyroid cancer (PTC) and in both familial and sporadic forms of medullary thyroid cancer (MTC).

Development of XL184
Exelixis Inc. (210 East Grand Avenue, P.O. Box 511, South San Francisco, CA 94083-0511 phone (650) 837-7000,fax (650) 837-8300), a biotechnology company focusing on the development of compounds targeting multiple receptor tyrosine kinases simultaneously as well as components of key components of downstream signaling pathways that play important roles in cancer and metabolic diseases, develops XL184 with Bristol-Myers Squibb Company (BMS), a global biopharmaceutical company.

The companies are currently conducting multiple clinical studies for XL184, in glioblastoma multiforme (GBM) and medullary thyroid cancer (MTC).Cursief John De Groot, MD, of The MD Anderson Cancer Center, and an investigator on the Phase 2 glioblastoma-trial, presented data during a poster session during the ASCO meeting.

The exploratory study evaluated the safety, tolerability and clinical activity of XL184 at a continuous daily dose of 175 mg in patients with previously treated glioblastoma multiforme. To date, 46 patients who make up the intent to treat (ITT) population have been enrolled in the trial, including 30 (65%) in first relapse and 16 (35%) in second or third relapse. Importantly, the trial did not exclude patients previously treated with an antiangiogenic agent.

The tumor response, as determined by an independent radiology facility (IRF), using MacDonald criteria were reported. By ITT analysis, 7 of 35 (20%) of the antiangiogenic naïve patients had a confirmed partial response. The overall rate of response in all patients, including the refractory population of previously treated patients with an antiangiogenic therapy, was 15%. The median duration of response by IRF was 2.9 months (range = 1.9-8.6 months). In an exploratory analysis, among 35 patients with at least one post baseline MRI scan, 12 (34%) had tumor shrinkage ≥50% as their best response as determined by investigator, including 1 patient who had received prior antiangiogenic therapy.

The efficacy evaluable population was defined as patients having received at least 1 dose of XL184 and either had at least 1 post-baseline tumor assessment per investigator or failed to return for any tumor assessments because of death or clinical determination of progression. In the anti-angiogenic naïve population, 7 of 31 (23%) of efficacy evaluable patients had a confirmed partial response by IRF. The 6-month progression-free survival (PFS) rate in patients receiving no prior antiangiogenic therapy was 23%, with 10 patients censored for PFS at the time of analysis, and the median PFS interval was 3.6 months.

“These initial data from our ongoing glioblastoma multiforme (GBM) program are encouraging, and suggest that XL184 could have utility in this underserved indication,” said Michael M. Morrissey, Ph.D., president of research and development at Exelixis. “We believe that these data support continued evaluation of XL184 in patients with GBM, and we intend to enroll additional patients in this study to better assess the compound’s anti-tumor activity and safety profile in this difficult to treat patient population.”

As of January 6, 2009 all 46 patients were evaluated for safety. At least 1 post-baseline tumor assessment at 4 weeks was available for 26 pts. Of these, 17 pts had not received prior therapy with an anti-angiogenic agent, whereas 9 pts had received prior therapy with bevacizumab (n = 6), vandetanib (n = 2), or VEGF-TRAP (n = 1). Most adverse events were of Grade 1 or 2 severity. The most frequently occurring Grade 3 and Grade 4 adverse events were: fatigue (30%), alanine aminotransferase increase (9%), confusional state (9%), lipase increase (9%), lymphopenia (9%), convulsion (7%), headache (7%), and hypophosphatemia (7%). Adverse events of special interest were: hypertension (all incidences, 39%; Grade 3/4, 7%), palmar-plantar erythrodysesthesia (30%; 7%), bleeding events (28%; 9%), proteinuria (26%; 0%), pulmonary embolism (9%; 7%) and craniotomy wound dehiscence (4%; 2%).

In the study, 87% of patients had a dose interruption of XL184, median average daily dose was 122 mg/day. XL184 will be evaluated at a lower dose of 125 mg daily in order to provide continuous and sustained exposure to the drug in this previously treated glioblastoma population.

Other studies with XL184
Correlative tumor profiling and biomarker evaluation and vascular imaging data from this trial was also presented in two additional posters in the same poster session. Abstract 2048, entitled “Neurovascular imaging in GBM patients quantifies early physiologic changes after treatment with XL184, an inhibitor of multiple receptor tyrosine kinases: results from a Phase 2 study” was presented by Gregory Sorensen, MD, from the Massachusetts General Hospital, Boston, MA, and abstract 2049, entitled "Correlative tumor molecular profiling and plasma biomarker analysis in a phase 2 study of XL184 in patients with progressive or recurrent glioblastoma multiforme" was presented by Samuel DePrimo, PhD, Exelixis Inc, South San Francisco, CA.

Medullary Thyroid Cancer
The American Cancer Society estimates that Medullary Thyroid Cancer (MTC) accounts for aproximately5% of all thyroid cancers. Medullary thyroid carcinoma (MTC) is a rare calcitonin-producing neuroendocrine tumour that originates from the parafollicular C-cells of the thyroid gland. The RET proto-oncogene encodes the RET receptor tyrosine kinase, which has essential roles in cell survival, differentiation and proliferation.

The disease occurs in sporadic and inherited forms (approximately 80% and 20% of MTC, respectively). Patients with the inherited form of medullary thyroid carcinoma (MTC) invariably have an activating mutation in RET in their germline DNA. Activating mutations in RET are also present in the tumor DNA of up to 50% of sporadic MTC patients with no familial history of thyroid cancer. MTC may metastasize to lymph nodes or other organs before it is ever diagnosed. Additionally, MTC does not take up radioactive iodine, which is commonly used to treat other types of thyroid cancers and to diagnose metastases. As a result, MTC is more difficult to treat than other thyroid cancers.

So far, there are no approved therapies for MTC; however, common treatments for MTC include surgery to remove malignant tissue, radiation therapy, and chemotherapy, all of which are associated with potential side effects, some of which may be long-term.

During 2008 annual meeting of the American Society of Clinical Oncology (ASCO) safety and clinical activity data were presented from an ongoing phase 1 trial of XL184 in 69 patients with various solid tumors, including 17 MTC patients evaluable for response. These data showed a disease control rate (percentage of patients with partial responses or prolonged stable disease greater than 3 months) of 100% in the evaluable MTC patients, with 53% of those patients (9 of 17) experiencing partial responses. In this trial, the median duration of partial responses and stable disease for patients with MTC had not yet been reached. Most of the MTC patients in the trial had previously failed other treatments, including tyrosine kinase inhibitors with anti-RET activity, including vandetanib (AstraZeneca, Zactima™, also known as ZD6474), sorafenib (Nexavar®, Bayer/Onyx), or motesanib (Amgen/Takeda) chemotherapeutic agents, immunotherapy, radioactive iodine, and radiotherapy. Patients are now recruited to participate in new and ongoing trials.

ASCO 2009 Abstracts
ASCO 2008 abstracts:

ASCO 2008 presentations:

Clinical trials:

  • Study of XL184 in Adults With Glioblastoma Multiforme (recruiting). The purpose of this study is to evaluate the objective response rate and 6-month progression-free survival rate of XL184 in subjects with recurrent or progressive glioblastoma multiforme. XL184 is a new chemical entity that inhibits VEGFR2, MET and RET, kinases implicated in tumor formation, growth and migration. Contact: Exelixis Contact Line 1-866-939-4041.
  • Phase III Efficacy Study of XL184 in Adults With Medullary Thyroid Cancer (recruiting). The purpose of this research study is to evaluate the progression-free survival (PFS) with XL184 as compared with placebo (an inactive substance) in subjects with unresectable, locally advanced, or metastatic medullary thyroid cancer (MTC). Subjects will be randomized to receive XL184 or placebo in a 2:1 ratio. XL184 is an investigational drug that inhibits VEGFR2, MET and RET, kinases implicated in tumor formation, growth and migration. Contact: Exelixis Contact Line 1-866-939-4041 Stanford University School of Medicine, Primary contact: Ruth Lira, (650) 723-1367)
  • Study of XL184 in Adults With Advanced Malignancies (ongoing, not recruiting) The purpose of this study is to determine the best and safest dose of XL184 administered orally. XL184 is a new chemical entity that inhibits VEGFR2, MET and RET, kinases implicated in tumor formation, growth and migration. To determine the highest safe dose, subjects will receive different amounts of the drug. The first group of subjects will receive the lowest dose of XL184. As long as no medically unacceptable side effects are noted, the dose will be increased for the next group. When the maximum tolerated dose (MTD) is reached, at least 20 subjects with Medullary Thyroid Cancer (MTC) will be enrolled to evaluate the effect of XL184 in this population.
  • Study of XL184 in Adults With Glioblastoma Multiforme (recruiting) The purpose of this study is to evaluate the objective response rate and 6-month progression-free survival rate of XL184 in subjects with recurrent or progressive glioblastoma multiforme. XL184 is a new chemical entity that inhibits VEGFR2, MET and RET, kinases implicated in tumor formation, growth and migration.

Also read PubMed Abstracts:

More information (General):

Illustrations courtesy of the American Society of Clinical Oncology

Thursday, June 25, 2009

The IMPAKT of a New Drug Target in Breast Cancer

New and exciting results presented at the first IMPAKT Breast Cancer Conference (Brussels, Belgium, May 7 - 9) an international medical meeting focusing on IMProving cAre and Knowledge through Translational Research, may help scientists develop treatments for women with a type of breast cancer that currently does not respond to targeted therapies.

Although most people generally think of breast cancer as a single disease, doctors have recently come to understand that it actually comes in a variety of different ‘subtypes’. Each different subtype has different risk factors, different rates of progression, different treatment options, and a different prognosis. They are diagnosed based upon the presence three ‘receptors’ found on cancer cells: estrogen receptors (ER), progesterone receptors (PR) and human epidermal growth factor receptor 2 (HER2/neu).

Over the years, effective treatments have been developed to target each of these receptors. Some cancers, however, are estrogen receptor-negative, progesterone receptor-negative and HER2-negative, and are better known as ‘triple-negative’ breast cancers.

Triple-negative tumors generally do not respond to receptor-targeted treatments and is clinically characterized as more aggressive and less responsive to standard treatments. This form of breast cancer is generally associated with poorer overall patient prognosis and is more common among women with BRCA1 gene mutations. Furthermore, for reasons not yet well understood, triple-negative breast cancer is also more frequently diagnosed in younger women and African-American women. Researchers include triple-negative breast cancers are part of the subgroup of ‘basal-type’ breast cancers.

The role of androgens (AR)
In recent years, scientists have begun looking for new targets in these triple-negative breast cancers. One of the targets that has been identified is the androgen-receptor.

Studies have shown that the risk of breast cancer is increased in postmenopausal women with high estrogen levels as well as in women with high androgen levels. While the mechanism by which androgens contribute to breast cancer is not well understood, but studies have shown that androgens can induce proliferative changes in breast tissue. Furthermore, animal models have shown that administration of both estrogen and androgens can induce tumor formation.
Other studies have show that BRCA1 is a coactivator of the androgen-receptor (AR), making this an interesting and viable target.

GeparTrio Trial
At the IMPAKT Breast Cancer Conference, Sibylle Loibl MD, PhD, and colleagues report results from the GeparTrio trial (n=1,711) in which all patients with primary breast cancer received treatment with three chemotherapy drugs, including docetaxel, doxorubicin and cyclophosphamide. Almost half of the 682 patients (47.8%) expressed androgen receptor.The patient population in this German Breast Group (GBG) study was made up of patients with histologically confirmed unilateral or bilateral primary carcinoma of the breast (confirmed histologically by core biopsy) and patients with a tumor lesion in the breast with a palpable size of .2 cm in maximum diameter.

The researchers found that among those with triple-negative tumors the expression of the androgen receptor was correlated with a lower likelihood of an effective treatment.

“This group has looked for the expression of androgen receptor in breast cancer and found a sub-group of the population who do express it, and have shown that these patients respond worse to chemotherapy than those whose tumors do not express androgen receptor,” said Professor Jose Baselga, co-chair of the IMPAKT Conference.

The study showed a significant correlation between androgen receptor and tumor grading (PP=.006), expression of estrogen/progesterone status (P<.001) and age, and further revealed a pathological complete response in 14.2% of androgen receptor-positive patients vs. 31.9% of androgen receptor-negative patients (P<.001). The total pathological complete response was 21.4%. Among 86 triple-negative tumors analyzed (12.6% of total), 40.7% had a pathological complete response. 27.9% of the analyzed tumors expressed androgen receptor (AR+). For the remaining triple-negative androgen receptor-negative tumors (AR-), the pathological complete response rate was 43.5% vs. 33.3% for the triple-negative androgen receptor-positive tumors (P=.387). Baselga noted that a clinical trial is currently underway to try and target the androgen receptor in breast cancer. “I think we are seeing the birth of a new concept in breast cancer—the androgen-receptor-positive breast cancer,” Professor Baselga said. “This is an important development in finding new targets that we can attack with new drugs in the future.”

More IMPAKT Results
Unrelated but interesting results presented during the IMPAKT conference, which is designed to present and discuss advances in translational research and ways to quickly transform laboratory discoveries into tools that clinicians can use to help make decisions about the way they treat patients in their daily practice, included a presentation about a genetic test that helps reduce the need for second surgery in Breast cancer treatment.

This new rapid test can confirm quickly and accurately that breast cancer has most likely not spread into adjacent lymph nodes, offering reassurance to patients and reducing the need for a second operation. The test takes roughly 35 minutes to produce results and can be performed while the patient is having the initial surgery to remove the primary tumour.

Earlier studies have shown that the test can detect cancer that has spread to nearby lymph nodes. Currently, when a woman is having surgery to remove a breast cancer, surgeons take a sample from the so-called 'sentinel node.' This is the lymph node most directly connected to the breast, and the place the cancer is likely to spread to first.

The sentinel node biopsy is normally analysed by a pathologist who looks carefully for the presence of cancerous cells, in a process that can take several hours. If these cells have grown to a diameter between 0.2 mm and 2 mm — known as a micro metastasis -- the patient is considered to be at risk of a worse outcome. She would then usually be advised to return to the operating theatre to have all the lymph nodes in that region removed.

“This process of trying to identify micro metastases takes a lot of time and money,” explains conference co-chair Prof Martine Piccart from Institut Jules Bordet in Brussels, Belgium. “The new technique allows you to make the diagnosis of micro metastases while the surgery is underway, meaning the patient does not have to suffer the disruption of undergoing another operation.” To see whether the test results predicted the spread of cancer to other lymph nodes in the armpit, researchers in Belgium, the US and the UK tested sentinel nodes removed from 1,138 patients.

Once removed, each node was cut into thin slices. Alternating slices were then tested using either the new gene test or traditional pathology methods. If either test returned a positive result, the patient then had all lymph nodes from that armpit removed and tested. The new test provided a particularly high 'negative predictive value', they found, meaning that it accurately predicted whether the remaining nodes were free of cancer. “Remarkably, when the new test gives a negative result — meaning it finds no spread of cancer to the sentinel node — it really predicts very well the status of the other lymph nodes,” said Prof Piccart.

Other interesting presentation
  • Gene Sinature Identifies Breast Cancer Pahtiens who will respond to chemotherapy. Researchers have identified a genetic signature that can predict which breast cancer patients will respond well to treatment with epirubicin, a widely used form of chemotherapy. Although among the most effective chemotherapies in breast cancer, a small proportion of women suffer severe side-effects. By identifying those women who are most likely to benefit from treatment, doctors may be able to ensure fewer women are unnecessarily exposed to that risk. The new study shows that this goal can be achieved by developing more sophisticated ways to use older drugs.
  • Gene Signature predicts good outcome in Breast Cancer. Researchers have identified a genetic signature that can predict an improved clinical outcome in patients with breast cancer, and which could help in the development of new targeted therapies. By analyzing the expression of different genes induced by a specific mutation in a molecule called PIK3CA, a critical part of the pathway commonly deregulated in breast cancer, they found that these genes were correlated with an improved clinical outcome in over 1500 women with the disease.

    For more information, see the presentation

    Also, read PubMed abstracts:

    Also Read:

    Wednesday, June 24, 2009

    Growing Attendance for International GI Cancer Congress Demonstrates Importance and Increased Impact.

    The 11th World Congress on Gastrointestinal Cancer, organized by ESMO, the European Society for Medical Oncology, opens today in Barcelona, Spain, with a substantial increase in registered attendees over previous years.

    The conference is expected to provide important practice updates and promising new research into the numerous types of cancers that affect the gastrointestinal tract.

    “Ongoing study and changing standards in the treatment of gastrointestinal cancers have made it mandatory for clinicians to continually update their knowledge to keep up with advances in the field,” says Congress co-chair Dr. Eric Van Cutsem. “The World Congress on Gastrointestinal Cancer addresses the immediate practice implications of these changes.”

    Researchers will present studies indicating prolonged progression-free survival and focusing on the importance of personalized cancer care.

    Gastrointestinal cancers include anal cancer, colorectal cancer, esophageal cancer, gallbladder cancer, gastric cancer, liver cancer (hepatoma), pancreatic cancer, and small intestine cancers. The most prevalent of these is colorectal cancer in the Western world and gastric cancer in Eastern World.

    Colorectal cancer is a major public health problem in Western countries, with the highest incidence rates in North America, Western Europe, Australia and New Zealand. It is the third most common cancer in both men and women, and the third most common cause of cancer death in both sexes. About 630,000 deaths from colorectal cancer are expected this year worldwide, accounting for 8% of all cancer deaths. Gastric is the second most frequent cause of cancer related mortality, accounting for nearly 800,000 deaths each year worldwide.

    Over 400 studies will be presented at the world’s largest GI cancer conference and published in the Annals of Oncology, the official journal of the European Society for Medical Oncology (ESMO), outlining research taking place across the globe. Some of the most important work in the field outlines improved patient outcomes through novel drug therapies including combination therapies and new applications of existing therapies.

    Six abstracts have been selected by the congress chairs as “top abstracts”. A common thread of these recognized papers is prolonged progression-free survival, enabling patients to live longer with the disease and with a better quality of life. Moreover, the experts will discuss the changing paradigm in gastrointestinal cancer toward a more personalized treatment approach for patients with gastrointestinal cancers.

    Also being recognized at the congress are researchers from developing nations who received grants based on the scientific merit of their submitted work.

    The ESMO Conference: 11th World Congress on Gastrointestinal Cancer, developed and managed by Imedex, will be held from 24-27 June at the CCIB convention center in Barcelona. The internationally recognized faculty will include 72 experts, chaired by Mario Dicato, MD of the Luxembourg Medical Center in Luxembourg and Eric Van Cutsem, MD, PhD of the University Hospital Gasthuisberg in Leuven, Belgium. 3,500 people from nearly 100 countries are expected to attend.

    Designed to promote a multidisciplinary approach to treatment, the scientific agenda offers targeted sessions for oncology surgeons and nurses as well as a comprehensive range of topics for researchers, gastroenterologists, as well as medical and radiation oncologists.

    The conference has received endorsements from leading professional societies and organizations, solidifying the reputation of the Congress as the premier platform for specialists in cancer research, leading oncologists and practicing clinicians to review the state-of-the-art advances in gastrointestinal cancer and share the latest information on its multidisciplinary management. Specialized sessions for nurses, surgeons and young medical oncologists provide enhanced educational opportunities.

    The 11th World Congress on Gastrointestinal Cancer Congress is endorsed by:
    • The Cholangiocarcinoma Foundation
    • ENETS (European Neuroendocrine Tumor Society)
    • EONS (European Oncology Nursing Society)
    • EORTC (European Organisation for Research and Treatment of Cancer) – GI Tumor Group
    • ESO (European School of Oncology)
    • ESSO (European Society of Surgical Oncology)
    • Europacolon

    For more information:

    For more information, read these PubMed abstract:

    Photos courtesy of the American Society of Clinical Oncology

    Olaparib Induces Tumor Response as Single Agent in BRCA-Deficient Breast Cancer

    A small, Phase II international multi-center study data presented during the 45th annual meeting of the American Society of Clinical Oncology (ASCO) for novel, oral anti-cancer treatment olaparib (AZD2281 / KU-0059436), demonstrate it is effective and well tolerated in women carrying the BRCA1 or BRCA2 gene mutation with advanced ovarian or breast cancer.

    The study has been selected for inclusion in the ‘Best of ASCO’ scientific program and reports that more than a third of women with BRCA1 or BRCA2 mutations and advanced breast cancer that persisted despite prior treatment experienced tumor shrinkage after receiving the investigational PARP inhibitor olaparib.

    Inhibition of PARP, short for poly [ADP-ribose] polymerases, is being explored as a new therapeutic approach in cancers with impaired DNA repair pathways, one example of which is cancers with BRCA deficiency.

    Different cancers
    Olaparib is a novel, potent inhibitor of poly [ADP-ribose] polymerases PARP-1 and PARP-2 that, in addition to undergoing clinical trials for the development of the treatment of BRCA1 and BCRA2-defective breast cancer, is being trialed in ovarian, pancreatic and colorectal tumors and melanoma. This targeted drug therapy candidate has the potential for use as a single agent or in combination with platinum-based DNA-damaging agents and cytotoxic drugs, as well as radiotherapy. Preliminary data supports the safety and oral bioavailability of the compound and warrant its further development as a potential clinical candidate in cancer therapy.

    Hopeful News
    About 8% of breast cancer cases are triggered by genetic factors. Although many of the exact causes remain unknown, defects on the BRCA-1 and BRCA-2 genes put women at much higher risk of developing aggressive cancers of the breast or ovaries. Increasingly women testing positive for BRCA1 or BECA2 mutations opt for drastic measures such as elective mastectomy as a precaution because they have an 80% risk of developing breast cancer.

    Scientists feel that the preliminary results with olaparib may therefore represent good news. If the results of these first tests are to be believed, the new drug candidate may help thousands of women suffering from genetic breast cancer look for less extreme, targeted drug therapies.

    Commenting on the results, lead author, Dr Andrew Tutt, MB ChB, PhD, director of the Breakthrough Breast Cancer Research Unit at Kings College in London, United Kingdom, confirms: “The findings of our study provide very promising evidence that the potent PARP inhibitor olaparib may be useful for treating BRCA-deficient breast cancers. However, this drug is in a very early stage of development, and additional clinical trials are necessary to determine the best way to use olaparib in women with BRCA-deficient breast cancer. We are actively discussing the design of future PARP inhibitor studies for women with BRCA1 and BRCA2 mutations.”

    This study, which was carried out at hospitals in Britain, Europe, the United States and Australia, is the first to evaluate olaparib when used alone in women with BRCA-deficient breast cancer. A prior Phase II study showed that some women with BRCA-deficient ovarian cancers responded to olaparib. Tumors that arise in patients with BRCA mutations have a defect in their ability to repair DNA. By adding olaparib, the tumor cells are deprived of another DNA repair mechanism. It is thought that this added inhibition of DNA repair with olaprib then leads to cancer cell death.

    Tutt and his colleagues examined the response rate to olaparib (as evidenced by tumor shrinkage) in 54 women with breast cancer that was deficient in BRCA1 or BRCA2 and that persisted despite several rounds of standard chemotherapy. An encouraging forty-one percent of the 27 evaluable patients responded to olaparib (experienced tumor shrinkage) at the higher, 400 mg , of the two doses used in the study. In one patient, the tumor seemed to have disappears completely. Furthermore, a 5.7 month progression free survival was noted

    A phase I trial identified 400 mg bd as the maximum tolerated dose (MTD) with an initial signal of efficacy in BRCA-deficient ovarian cancers (ASCO 2008; abst 5510). The researchers in this trial concluded that olaparib at 400 mg 100mg monotherapy twice a day in women with advanced breast cancer was well tolerated, with the most common side effects being mild fatigue, nausea and vomiting.

    “These encouraging data demonstrate the potential for olaparib to make a significant impact on the outcomes of patients with BRCA-deficient breast and ovarian cancer. AstraZeneca is fully evaluating the development of this drug in these diseases, and is exploring its potential in other populations of patients with cancers associated with defective DNA repair,” explained Alan Barge, Vice President and Head for Oncology and Infection at AstraZeneca, the manufacturer of the new drug.

    A second study conducted in women with advanced ovarian cancer also showed encouraging activity, with objective responses observed in about one third of the women receiving olaparib 400mg monotherapy.

    Safety and toxicity
    Olaparib is highly active in advanced chemotherapy-refractory BRCA-deficient breast cancer. Toxicity in BRCA and BRCA2 carriers was similar to that reported previously in non-carriers. This first study in BRCA-deficient breast cancers provides positive proof-of-concept for high activity and tolerability of a genetically defined targeted therapy.

    Rewarding results
    These early, non comparative studies provide optimism about the role of PARP inhibition in certain cancers with DNA repair deficiency. Comments Tutt: “It is rewarding to see our earlier laboratory findings, showing that PARP inhibitors such as olaparib specifically kill BRCA-deficient cells, now seem to be holding true for our patients in the clinic. We are hopeful that olaparib could provide a targeted treatment for women with BRCA-deficient breast cancer.”

    Olaparib was originally developed by the UK biotechnology company KuDOS Pharmaceuticals, which has been a wholly owned subsidiary of AstraZeneca since 2006.

    ASCO 2009 Abstract:

    Journal of Clinical Oncology (ASCO Post Meeting edition):

    For more information, read these PubMed abstracts:

    More information:

    Clinical Trials:

    • Efficacy and Safety of Olaparib in Pretreated Patients With Measurable Colorectal Cancer, Stratified by Microsatellite Instability (MSI) Status. (NCT00912743)
    Photos courtesy of the American Society of Clinical Oncology.

    Tuesday, June 23, 2009

    BSI-201, an Investigational Drug, plus Chemotherapy May Offer New Treatment Option for Triple-Negative Breast Cancer

    A randomized Phase II study, featured during the plenary session of the 45th Annual Meeting of the American Society of Clinical Oncology (ASCO) , shows that women with metastatic triple-negative breast cancer who received the investigational PARP inhibitor BSI-201, in combination with conventional chemotherapy, lived significantly longer and experienced significantly better progression-free survival than women who received standard chemotherapy alone.

    The results of this study provide early evidence that BSI-201, a potent inhibitor of PARP1, or poly (ADP-ribose) polymerase-1, is a promising treatment for women with triple-negative breast cancer, an aggressive form of the disease for which we need new, more effective therapies,” said Joyce O’Shaughnessy, MD, co-director of the Breast Cancer Research Program at Baylor-Charles A. Sammons Cancer Center in Dallas, Texas.

    Triple-negative breast cancers (TNBC) are particularly hard to treat since they lack receptors for estrogen, progesterone and HER2, which are targeted by widely available and effective drugs. African American women are 3 times more likely than white or Hispanic women to be diagnosed with triple-negative breast cancer.

    In this study, clinical benefit rate (defined by complete and partial responses and stable disease of at least 6 months), response rate, progression-free survival (the time it takes for cancer to progress), and overall survival were compared among 116 women with metastatic triple-negative breast cancer who were randomly assigned to receive a standard chemotherapy treatment (gemcitabine and carboplatin) plus BSI-201, or standard treatment alone.

    Approximately 62 percent of patients receiving BSI-201 showed clinical benefit, compared with 21 percent in the chemotherapy only group. The overall response rate to treatment with the drug combination containing BSI-201 was significantly greater (48 percent) than in the group receiving only standard chemotherapy (16 percent). Women who received BSI-201 had a median survival of 9.2 months and median progression-free survival of 6.9 months compared with 5.7 months and 3.3 months, respectively, in women who received standard treatment alone.

    Efficacy and Safety
    BiPar Sciences Inc, a California-based subsidiary of French drug maker Sanofi–Aventis involved in the development of novel cancer therapies, reported interim safety data from this trial during the annual San Antonio Breast Cancer Symposium (SABCS) in December 2008, showing that the drug was well tolerated with no added toxicities compared with chemotherapy alone.

    While inhibition of PARP has demonstrated significant anti-tumor effects in several cancers, its activity does not appear to be critical for normal, non-cancerous cells. Thus, PARP inhibition has the potential to impair a fundamental mechanism of tumor growth without rendering damage to normal cells, implying a lower risk for side effects in patients who receive PARP-inhibitor-based therapies

    In general, BSI-201 has shown a strong safety profile and no significant toxicities attributable to drug in studies of more than 200 patients treated to date with monotherapy, as well as in combination with chemotherapeutic regimens.

    In the trial, the incidence of side effects was similar between the two groups. BSI-201 itself was well-tolerated and did not contribute any new side effects nor add to the known side effects of gemcitabine and carboplatin.

    Future research
    The researchers believe that BSI-201 has first-in-class and best-in-class potential as targeted therapy for several types of cancer. The trial drug is a leading candidate in the field of PARP inhibitors and is the furthest along in clinical development of this novel therapeutic approach.

    Based on the results of the Phase II trial, California based BiPar Sciences Inc will be initiating a Phase III clinical trial in triple negative metastatic breast cancer in the second half of 2009. This Phase III program has been guided by preliminary safety and efficacy data from a Phase II study in the same patient population.

    ASCO 2009 abstract:

    For more information (posters):

    Also read these Pubmed abstracts:

    Help your Patient to better understand:

    Photo courtesy of the American Society of Clinical Oncology.

    PARP Inhibitors Show Promise for Hard-to-Treat (Breast) Cancers

    Two studies, including one featured during the plenary session of the 45th Annual Meeting of the American Society of Clinical Oncology (ASCO), report promising data on a new class of targeted drugs called PARP inhibitors. The plenary study reports that women with hard-to-treat 'triple-negative' breast cancer who received the PARP inhibitor BSI-201 along with conventional chemotherapy had better outcomes than women who received chemotherapy alone. A second study reports that women with BRCA-deficient advanced breast cancer experienced tumor shrinkage after receiving the PARP inhibitor olaparib as a single agent.

    The two new studies report results on the effect of a new class of targeted therapy called PARP inhibitors on traditionally difficult-to-treat breast cancers – so-called 'triple-negative' breast cancer and BRCA1- and BRCA2 deficient breast cancers.

    PARP is short for ‘poly (ADP-ribose) polymerase.’ Cancer cells use the PARP enzyme to repair DNA damage, including the damage inflicted by chemotherapy drugs. Preclinical studies indicate that PARP inhibitors could enhance the efficacy of radiation therapy and chemotherapies such as alkylating agents and platinum-based drugs by preventing malignant cells from repairing damaged DNA, ultimately leading to impaired tumor growth and apoptosis.

    PARP Concept
    The concept is based on the fact that BRCA1 and BRCA2 are tumor suppressor genes that help control normal cell growth and cell death by regulating the repair of double strand breaks in DNA. Mutations in the BRCA1 and BRCA2 genes can impair this function, leaving cells unable to repair their own DNA, as well as causing the uncontrolled growth that is characteristic of cancer cells. Women who inherit mutations in the BRCA1 or BRCA2 genes have significantly higher risks for breast and ovarian cancer

    Exploiting impaired DNA repair function
    PARP inhibitors work by exploiting the impaired DNA repair function inherent in BRCA-associated cancers. In this case, inhibition of PARP leads to failure to repair DNA single strand breaks, which in turn, result in DNA double strand breaks. These effects are particularly detrimental to BRCA-associated cancer cells. Ultimately, failure to repair both DNA single strand breaks and double strand breaks, leads to cancer cell death.

    Researchers interested in understanding how to exploit the DNA damage on tumor cells inflicting by anti-cancer agents, are now examining whether drugs that inhibit the PARP enzyme will indeed diminish the self-repair mechanism and make cancer cells more sensitive to treatment and promote cancer cell death.

    Currently, a number of PARP inhibitors are studied in Phase I, II and III trials for a variety of cancer indications. These include:
    • ABT-888 in Metastatic melanoma (Abbott Laboratories). Preliminary trial results show that this drug candidate has good oral bioavailability, can cross the blood-brain barrier, and potentiates temozolomide, platinums, cyclophosphamide, and radiation in syngeneic and xenograft tumor models. Broad spectrum chemopotentiation and radiopotentiation makes this compound an attractive candidate for further clinical evaluation.
    • AG-014699 in Breast cancer, ovarian cancer and melanoma (Agouron/Pfizer Inc.). Preliminary results of a phase II trial of AG-014699 and temozolomide in patients with metastatic melanoma indicated that the addition of AG-14699 enhanced temozolomide-associated myelosuppression, and that the response rate for combination treatment was higher than for temozolomide alone.
    • Olaparib (AZD2281 / KU-0059436) in Breast cancer and ovarian cancer (AstraZeneca). Combination of AZD2281 with cisplatin or carboplatin increased the recurrence-free and overall survival, suggesting that AZD2281 potentiates the effect of these DNA-damaging agents. Preliminary results demonstrate in vivo sensitivity and efficacy of AZD2281, alone or in combination with cisplatin, and provide strong support for AZD2281 as a novel targeted therapeutic against BRCA-deficient cancers.
    • BSI-201 in Breast cancer, ovarian cancer, uterine cancerand glioblastoma multiforme (BiPar Sciences Inc.). Data from a Phase II trial of BSI-201 in metastatic breast cancer patients whose tumors were negative for three common breast cancer markers: estrogen receptor, progesterone receptor, and HER2, confirmed that the patients' tumors had significant upregulation of PARP, compared with normal breast tissue, supporting the targeting of this enzyme with BSI-201.

    ASCO 2009 Abstracts

    For more information, read these PubMed abstracts:

    For more information:

    Also read:

    Public Health Emergency in Libby, Montana: Asbestos Cleanup Effort Starts

    On June 17, 2009 the United States Environmental Protection Agency declared a public health emergency in the towns of Libby and Troy in Northwest Montana. Asbestos-contaminated vermiculite was mined in the town of Libby until 1990. Thousands of asbestos-related diseases have been documented in both Troy and Libby.

    Asbestos is a naturally occurring mineral that was used extensively throughout the 20th century for a number of military and industrial applications because of its durability and resistance to fire. Unfortunately, asbestos exposure has been found to be the primary cause of respiratory condition called asbestosis and an aggressive cancer that attacks the linings of the lungs, abdomen or heart known as mesothelioma.

    This type of cancer is difficult to treat as it has an unusually long latency period. Mesothelioma symptoms do not begin to show until 20 to 50 years after exposure to asbestos. Also, the initial symptoms can resemble those of less serious respiratory illnesses and can sometimes go unnoticed. Because of the latency period, mesothelioma is typically diagnosed in its later stages and is more difficult to treat effectively.

    In general, life expectancy for patients diagnosed with mesothelioma patients is reported as less than one year following diagnosis, however this prognosis is affected by numerous factors including how early the cancer is diagnosed and how aggressively it is treated.


    The vermiculite in Libby was originally discovered in 1881 by gold miners. In the 1920s the Zonolite Company was formed and began mining the vermiculite. In 1963, W.R. Grace Company bought the Zonolite mining operations. While in operation, the Libby mine may have produced upwards of 80% of the world's supply of vermiculite.

    Vermiculite is a shiny mineral, similar to mica, which pops like popcorn when heated. The puffy product is as light as cork and was once a popular form of building insulation. Today it is still used as an ingredient in potting soil. Vermiculite itself is harmless. However, the layers of igneous rock where it is found almost always contain asbestos, exposure to which has been definitively linked to mesothelioma and other fatal lung diseases for more than 70 years. Unfortunately, the vermiculite deposit from the Libby, Montana mine was particularly dangerous because it is contaminated with naturally-occurring asbestos called tremolite-actinolite, the most toxic form of of asbestiform mineral fibers.

    Since the official closing of the vermiculite mine in 1990, approximately 400 residents of Libby have passed away from asbestos-related diseases like mesothelioma. Out of the roughly 3,000 residents of the town, nearly 2,000 have become sick because of asbestos. The asbestos has spread so widely over the town that even the tree bark that the residents burn for heath has been contaminated.

    A tragic situation

    Commenting on the situation in both Troy and Libby, the new EPA Administrator Lisa Jackson said: "This is a tragic public health situation that has not received the recognition it deserves by the federal government for far too long. We’re making a long-delayed commitment to the people of Libby and Troy. Based on a rigorous re-evaluation of the situation on the ground, we will continue to move aggressively on the cleanup efforts and protect the health of the people."

    The government will spend more than $130 million on asbestos cleanup efforts and improve the health care system for those with asbestos-related illnesses. Approximately $125 million will come from the EPA over the next five years to clean up both Libby and Troy. An additional $6 million will be spent by the Health and Human Services Department (HSS) on medical assistance.

    For more information, read these PubMed abstracts:

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    No survival benefit with treatment based on rising CA125 blood levels in Recurrent Ovarian Cancer

    There appears to be no survival advantage to treating ovarian cancer relapse based on rising CA125 levels, compared with waiting for symptoms. This is the conclusion from a study that was featured during the 45th Annual Meeting of the American Society of Clinical Oncology (ASCO), the world’s leading professional organization representing physicians who care for people with cancer.

    A team of researchers, lead by Gordon J. Rustin, MD professor of oncology at Mount Vernon Cancer Center, Hertfordshire, United Kingdom, reported that starting treatment immediately for an ovarian cancer relapse based on CA125 protein levels found in the blood does not improve overall survival, compared with delaying treatment until symptoms arise. The findings should allow women to avoid the anxiety and cost associated with frequent blood testing and the toxicity of early treatment.

    “Women who’ve completed ovarian cancer treatment often worry about a relapse, and they undergo frequent blood tests for CA125 in the hope of catching it early,” Rustin said.

    CA125 often rises several months before women with OC have symptoms or clinical signs of relapse. This study (MRC OV05/EORTC 55955 trials), conducted by the MRC/NCRI and EORTC Gynae Cancer Intergroups, was designed to determine whether there were benefits from early treatment based on a confirmed elevation of CA125 levels versus delaying treatment until clinically indicated.

    “We thought that delaying chemotherapy might make overall quality of life worse, due to the symptoms of ovarian cancer, but this was not seen in women on this trial. Since there is no benefit from early chemotherapy, patients may choose to avoid the inconvenience and anxiety associated with frequent retesting for CA125 levels as well as unnecessary early initiation of treatment for relapse,” Rustin explains.

    CA125 is a marker of growth for several cancers, including ovarian cancer, and is measured by a blood test. Women who have undergone treatment for ovarian cancer may have their CA125 levels tested as often as every three months for several years after initial treatment.

    In this study, investigators compared overall survival between 265 women with ovarian cancer in remission after initial chemotherapy who began second-line chemotherapy after experiencing a rise in CA125, and 264 women with rising CA125 whose treatment was delayed until symptoms of relapse appeared (such as pelvic pain or bloating).

    Even though the early treatment group started second-line chemotherapy an average five months before the delayed treatment group, overall survival was the same between both groups: 41 months since completion of first-line chemotherapy.

    The researchers added that this trial provides important information that will help women make informed choices about their follow-up and treatment. They can be reassured that treatment can safely be delayed until symptoms develop.

    ASCO 2009 abstract:

    For more information, read these PubMed abstracts:

    Help your patients understand:

    • For consumer-oriented information about the studies in this article, please refer your patients to ASCO’s patient website.

    Photo and illustration courtesy of the American Society of Clinical Oncology.

    Monday, June 22, 2009

    Progress Against Breast and Gynecologic Cancers: Highlights from ASCO

    Advances in the treatment of cancers that primarily affect women, including breast and gynecologic cancers, were presented in Orlando at the 45th Annual Meeting of the American Society of Clinical Oncology (ASCO), the world’s leading professional organization representing physicians who care for people with cancer.

    Studies presented during the 45th Annual Meeting of the American Society of Clinical Oncology demonstrate continued progress against breast, ovarian and cervical cancers, which are major causes of cancer mortality worldwide,” said Eric P. Winer, MD, Chair of ASCO’s Cancer Communications Committee and professor of medicine at Harvard Medical School. “One study tells us that women can safely avoid unnecessary blood tests and can delay toxic treatment for ovarian cancer recurrence without compromising their longevity. Others report on a promising new class of targeted drugs for some of the most difficult-to-treat breast cancers. And others provide more effective and less invasive options for treating cervical cancer, which is a particularly significant problem in developing countries.”

    Studies highlighted during ASCO include:

    • No survival advantage to treating ovarian cancer relapse based on rising CA125 levels, compared with waiting for symptoms. A study featured in ASCO’s plenary session reports that starting treatment immediately for an ovarian cancer relapse based on CA125 protein levels found in the blood does not improve overall survival, compared with delaying treatment until symptoms arise. The findings should allow women to avoid the anxiety and cost associated with frequent blood testing and the toxicity of early treatment.
    • PARP inhibitors show promise for hard-to-treat breast cancers. Two studies, including one featured in ASCO’s plenary session, report promising data on a new class of targeted drugs called PARP inhibitors. Poly (ADP-ribose) Polymerase (PARP) has a well-established role in DNA repair processes, and small molecule inhibitors of PARP have been developed as chemotherapy sensitisers for the treatment of cancer. The subsequent demonstration that PARP inhibition is selective for BRCA1 or BRCA2 deficiency suggests that PARP inhibitors may be particularly useful for the treatment of cancer with BRCA mutations. The plenary study reports that women with hard-to-treat “triple-negative” breast cancer who received the PARP inhibitor BSI-201 (BiPar Sciences Inc) along with conventional chemotherapy had 60% better survival outcomes compared with chemotherapy alone than women who received chemotherapy alone. A second study reports that women with BRCA-deficient advanced breast cancer experienced tumor shrinkage after receiving the PARP inhibitor olaparib as a single agent.
    • Gemcitabine plus chemoradiation improves cervical cancer survival. Adding the drug gemcitabine (Gemzar) to cisplatin-based chemotherapy and radiation therapy extends overall survival among women with locally advanced cervical cancer. This study was primarily conducted in developing countries, where cervical cancer screening programs are limited.
    • Sentinel node biopsy is an effective option for early-stage cervical cancer. Most women with early-stage cervical cancer can safely undergo sentinel node biopsy – a technique in which only one or two lymph nodes are removed to determine whether cancer has spread – in lieu of the traditional, more invasive pelvic lymph node removal, which can lead to more significant side effects. Sentinel node biopsy was also as effective for detecting cancer spread to atypical areas of the pelvis.

    For more information, read these PubMed abstracts

    Help your patients understand:

    • For consumer-oriented information about the studies in this article, please refer your patients to ASCO’s patient website.

    New National Physician Practice Certification Program to Enhance the Quality of Cancer Care in the U.S.

    Providing high quality of care to cancer patients is paramount. To help oncologists create a culture of self-examination and improvement, the American Society of Clinical Oncology (ASCO), the world’s leading professional organization representing physicians who care for people with cancer, in early June 2008 announced the Quality Oncology Practice Initiative (QOPI®) Certification Program, a new program to certify oncology practices that achieve rigorous standards for high-quality cancer care.

    “Increasingly, oncology practices are being asked by payors, patients, and others to attest to the quality of care they provide,” said incoming ASCO President Douglas W. Blayney, MD. “ASCO QOPI Certification will demonstrate a practice’s commitment to delivering high-quality cancer care.”

    QOPI is a voluntary, oncologist-led, practice-based quality improvement program. The process employed for improving cancer care includes measurement, feedback and improvement tools for hematology-oncology practices. This self-assessment program launched by ASCO in 2006 to help hematology-oncology and medical oncology practices assess the quality of care they provide to patients. Through the QOPI program, practices abstract data from patients’ medical charts twice a year and enter this information into a secure database. Currently, nearly 500 oncology practices are enrolled in the program.

    ASCO analyzes this data for adherence to more than 80 evidence-based and consensus quality measures and provides feedback reports to participating practices to help them identify areas for improvement. Individual practices are also able to compare their performance to aggregate data from other practices across the country. Based on these data, doctors can focus on specific areas for quality improvement.

    A study by Douglas Blayney, Kristen McNiff, David Hanauer, Gretchen Miela, Denise Markstrom, and Michael Neuss, published earlier this month in the Journal of Clinical Oncology documents the experience of the University of Michigan Comprehensive Cancer Center with the ASCO QOPI program.

    While the study authors determined that the Center was in compliance with the majority of quality measures, the QOPI data showed that use of chemotherapy within two weeks of death was significantly higher than other practices. After this data was presented to the cancer center faculty, use of chemotherapy at the end of life declined from 50 percent to 20 percent.

    “It is rewarding to see that through the QOPI program we found areas where we could make striking, rapid improvements in the already high quality of care we were delivering,” said Dr. Blayney. “The QOPI Certification Program puts oncologists at the forefront of defining the highest level of clinical care for people with cancer. We hope that health plans will recognize the QOPI measures, and use QOPI as a best practices model for their own quality initiatives.”

    The QOPI Certification Program will be available to all practices that meet specific performance requirements and that pass a new site assessment. Practices that participate in the fall 2009 QOPI data collection process will be the first eligible to receive certification in early 2010.

    Read Pubmed abstracts:

    For more information:

    Illustration courtesy of the American Society of Clinical Oncology.