U.S. Food & Drug Administration Acts to Bolster Supply of Critically Needed Cancer Drugs Including Doxil

The U.S. Food and Drug Administration today announced a series of steps to (i) increase the supply of critically needed cancer drugs, and (ii) build upon President Obama’s Executive Order to help prevent future drug shortages.  To alleviate the Doxil cancer drug shortage, the FDA approved  the temporary importation of a replacement drug named “Lipodox” (doxorubicin hydrochloride liposome injection), with the expectation of  ending the U.S. shortage and fully meeting patient needs in the coming weeks. Doxil is an important weapon in the fight against recurrent ovarian cancer.

The U.S. Food and Drug Administration today announced a series of steps designed to increase the supply of critically needed cancer drugs, and build upon President Obama’s Executive Order, dated October 31, 2011 (No. 13588), in an attempt to prevent future drug shortages.

Margaret Hamburg, M.D., Commissioner, U.S. Food & Drug Administration

“A drug shortage can be a frightening prospect for patients and President Obama made it clear that preventing these shortages from happening is a top priority of his administration,” said FDA Commissioner Margaret A. Hamburg, M.D. “Through the collaborative work of the FDA, industry, and other stakeholders, patients and families waiting for these products or anxious about their availability should now be able to get the medication they need.”

In response to the critical shortage of the cancer drug Doxil (doxorubicin hydrochloride liposome injection) and rapidly declining supplies of methotrexate, the FDA took proactive steps needed to increase available supply for patients in the U.S.

For Doxil, there will be temporary importation of a replacement drug named “LipoDox” (doxorubicin hydrochloride liposome injection), which is expected to end the shortage and fully meet patient needs in the coming weeks.

For methotrexate, in addition to already announced actions, the FDA approved a new manufacturer of preservative-free formulation of methotrexate that is expected to further bolster supply and help avert a shortage of this lifesaving medicine. the FDA expedited review of the application to help address this potential shortage.

In response to President Obama’s Executive Order #13588 regarding prescription drug shortages, the FDA today issued draft guidance to industry which provides detailed requirements for both mandatory and voluntary notifications to the FDA of issues that could result in a drug shortage or supply disruption. Because of President Obama’s Executive Order #13588 and the FDA’s letter to manufacturers on the same day, increased awareness of the importance of early notification has resulted in a sixfold increase in voluntary notifications by industry of potential shortages. In 2011, there were a total of 195 drug shortages prevented. Since the issuance of Presidential Executive Order #13588, the FDA has prevented 114 drug shortages.

Under the FDA’s exercise of enforcement discretion, the chemotherapeutic drug LipoDox will be imported as an alternative to Doxil. Doxil is used in multiple treatment regimens, including treatment of ovarian cancer after failure of platinum-based chemotherapy (e.g., carboplatin or cisplatin). The drug is also indicated for use in AIDS-related Kaposi’s sarcoma and multiple myeloma. The FDA anticipates that the incoming supply of LipoDox will be able to fully meet patient needs.

The FDA’s exercise of enforcement discretion for Lipodox is a temporary, limited arrangement specific to Sun Pharma Global FZE (a United Arab Emirates entity) and its authorized distributor, Caraco Pharmaceutical Laboratories Ltd. (a U.S. subsidiary of Sun Pharmaceutical Industries Ltd., a leading Indian pharmaceutical company).

Temporary importation of unapproved foreign drugs is considered in rare cases when there is a shortage of an approved drug that is critical to patients and the shortage cannot be resolved in a timely fashion with FDA-approved drugs.

When a company is identified that is willing and able to import the needed drug product, the FDA evaluates the foreign-approved drug to ensure that it is of adequate quality and that the drug does not pose significant risks for U.S. patients. Only after successful evaluation of these factors does the FDA exercise its enforcement discretion for the temporary importation of an overseas drug into the U.S. market.

Methotrexate is a drug that is needed for the treatment of many forms of cancer and other serious diseases. For example, preservative-free methotrexate is needed for the intrathecal (injection into the fluid surrounding the brain and spinal cord) treatment of children with acute lymphocytic leukemia (ALL), as well as high-dose therapy of osteosarcoma.

To alleviate the shortage of methotrexate, the FDA has successfully engaged several firms to assist in maintaining supplies to meet all patient needs. First, the FDA has prioritized the review and approval of a preservative-free methotrexate generic drug manufactured by APP Pharmaceuticals (APP) and expects that product to become available in March 2012 and continue indefinitely. Second, Hospira expedited release of additional methotrexate supplies, resulting in 31,000 vials of new product – enough for more than one month’s worth of demand – being shipped to hundreds of U.S. hospitals and treatment centers today. The FDA is actively working with other manufacturers of methotrexate who have also stepped up to increase drug production for the purpose of meeting patient needs, including Mylan and Sandoz Pharmaceuticals.

APP’s application for preservative-free methotrexate is a supplement to its already approved generic drug application that the firm had previously discontinued. When the FDA became aware of potential problems with the supply of the drug (attributable to the voluntary plant closing of the largest methotrexate manufacturer, Ben Venue Laboratories), the agency reached out to other firms to see how the FDA could assist to meet the shortfall.

Prior to the approval of APP’s application, and the subsequent Ben Venue Laboratories’ voluntary shutdown, the FDA worked with Ben Venue on release of already manufactured preservative-free methotrexate, following its confirmation of the safety of remaining drug inventory. This supply is available already and will provide emergency supplies as the other firms also work to increase production of methotrexate in response to requests by the FDA and the public.

On October 31, 2011, the Obama Administration also announced its support for bipartisan legislation that would (i) require all prescription drug shortages to be reported to the FDA, and (ii) give the FDA new authority to enforce these requirements. While additional manufacturing capacity is necessary to fully address the drug shortage problem, additional early notification to the FDA can have a significant, positive impact on addressing the incidence and duration of drug shortages.

For more FDA information relating to the U.S. drug shortage, please click on the topics listed below:

Drug Shortages

Drug Shortage Guidance (“Guidance for Industry — Notification to FDA of Issues that May Result in a Prescription Drug or Biological Product Shortage – Draft Guidance,” dated February 2012)

Labeling for Doxil (doxorubicin hydrochloride liposome injection)

Letter from Sun Pharma Global FZE to healthcare professionals regarding doxorubicin, dated January 27, 2012.

FDA letter to Industry regarding drug shortage, dated October 31, 2011.

Labeling for methotrexate

Consumer Inquiries: 888-INFO-FDA

About the U.S. Food & Drug Administration (FDA)

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The FDA is also responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

Source: FDA acts to bolster supply of critically needed cancer drugs, FDA News Release, U.S. Food & Drug Administration, February 21, 2012.

Can Iran Solve the Current U.S. Doxil/Caelyx Cancer Drug Shortage?

Iran expects to bring a  cancer nanodrug called “Sinadoxosome” to market next month. Sinadoxosome is apparently similiar to pegylated liposomal doxorubicin which is marketed under the brand name “Doxil” in the U.S. and “Caelyx” in Europe. Doxil/Caelyx has been in extreme short supply in the U.S. and Europe, thereby causing potential detriment to many ovarian cancer patients.

Iran inaugurated the production line of an anti-cancer nanodrug under the name “Sinadoxosome” in the Northern city of Rasht, and the medicine will soon come to market.

In addition to producing the amount of nanodrug required by Iran, the new drug production line makes possible the exportation of the drug to other countries. The drug acquired the necessary certificates from Nanotechnology Committee of the Ministry of Health, Treatment, and Medical Education in November 2011.

Dr. Mahmoud Reza Ja’fari, the Managing Director of Exir Nano Sina Company, told the Iran Nanotechnology Initiative Council’s reporter that the anti-cancer drug Sinadoxosome would be presented to the market next month.

“This product has been produced by the knowledge-based company Exir Nano Sina in association with Iran Nanotechnology Initiative Council. It has acquired the production certificate from the Ministry of Health, Treatment, and Medical Education,” Dr. Ja’fari added.

Pointing to the fact that the production of this medicine had been “monopolized” by European countries (under the “Caelyx” brand name) and by the United States (under the “Doxil” brand name), the Head of Nanotechnology Research Centre of Mashhad University of Medical Sciences said: “The importation of this medicine cost [sic] $5 mln annually. However, this medicine will be presented to the patients at one-third of the price of the foreign drug after the establishment of Sinadoxosome production line.”

Sinadoxosome contains nano liposomes that contain doxorubicin anti-cancer medicine. It targets the tumor tissue and boosts the effect of the medicine but decreases its side effects. The medicine has applications in the treatment of ovarian cancer, breast cancer, leukemia, and Kaposi’s sarcoma (a type of soft tissue cancer).

The production line involving the Sinadoxosome anti-cancer drug was established on February 8, 2012, in the presence of Iran Nanotechnology Initiative Council’s authorities and the managing director and researchers of the Sobhan Oncology Pharmaceutical Company.

*          *          *

In the YouTube video presented below, U.S. Senator Orrin Hatch (R-Utah), Ranking Member of the Senate Finance Committee, delivered the opening statement at a 2011 committee hearing examining the impact of drug shortages in America.

Source: Iran to Present New Anti-Cancer Nanodrug to Market Soon, Iran Nano-Technology Initiative Council, February 15, 2012.

Additional Doxil & Drug Shortage Information:

FDA Revokes Approval of Avastin Use For Metastatic Breast Cancer; Major U.S. Ovarian Cancer Advocacy Organization Concerned

Today, the U.S. Food and Drug Administration (FDA) Commissioner Hamburg revoked approval of Avastin for treatment of metastatic breast cancer in the U.S. The decision does not impact Avastin’s availability for its approved uses for other cancer types in the U.S. A major U.S. ovarian cancer advocacy organization is concerned that the FDA decision will make it more difficult for ovarian cancer patients to gain access to Avastin.

FDA Revocation of Avastin Approval For Metastatic Breast Cancer

FDA Commissioner Margaret A. Hamburg, M.D., said today she is revoking the agency’s approval of the breast cancer indication for Avastin® (bevacizumab) after concluding that the drug has not been shown to be safe and effective for that use.

Avastin will still remain on the market as an approved treatment for certain types of colon, lung, kidney and brain cancer (glioblastoma multiforme).

“This was a difficult decision. FDA recognizes how hard it is for patients and their families to cope with metastatic breast cancer and how great a need there is for more effective treatments. But patients must have confidence that the drugs they take are both safe and effective for their intended use,” Dr. Hamburg said. “After reviewing the available studies it is clear that women who take Avastin for metastatic breast cancer risk potentially life-threatening side effects without proof that the use of Avastin will provide a benefit, in terms of delay in tumor growth, that would justify those risks. Nor is there evidence that use of Avastin will either help them live longer or improve their quality of life.”

Avastin’s risks include severe high blood pressure; bleeding and hemorrhaging; heart attack or heart failure; and the development of perforations in different parts of the body such as the nose, stomach, and intestines.

Today’s decision, outlined in Dr. Hamburg’s 69-page opinion, involves Avastin used in combination with the cancer drug paclitaxel (Taxol) for those patients who have not been treated with chemotherapy for their form of metastatic breast cancer known as “HER-2 negative.” This indication must now be removed from Avastin’s product labeling.

Dr. Hamburg’s decision is based on an extensive record, which includes thousands of pages submitted to a public docket, data from several clinical trials, and the record from a two-day hearing held in June, 2011.

Avastin was approved for metastatic breast cancer in February 2008 under the FDA’s accelerated approval program, which allows a drug to be approved based on data that are not sufficiently complete to permit full approval. The accelerated approval program provides earlier patient access to promising new drugs to treat serious or life-threatening conditions while confirmatory clinical trials are conducted. If the clinical trials do not justify the continued approval of the drug or a specific drug indication, the agency may revoke its approval. In this case, the accelerated approval was based on promising results from one study that suggested that the drug could provide a meaningful increase in the amount of time from when treatment is started until the tumor grows or the death of the patient.

After the accelerated approval of Avastin for breast cancer, the drug’s sponsor, Genentech (a member of the Roche Group) completed two additional clinical trials and submitted the data from those studies to the FDA. These data showed only a small effect on tumor growth without evidence that patients lived any longer or had a better quality of life compared to taking standard chemotherapy alone – not enough to outweigh the risk of taking the drug.

The FDA’s Center for Drug Evaluation and Research (CDER), which is responsible for the approval of this drug, ultimately concluded that the results of these additional studies did not justify continued approval and notified Genentech that it was proposing to withdraw approval of the indication.

Genentech did not agree with CDER’s evaluation of the data and, following the procedures set out in FDA regulations, requested a hearing on CDER’s withdrawal proposal, with a decision to be made by the FDA Commissioner. That two-day hearing, which took place June 28-29, 2011, included recommendations from the FDA’s Oncologic Drugs Advisory Committee (ODAC), voting 6-0 in favor of withdrawing approval of Avastin’s breast cancer indication. After the hearing, the public docket remained open until August 4, 2011. In an earlier meeting of the ODAC, that committee had voted 12-1 in favor of the removal of the breast cancer indication from the Avastin label.

“FDA is committed to working with sponsors to bring promising cancer drugs to market as quickly as possible using tools like accelerated approval,” Dr. Hamburg said. “I encourage Genentech to consider additional studies to identify if there are select subgroups of women suffering from breast cancer who might benefit from this drug.”

Genentech Response

In a press release issued earlier today, Genentech’s Hal Barron, M.D., chief medical officer and head, Global Product Development, stated:

“We are disappointed with the outcome. We remain committed to the many women with this incurable disease and will continue to provide help through our patient support programs to those who may be facing obstacles to receiving their treatment in the United States. Despite today’s action, we will start a new Phase III study of Avastin in combination with paclitaxel in previously untreated metastatic breast cancer and will evaluate a potential biomarker that may help identify which people might derive a more substantial benefit from Avastin.”

Genentech emphasizes the following points in its press release:

  • The FDA Commissioner revoked approval of Avastin for treatment of metastatic breast cancer in the U.S.
  • The FDA’s action concludes its review of Avastin’s use for metastatic breast cancer.
  • The FDA decision does not impact Avastin’s approved uses for other cancer types in the U.S. or other countries.
  • The FDA decision does not impact the approval of Avastin for metastatic breast cancer in more than 80 foreign countries.
  • Roche will initiate a new clinical trial of Avastin plus paclitaxel in metastatic breast cancer.
  • Genentech will issue a letter to healthcare providers and will also provide them with a letter to distribute to their patients. Both letters will be made available on Genentech’s website.
  • Patients with questions or concerns about insurance coverage, or doctors with questions about reimbursement, can call Genentech’s Access Solutions Group at (866)-4- ACCESS.
  • Doctors with questions about Avastin can call Genentech’s Medical Communications group at (800) 821-8590.
  • The FDA’s action does not impact ongoing clinical trials with Avastin in breast cancer. For more information, please call Genentech’s Trial Information Support Line at (888) 662-6728 or visit clinicaltrials.gov.

Major U.S. Ovarian Cancer Advocacy Organization Concerned About Future Impact of FDA Decision

Karen Orloff Kaplan, MSW, MPH, ScD, Chief Executive Officer, Ovarian Cancer National Alliance

Karen Orloff Kaplan, MSW, MPH, ScD, the Chief Executive Officer for the Ovarian Cancer National Alliance (OCNA), expressed concern that the removal of metastatic breast cancer from the Avastin label could negatively affect women with ovarian cancer, for whom the drug is used “off-label.”  OCNA is one of the most influential advocates for women with ovarian cancer in the United States.

Dr. Kaplan stated:

“Results from three Phase III clinical studies show that Avastin is beneficial for some women with ovarian cancer. We are deeply concerned that the Food and Drug Administration’s decision regarding metastatic breast cancer will make it difficult for women with ovarian cancer to access Avastin, and that patients could be denied insurance coverage for this treatment. The Ovarian Cancer National Alliance will continue our work to ensure that drugs that are useful and medically appropriate are available to women with this disease.”

In the FDA report accompanying her decision, Commissioner Hamburg cited a lack of evidence that Avastin improved overall survival for women with metastatic breast cancer in its decision. “Given how difficult it is to measure overall survival in ovarian cancer clinical trials, we are concerned that today’s ruling may set an unfortunate precedent,” said Dr. Kaplan.

Currently, various national cancer treatment guidelines, such as the National Comprehensive Cancer Network (NCCN) Compendium™, include Avastin as a treatment for ovarian cancer. Despite that fact, the FDA’s decision could prompt a reexamination of industry treatment guidelines by various groups, including the NCCN. The NCCN  is a nonprofit alliance which consists of 21 leading U.S. cancer centers.

Specifically, OCNA is concerned that the FDA Avastin label change, mandated by today’s FDA decision, will lead to restrictions by third party payers, including the U.S. Medicare federal insurance program, who generally reimburse for Avastin when a woman’s cancer has returned. OCNA’s concern may be warranted because Reuters reported earlier today that some healthcare insurers have already started pulling back on Avastin reimbursement coverage for breast cancer.

As of now, according to Reuters, Medicare will continue to pay for Avastin used in the treatment of breast cancer, despite  the FDA’s revocation decision. “Medicare will continue to cover Avastin,” said Don McLeod, a spokesman for the Centers for Medicare and Medicaid Services (CMS). “CMS will monitor the issue and evaluate coverage options as a result of action by the FDA but has no immediate plans to change coverage policies.” The CMS statement may mitigate concerns that patients using the drug would lose critical drug reimbursement insurance coverage in the future.

Sources:

Addtional Information:

FDA Awards $1.6M Orphan Drug Grant for Clinical Phase II Development of EGEN-001 for Treatment of Ovarian Cancer

EGEN, Inc. announced that the Food and Drug Administration (FDA) awarded the company a four-year grant of $1.6 million to assist in the phase II clinical development of EGEN-001, the company’s lead product. EGEN-001 is under clinical development for the treatment of advanced recurrent ovarian cancer.

EGEN, Inc. announced that the Food and Drug Administration (FDA) awarded the company a four-year grant of $1.6 million to assist in the phase II clinical development of EGEN-001, the company’s lead product. EGEN-001 is under clinical development for the treatment of advanced recurrent ovarian cancer.[1]

EGEN, Inc. is developing gene-based biopharmaceuticals that rely on proprietary delivery technologies such as TheraPlas™ (illustrated above). In preclinical studies, the application of this approach produced anti-cancer activity in the treatment of disseminated abdominal cancers, solid tumors and metastatic cancers. (Photo: EGEN, Inc.)

EGEN-001 was developed as an interleukin-12 (IL‑12) gene therapy for the treatment of disseminated epithelial ovarian cancer. It is a low concentration formulation composed of a human IL-12 plasmid formulated with a proprietary PPC delivery system. EGEN-001 is designed for intraperitoneal (IP) administration. The subsequent IL-12 protein expression is associated with an increase in immune system activity, including T-lymphocyte and natural killer (NK) cell proliferation, and cytotoxic activation and secretion of interferon gamma (IFN-g), which in turn, leads to tumor inhibition. Additionally, IL-12 inhibits angiogenesis and formation of tumor vascularization.

EGEN has successfully completed two Phase I trials of EGEN-001 in ovarian cancer patients.  In the first study, EGEN-001 was administered as monotherapy in platinum-resistant ovarian cancer patients[2] and in the second study in combination with carboplatin/docetaxel chemotherapy in platinum-sensitive ovarian cancer patients.[3] In both studies, EGEN-001 treatment resulted in good safety, biological activity and encouraging efficacy.[4-5] EGEN-001 received Orphan Drug Status from the FDA in 2005, and its first $1 million FDA orphan grant in 2005.

“This is a significant milestone and accomplishment for the company,” commented Dr. Khursheed Anwer, President and Chief Science Officer of EGEN. “We are pleased to receive this FDA support, which has been very useful in the advancement of our novel EGEN-001 product in the clinic for the treatment of recurrent ovarian cancer. The product utilizes the Company’s proprietary TheraPlas® delivery technology and is composed of interleukin-12 (IL-12) gene formulation with a biocompatible delivery polymer. IL-12 is a potent cytokine which works by enhancing the body’s immune system against cancer and inhibiting tumor blood supply.”

About EGEN, Inc.

EGEN, Inc. (EGEN), with laboratories and headquarters in Huntsville, Alabama, is a privately held biopharmaceutical company focused on developing therapeutics for the treatment of human diseases including cancer. The Company specializes in the delivery of therapeutic nucleic acids (DNA and RNAi) and proteins aimed at specific disease targets. The Company has a significant intellectual property position in synthetic carriers, their combination with DNA, and their therapeutic applications. EGEN’s research pipeline products are aimed at treatment of various cancer indications. In addition, the Company has its TheraSilence® delivery technology aimed at delivery of therapeutic siRNA for the treatment of human diseases. EGEN collaborates with outside investigators, biotech organizations, and universities on various projects in these areas.

References:

1/ A Phase II Evaluation of Intraperitoneal EGEN-001 (IL-12 Plasmid Formulated With PEG-PEI-Cholesterol Lipopolymer) in the Treatment of Persistent or Recurrent Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancer, Clinical Trial Summary, ClinicialTrials.gov (Identifier:  NCT01118052).

2/A Phase 1, Open Label, Dose Escalation Study of the Safety, Tolerability and Preliminary Efficacy of Intraperitoneal EGEN-001 in Patients With Recurrent Epithelial Ovarian Cancer, Clinical Trial Summary, ClinicialTrials.gov (Identifier: NCT00137865).

3/A Phase 1, Open-Label, Dose Escalation Study of the Safety and Preliminary Efficacy of EGEN-001 in Combination With Carboplatin and Docetaxel in Women With Recurrent, Platinum-Sensitive, Epithelial Ovarian Cancer, Clinical Trial Summary, ClinicialTrials.gov (Identifier:  NCT00473954).

4/Kendrick JE, Matthews KS, Straughn JM, et. al.  A phase I trial of intraperitoneal EGEN-001, a novel IL-12 gene therapeutic, administered alone or in combination with chemotherapy in patients with recurrent ovarian cancer.  J Clin Oncol 26: 2008 (May 20 suppl; abstr 5572).

5/Anwar K, Barnes MN, Kelly FJ, et. al. Safety and tolerability of a novel IL-12 gene therapeutic administered in combination with carboplatin/docetaxel in patients with recurrent ovarian cancer.  J Clin Oncol 28:15s, 2010 (suppl; abstr 5045).

Source: FDA Awards EGEN, Inc. Orphan -Drug Grant for Clinical Development of EGEN-001 for Treatment of Ovarian Cancer, Press Release, EGEN, Inc., February 2, 2011.

Novel Cancer-Targeting “Cornell Dot” Nanoparticle Approved for First-In-Human Clinical Trial

“Cornell Dots” — brightly glowing nanoparticles — may soon be used to light up cancer cells to aid in diagnosing and treating cancer. The U.S. Food and Drug Administration (FDA) has approved the first clinical trial in humans of the new technology. It is the first time the FDA has approved using an inorganic material in the same fashion as a drug in humans.

“Cornell Dots” (or “C dots”) — brightly glowing nanoparticles — may soon be used to light up cancer cells to aid in diagnosing and treating cancer. The U.S. Food and Drug Administration (FDA) has approved the first clinical trial in humans of the new technology. It is the first time the FDA has approved using an inorganic material in the same fashion as a drug in humans.

Michelle Bradbury, M.D., Ph.D., Clinician-Scientist, Neuroradiology Service, Memorial Sloan-Kettering Cancer Center; Assistant Professor, Radiology, Weill Cornell Medical College; Lead Study Investigator

Researchers at Memorial Sloan-Kettering Cancer Center’s Nanotechnology Center, along with collaborators at Cornell University and Hybrid Silica Technologies, have received approval for their first Investigational New Drug Application (IND) from the FDA for an ultrasmall silica inorganic nanoparticle platform for targeted molecular imaging of cancer, which may be useful for cancer treatment in the future. Center researchers are about to launch their first-in-human clinical trial in melanoma patients using this first-of-its-kind inorganic nanoparticle to be approved as a drug. “This is a very exciting and important first step for this new particle technology that we hope will ultimately lead to significant improvements in patient outcomes and prognoses for a number of different cancers,” said Michelle Bradbury, M.D., Ph.D., a clinician-scientist on Memorial Sloan-Kettering’s Neuroradiology Service and an assistant professor of radiology at Weill Cornell Medical College, who is the lead investigator of the study, along with Snehal Patel, M.D., a surgeon on Memorial Sloan-Kettering’s Head and Neck Service, who is a co-principal investigator.

“This is a very exciting and important first step for this new particle technology that we hope will ultimately lead to significant improvements in patient outcomes and prognoses for a number of different cancers.”

— Michelle Bradbury, M.D., Ph.D., lead investigator of the study and clinician-scientist on Memorial Sloan-Kettering’s Neuroradiology Service and an assistant professor of radiology at Weill Cornell Medical College

C dots were initially developed as optical probes at Cornell University, Ithaca, by Ulrich Wiesner, Ph.D., a professor of materials science and engineering who, along with Hybrid Silica Technologies, the supplier of C dots, has spent the past eight years precisely engineering these particles. C dots are silica spheres less than 8 nanometers in diameter that enclose several dye molecules. (A nanometer is one-billionth of a meter, about the length of three atoms in a row.) The silica shell, essentially glass, is chemically inert and small enough to pass through the body and out in the urine. For clinical applications, the dots are coated with polyethylene glycol so the body will not recognize them as foreign substances.

C dots were subsequently modified at Memorial Sloan-Kettering for use in PET (positron emission tomography) imaging. C dots are tiny silica spheres that contain dye that glows three times more brightly than simple free dyes when excited by light of a specific wavelength. C dots can “light up” cancer cells, and act as tumor tracers for tracking the movement of cells and assisting in the optical diagnosis of tumors near the skin surface. The attachment of a radioactive label produces a new generation of multimodal (PET-optical) particle probes that additionally enable deeper detection, imaging, and monitoring of drug delivery using three-dimensional PET techniques.

Ulrich Wiesner, Ph.D. (left), a Cornell University Professor of Materials Science & Engineering, works with graduate students Jennifer Drewes & Kai Ma to characterize the size & brightness of C dots in their Bard Hall lab. (Photo: Jason Koski/University Photography)

C dots can be tailored to any particle size. Previous imaging experiments in mice conducted by the Memorial Sloan-Kettering team showed that particles of a very small size (in the 5 to 7 nanometer range) could be retained in the bloodstream and efficiently cleared through the kidneys after applying a neutral surface coat. More recently, the research team molecularly customized C dots to create a new particle platform, or probe, that can target surface receptors or other molecules expressed on tumor surfaces and that can be cleared through the kidneys.

Using PET scans, C dots can be imaged to evaluate various biological properties of the tumors, including tumor accumulation, spread of metastatic disease to lymph nodes and distant organs, and treatment response to therapy. The information gained from imaging tumors targeted with this multimodal platform may also assist physicians in defining tumor borders for surgery, and improving real-time visualization of small vascular beds, anatomic channels, and neural structures during surgery.

The purpose of this trial is to evaluate the distribution, tissue, uptake, and safety of the particles in humans by PET imaging. This study will provide data that will serve as a baseline to guide the design of future surgical and oncologic applications in the clinic. “The use of PET imaging is an ideal imaging technology for sensitively monitoring very small doses of this new particle probe in first-in-human trials,” added Steven Larson, M.D., Chief of Memorial Sloan-Kettering’s Nuclear Medicine Service.

Memorial Sloan-Kettering nanochemist Oula Penate Medina, Ph.D., notes that “this is an important trial in that it will help to answer a number of key questions regarding future potential applications of this multimodal system. Once the door has been opened, new and emerging fields, such as targeted drug delivery, can be investigated. We expect that these particles can be adapted for multiple clinical uses, including the early diagnosis and treatment of various cancers, as well as for sensing changes in the microenvironment.”

“This clinical trial is the culmination of a longstanding collaborative effort with our colleagues at Cornell and Hybrid Silica Technologies, as well as a testament to our own institutional colleagues here at the Center,” Dr. Bradbury said. “With the support of many, in particular the Office of Clinical Research, we’ve pushed to translate the C dots from a laboratory idea to our first FDA IND-approved inorganic nanomedicine drug product to be tested in the clinic,” Dr. Bradbury said.

The work was funded in part by the Clinical and Translational Science Center, Weill Cornell Medical College, the Cornell Nanobiology Center, and the National Institutes of Health (NIH) Small-Animal Imaging Research Program (SAIRP). In addition to Drs. Bradbury, Penante-Medina, Larson, Patel, and Wiesner, the following Memorial Sloan-Kettering investigators contributed to and/or supported this work: Pat Zanzonico, Ph.D.; Heiko Schöder, M.D.; Elisa De Stanchina, Ph.D.; Hedvig Hricak, M.D., Ph.D., Chair of the Department of Radiology; as well as Hooisweng Ow, Ph.D., of Hybrid Silica Technologies, Inc.; Memorial Sloan-Kettering’s Office of Clinical Research; and the Cyclotron Core.

Sources:

Peptide Being Tested for Atherosclerosis Inhibits Ovarian Cancer Growth; Clinical Trial Planned

A drug in testing to treat atherosclerosis significantly inhibited growth of ovarian cancer in both human cell lines and mouse models, marking the first such report of a peptide being used to fight malignancies, according to a study by researchers at UCLA’s Jonsson Comprehensive Cancer Center.

A drug in testing to treat atherosclerosis significantly inhibited growth of ovarian cancer in both human cell lines and mouse models, marking the first such report of a peptide being used to fight malignancies, according to a study by researchers at UCLA’s Jonsson Comprehensive Cancer Center.

The study follows a previous discovery by the same group showing that a protein called apolipoprotein A-I (apoA-I) may be used as a biomarker to diagnose early stage ovarian cancer in patients, when it typically is asymptomatic and much easier to treat. These earlier findings could be vital to improving early detection, as more than 85 percent of ovarian cancer cases present in the advanced stages, when the cancer has already spread and patients are more likely to have a recurrence after treatment, said Dr. Robin Farias-Eisner, chief of gynecologic oncology and co-senior author of the study with Dr. Srinu Reddy, a professor of medicine.

Robin Farias-Eisner, M.D., Ph.D., Chief of Gynecologic Oncology, UCLA Jonsson Comprehensive Cancer Center

“The vast majority of ovarian cancer patients are diagnosed with advanced disease and the vast majority of those, after surgery and chemotherapy, will eventually become resistant to standard therapy,” Farias-Eisner said. “That’s the reason these patients die. Now, with this peptide as a potential therapy, and if successful in clinical trials, we may have a novel effective therapy for recurrent, chemotherapy-resistant ovarian cancer, without compromising the quality of life during treatment.”

The study was published Nov. 1, 2010 in the early online edition of the peer-reviewed journal Proceedings of the National Academy of Sciences.

In their previous work, Farias-Eisner, Reddy and their research teams identified three novel biomarkers that they used to diagnose early stage ovarian cancer. In September 2009, the U.S. Food and Drug Administration cleared the first laboratory test that can indicate the likelihood of ovarian cancer, OVA1™ Test, which includes the three biomarkers identified and validated by Farias-Eisner, Reddy and their research teams.

They observed that one of the markers, apoA-I, was decreased in patients with early stage disease. They wondered why the protein was decreased and set out to uncover the answer. They speculated that the protein might be protective, and may be preventing disease progression.

The protein, apoA-I, is the major component of HDL [high-density lipoprotein], the good cholesterol, and plays an important role in reverse cholesterol transport by extracting cholesterol and lipids from cells and transferring it to the liver for extraction. The protein also has anti-inflammatory and antioxidant properties. Because lipid transport, inflammation and oxidative stress are associated with the development and progression of cancer, Farias-Eisner and Reddy hypothesized that the reduced levels of apoA-I in ovarian cancer patients may be causal in disease progression.

Mice that were engineered to have many copies of human apoA-I gene showed very little cancer development when induced with ovarian cancer, while the mice without the extra copies of apoA-I showed much more disease. The mice with extra copies of the apoA-I gene also lived 30 to 50 percent longer than those who didn’t receive it.

Farias-Eisner and Reddy wanted to treat the mice that had more cancer with the protein apoA-I, but it was too large to conveniently administer, having 243 amino acids. The researchers then turned to apoA-I mimetic peptides—only 18 amino acids in length—that are being tested for cardiovascular diseases. That project had been ongoing for a number of years at UCLA, said Reddy, who is also a part of the cardiovascular research team led by Dr. Alan M. Fogelman, executive chair of the Department of Medicine.

Srinivasa T. Reddy, Ph.D., M.Sc., Professor, Division of Cardiology, Depart. of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California at Los Angeles

“The smaller peptides mimic the larger apoA-I protein and provided us with agents we could give to the mouse to see if it was effective in fighting ovarian cancer,” said Reddy. “One of the peptides was being tested as an experimental therapy for atherosclerosis, so we already have some information on how it’s being tolerated in humans, which would be vital information to have if we progressed to human studies in ovarian cancer.”

The peptide, thus far, has caused little to no side effects in atherosclerosis patients, Reddy said, a hopeful sign that it might be well tolerated in ovarian cancer patients.

The mice that were given the peptide by injection had about 60 percent less cancer than the mice that did not receive the peptide, Farias-Eisner said. The peptide also was given in drinking water or in mouse food and proved to be as effective when administered that way.

“It was an exciting result,” Farias-Eisner said. “It looked like we had something that could be ingested or injected that might be very effective against ovarian cancer progression.”

Farias-Eisner said the peptide avidly binds oxidized lipids, one of which is known to stimulate cancer cells to survive and multiply. In the mouse studies, the mice that received peptide had significantly lower levels of this cancer promoting lipid.

An early phase clinical trial is being planned testing the peptide in patients with aggressive ovarian cancers that are resistant to chemotherapy, a group of patients whose median survival is just 40 months. Farias-Eisner hopes the study will be started and completed within two years.

The study was funded by the Womens Endowment, the Carl and Roberta Deutsch Family Foundation, the Joan English Fund for Women’s Cancer Research, the National Institutes of Health and the West Los Angeles Veterans Affairs Medical Center.

UCLA’s Jonsson Comprehensive Cancer Center has more than 240 researchers and clinicians engaged in disease research, prevention, detection, control, treatment and education. One of the nation’s largest comprehensive cancer centers, the Jonsson center is dedicated to promoting research and translating basic science into leading-edge clinical studies. In July 2010, the Jonsson Cancer Center was named among the top 10 cancer centers nationwide by U.S. News & World Report, a ranking it has held for 10 of the last 11 years. For more information on the Jonsson Cancer Center, visit our website at http://www.cancer.ucla.edu.

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