Guidance for Industry Expedited Programs for Serious Conditions––Drugs and Biologics

Posted by Lainie Shapiro:  FDA recently published draft guidance for industry on developing new drugs and biologics and expedited approval systems.  The document is here:

The following four FDA programs are intended to facilitate and expedite development and 15 review of new drugs to address unmet medical need in the treatment of a serious or life- threatening condition: fast track designation, breakthrough therapy designation, accelerated approval, and priority review designation (see the FDA Guidance for an overview of the programs).


Fast Track, Breakthrough Therapy, Accelerated Approval and Priority Review

Posted by Lainie Shapiro….Here is an example of what the FDA is doing to help accelerate drug approvals.

Fast Track, Breakthrough Therapy, Accelerated Approval and Priority Review

Expediting Availability of New Drugs for Patients with Serious Conditions

Speeding the development and availability of drugs that treat serious diseases are in everyone’s interest, especially when the drugs are the first available treatment or have advantages over existing treatments.  The Food and Drug Administration (FDA) has developed three distinct and successful approaches to making such drugs available as rapidly as possible: Priority Review, Accelerated Approval, and Fast Track.  Because each of these approaches implies speed, there can be confusion about the specific meaning of each and the distinctions among them.

The following summary describes each element, how they differ, and how they complement each other.

Fast Track
Breakthrough Therapy
Accelerated Approval
Priority Review

Fast Track
Fast track is a process designed to facilitate the development, and expedite the review of drugs to treat serious conditions and fill an unmet medical need.  The purpose is to get important new drugs to the patient earlier. Fast Track addresses a broad range of serious conditions.
Determining whether a condition is serious is a matter of judgment, but generally is based on whether the drug will have an impact on such factors as survival, day-to-day functioning, or the likelihood that the condition, if left untreated, will progress from a less severe condition to a more serious one.  AIDS, Alzheimer’s, heart failure and cancer are obvious examples of serious conditions.   However, diseases such as epilepsy, depression and diabetes are also considered to be serious conditions.
Filling an unmet medical need is defined as providing a therapy where none exists or providing a therapy which may be potentially better than available therapy.
Any drug being developed to treat or prevent a condition with no current therapy obviously is directed at an unmet need.  If there are available therapies, a fast track drug must show some advantage over available therapy, such as:
  • Showing superior effectiveness, effect on serious outcomes or improved effect on serious outcomes
  • Avoiding serious side effects of an available therapy
  • Improving the diagnosis of a serious condition where early diagnosis results in an improved outcome
  • Decreasing a clinically significant toxicity of an available therapy that is common and causes discontinuation of treatment
  • Ability to address emerging or anticipated public health need
A drug that receives Fast Track designation is eligible for some or all of the following:
  • More frequent meetings with FDA to discuss the drug’s development plan and ensure collection of appropriate data needed to support drug approval
  • More frequent written correspondence from FDA about such things as the design of the proposed clinical trials and use of biomarkers
  • Eligibility for Accelerated Approval and Priority Review, if relevant criteria are met
  • Rolling Review, which means that a drug company can submit completed sections of its Biological License Application (BLA) or New Drug Application (NDA) for review by FDA, rather than waiting until every section of the application is completed before the entire application can be reviewed.  BLA or NDA review usually does not begin until the drug company has submitted the entire application to the FDA
Fast Track designation must be requested by the drug company.  The request can be initiated at any time during the drug development process.  FDA will review the request and make a decision within sixty days based on whether the drug fills an unmet medical need in a serious condition.
Once a drug receives Fast Track designation, early and frequent communication between the FDA and a drug company is encouraged throughout the entire drug development and review process.  The frequency of communication assures that questions and issues are resolved quickly, often leading to earlier drug approval and access by patients.

Breakthrough Therapy

Breakthrough Therapy designation is a process designed to expedite the development and review of drugs that are intended to treat a serious condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapy on a clinically significant endpoint(s).
To determine whether the improvement over available therapy is substantial is a matter of judgment and depends on both the magnitude of the treatment effect, which could include duration of the effect, and the importance of the observed clinical outcome. In general, the preliminary clinical evidence should show a clear advantage over available therapy. 
For purposes of Breakthrough Therapy designation, clinically significant endpoint generally refers to an endpoint that measures an effect on irreversible morbidity or mortality (IMM) or on symptoms that represent serious consequences of the disease. A clinically significant endpoint can also refer to findings that suggest an effect on IMM or serious symptoms, including:
  • An effect on an established surrogate endpoint
  • An effect on a surrogate endpoint or intermediate clinical endpoint considered reasonably likely to predict a clinical benefit (i.e., the accelerated approval standard)
  • An effect on a pharmacodynamic biomarker(s) that does not meet criteria for an acceptable surrogate endpoint, but strongly suggests the potential for a clinically meaningful effect on the underlying disease
  • A significantly improved safety profile compared to available therapy (e.g., less dose-limiting toxicity for an oncology agent), with evidence of similar efficacy
A drug that receives Breakthrough Therapy designation is eligible for the following:
  • All Fast Track designation features
  • Intensive guidance on an efficient drug development program, beginning as early as Phase 1
  • Organizational commitment involving senior managers
Breakthrough Therapy designation is requested by the drug company. If a sponsor has not requested breakthrough therapy designation, FDA may suggest that the sponsor consider submitting a request if: (1) after reviewing submitted data and information (including preliminary clinical evidence), the Agency thinks the drug development program may meet the criteria for Breakthrough Therapy designation and (2) the remaining drug development program can benefit from the designation. 

Ideally, a Breakthrough Therapy designation request should be received by FDA no later than the end-of-phase-2 meetings if any of the features of the designation are to be obtained. Because the primary intent of Breakthrough Therapy designation is to develop evidence needed to support approval as efficiently as possible, FDA does not anticipate that Breakthrough Therapy designation requests will be made after the submission of an original BLA or NDA or a supplement. FDA will respond to Breakthrough Therapy designation requests within sixty days of receipt of the request.

Accelerated Approval
When studying a new drug, it can sometimes take many years to learn whether a drug actually provides a real effect on how a patient survives, feels, or functions.  A positive therapeutic effect that is clinically meaningful in the context of a given disease is known as “clinical benefit”.  Mindful of the fact that it may take an extended period of time to measure a drug’s intended clinical benefit, in 1992 FDA instituted the Accelerated Approval regulations. These regulations allowed drugs for serious conditions that filled an unmet medical need to be approved based on a surrogate endpoint. Using a surrogate endpoint enabled the FDA to approve these drugs faster.
 In 2012, Congress passed the Food and Drug Administration Safety Innovations Act (FDASIA). Section 901 of FDASIA amends the Federal Food, Drug, and Cosmetic Act (FD&C Act) to allow the FDA to base accelerated approval for drugs for serious conditions that fill an unmet medical need on whether the drug has an effect on a surrogate or an intermediate clinical endpoint.
A surrogate endpoint used for accelerated approval is a marker – a laboratory measurement, radiographic image, physical sign or other measure that is thought to predict clinical benefit, but is not itself a measure of clinical benefit.  Likewise, an intermediate clinical endpoint is a measure of a therapeutic effect that is considered reasonably likely to predict the clinical benefit of a drug, such as an effect on irreversible morbidity and mortality (IMM).
The FDA bases its decision on whether to accept the proposed surrogate or intermediate clinical endpoint on the scientific support for that endpoint.  Studies that demonstrate a drug’s effect on a surrogate or intermediate clinical endpoint must be “adequate and well controlled” as required by the FD&C Act.
Using surrogate or intermediate clinical endpoints can save valuable time in the drug approval process.  For example, instead of having to wait to learn if a drug actually extends survival for cancer patients, the FDA may approve a drug based on evidence that the drug shrinks tumors, because tumor shrinkage is considered reasonably likely to predict a real clinical benefit.  In this example, an approval based upon tumor shrinkage can occur far sooner than waiting to learn whether patients actually lived longer.  The drug company will still need to conduct studies to confirm that tumor shrinkage actually  predicts that patients will live longer. These studies are known as phase 4 confirmatory trials.
Where confirmatory trials verify clinical benefit, FDA will generally terminate the requirement.  Approval of a drug may be withdrawn or  the labeled indication of the drug changed if trials fail to verify clinical benefit or do not demonstrate sufficient clinical benefit to justify the risks associated with the drug (e.g., show a significantly smaller magnitude or duration of benefit than was anticipated based on the observed effect on the surrogate).

Priority Review
Prior to approval, each drug marketed in the United States must go through a detailed FDA review process.  In 1992, under the Prescription Drug User Act (PDUFA), FDA agreed to specific goals for improving the drug review time and created a two-tiered system of review times – Standard Review and Priority Review. A Priority Review designation means FDA’s goal is to take action on an application within 6 months (compared to 10 months under standard review).
A Priority Review designation will direct overall attention and resources to the evaluation of applications for drugs that, if approved, would be significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions when compared to standard applications.
Significant improvement may be demonstrated by the following examples:
  • evidence of increased effectiveness in treatment, prevention, or diagnosis of  condition;
  • elimination or substantial reduction of a treatment-limiting drug reaction;
  • documented enhancement of patient compliance that is expected to lead to an improvement in serious outcomes; or
  • evidence of safety and effectiveness in a new subpopulation.
FDA decides on the review designation for every application. However, an applicant may expressly request priority review as described in the Guidance for Industry Expedited Programs for Serious Conditions – Drugs and Biologics.  It does not affect the length of the clinical trial period.  FDA informs the applicant of a Priority Review designation within 60 days of the receipt of the original BLA, NDA, or efficacy supplement.  Designation of a drug as “Priority” does not alter the scientific/medical standard for approval or the quality of evidence necessary.

Fast Track, Breakthrough Therapy, Accelerated Approval and Priority Review are approaches that are intended to make therapeutically important drugs available at an earlier time.  They do not compromise the standards for the safety and effectiveness of the drugs that become available through this process.
Fast Track, Accelerated Approval, and Priority Review have evolved over time. Breakthrough Therapy is a new program at FDA that will complement these existing programs and facilitate and expedite drug development and review for serious conditions. FDA has been vigilant in assuring that reducing the time necessary for drug development has not compromised the safety and effectiveness of drugs for patients with serious conditions.

Page Last Updated: 06/26/2013

Utah researchers discover possible new treatment for a childhood cancer (+video)

SALT LAKE CITY — Chante Wouden was nearly given a death sentence with the diagnosis of Ewing’s sarcoma at age 3.

A treatment cocktail of various chemotherapy drugs didn’t completely kill the cancer in her hip the first time around, and at age 5, she found herself again living at Primary Children’s Medical Center — this time with cancer in her head and back.

“The world outside of that hospital ceases to exist because you are so focused on battling for your life,” the now-31-year-old survivor said Tuesday. “Your family becomes other patients who are also fighting for their lives and the doctors and nurses who are fighting with you.”

A new discovery by researchers at the Huntsman Cancer Institute and the University of Utah may someday spare many more lives of Ewing’s sarcoma patients. The findings and details of a possible new treatment for the often deadly childhood cancer, appears in Tuesday’s online issue of the journal Oncogene.

Wouden had few options, but an experimental treatment was available. With a mother who strongly believed in the power of positive thinking, “we focused on life and living,” she said.

“Looking back, I know the treatments I received kept me alive long enough to receive new treatments,” Wouden said. “The treatment I received at age 5 wasn’t available when I was 3. It’s like jumping from one stepping stone in a river to another.”

The ongoing research, she said, always gave and continues to give her hope. She still deals with the latent effects of the cancer and the cancer treatment she received as a child, but she remains optimistic that medical research will continue to keep her alive.

Ewing’s sarcoma, which is diagnosed in an average of 225 young men and young women each year in the United States, is a cancer that occurs primarily in the bone or soft tissue. It is often evidenced by localized pain or swelling in long bones, such as the femur (thigh), tibia (shin) or humerus (upper arm), and is believed to be caused by the actions of a cancer-causing protein (EWS/FLI) existing within the human genetic code.

However, the cause is not fully understood and risk factors or prevention measures are not known.

Discovery of a new drug and the previously unknown mechanism behind it has led researchers at the Huntsman Cancer Institute to believe turning off specific genes could combat the pediatric cancer, which is the second-most common malignant bone tumor in children and adolescents, with diagnosis between the ages of 10 and 20.

“The beauty, if there’s anything beautiful about a nasty disease like this, is that if we can inhibit EWS/FlI, we can inhibit this cancer, because EWS/FLI is the master regulator of Ewing sarcoma,” said Dr. Stephen Lessnick, director of the institute’s Center for Children’s Cancer Research and a professor in the University of Utah School of Medicine’s department of pediatrics.

Lessnick and his colleagues found that an enzyme, called lysine specific demethylase (LSD-1), interacts with EWS/FLI to turn off gene expression in Ewing’s sarcoma. By turning off specific genes, the complex causes Ewing’s sarcoma development.

“This makes LSD-1 an important target for the development of new drugs to treat Ewing sarcoma,” he said. “For a long time, we’ve know that EWS/FLI works by binding to DNA and turning on genes that activate cancer formation, it was a surprise to find out that it turns genes off as well.”

Dr. Sunil Sharma, director of Huntsman’s Center for Investigational Therapeutics, had already focused on LSD-1 as a possible target for new cancer treatments and had been working for several years to design drugs that would inhibit its actions.

He said the enzyme was important “for regulation of a variety of properties in several different cancers, including acute leukemias, breast and prostate cancers.”

The two researchers teamed up to test Ewing’s sarcoma tissue cultures, which proved beneficial. They are now working together in animal testing, aiming at future human trials.

Wouden said she cheers for any advancement in cancer research, however seldom they may come along.

“When you see how fragile and temporary life is, you also see more clearly how you want to cherish it and how you want to spend it,” she said.

Wouden lives in Bountiful and works at her “dream job,” producing various media products for The Church of Jesus Christ of Latter-day Saints, and is planning to marry her fiance in February.

“There are so many forms of cancer, it could be so overwhelming that we all just give up,” she said. “I am a firm believer in the role that medicine plays in healing and that it played in healing me. It was integral to my survival. I owe my life to it.”

The Ewing’s sarcoma-related research is funded by a variety of sources, including grants from the National Institutes of Health and the Howard Hughes Medical Institute.

“This is a great example of how collaboration between the therapeutics and basic science programs can lead to new treatments for patients — one of Huntsman Cancer Institute’s highest goals,” Sharma said.

Existing treatment options for Ewing’s sarcoma include surgery to remove the tumor, chemotherapy, radiation and ultimate amputation of the affected arm or leg, among others. Prognosis greatly depends on the extent of the disease, size and location of the tumor, response to therapy, age and overall health, tolerance of medications and procedures, but it also relies heavily on new developments in treatment.


Twitter: wendyleonards

A Report From the Children’s Oncology Group

* ©American Society of Clinical Oncology

Randomized Controlled Trial of Interval-Compressed Chemotherapy for the Treatment of Localized Ewing Sarcoma: A Report From the Children’s Oncology Group

1. Richard B. Womer, 2. Daniel C. West, 3. Mark D. Krailo, 4. Paul S. Dickman, 5. Bruce R. Pawel, 6. Holcombe E. Grier, 7. Karen Marcus, 8. Scott Sailer, 9. John H. Healey, 10. John P. Dormans and 11. Aaron R. Weiss

+ Author Affiliations

1. Richard B. Womer, Bruce R. Pawel, and John P. Dormans, Children’s Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA; Daniel C. West, University of California, San Francisco, San Francisco; Mark D. Krailo, Children’s Oncology Group, Arcadia, CA; Paul S. Dickman, Phoenix Children’s Hospital, Phoenix, AZ; Holcombe E. Grier, Karen Marcus, Dana-Farber Cancer Institute, Boston, MA; Scott Sailer, University of North Carolina, Chapel Hill, NC; John H. Healey, Memorial Sloan-Kettering Cancer Center, New York, NY; Aaron R. Weiss, University of Medicine and Dentistry of New Jersey–Robert Wood Johnson University Hospital, New Brunswick, NJ.

1. Corresponding author: Richard B. Womer, MD, Division of Oncology, CTRB 10, The Children’s Hospital of Philadelphia, 3501 Civic Center Blvd, Philadelphia, PA 19104; e-mail:


Purpose Chemotherapy with alternating vincristine-doxorubicin-cyclophosphamide and ifosfamide-etoposide cycles and primary tumor treatment with surgery and/or radiation therapy constitute the usual approach to localized Ewing sarcoma in North America. We tested whether chemotherapy intensification through interval compression could improve outcome.

Patients and Methods This was a prospective, randomized controlled trial for patients younger than 50 years old with newly diagnosed localized extradural Ewing sarcoma. Patients assigned to standard and intensified treatment were to begin chemotherapy cycles every 21 and 14 days, respectively, provided an absolute neutrophil count greater than 750 × 106/L and a platelet count greater than 75 × 109/L. Patients received vincristine (2 mg/m2), doxorubicin (75 mg/m2), and cyclophosphamide (1.2 g/m2) alternating with ifosfamide (9 g/m2) and etoposide (500 mg/m2) for 14 cycles, with filgrastim (5 mg/kg per day; maximum, 300 mg) between cycles. Primary tumor treatment (surgery, radiation, or both) was to begin at week 13 (after four cycles in the standard arm and six cycles in the intensified arm). The primary end point was event-free survival (EFS). The study is registered at (identifier: NCT00006734).

Results Five hundred eighty-seven patients were enrolled and randomly assigned, and 568 patients were eligible, with 284 patients in each regimen. For all cycles, the median cycle interval for standard treatment was 21 days (mean, 22.45 days); for intensified treatment, the median interval was 15 days (mean, 17.29 days). EFS at a median of 5 years was 65% in the standard arm and 73% in the intensified arm (P = .048). The toxicity of the regimens was similar.

Conclusion For localized Ewing sarcoma, chemotherapy administered every 2 weeks is more effective than chemotherapy administered every 3 weeks, with no increase in toxicity.

* Received January 6, 2012. * Accepted July 24, 2012.

Merck Receives Complete Response Letter from U.S. Food and Drug Administration for Investigational Medicine Ridaforolimus

Merck Receives Complete Response Letter from U.S. Food and Drug Administration for Investigational Medicine Ridaforolimus

WHITEHOUSE STATION, N.J., June 5, 2012 – Merck (NYSE: MRK), known as MSD outside the United States and Canada, announced today that the U.S. Food and Drug Administration (FDA) has issued a complete response letter regarding the New Drug Application (NDA) for ridaforolimus. Ridaforolimus is an investigational oral mTOR inhibitor under development for maintenance therapy for patients with metastatic soft tissue or bone sarcoma who have stable disease or better after four or more cycles of chemotherapy.

The complete response letter states that FDA cannot approve the application in its present form, and that additional clinical trial(s) would need to be conducted to further assess safety and efficacy. Merck also is in ongoing discussions with health authorities in Europe and other countries as part of their application procedures for ridaforolimus for the treatment of metastatic soft-tissue or bone sarcomas in patients who had a favorable response to chemotherapy. Additionally, Merck is studying ridaforolimus in combination with other mechanisms in several tumor types.

“Merck remains confident in the potential of ridaforolimus,” said Eric Rubin, M.D., vice president, Clinical Research Oncology, Merck. “We will continue to work closely with the FDA to define potential paths forward for this investigational therapy.”

Sarcomas are a group of cancers of connective tissue of the body for which there are currently limited treatment options. Sarcomas can arise anywhere in the body and are divided into two main groups – bone tumors and soft-tissue sarcomas.

Ridaforolimus is an investigational small-molecule inhibitor of the protein mTOR, a protein that acts as a central regulator of protein synthesis, cell proliferation, cell cycle progression and cell survival, integrating signals from proteins, such as PI3K, AKT and PTEN, known to be important to malignancy.

As part of an exclusive license agreement with ARIAD Pharmaceuticals, Inc (Nasdaq: ARIA), Merck is responsible for the development and worldwide commercialization of ridaforolimus in oncology.

About Merck

Today’s Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies, and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information, visit and connect with us on Twitter, Facebook and YouTube.

Merck Forward-Looking Statement

This news release includes “forward-looking statements” within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. Such statements may include, but are not limited to, statements about the benefits of the merger between Merck and Schering-Plough, including future financial and operating results, the combined company’s plans, objectives, expectations and intentions and other statements that are not historical facts. Such statements are based upon the current beliefs and expectations of Merck’s management and are subject to significant risks and uncertainties. Actual results may differ from those set forth in the forward-looking statements.

The following factors, among others, could cause actual results to differ from those set forth in the forward-looking statements: the possibility that all of the expected synergies from the merger of Merck and Schering-Plough will not be realized, or will not be realized within the expected time period; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; Merck’s ability to accurately predict future market conditions; dependence on the effectiveness of Merck’s patents and other protections for innovative products; and the exposure to litigation and/or regulatory actions.

Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck’s 2011 Annual Report on Form 10-K and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (

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Cancer Cell Line Encyclopedia Released to Aid Drug Discovery and Clinical Trials

From Genetic Engineering and Biotechnology News: GEN News Highlights: Mar 29, 2012

Mar 29, 2012 Cancer Cell Line Encyclopedia Released to Aid Drug Discovery and Clinical Trials

Scientists have made a catalogue of genetic and molecular data on nearly 1,000 cancer cell lines publicly available. They hope it will aid the design of anticancer therapeutics and clinical trials. The Cancer Cell Line Encyclopedia (CCLE) has been drafted by a team led by researchers at the Broad Institute, Harvard Medical School, and the Novartis Institutes for Biomedical Research. It comprises a compilation of gene expression, chromosomal copy number, and massively parallel sequencing data from 947 human cancer cell lines used in drug research and development.

The cell lines were acquired from commercial vendors in the U.S., Europe, Japan, and Korea and represent what the researchers say is a diverse picture of cancer as a disease by including subtypes of both common and rare forms of cancer. Each cell line has been genetically characterized through a series of high-throughput analyses at the Broad Institute, including global RNA-expression patterns and DNA sequence variations in about 1,600 cancer-associated genes. Pharmacologic profiling for several drugs was possible in about half of the cell lines. Algorithms were developed to predict drug responses based on the genetic and molecular makeup of cancer cells.

The Broad Institute’s Levi A. Garraway, Ph.D., and colleagues report on the CCLE in a paper in Nature titled “The CancerCell Line Encyclopedia enables predictive modeling of anticancer drug sensitivity.” The paper runs alongside another study, led by researchers at the Wellcome Trust Sanger Institute, Harvard Medical School, and Dana Farber Cancer Institute, which involved screening a panel of several hundred diverse cancer cell lines with 130 drugs under clinical and preclinical investigation to help identify new biomarkers of drug response. This paper is titled “Systematic identification of genomic markers of drug sensitivity in cancer cells.”

Outlining their development of the CCLE, Dr. Garraway’s team describe proof-of-principal studies in which the resource was coupled with pharmacological profiles for 24 anticancer drugs to identify genetic, lineage, and gene-expression-based predictors of drug sensitivity. Interestingly, the results suggested that cell lineage is a major predictive feature for response of cells to a number of compounds, including that of hematological lineage cell lines to HDAC inhibitor panobinostat.

The results similarly indicated that enhanced sensitivity of some NRAS-mutant cell lines to MEK inhibitors relates to a dependence on aryl hydrocarbon receptor (AHR) function and that in some instances elevated AHR may serve as a mechanistic biomarker for enhanced MEK inhibitor sensitivity. Further analyses indicated that multiple myeloma may respond to IGF1 receptor inhibitors, while SLFN11 expression was identified as the top correlate of sensitivity to irinotecan therapy. In fact all three Ewing’s sarcoma cell lines screened showed high SLFN11 expression and sensitivity to irinotecan.

“Ewing’s sarcomas also exhibited the highest SLFN11 expression among 4,103 primary tumor samples spanning 39 lineages, suggesting that topoisomerase I inhibitors might offer an effective treatment option for this cancer type,” the authors write. “Towards this end, several ongoing trials in Ewing’s sarcoma are examining irinotecan-based combinations or the addition of topotecan to standard regimen.”

The authors aim to build on the CCLE resource by adding in analyses based on deeper sequencing, metabolic activity profiles and epigenetic modifications. The current knowledge base represents what the authors claim is just the tip of the iceberg in terms of potential. “With this initial effort, we have taken some critical first steps,” comments co-author Todd Golub, Ph.D., director of the Broad Institute’s cancer program and Charles A. Dana Investigator in Human Cancer Genetics at the Dana-Farber Cancer Institute. “The challenge now is to greatly expand the number of compounds tested across the panel of cell lines.”

The published work by the Sanger Institute-led team separately identified a strong association between the EWS-FLI1 rearrangement characteristic of Ewing’s sarcoma tumors and sensitivity to the PARP inhibitor olaparib (AZD2281) and a structurally distint PARP inhibitor AG-014699. PARP inhibitors are known to be active against BRCA1- and BRCA2-mutant cancers, and the effectiveness of these drugs against the EWS-FLI1-carrying Ewing’s sarcoma cells was comparable to that in BRCA-deficient cells.

“The observation of PARP inhibitor sensitivity by EWS-FLI1-positive Ewing’s sarcoma cell lines points to the likelihood of new potent gene-drug associations, as novel chemical and genomic space are explored,” write Massachusetts General Hospital Cancer Center lead author Cyril H. Benes, M.D., et. al. “By linking drug activity to the functional complexity of cancer genomes, systematic pharmacogenomic profiling in cancer cell lines provides a powerful biomarker discovery platform to guide rational cancer therapeutic strategies.”

Combination Targeted Therapy Well Tolerated, Effective for Refractory Ewing’s Sarcoma Tumors

Combination Targeted Therapy Well Tolerated, Effective for Refractory Ewing’s Sarcoma Tumors

Released: 3/27/2012 1:00 PM EDT Embargo expired: 3/31/2012 2:30 PM EDT Source: American Association for Cancer Research (AACR)

This abstract will be presented at an AACR press conference on Saturday, March 31 at 1:30 p.m. CT in room CC20 A/B/C of the Hyatt McCormick Conference Center. Reporters who cannot attend in person may participate by calling in with the following information: U.S. & Canada: (888) 647-7462 International: (201) 604-0169

Newswise — CHICAGO — A combination of targeted therapies may be effective against relapsed or recurrent Ewing’s sarcoma or desmoplastic small-round-cell tumors, according to results of a phase I trial presented at the AACR Annual Meeting 2012, held here March 31 – April 4, and published simultaneously in Clinical Cancer Research, a journal of the American Association for Cancer Research.

“Ewing’s sarcoma (EWS) is the second most common bone malignancy striking children, adolescents and young adults in the prime of their lives,” said lead researcher Aung Naing, M.D., assistant professor in the department of investigational cancer therapeutics in the division of cancer medicine at The University of Texas MD Anderson Cancer Center in Houston, Texas. “More treatment options are needed for this disease, because relapse of the disease is quite frequent.

“When tested in the treatment of the EWS family of tumors, single-agent insulin growth factor-1 receptor (IGF-1R) inhibitors and the mTOR inhibitors given as monotherapy have produced variable outcomes.”

The researchers evaluated a subset of 20 patients, including 17 with EWS and three with desmoplastic small-round-cell tumors (DSRCT), who were treated as part of an expansion cohort from a phase I study of an IGF-1R inhibitor, cixutumumab, and the mTOR inhibitor temsirolimus.

All patients had been pretreated heavily before enrolling in the study. Researchers assigned patients to four-week cycles of 6 mg/kg cixutumumab and 25 mg to 37.5 mg of temsirolimus.

At a median follow-up of 8.9 months, they observed prolonged stable disease lasting more than six months and two complete responses in 29 percent of the patients with EWS. Notably, in one patient who had previously demonstrated a marked clinical response to a different IGF-1R targeted antibody before acquiring resistance, combining IGF-1R inhibition and mTOR inhibition induced a complete response, which provides strong evidence for synergy between mTOR and IGF-1R antagonists. Four responders developed grade 3 mucositis, myelosuppression or hyperglycemia, which were treated with supportive therapy.

“This study demonstrated early evidence that this combination can be considered for patients with relapsed and recurrent diseases,” Naing said. “Further studies in larger numbers of patients with EWS and DSRCT as well as additional investigation into underlying resistance mechanisms in individual patients are needed.”

Press registration for the AACR Annual Meeting 2012 is free to qualified journalists and public information officers:

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About the AACR Founded in 1907, the American Association for Cancer Research (AACR) is the world’s first and largest professional organization dedicated to advancing cancer research and its mission to prevent and cure cancer. AACR’s membership includes 34,000 laboratory, translational and clinical researchers; population scientists; other health care professionals; and cancer advocates residing in more than 90 countries. The AACR marshals the full spectrum of expertise of the cancer community to accelerate progress in the prevention, biology, diagnosis and treatment of cancer by annually convening more than 20 conferences and educational workshops, the largest of which is the AACR Annual Meeting with more than 18,000 attendees. In addition, the AACR publishes seven peer-reviewed scientific journals and a magazine for cancer survivors, patients and their caregivers. The AACR funds meritorious research directly as well as in cooperation with numerous cancer organizations. As the Scientific Partner of Stand Up To Cancer, the AACR provides expert peer review, grants administration and scientific oversight of individual and team science grants in cancer research that have the potential for patient benefit. The AACR actively communicates with legislators and policy makers about the value of cancer research and related biomedical science in saving lives from cancer.

For more information about the AACR, visit

Presenter: Aung Naing, M.D.

Abstract Number: LB-124/CCR-12-0061

Title: Insulin Growth Factor-Receptor (IGF-1R) Antibody Cixutumumab Combined with the mTOR Inhibitor Temsirolimus in Patients with Refractory Ewing’s Sarcoma Family Tumors

Author Block: Aung Naing, Patricia LoRusso, Vivek Subbiah, Siqing Fu, David Hong, Peter Anderson, Robert Benjamin, Joseph Ludwig, Helen X. Chen, Austin Doyle, Razelle Kurzrock. UT MD Anderson Cancer Ctr., Houston, TX, Karmanos Cancer Institute, Detroit, MI, CTEP National Cancer Insititute, Rockville, MD, National Cancer Institute, Rockville, MD

Background: Temsirolimus was combined with cixutumumab, a fully human IgG1 monoclonal antibody directed at insulin growth factor-1 receptor (IGF-1R), on the basis of preclinical data suggesting that the combination could overcome resistance in Ewing’s sarcoma (EWS).

Methods: Patients received cixutumumab, 6 mg/kg IV weekly, and temsirolimus, 25 mg-37.5 mg IV weekly (4-week cycles), with restaging after 8 weeks. Median follow up was 8.9 months.

Results: Twenty patients (17 with EWS, 3 with desmoplastic small-round-cell tumor [DSCRT]) were enrolled. Twelve patients (60%) were men; median age, 24 years; median number of prior therapies, 6. Six patients previously received an IGF-1R inhibitor and two, temsirolimus. The most frequent toxicities, at least possibly drug-related, were thrombocytopenia (85%), mucositis (80%), hypercholesterolemia (75%), hypertriglyceridemia (70%), and hyperglycemia (65%) (mostly grade 1-2). Seven of 20 patients (35%) achieved stable disease (SD) >5 months or complete/partial (CR/PR) responses (duration = 5.6, 5.7, 8, 2 +, 18+, 15, 22+ months). Tumor regression of over 20% (100%, 100%, 27%, 23%, 23%) occurred in 5/17 (29%) EWS patients with time to treatment failure lasting 22, 2+, 15, 18 and 8 months, respectively. Biopsy samples of one patient taken at the time of emergence of resistance to a different IGF-1R inhibitor, demonstrated upregulation of mTOR pathway proteins, as determined by morphoproteomic analysis of the resistant tumor; and this particular patient achieved a CR with a time to treatment failure of 22 months on our trial. A second patient with EWS had a PR with prior IGF-1R treatment and then had a mixed response with remarkable regression in three lung modules after instituting cixutumumab and temsirolimus, but progression in a fourth lesion. Morphoproteomic analysis of this patient’s resistant tumor demonstrated upregulation of mTOR and ERK/MEK signals . The latter suggests the possibility that a combination of IGFR/mTOR and MEK inhibitors might warrant investigation in order to reverse resistance. Four of the seven best responders developed grade 3 mucositis, myelosuppression, or hyperglycemia, which was controlled while maintaining drug dose. Side effects of this regimen were well controlled with medication and the assistance of an endocrinologist, when necessary

Conclusions: This mechanism-based approach shows evidence of activity for temsirolimus and cixutumumab in EWS family tumors. The majority of best responders developed grade 3 side effects which were well controlled by supportive measures, suggesting that drug dose should not be compromised.

This study was supported by R21CA13763301A1 (Aung Naing), U01CA62461 (Razelle Kurzrock), and U01CA62487 (Patricia LoRusso)

FDA approves first cord blood product, Hemacord

FDA NEWS RELEASE For Immediate Release: November 10, 2011 Media Inquiries: Shelly Burgess, 301-796-4651, Consumer Inquiries: 888-INFO-FDA

FDA approves first cord blood product

The U.S. Food and Drug Administration today approved HEMACORD, the first licensed hematopoietic progenitor cells-cord (HPC-C) cell therapy.

HEMACORD is indicated for use in hematopoietic stem cell transplantation procedures in patients with disorders affecting the hematopoietic (blood forming) system. For example, cord blood transplants have been used to treat patients with certain blood cancers and some inherited metabolic and immune system disorders.

“The use of cord blood hematopoietic progenitor cell therapy offers potentially life-saving treatment options for patients with these types of disorders,” said Karen Midthun, M.D., director, FDA’s Center for Biologics Evaluation and Research.

HEMACORD contains hematopoietic progenitor cells (HPCs) from human cord blood. Cord blood is one of three sources of HPCs used in transplants; the other two are bone marrow and peripheral blood. Once these HPCs are infused into patients, the cells migrate to the bone marrow where they divide and mature. When the mature cells move into the bloodstream they can partially or fully restore the number and function of many blood cells, including immune function.

In an effort to assist manufacturers in applying for licensure for certain cord blood units, FDA issued the 2009 guidance document entitled “Guidance for Industry: Minimally Manipulated, Unrelated Allogeneic Placental/Umbilical Cord Blood Intended for Hematopoietic Reconstitution for Specified Indications.” FDA instituted a two-year phase-in period for HPC-C manufacturers to submit either a license application or an investigational new drug application. That phase-in period ended Oct. 20, 2011, and these manufacturers now must submit such applications.

Approval of HEMACORD was based on reliance on safety and effectiveness data submitted to a public docket and data submitted in the license application demonstrating compliance with other regulatory requirements. This is the first approval of a license application for cord blood.

HEMACORD has a boxed warning regarding the risks of Graft Versus Host Disease (GVHD), engraftment syndrome, graft failure, and infusion reactions, each of which may be fatal. Patients who receive HEMACORD should be monitored carefully. A risk benefit assessment, unit selection and administration of HEMACORD should be done under the direction of a physician experienced in hematopoietic stem cell transplantation.

HEMACORD is manufactured by the New York Blood Center, Inc., based in New York, NY.

For more information:

BLA Guidance

Product Approval -Hemacord

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 agency also is 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.


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