ASCO 2011: Novel Multi-targeted Agent Cabozantinib (XL184) Has Significant Effect on Several Advanced Solid Tumors

Cabozantinib (XL184) demonstrated high rates of disease control in patients with prostate, ovarian and liver cancers. The investigators concluded that cabozantinib exhibits clinical activity in ovarian cancer patients with advanced disease, regardless of prior platinum drug status, as reflected by the high rates of response. 

ASCO Releases Studies From Upcoming Annual Meeting – Important Advances in Targeted Therapies, Screening, and Personalized Medicine

The American Society of Clinical Oncology (ASCO) today highlighted several studies in a press briefing from among more than 4,000 abstracts publicly posted online at http://www.asco.org in advance of ASCO’s 47th Annual Meeting. An additional 17 plenary, late-breaking and other major studies will be released in on-site press conferences at the Annual Meeting.

The meeting, which is expected to draw approximately 30,000 cancer specialists, will be held June 3-7, 2011, at McCormick Place in Chicago, Illinois. The theme of this year’s meeting is “Patients. Pathways. Progress.”

“This year marks the 40th anniversary of the signing of the National Cancer Act, a law that led to major new investments in cancer research. Every day in our offices, and every year at the ASCO meeting, we see the results of those investments. People with cancer are living longer, with a better quality of life, than ever before,” said George W. Sledge Jr., M.D., President of ASCO, Ballve-Lantero Professor of Oncology and professor of pathology and laboratory medicine at the Indiana University School of Medicine.

“With our growing understanding of the nature of cancer development and behavior, cancer is becoming a chronic disease that a growing number of patients can live with for many years,” said Dr. Sledge. “The studies released today are the latest examples of progress against the disease, from new personalized treatments, to new approaches to screening and prevention.”

The study results from a phase II clinical trial involving cabozantinib (XL184) were highlighted today in the ASCO press briefing, as summarized below.

Novel Multi-targeted Agent Cabozantinib (XL184) Has Significant Effect on Several Advanced Solid Tumors, and Can Shrink or Eliminate Bone Metastases 

Cabozantinib (XL184) – an oral inhibitor of MET and VEGFR2 kinases involved in the development and progression of many cancers – showed strong responses in patients with various advanced cancers in a phase II trial. The drug demonstrated particularly high rates of disease control for advanced prostate, ovarian and liver cancers, which are historically resistant to available therapies. The drug also fully or partially eliminated bone metastases in patients with breast and prostate cancers and melanoma.

Michael S. Gordon, M.D., President & Chief Executive Officer, Pinnacle Oncology Hematology.

“Cabozantinib appears to have significant effects on several treatment-resistant tumors, as well as impressive effects on bone metastases. In addition, these effects are associated with rapid improvement in pain, a reduction in opiate narcotic requirements and improvement in anemia,” said lead author Michael S. Gordon, M.D., a medical oncologist at Pinnacle Oncology Hematology located in Scottsdale, Arizona. “The implications of these results are very exciting—it is unusual to find a targeted therapy, absent of a molecular mutation in tumors, that works in bony disease and has this activity.”

To be eligible for the study, patients had to have advanced, progressive solid tumors, with or without bone metastases. Of 398 evaluable patients (of 483 enrolled in the trial), 39 percent had bone metastases at baseline. Patients received cabozantinib over 12 weeks. The trial was designed as a “discontinuation” trial, in which those who had partial responses stayed on the drug; those with stable disease were randomized to cabozantinib or placebo; and patients with progressive disease were removed from the trial. This novel type of clinical trial design more quickly evaluates the disease-stabilizing activity of growth-inhibitory agents like cabozantinib, compared to the traditional model of randomizing all patients to either the experimental arm or placebo.

Among 398 patients evaluable with all types of cancer included in the trial, the collective overall response rate was 9 percent (34 of 398). The highest disease control rates (partial response and stable disease) at week 12 were 76 percent for liver cancer (22 of 29 patients), 71 percent for prostate cancer (71 of 100 patients), and 58 percent for ovarian cancer (32 of 51 patients). [emphasis added].

Of the 51 evaluable ovarian cancer patients noted above, 28 are platinum drug resistant, 17 are platinum drug sensitive, and 6 have unknown status. The median number of systemic treatments prior to trial enrollment was 2. The overall response rate (complete response and partial response based on modified RECIST criteria) for ovarian cancer was 12/51 (24%).  Upon breakdown, the response rate was 5/28 (18%) for platinum drug resistant patients, and 5/17 (29%) for platinum drug sensitive patients. Five additional partial responses await confirmation. After a median follow-up of 4 months (range: 1 to 11 months), the median duration of response and median progression free survival have not been reached. The most common related adverse events ( ≥grade 3) among ovarian cancer patients were hand-foot syndrome (10%), diarrhea (8%) and fatigue (4%). Drug dose reductions and permanent discontinuations for adverse events occurred in 43% and 10% of the ovarian cancer patients, respectively. Based on these findings, the investigators concluded that cabozantinib exhibits clinical activity in ovarian cancer patients with advanced disease, regardless of prior platinum drug status, as reflected by the high rates of response. [emphasis added] Accordingly, randomization in the ovarian cancer cohort was halted & patients unblinded due to the observed high efficacy.

Fifty-nine of 68 patients with bone metastases (including patients with breast and prostate cancers and melanoma) experienced either partial or complete disappearance of the cancer on bone scans, often with significant pain relief and other improved cancer-related symptoms.

The reduction of bone metastases and pain relief was an unexpected finding in this study, Dr. Gordon said. Independent review by radiologists confirmed that bone metastases disappeared in the majority of patients who had bone metastases when they entered the study. The majority of these patients had castration-resistant prostate cancer (CRPC), but patients with breast cancer and melanoma also had disappearance of bone metastases. Bone metastases greatly contribute to morbidity and mortality in patients with these types of cancer, which typically spread to the bone.

Due to these results, the study has been expanded to include more CRPC patients. Similarly, the high rate of lasting responses in ovarian cancer patients led researchers to also expand the study to evaluate the drug’s effect on patients with a particularly resistant form of the disease known as platinum drug resistant/refractory ovarian cancer. [emphasis added]

This study expansion results will help determine the design of future phase III trials, which will assess whether the drug extends patients lives or has other longer-term benefits among patients with specific cancer types. At present, cabozantinib is being investigated for use as a single agent. Additional studies will evaluate the efficacy and tolerability of appropriate combinations with other agents for future indications.

For the solid tumor patients collectively, the most common grade three or above adverse events were fatigue (9 percent) and hand-foot syndrome (8 percent). Dose reductions were required in 41 percent of patients due to side effects; 12 percent were removed from the trial for adverse events.

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Cabozantinib (XL184) Clinical Trials:

Related Libby’s H*O*P*E*™ Postings:

Outside-the-Box: The Rogosin Institute Is Fighting Cancer With Cancer Cells In Clinical Trials

Researchers at the Rogosin Institute are using cancer “macrobeads” to fight cancer.  Cancer cells in the beads secrete proteins which researchers believe could signal a patient’s cancer to stop growing, shrink or even die. The treatment is currently being tested in human clinical trials.

Two groundbreaking preclinical studies demonstrate for the first time that encapsulated mouse kidney cancer cells inhibit the growth of freely-growing cancer cells of the same or different type in a laboratory dish and in tumor-bearing animals. These findings support the hypothesis that cancer cells entrapped in seaweed-based gel, called “macrobeads,” send biological feedback or signals to freely-growing tumors outside the macrobead to slow or stop their growth. Both studies (cited below) are published in the on-line January 24, 2011 issue of Cancer Research, a publication of the American Association For Cancer Research.

Barry H. Smith, M.D., Ph.D., Director, The Rogosin Institute; Professor, Clinical Surgery, Weill Cornell Medical College

The Rogosin Institute, an independent not-for-profit treatment and research center associated with New York-Presbyterian Hospital and Weill Cornell Medical College, developed the cell encapsulation technology that facilitated production of the macrobead and applied this technology in conducting preclinical studies. The research team was headed by Barry H. Smith, M.D., Ph.D.,  the Director of The Rogosin Institute, Professor of Clinical Surgery at the Weill Cornell Medical College, and lead author of the studies. Findings in the studies to date are consistent with the hypothesis that when macrobeads are implanted in a host, the encapsulated cells are isolated from the host’s immune system but continue to maintain their functionality.

In addition to the standard preclinical in vivo and in vitro experiments, a clinical veterinary study was conducted in cats and dogs suffering from various spontaneous (non-induced) cancers. More than 40 animals were treated with the macrobead technology. Consistent results, measured both in terms of tumor response and animal well-being, occurred with prostate, liver and breast cancer, as well as lymphoma. Additional research revealed that regardless of the animal specie or type of cancer cell that was encapsulated, the macrobead technology inhibited cancer growth across all species and cancer types tested.  The results have included slowed tumor growth or, in some cases, necrosis and elimination of tumors and the restoration of a normal animal lifespan.

Cancer macrobead therapy has proceeded to human clinical testing. A Phase 1 trial in more than 30 patients evaluated the safety of macrobeads implanted in the abdominal cavity as a biological treatment of end-stage, treatment-resistant, epithelial-derived cancer. Based on the safety profile data, Phase 2 efficacy trials are in progress in patients with colorectal cancer, pancreatic cancer and prostate cancer. The Phase 1 trial remains open to a range of epithelial-derived cancers, including ovarian.  To date, the Rogosin Institute research team has not found evidence to indicate that placing mouse tumors in humans or other animal species causes harm or side-effects.

Scientists are testing whether macrobeads containing cancer cells can be implanted into patients and communicate with the patient’s tumor to stop growing, shrink or die.

Step 1:  Small beads are made from a seaweed-derived sugar called agarose and mixed with 150,000 mouse kidney cancer cells, and a second layer of agarose is added, encapsulating the cancer cells.

Step 2:  Within 3-to-10 days, 99% of the kidney cancer cells die.  The remaining cells have traits similar to cancer stem cells.

Step 3:  The stem cells begin to recolonize the bead.  The colonies increase in sufficient numbers within a few weeks to reach a stable state.

Step 4:  The beads begin to release proteins —  chemical signals reflecting that the beads have sufficient numbers of cells for growth regulators to kick in.

Step 5: Several hundred beads (depending on patient’s weight) are implanted in the abdominal cavity in a laparoscopic surgical procedure.  The cancer cells are trapped in the beads; preventing their circulation elsewhere in the body and protecting them from attack by the body’s immune system.

Step 6: In animal studies, researchers believe some proteins released from the beads reached tumors elsewhere in the body and tricked them into sensing that other tumor cells are nearby.

Step 7:  As a result, researchers believe tumors in some animals stopped growing, shrank or died.  The hypothesis is being tested in people with cancer.

Howard Parnes, M.D., Chief, Prostate & Urologic Cancer Research Group, Division of Cancer Prevention, National Cancer Institute

“This is a completely novel way of thinking about cancer biology,” says Howard L. Parnes, a researcher in the Division of  Cancer Prevention at the National Cancer Institute who is familiar with the work but was not involved with it. “We talk about thinking outside the box. It’s hard to think of a better example.” “They demonstrate a remarkable proof of principle that tumor cells from one animal can be manipulated to produce factors that can inhibit the growth of cancers in other animals,” Dr. Parnes says. “This suggests that these cancer inhibitory factors have been conserved over millions of years of evolution.”

“Macrobead therapy holds promise as a new option in cancer treatment because it makes use of normal biological mechanisms and avoids the toxicities associated with traditional chemotherapy,” said Dr. Barry Smith. “The results of our research show that this approach is not specific to tumor type or species so that, for example, mouse cells can be used to treat several different human tumors and human cells can be used to treat several different animal tumors.”

“Because cancer and other diseases are their own biological systems, we believe that the future of effective disease treatment must likewise be biological and system-based,” said Stuart Subotnick, CEO of Metromedia Bio-Science LLC. “Many of the existing therapies are narrow, targeted approaches that fail to treat diseases comprehensively. In contrast, our unique macrobead technology delivers an integrated cell system that alters disease processes and utilizes the body’s natural defense mechanisms. The goal is to repair the body and not merely treat the symptoms.”

It is well-known that proof of anti-tumor activity in treating animals does not represent guaranteed effectiveness in humans. But, assuming the macrobead therapy proves ultimately effective in humans, it would represent a novel approach to treating cancer and challenge existing scientific dogmas.

The cancer macrobead therapy described above is backed by Metromedia Company, a privately held telecommunications company which was run by billionaire John Kluge until his recent death. The Metromedia Biosciences unit has invested $50 million into the research.  If the treatment proves successful in humans, a large part of the revenue generated will be contributed to Mr. Kluge’s charitable foundation.

About Metromedia Bio-Science LLC

Metromedia Bio-Science LLC, in conjunction with The Rogosin Institute, utilizes the novel cell encapsulation technology to conduct research into the treatment of various diseases, including cancer and diabetes, and the evaluation of disease therapies. Metromedia Bio-Science LLC is an affiliate of Metromedia Company, a diversified partnership founded by the late John W. Kluge and Stuart Subotnick.

About The Rogosin Institute

The Rogosin Institute is an independent not-for-profit treatment and research center associated with New York-Presbyterian Hospital (NYPH) and Weill Cornell Medical College. It is one of the nation’s leading research and treatment centers for kidney disease, providing services from early stage disease to those requiring dialysis and transplantation. It also has programs in diabetes, hypertension and lipid disorders. The Institute’s cancer research program, featuring the macrobeads, began in 1995. The Rogosin Institute is unique in its combination of the best in clinical care with research into new and better ways to prevent and treat disease.

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National Comprehensive Cancer Network® Posts New Guidelines for Treatment of Ovarian Cancer Patients

National Comprehensive Cancer Network® Posts New “Patient Friendly” Guidelines for Treatment of Ovarian Cancer.

Women with ovarian cancer now have a new resource that provides them with the same credible information their physicians use when determining treatment options. The National Comprehensive Cancer Network® (NCCN®) announces three new additions to the library of NCCN Guidelines for Patients™, patient-friendly translations of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™). NCCN Guidelines for Patients™: Melanoma, Ovarian Cancer, and Prostate Cancer are now available free of charge at NCCN.com.

The NCCN Guidelines for Patients™ are designed to provide people with cancer and their caregivers with state-of-the-art treatment information in easy-to-understand language. Given the prevalence of melanoma and prostate cancer – both among the most frequently diagnosed cancers in men – and the challenges in detecting ovarian cancer in women, it is critical that patients have resources to empower them to take a more active role in their treatment.

The NCCN Guidelines™ are developed by multidisciplinary panels of experts from NCCN Member Institutions and feature algorithms or “decision trees” that address every appropriate treatment option from initial work up throughout the course of the disease. The NCCN Guidelines for Patients™ translate these professional guidelines in a clear, step-by-step manner that patients can use as the basis for making decisions and discussing options with their physicians.

The NCCN Guidelines for Patients™ are available free of charge at NCCN.com, which also features additional informative articles for patients and caregivers.

About the National Comprehensive Cancer Network

The National Comprehensive Cancer Network (NCCN), a not-for-profit alliance of 21 of the world’s leading cancer centers, is dedicated to improving the quality and effectiveness of care provided to patients with cancer. Through the leadership and expertise of clinical professionals at NCCN Member Institutions, NCCN develops resources that present valuable information to the numerous stakeholders in the health care delivery system. As the arbiter of high-quality cancer care, NCCN promotes the importance of continuous quality improvement and recognizes the significance of creating clinical practice guidelines appropriate for use by patients, clinicians, and other health care decision-makers. The primary goal of all NCCN initiatives is to improve the quality, effectiveness, and efficiency of oncology practice so patients can live better lives.

The NCCN Member Institutions are:

City of Hope Comprehensive Cancer Center, Los Angeles, CA;

Dana-Farber/Brigham and Women’s Cancer Center | Massachusetts General Hospital Cancer Center, Boston, MA;

Duke Comprehensive Cancer Center, Durham, NC;

Fox Chase Cancer Center, Philadelphia, PA;

Huntsman Cancer Institute at the University of Utah, Salt Lake City, UT;

Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance, Seattle, WA;

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD;

Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL;

Memorial Sloan-Kettering Cancer Center, New York, NY;

H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL;

The Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute, Columbus, OH;

Roswell Park Cancer Institute, Buffalo, NY;

Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, MO;

St. Jude Children’s Research Hospital/University of Tennessee Cancer Institute, Memphis, TN;

Stanford Comprehensive Cancer Center, Stanford, CA;

University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL;

UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA;

University of Michigan Comprehensive Cancer Center, Ann Arbor, MI;

UNMC Eppley Cancer Center at The Nebraska Medical Center, Omaha, NE;

The University of Texas MD Anderson Cancer Center, Houston, TX; and

Vanderbilt-Ingram Cancer Center, Nashville, TN.

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PhRMA Report Shows Record Number of Development Drugs to Treat Cancer; 63 Ovarian Cancer & 203 Solid Tumor Drugs Listed

“Responding to President Obama’s call for ‘a cure for cancer in our time,’ the Pharmaceutical Research and Manufacturers of America (PhRMA) delivered a new report today on medicines in the research pipeline for cancer. The report shows that America’s pharmaceutical research and biotechnology companies are testing a record 861 new cancer medicines and vaccines. The medicines listed in the report are being tested in human clinical trials or are awaiting approval by the U.S. Food and Drug Administration. [Libby’s H*O*P*E*™ : 63 Ovarian Cancer Drugs & 203 Solid Tumor Drugs are listed in the 2009 PhRMA report (pp. 51 – 55)]. …”

“New Report Shows Record Number of Medicines In Development to Treat Leading Causes of Cancer

phrmalogoDenver, CO (April 1, 2009) – Responding to President Obama’s call for ‘a cure for cancer in our time,’ the Pharmaceutical Research and Manufacturers of America (PhRMA) delivered a new report today on medicines in the research pipeline for cancer. The report shows that America’s pharmaceutical research and biotechnology companies are testing a record 861 new cancer medicines and vaccines. The medicines listed in the report are being tested in human clinical trials or are awaiting approval by the U.S. Food and Drug Administration. [Libby’s H*O*P*E*™ Note: 63 Ovarian Cancer Drugs & 203 Solid Tumor Drugs are listed in the 2009 PhRMA report (pp. 51-55)].

Nationwide, cancer is the second leading cause of death, affecting more than 10 million Americans, according to the National Cancer Institute. This year, more than half a million Americans are expected to die of cancer-more than 1,500 a day. In Colorado, the lifetime risk of cancer is 1 in 2 for males and 2 in 5 for females. The most commonly diagnosed cancer in the state is breast cancer, followed by prostate and lung cancer.

‘We released this report in Denver because of Colorado’s growing role in developing cancer medicines,’ said PhRMA Senior Vice President Ken Johnson, who unveiled the report at the State Capitol Building.

‘Oncology is one of Colorado’s core research competencies, so the President’s call to cure cancer resonates powerfully in our state,’ said Colorado Lt. Governor Barbara O’Brien. ‘We are proud that the cancer medicines now in the research pipeline in Colorado are contributing substantially to the incredible progress made in the last five years by biopharmaceutical companies in developing new and more effective cancer treatments. The nation must continue its strong commitment to the cutting-edge pharmaceutical research that will enable cancer patients to live longer, healthier, and more productive lives.’

billytauzin

Billy Tauzin, President and Chief Executive Officer, The Pharmaceutical Research and Manufacturers of America (PhRMA). PhRMA's mission is to conduct effective advocacy for public policies that encourage discovery of important new medicines for patients by pharmaceutical & biotechnology research companies.

‘I am one of those patients who was diagnosed with cancer and was given a new treatment that brought me from the brink of death back to life,’ says PhRMA President and CEO Billy Tauzin. ‘The men and women working for America’s pharmaceutical research companies are committed to developing new cancer medicines that, one day, could eradicate cancer all together.’

Cancer medicines being developed include 122 for lung cancer, the leading cause of cancer death in the United States; 107 for breast cancer, which is expected to strike more than 180,000 American women this year; 70 for colorectal cancer, which is the third most common cancer in both men and women; and 103 for prostate cancer, which this year is expected to kill 28,000 American men. Additional medicines target brain cancer, kidney cancer, ovarian cancer, pancreatic cancer, skin cancer, and others.

The medicines represent many cutting-edge approaches, including a drug that delivers a synthetic version of a substance derived from scorpions directly to brain tumor cells; a number of cancer vaccines; medicines that target and kill specific cancer cells; and treatments that activate the patient’s general immune system to destroy cancer.

‘Researchers are making exciting progress in the search for new cures and treatments for cancer. But these efforts are wasted if the medicines we develop aren’t accessible to patients who need them,’ said Johnson.

Help is available to patients in need through the Partnership for Prescription Assistance (PPA), a program sponsored by America’s pharmaceutical research companies. To date, the PPA has helped more than 5.7 million patients nationwide, including more than 72,000 people in Colorado. Since its launch in April 2005, the PPA bus tour has visited all 50 states and more than 2,500 cities to educate people about patient assistance programs.

The “Help is Here Express” is staffed by trained specialists able to quickly help uninsured and financially struggling patients access information on more than 475 patient assistance programs, including nearly 200 programs offered by pharmaceutical companies. When the “Help is Here Express” moves on, patients can visit PPA’s easy-to-use Web site (www.pparx.org) or call the toll-free phone number (1-888-4PPA-NOW).

Click here to read Medicines in Development for Cancer 2009. [Adobe Reader PDF Doc.]

Read the backgrounder fact sheet here.

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Pharmaceutical Research & Manufacturers of America

The Pharmaceutical Research and Manufacturers of America (PhRMA) represents the country’s leading pharmaceutical research and biotechnology companies, which are devoted to inventing medicines that allow patients to live longer, healthier, and more productive lives. PhRMA companies are leading the way in the search for new cures. PhRMA members alone invested an estimated $50.3 billion in 2008 in discovering and developing new medicines. Industry-wide research and investment reached a record $65.2 billion in 2008.

PhRMA Internet Address: www.phrma.org

For information on stories of hope and survival, visit: http://sharingmiracles.com/

PhRMA en Español: www.nuestraphrma.org

For information on how innovative medicines save lives, visit: www.innovation.org

For information on the Partnership for Prescription Assistance, visit: www.pparx.org

For information on the danger of imported drugs, visit: www.buysafedrugs.info”

SourceNew Report Shows Record Number of Medicines In Development to Treat Leading Causes of Cancer, Press Release, Pharmaceutical Research and Manufacturers of America, April 1, 2009.