Original Article

Bone Marrow Transplantation advance online publication 4 February 2008; doi: 10.1038/bmt.2008.2

Myeloablative therapy with autologous stem cell rescue for patients with Ewing sarcoma

S L Gardner¹, J Carreras², C Boudreau³, B M Camitta⁴, R H Adams⁵, A R Chen⁶, S M Davies⁷, J R Edwards⁸, A C Grovas⁹, G A Hale¹⁰, H M Lazarus¹¹, M Arora¹², P J Stiff¹³ and M Eapen²

1. ¹Department of Pediatric Oncology, New York University, New York, NY, USA
2. ²Statistical Center, Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, WI, USA
3. ³Department of Statistics & Actuarial Science, University of Waterloo, Waterloo, Ontario, Canada
4. ⁴Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA
5. ⁵BMT Internal Medicine, Mayo Clinic Arizona, Phoenix, AZ, USA
6. ⁶Department of Pediatric Oncology, John Hopkins Hospital, Baltimore, MD, USA
7. ⁷Department of Bone Marrow Transplantation, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
8. ⁸Department of Bone Marrow Transplantation, Florida Hospital Cancer Institute, Orlando, FL, USA
9. ⁹Department of Pediatrics, University of Nebraska Medical Center, Omaha, NE, USA
10. ¹⁰Department of Bone Marrow Transplantation, St Jude Children's Research Hospital, Memphis, TN, USA
11. ¹¹Department of Hematology/Oncology, University Hospitals of Cleveland, Cleveland, OH, USA
12. ¹²Department of Hematology/Oncology, University of Minnesota, Minneapolis, MN, USA
13. ¹³Department of Bone Marrow Transplantation, Loyola University Medical Center, Maywood, IL, USA

Correspondence: Dr M Eapen, Statistical Center, Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA. E-mail: meapen@mcw.edu

Received 20 August 2007; Revised 19 December 2007; Accepted 20 December 2007; Published online 4 February 2008.

The aim of this study was to identify risk factors associated with PFS in patients with Ewing sarcoma undergoing ASCT; 116 patients underwent ASCT in 1989–2000 and reported to the Center for International Blood and Marrow Transplant Research. Eighty patients (69%) received ASCT as first-line therapy and 36 (31%), for recurrent disease. Risk factors affecting ASCT were analyzed with use of the Cox regression method. Metastatic disease at diagnosis, recurrence prior to ASCT and performance score <90 were associated with higher rates of disease recurrence/progression. Five-year probabilities of PFS in patients with localized and metastatic disease at diagnosis who received ASCT as first-line therapy were 49% (95% CI 30–69) and 34% (95% CI 22–47) respectively. The 5-year probability of PFS in patients with localized disease at diagnosis, and received ASCT after recurrence was 14% (95% CI 3–30). PFS rates after ASCT are comparable to published rates in patients with similar disease characteristics treated with conventional chemotherapy, surgery and irradiation suggesting a limited role for ASCT in these patients. Therefore, ASCT if considered should be for high-risk patients in the setting of carefully controlled clinical trials.

http://www.ncri.org.uk/ncriconference/info/releases/pr5.pdf

Early Stage Drug Shows Promise
Against Cancer Cells from Young Patients

A NEW drug has shown promising pre-clinical activity
against cells from several types of children’s cancers,
scientists reveal at the National Cancer Research
Institute Conference in Birmingham today (Tuesday).
http://www.ncri.org.uk/ncriconference
Scientists from Cancer Research UK’s Paterson
Institute at the University of Manchester have shown
in laboratory tests that the drug RH1 can kill tumour
cells from neuroblastoma, osteosarcoma and Ewing’s
sarcoma, three types of childhood and adolescent cancer
that are often resistant to current types of chemotherapy.
Despite increases in survival rates for childhood cancers,
new drugs are needed to combat drug resistance seen in
current treatments. On the strength of these pre-clinical
results, the researchers are planning a phase 1 trial for
the drug involving children with cancer.
All cells have natural suicide mechanisms that become
active when cells are damaged or grow uncontrollably.
In cancer cells, this suicide mechanism switches off or
becomes faulty and treatment is needed to encourage
the process.
The researchers – based at the Paterson Institute for
Cancer Research Manchester ( http://www.mcrc.manchester.ac.uk ) and the Royal Manchester
Children’s Hospital ( http://www.cmmc.nhs.uk ) – found in their pre-clinical study
that even very low doses of RH1 could increase cancer
cell death by around 50 per cent when compared with
untreated cells.
RH1’s activity is greatly enhanced by an enzyme, DTdiaphorase
(DTD), which is found in higher quantities
in many adult tumours, including lung, liver and breast
cancers, and the drug has recently completed phase 1
studies in adults.
Dr Guy Makin, the study’s lead researcher from the
Paterson Institute ( http://www.paterson.man.ac.uk ) said: “We are very excited that we
have been able to work with a new drug that has only
just completed an adult phase 1 study. RH1 is a very
potent agent and our pre-clinical results suggest that
it could be effective against childhood tumours that
express DTD. We hope that this will be just the first
of many new agents that we can show are useful for
treating childhood cancer.”
The planned trial would be the first for a drug tested
for children through Cancer Research UK’s drug
development office.
Dr Bruce Morland, chairman of the Children’s Cancer and
Leukaemia Group (CCLG, http://www.ukccsg.org ), who were instrumental in the
selection of RH1 for evaluation, said: “Survival rates for
children with cancer are already high at 75 per cent. But
in many cases, patients become resistant to their drugs
and need new options.
“This is an exciting moment in the history of the CCLG.
Our increasingly close relationship with the Cancer
Research UK drug development office means new
potentially promising anticancer drugs can be tested in
children at a much earlier point in their development.
In this way we hope that new, effective drugs are
introduced in the fight against children’s cancer at
the earliest opportunity, saving even more lives in the
process.”
RH1 was synthesised from MeDZQ, an anti-tumour
chemical that selectively kills cancer cells. The RH1
compound was manufactured by scientists to be a watersoluble
version of MeDZQ, making it more effective as a
drug for potential clinical use.
Dr Sally Burtles, Cancer Research UK’s ( http://www.cancerresearchuk.org ) director of drug
development, said: “Helping more children survive
cancer by finding new treatments is a top priority for
the charity. Currently, not many drugs are developed
specifically for children so it’s great news that the drug is
showing such encouraging effects in preclinical studies.
We hope this type of drug development will continue
and help improve the treatment of childhood cancer
patients.”

How to contact the Manchester Cancer Research Centre:
Manchester Cancer Research Centre
The University of Manchester
Wilmslow Road
Withington
Manchester
M20 4BX
England
Tel: +44 0161 446 3156 (From the USA, 011-44-161-446-3156)
Fax: +44 0161 446 3109
email mcrc@manchester.ac.uk

Central Manchester and Manchester Children's University Hospitals NHS Trust
Trust Headquarters, Cobbett House
Manchester Royal Infirmary
Oxford Road
Manchester
M13 9WL
Tel: +44 (0)161 276 1234 (From the USA, 011-44-161-276-1234
Fax: +44 (0)161 273 6211 (Trust HQ)

http://www.rocheusa.com/newsroom/current/2007/pr2007102302.html

October 23, 2007 -- Nutley N.J.
 
Roche Announces Positive Results in Solid Tumors Using Human Monoclonal Antibody against IGF-1R (R1507)
 
Today, Roche announced positive results from a Phase I trial of R1507, a human monoclonal antibody to target IGF-1R (insulin-like growth factor receptor), in patients with solid tumors. IGF-1 is one of the most potent natural activators of the AKT and MAPK signaling pathways, which promote cell growth and cell survival. The IGF-1R pathway has also been shown to have an important role in mediating the resistance to cytotoxic drugs and EGFR/HER2-targeted agents. The results were reported during the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, held in San Francisco.

Study Results
In the Phase I study, R1507 was administered by intravenous infusion. Nine of 34 adult patients with advanced solid tumors experienced disease stabilization. Four of the seven heavily pretreated patients with Ewing’s sarcoma demonstrated clinical benefit with two of these patients achieving durable, objective partial responses.

Once a week administration of R1507 was well tolerated with very few side effects. Treatment with R1507 was not associated with the typical side-effects normally observed with cancer therapy (e.g., low blood counts, infection, hair loss, severe nausea and vomiting).  The most frequent side effects observed were fatigue, anorexia and weight loss, symptoms that are commonly observed in patients with advanced cancer.

 “We are very encouraged by these early results with R1507 in patients with refractory Ewing’s sarcoma,” said Kapil Dhingra, MD, Head, Oncology Disease Biology Area at Roche. “As a result, we have given this program a very high priority as we believe this molecule has the potential to be very beneficial in treating patients with sarcoma as well as a variety of other solid tumors.”

The antibody (R1507) was initially developed under Roche’s broad antibody development collaboration with Genmab, which began in 2001.

The Phase I study is being conducted at four sites in the U.S., including the University of Colorado Cancer Center (Aurora, CO), The University of Texas M.D. Anderson Cancer Center (Houston, TX), Cancer Institute of New Jersey (New Brunswick, NJ) and The Institute for Drug Development (San Antonio, TX).  R1507 has also been investigated in 26 patients on a three week schedule in the Phase I study.  This treatment schedule was also generally well tolerated with a side effect profile similar to the weekly schedule.

“This drug attacks the IGF pathway and may provide a new class of drugs to treat a variety of cancers, including breast, prostate, colon, melanoma, myeloma and a variety of sarcomas, which could greatly add to the way that we currently treat these patients,” says Stephen Leong, M.D., assistant professor of Medical Oncology at the University of Colorado Cancer Center and lead author of the abstract.

Razelle Kurzrock, MD,  investigator at the M.D. Anderson Cancer Center and the senior author of the abstract, noted that some of the responses were very impressive.  For instance, one 28 year-old Ewing’s sarcoma patient with large tumors unresponsive to many other treatments showed dramatic tumor shrinkage within six weeks, without side effects.  "This is one of the best responses I've seen in over 20 years of oncology experience," stated Dr. Kurzrock.  

Based on these initial results with R1507, Roche plans to conduct additional trials and work with a global consortium of sarcoma experts, including the Sarcoma Alliance for Research through Collaboration (SARC). “We are very excited about our collaboration with SARC, which represents a new approach to sarcoma clinical trials, and we look forward to combining our expertise with that our colleagues at SARC to expedite new sarcoma treatments,” added Dhingra.

“We are excited to be partnering with Roche on the development of a new treatment against an important target, which could result in a potential breakthrough treatment for sarcoma as well as other cancers,” said Laurence Baker, DO, professor of Medicine and Pharmacology at the University of Michigan and the Executive Director, SARC. “With Roche’s considerable expertise in oncology and SARC’s vast network of physicians and institutions, we look forward to determining the potential of R1507 in this important disease area.”

About Ewing’s Sarcoma
The Ewing’s family of tumors (EFT) includes primary tumors of bone (classic Ewing’s sarcoma, primitive neuroectodermal tumor, and Askin tumor) and extraosseous primary tumors {National Cancer Institute}. Studies using immunohistochemical markers, cytogenetics, molecular genetics, and tissue culture indicate that these tumors are all derived from the same primordial stem cell. EFTs account for 4 percent of childhood and adolescent malignancies.  The estimated incidence (US) is approximately 300 new cases per year. The median age for patients with EFT is 15 years and more than 50 percent of patients are adolescents. There is a slight male predominance and the lower limbs are affected in 40 percent of the patients.

Approximately 20 to 30 percent of the patients with ETB have overt metastases at the time of diagnosis. However, outcomes for patients with metastatic disease have improved little during the last 20 years. Approximately 25-30 percent survival could be achieved with current therapies for patients who present with metastatic disease at initial diagnosis.

About Roche
Hoffmann-La Roche Inc. (Roche), based in Nutley, N.J., is the U.S. pharmaceuticals headquarters of the Roche Group, one of the world’s leading research-oriented healthcare groups with core businesses in pharmaceuticals and diagnostics. For more than 100 years in the U.S., Roche has been committed to developing innovative products and services that address prevention, diagnosis and treatment of diseases, thus enhancing people's health and quality of life. An employer of choice, in 2007 Roche was named Top Company of the Year by Med Ad News and one of the Top 20 Employers (Science magazine). In 2006, Roche was ranked the    No. 1 Company to Sell For (Selling Power), and one of AARP’s Top Companies for Older Workers, and in 2005, Roche was named one of Fortune magazine’s Best Companies to Work For in America. For additional information about the U.S. pharmaceuticals business, visit our websites: http://www.rocheusa.com or www.roche.us.

About SARC
The purpose of the Sarcoma Alliance for Research through Collaboration (SARC) is to engage all appropriate and necessary resources to cure and prevent sarcoma.  SARC brings together expert sarcoma researchers and clinicians from 29 centers of excellence in the United States.  SARC by the charter, promotes international collaboration in sarcoma clinical trials through is association with European sarcoma experts.  SARC is unique as a clinical trial organization in that its trials at the inception include pediatric and medical patients with sarcoma, because sarcomas affect people of all ages.  SARC is a 501c3, non-profit organization that is  headquartered in Ann Arbor, Michigan.

###
Contacts:     973-562-2699

Hyperthermia Plus Chemotherapy Nearly Doubles Disease-Free Survival Compared to Chemotherapy Alone for Sarcoma Cancer Patients

SALT LAKE CITY---June 4, 2007--- BSD Medical Corp. (AMX:BSM) announced today that the results of a 340 patient randomized Phase III clinical trial testing the benefit of adding hyperthermia therapy to chemotherapy were presented at the annual American Society of Clinical Oncology (ASCO) conference underway in Chicago, Illinois. According to the results of this clinical study, which was conducted at nine major European cancer treatment institutions and at Duke University Medical Center in the USA, both disease-free survival time and local progression free survival time for patients with locally advanced, high-grade soft tissue sarcomas nearly doubled when hyperthermia therapy was added to chemotherapy, as compared to patients who received chemotherapy alone.

The patients enrolled in this clinical study were very ill, with high-grade (II/III) soft tissue sarcomas and were at significant risk of local failure and metastasis. The patients were randomly assigned to receive either chemotherapy alone or chemotherapy combined with hyperthermia therapy. The patient characteristics were well balanced between these two groups. Their treatments were administered in 4 cycles every 3 weeks before and after surgery and radiation therapy. For patients who received both hyperthermia therapy and chemotherapy the median disease free survival was 31.7 months, compared to 16.2 months for those who received chemotherapy alone (p=0.004), a 95% increase. The median local progression free survival rate was estimated at 45.3 months for patients who received chemotherapy plus hyperthermia therapy, compared to 23.7 months for patients who received chemotherapy alone (p=0.01), a 91% increase.

The study was conducted under the direction of the European Society of Hyperthermic Oncology (ESHO RHT-95) and the European Organization for Research and Treatment of Cancer (EORTC 62961). Rolf Issels, MD PhD of the Munich University Medical School in Germany, was the principal investigator. Duke University was a participant in the international study listed on the National Cancer Institute's website at http://www.cancer.gov/clinicaltrials/EORTC-62961 under the NCI number NCT00003052.

All hyperthermia treatments performed in the study were conducted using BSD-2000 hyperthermia systems developed and produced by BSD Medical Corp. The BSD-2000 hyperthermia therapy system non-invasively delivers precision focused hyperthermia therapy to cancerous tumors, including tumors located deep in the body. The BSD-2000 is a recipient of the Frost and Sullivan Technology Innovation of the Year Award for cancer therapy devices.

About BSD Medical

BSD Medical Corp. is the leading developer of systems used to deliver hyperthermia therapy for the treatment of cancer. Hyperthermia therapy is used to kill cancer directly and increase the effectiveness of companion radiation treatments. Research has also shown promising results from the use of hyperthermia therapy in combination with chemotherapy, and for tumor reduction prior to surgery. For further information visit BSD Medical's website at www.BSDMedical.com or BSD's patient website at www.treatwithheat.com.

Statements contained in this press release that are not historical facts are forward-looking statements, as defined in the Private Securities Litigation Reform Act of 1995. All forward-looking statements are subject to risks and uncertainties detailed in the Company's filings with the Securities and Exchange Commission.

http://www.eurekalert.org/pub_releases/2006-11/eofr-frt110906.php

Public release date: 10-Nov-2006

Contact: Emma Mason
wordmason@mac.com
44-077-112-96986
European Organisation for Research and Treatment of Cancer

First report that apoptotic and anti-angiogenic therapies work better together than alone

Prague, Czech Republic: American researchers have found that giving a combination of imantanib (Glivec [1]) and a drug that induces cell death (apoptosis) was better at inhibiting the growth of Ewing's sarcoma in mice than either therapy on its own.

Imantanib works by preventing the creation of new blood vessels to supply the growing tumour (anti-angiogenesis) and the researchers believe that this is the first report of synergy between apoptosis and anti-angiogenic therapy in pre-clinical work.

Professor Andrea Hayes-Jordan reported to the EORTC-NCI-AACR [2] Symposium on Molecular Targets and Cancer Therapeutics in Prague today (Friday 10 November) that treating sarcoma cells with imantanib inhibited a growth factor called PDGFR-beta. This had the effect of increasing the sensitivity of the cells to a drug called tumour necrosis factor-related apoptosis-inducing ligand (TRAIL).

Prof Hayes-Jordan, assistant professor of surgery and pediatrics at the MD Anderson Cancer Center, Houston, USA, said: "When I treated the tumour cells with imantanib, the anti-angiogenic drug, the receptors for TRAIL, the apoptotic drug, increased, thus increasing the efficacy of TRAIL. This was supported by the mouse studies, which showed increased inhibition of pulmonary metastases and primary tumour growth when both were used simultaneously. These findings are important because, if it proves to be effective in humans, it would be well tolerated and have significantly fewer side effects than traditional cytotoxic therapy. Also, at present, we have no effective chemotherapy for pulmonary metastases – the only effective treatment is surgery – so this would give us another option."

Prof Hayes-Jordan hopes to investigate the dual therapy in humans in a clinical trial within 12-18 months.

http://www.clinicaltrials.gov/ct/show/NCT00365872?order=37

External Beam Radiation With Intratumoral Injection Of Dendritic Cells As Neo-Adjuvant Treatment for Sarcoma

This study is currently recruiting patients.
Verified by H. Lee Moffitt Cancer Center and Research Institute August 2006
Sponsors and Collaborators:     H. Lee Moffitt Cancer Center and Research Institute
Cancer Treatment Research Foundation
Information provided by:     H. Lee Moffitt Cancer Center and Research Institute
ClinicalTrials.gov Identifier:     NCT00365872

Purpose

This is a Phase II study using a combination of external beam radiation with intratumoral injection of dendritic cells (white blood cells) as neo-adjuvant treatment for patients with high-risk soft tissue sarcoma. The purpose is to determine if an injection of the patient’s own immune related white blood cells into their tumor will strengthen the immune system to fight against their cancer.

Pre-treatment tests include a blood draw for anti-tumor immune response and Hepatitis B, Hepatitis C, HIV tests. Labs are drawn for baseline immunity assays; pre-treatment biopsy with collection of tumor cells, immunological studies, surgical specimen and post-therapy immunity assays.

Conventional therapy on day 1 is the external beam radiation which will be delivered in 25 equal fractions – daily for 5 days (M-F) over a 5-week period. Experimental therapy consists of leukapheresis which is the separation and removal of leukocytes from withdrawn blood, frozen for later use. There will be four DC injections occurring during the course of the external beam radiation therapy.

DCs will be labeled (with a radioisotope) and injected intratumorally before surgery. You will be randomized into one of three groups. One group will receive injection of labeled DCs 72 hrs before surgery, second group – 48 hrs, and third group 24 hrs before surgery. On day 50 of treatment,surgery will be performed to remove the tumor.

Results will be correlated with the level of specific immune response. If the experimental treatment causes a measurable change in the immune blood tests, there will be office visits, every 3 months for 2 years. In the longer term, there will be office visits at 6 month intervals for the third year, and yearly thereafter. A CT scan of chest and MRI scan of extremity will be performed at every office visit.
Condition     Intervention     Phase
Soft Tissue Sarcoma
     Vaccine: Dendritic cell injections
 Procedure: Radiation therapy
 Procedure: Surgery for tumor removal
    Phase II

MedlinePlus related topics:  Soft Tissue Sarcoma
Genetics Home Reference related topics:  Soft Tissue Sarcoma

Study Type: Interventional
Study Design: Treatment, Randomized, Open Label, Uncontrolled, Single Group Assignment, Safety/Efficacy Study

Official Title: Combination of External Beam Radiation With Intratumoral Injection of Dendritic Cells as Neo-Adjuvant Treatment of High-Risk Soft Tissue Sarcoma Patients
Further study details as provided by H. Lee Moffitt Cancer Center and Research Institute:
Primary Outcomes: Determine if combined neo-adjuvant treatment with apoptosis-inducing therapy (gamma-irradiation) plus intratumoral DC administration will induce a T lymphocyte immune response specific for soft tissue sarcoma associated antigens.; Study the functional activity of T cells, as well as the presence, and function of DCs in patients treated with combined administration of apoptosis-inducing agents and DCs.; Assess the toxicity of the investigational treatment, and the primary tumor responses.; Analysis of DC migration will compare the ratio of radioactive count within lymph nodes and the tumor site to the background counts.
Expected Total Enrollment:  22

Study start: June 2006

This is a Phase II study using a combination of external beam radiation with intratumoral injection of dendritic cells (white blood cells) as neo-adjuvant treatment for patients with high-risk soft tissue sarcoma. The purpose is to determine if an injection of the patient’s own immune related white blood cells into their tumor will strengthen the immune system to fight against their cancer.

Pre-treatment test will consist of a blood draw for anti-tumor immune response and Hepatitis B, Hepatitis C, HIV tests. A biopsy with collection of tumor cells. Assays (ELISPOT and flow cytometry) to test for the intended anti-tumor cell T cell response will be performed on biopsy specimens as well as standard pathology department review of specimens for diagnosis and assessment of necrosis and apoptosis. Labs are also drawn for surgical specimens and post-therapy immunity assays.

Prior to commencing therapy, a procedure called leukapheresis (peripheral blood mononuclear cell) isolation will be conducted and twenty-four hours prior to intended injection, the dendritic cells will be harvested and assessed for quality control. Prior to injection (the clinical target is the gross tumor), history and physical examination will be performed. Toxicity will be assessed according to CTC criteria. The plan will be to inject the entire dendritic cell product evenly throughout the tumor.

Conventional therapy consists of external beam radiation therapy, 25 fractions from day 1-33 administered Monday through Friday only. The experimental therapy, dendrite cell (DC) injections will occur during the course of the external beam radiation therapy. DC injections will be prepared from frozen white blood cells and injected at four intervals on day 12, 19, 26, and day 33.

DCs will be labeled (with a radioisotope) and injected intratumorally before surgery. You will be randomized into one of three groups. One group will receive injection of labeled DCs 72 hrs before surgery, second group – 48 hrs, and third group 24 hrs before surgery. Surgery will occur on day 50 for tumor removal.

If the experimental treatment causes a measurable change in the immune blood tests, there will be office visits, every 3 months for 2 years. In the longer term, there will be office visits at 6 month intervals for the third year, and yearly thereafter. A CT scan of chest and MRI scan of extremity will be performed at every office visit.

Eligibility
Genders Eligible for Study:  Both
Criteria

Inclusion Criteria:

    * Histologically diagnosed high-grade (intermediate or high grade) soft tissue sarcoma of clinical and radiographic histological lineage.
    * Musculoskeletal tumor in extremities, trunk or chest wall.
    * Primary tumor or isolated locally recurrent tumor greater than 5 cm in diameter.
    * Clinical Stage T2N0M0 or T3N0M0
    * Patient is not a candidate for neoadjuvant chemotherapy.
    * Performance status ECOG 0 or 1.
    * No steroid therapy within 4 weeks of first dendritic cell administration.
    * No coagulation disorder.
    * Patient’s written informed consent.
    * No contraindication to resection.
    * Adequate organ function (measured within a week of beginning treatment).
    * WBC > 3,000/mm to the third power and ANC >1500/mm to the third power
    * Platelets > 100,000/mm to the third power
    * Hematocrit > 25%
    * Bilirubin < 2.0 mg/dL
    * Creatinine < 2.0 mg/dL, or creatinine clearance > 60 mL/min

Exclusion Criteria:

    * Retroperitoneal location.
    * Gastrointestinal stromal tumor (GIST).
    * Demonstrated metastatic disease.
    * Prior radiation therapy if the current tumor is locally recurrent after prior resection.
    * Concurrent treatment with any anticancer agent other than radiation as dictated by the protocol.
    * Bleeding disorder.
    * H.I.V. infection or other primary immunodeficiency disorder.
    * Ongoing systemic therapy with immunosuppressant drugs (e.g. corticosteroids, azathioprine, cyclosporin, methotrexate).
    * Any serious ongoing infection.
    * Pregnant or lactating women -- Patients in reproductive age must agree to use contraceptive methods for the duration of the study (a pregnancy test will be obtained before treatment).
    * ECOG performance status of 2, 3 or 4.

Location and Contact Information
Please refer to this study by ClinicalTrials.gov identifier  NCT00365872

Mary N Dunn, CRN      813-745-8356    dunnmn@moffitt.usf.edu

Florida
      H. Lee Moffitt Cancer Center & Research Institute, Tampa,  Florida,  33612,  United States; Completed

      H Lee Moffitt Cancer Center & Research Institute, Tampa,  Florida,  33612,  United States; Recruiting

Study chairs or principal investigators

Scott Antonia, M.D.,  Principal Investigator,  H. Lee Moffitt Cancer Center and Research Institute  

More Information

Active Clinical Trials at Moffitt Cancer Center

Study ID Numbers:  MCC-14497
Last Updated:  August 18, 2006
Record first received:  August 17, 2006
ClinicalTrials.gov Identifier:  NCT00365872
Health Authority: United States: Food and Drug Administration
ClinicalTrials.gov processed this record on 2006-09-25

http://www.jco.org/cgi/content/abstract/24/24/3997

Impact of High-Dose Busulfan Plus Melphalan As Consolidation in Metastatic Ewing Tumors: A Study by the Société Française des Cancers de l'Enfant

Journal of Clinical Oncology, Vol 24, No 24 (August 20), 2006: pp. 3997-4002
© 2006 American Society of Clinical Oncology
DOI: 10.1200/JCO.2006.05.7059

Odile Oberlin, Annie Rey, Anne Sophie Desfachelles, Thierry Philip, Dominique Plantaz, Claudine Schmitt, Emmanuel Plouvier, Odile Lejars, Hervé Rubie, Philippe Terrier, Jean Michon

From the Departments of Paediatric Oncology, Biostatistics, and Pathology, Institut Gustave Roussy, Villejuif; Department of Paediatric Oncology, Centre Oscar Lambret, Lille; Department of Paediatric Oncology, Centre Léon Bérard, Lyon, France; Department of Paediatric Oncology, Hôpital Michalon, Grenoble; Department of Paediatric Oncology, Hôpital d'enfants, Nancy; Department of Paediatric Oncology, Centre hospitalo-universitaire, Besançon; Department of Paediatric Oncology, Hôpital Clocheville, Tours; Department of Paediatric Oncology, Hôpital Purpan, Toulouse; and the Department of Paediatric Oncology, Institut Curie, Paris, France

Address reprint requests to Odile Oberlin, MD, Department of Paediatric Oncology, Institut Gustave-Roussy, Rue Camille Desmoulins, 94805 Villejuif Cedex, France; e-mail: oberlin@igr.fr

PURPOSE: To improve the prognosis for patients with metastatic Ewing sarcoma/primitive neuroectodermal tumors (ES/PNET) using conventional chemotherapy and consolidation high-dose chemotherapy (HDCT) containing busulfan and melphalan.

PATIENTS AND METHODS: Ninety-seven unselected patients with newly diagnosed metastatic ES/PNET received induction chemotherapy that included five cycles of cyclophosphamide 150 mg/m2/d for 7 days, doxorubicin 35 mg/m2/d once, followed by two cycles of ifosfamide 1.8 g/m2/d for 5 days, and etoposide 100 mg/m2/d for 5 days. Patients in complete or very good partial remission received HDCT with busulfan total dose 600 mg/m2 and melphalan 140 mg/m2 followed by autologous blood stem cells. Local therapy (surgery and/or radiation therapy) was performed before or after HDCT.

RESULTS: Ninety-seven patients were enrolled from 1991 to 1999 (median age, 12.3 years; range, 0.2 to 25 years). Among them, 75 received HDCT. The 5-year event-free survival (EFS) rate for all 97 patients was 37% and the overall survival (OS) rate was 38%. The EFS after HDCT was 47%. The EFS for the 44 patients with lung-only metastases was 52%, whereas it was 36% for patients with bone metastases without bone marrow involvement. Among the 23 patients with bone marrow metastases, only one survived. The multivariate analysis for both EFS and for OS identified three independent prognostic factors: age, fever at diagnosis, and bone marrow involvement.

CONCLUSION: Compared with conventional chemotherapy, HDCT may yield benefits for patients with lung-only metastases or bone metastases. These results warrant confirmation in a randomized trial and provide part of the background data for the ongoing Euro-Ewing study.

Supported by Institut Gustave Roussy and by Société Française des Cancers de l'Enfant.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

http://clinicaltrials.mayo.edu/clinicaltrialdetails.cfm?trial_id=100300

The Use of Chemotherapy Medications, Gemcitabine (Gemzar) and Docetaxel
(Taxotere) in the Treatment of Ewing's Sarcoma, Osteosarcoma, or
Chondrosarcoma

IRB Number : 1693-05

Trial Status : Open for Enrollment

Phase: II

Why is this study being done?
This study is being done to:
-See if the chemotherapy drugs gemcitabine (Gemzar) and docetaxel
(Taxotere), when given together, may help to fight cancer of the bone or
soft tissue. Each of these drugs is approved by the US Food and Drug
Administration (FDA) for the treatment of some kinds of cancer, such as
cancer of the pancreas and lung, but they are not approved for this type
of cancer, so in this study they are called investigational drugs.
-See what effects (good and bad) gemcitabine and docetaxel have on the
patient and the tumor.
-See how a patients body processes the gemcitabine and docetaxel.
-(When possible), to do genetic research studies on a sample of a
patients tumor tissue.

Who is Eligible to Participate in the Study?
-Patients diagnosed with Ewings sarcoma or Osteosarcoma, and have
received standard treatments for this type of cancer, but the tumor has
come back after treatment.
-Patients diagnosed with chondrosarcoma and the tumor cannot be
completely removed by surgery or has come back after surgery.
- Patients age 4 and older
-No prior treatment with gemcitabine or taxanes

*More specific, detailed eligibility and/ or exclusion criteria are
associated with this trial.

What is Involved With this Study?
-Medication given through a vein 2 times in a 3 week cycle, for up to 14
cycles
-Physical Exams
-Weekly Blood Tests
-X-rays, CT scans, MRI scans and/ or nuclear medicine scans including a
bone scan to measure patients tumor

How long will the Study run?
Patients will be in the study and receive treatment as long as the tumor
has stayed the same or has gotten smaller and patient has not had any
bad side effects, for up to 14 cycles (each cycle is 3 weeks). Treatment
will be stopped if patients tumor gets larger, if bad side effects, if
doctor thinks further treatment would not be in patients best interest,
if study closes, or if patient chooses to stop treatment.

Sponsor(s): MD Anderson Cancer Center

Study Activation: 12-19-2005

IRB Review and Approval Date: 9-8-2005

Study Type: Treatment

Projected Accrual: 10 patients

Costs of Study:There may be standard patient care costs related to
participating in a cancer research study.

Principal Investigator: Dr. Scott Okuno

Who can I Contact for Additional Information on this Trial?
If you are interested in participating in this study or would like
additional information, please contact Mayo Clinic's Cancer Center
Clinical Trials Referral Coordinator at (507) 538-7623.

What is/are the Locations of this Clinical Trial?
Rochester, MN

http://www.clinicaltrials.gov/ct/gui/show/NCT00318526

Ixabepilone to Treat Children and Young Adults with Solid Tumors

This study is currently recruiting patients.
Verified by National Institutes of Health Clinical Center (CC) March 29, 2006

Sponsored by: National Cancer Institute (NCI) Information provided by: National Institutes of Health Clinical Center (CC) ClinicalTrials.gov Identifier: NCT00318526

Purpose

MedlinePlus consumer health information 

Study Type: Interventional
Study Design: Treatment, Safety/Efficacy

Official Title: Phase II Trial of Ixabepilone (BMS-247550), an Epothilone B Analog, in Children and Young Adults with Refractory Solid Tumors

Study start: April 20, 2006

Eligibility

Location and Contact Information

More Information

Detailed Web Page

Publications

Jordan A, Hadfield JA, Lawrence NJ, McGown AT. Tubulin as a target for anticancer drugs: agents which interact with the mitotic spindle. Med Res Rev. 1998 Jul;18(4):259-96. Review.

Wilson L, Jordan MA. Microtubule dynamics: taking aim at a moving target. Chem Biol. 1995 Sep;2(9):569-73. Review.

Huizing MT, Misser VH, Pieters RC, ten Bokkel Huinink WW, Veenhof CH, Vermorken JB, Pinedo HM, Beijnen JH. Taxanes: a new class of antitumor agents. Cancer Invest. 1995;13(4):381-404. Review.

http://www.pharming.com/index.php?act=show&pg=278

Pharming Recieves Orphan Drug Designations For rhC1INH From US FDA

Leiden, The Netherlands, June 14, 2006. Biotech company Pharming Group NV (“Pharming” or “the Company”) (Euronext: PHARM) announced today it has received orphan drug designations for recombinant human C1 inhibitor (rhC1INH) from the Food and Drug Administration (FDA). The Company has obtained designations on rhC1INH for two separate disease indications - the prevention and/or the treatment of Delayed Graft Function (DGF) after solid organ transplantation and the treatment of Capillary Leakage Syndrome (CLS).

Over 25,000 solid organs were transplanted in the US in 2005, including kidney, liver, lung and heart transplants. Delayed Graft Function is a common complication affecting all solid organs in the post-transplant period. DGF results in significant morbidity and mortality from early graft dysfunction and from decreased long-term graft survival. The condition also prolongs hospitalization and requires substitute therapies for these patients, such as dialysis or ventilatory support. DGF remains a critical unmet medical need despite improvements in immunosuppression, organ preservation, and surgical technique. C1 inhibitor has been shown in numerous models of organ transplantation to improve early graft function.

Over 100,000 patients in the US develop Capillary Leakage Syndrome annually as a complication of various disease states, including bone marrow/stem cell transplantation, IL-2 therapy, sepsis, and neonatal cardiac surgery. CLS is a severe life-threatening condition characterized by excessive fluid loss into the tissue space, which can result in hemodynamic instability, pulmonary edema, ascites, and death. Current therapies for patients with CLS are limited to supportive care and treatment of the underlying condition. Previous clinical work has demonstrated that C1 inhibitor may be an effective anti-inflammatory that can control the mechanisms contributing to CLS.

"Pharming’s rhC1INH product could provide new treatments for immune mediated diseases such as Delayed Graft Function in organ transplantation and Capillary Leakage Syndrome, conditions with a high burden and limited treatment options for patients,” said Dr. Francis Pinto, CEO of Pharming. “The Orphan Drug designations from the FDA further validate the potential of rhC1INH as an innovative therapy and are a significant achievement as we advance development of rhC1INH for these indications.”

The FDA Orphan Drug designation is reserved for promising new therapies being developed to treat diseases that affect fewer than 200,000 people in the United States. This designation provides an accelerated review process, tax advantages and a seven-year period of market exclusivity in the US upon product approval. Pharming also has an Orphan Drug designation on rhC1INH for the treatment of Hereditary Angioedema.

Background on Pharming Group NV
Pharming Group NV is developing innovative protein products for unmet needs. The Company’s products include potential treatments for genetic disorders, specialty products for surgical indications, intermediates for various applications and food products. Pharming has two products in late stage development - recombinant human C1 inhibitor for Hereditary Angioedema (Phase III) and recombinant human lactoferrin for use in functional foods. The advanced technologies of the Company include innovative platforms for the production of protein therapeutics, as well as technology and processes for the purification and formulation of these products. Additional information is available on the Pharming website: http://www.pharming.com.

This press release contains forward looking statements that involve known and unknown risks, uncertainties and other factors, which may cause the actual results, performance or achievements of the Company to be materially different from the results, performance or achievements expressed or implied by these forward looking statements. The press release also appears in Dutch. In the event of any inconsistency, the English version will prevail over the Dutch version.

Contact:

Carina Hamaker, Investor Voice, T: +31 (0)6 537 49959
Sarah MacLeod, Financial Dynamics, T: +44 (0)20 7269 7148
Samir Singh, Pharming Group NV, T: +31 (0)71 524 7429

http://www.clinicaltrials.gov/ct/show/NCT00207350

Neurosurgical Use of Interstitial Laser Therapy (ILT)

This study is currently recruiting patients.
Verified by Brigham and Women's Hospital September 2005

Sponsored by: Brigham and Women's Hospital Information provided by: Brigham and Women's Hospital ClinicalTrials.gov Identifier: NCT00207350

Purpose

MedlinePlus related topics:  Brain Cancer

Study Type: Interventional
Study Design: Treatment, Non-Randomized, Open Label, Uncontrolled, Single Group Assignment, Efficacy Study

Study start: January 2002
Last follow-up: December 2004

Eligibility

Location and Contact Information

More Information

Website for Image Guided Therapy Program at Brigham & Women's Hospital

Publications

Schulze PC, Vitzthum HE, Goldammer A, Schneider JP, Schober R. Laser-induced thermotherapy of neoplastic lesions in the brain--underlying tissue alterations, MRI-monitoring and clinical applicability. Acta Neurochir (Wien). 2004 Aug;146(8):803-12. Epub 2004 Jun 7. Review.

Peller M, Muacevic A, Reinl H, Sroka R, Abdel-Rahman S, Issels R, Reiser MF. [MRI-assisted thermometry for regional hyperthermia and interstitial laser thermotherapy] Radiologe. 2004 Apr;44(4):310-9. German.

McNichols RJ, Gowda A, Kangasniemi M, Bankson JA, Price RE, Hazle JD. MR thermometry-based feedback control of laser interstitial thermal therapy at 980 nm. Lasers Surg Med. 2004;34(1):48-55.

Leonardi MA, Lumenta CB. Stereotactic guided laser-induced interstitial thermotherapy (SLITT) in gliomas with intraoperative morphologic monitoring in an open MR: clinical expierence. Minim Invasive Neurosurg. 2002 Dec;45(4):201-7.

Straube T, Kahn T. Thermal therapies in interventional MR imaging. Laser. Neuroimaging Clin N Am. 2001 Nov;11(4):749-57. Review.

Muacevic A, Peller M, Sroka R, Kalusche B, Pongratz T, Kreth FW, Steiger HJ, Reiser M, Reulen HJ. [Brain protective interstitial laser thermotherapy. Therapy of brain tumors without secondary damage] MMW Fortschr Med. 2001 May 28;143 Suppl 2:87-8. German.

http://www3.interscience.wiley.com/cgi-bin/abstract/112476870

High histologic and overall response to dose intensification of ifosfamide, carboplatin, and etoposide with cyclophosphamide, doxorubicin, and vincristine in patients with high-risk ewing sarcoma family tumors

The Bambino Gesù Children's Hospital experience
Giuseppe Maria Milano, M.D. 1 *, Raffaele Cozza, M.D. 1, Ilaria Ilari, M.D. 1, Luigi De Sio, M.D. 1, Renata Boldrini, M.D. 2, Alessandro Jenkner, M.D. 1, Maretta De Ioris, M.D. 1, Alessandro Inserra, M.D. 3, Carlo Dominici, M.D. 1 4, Alberto Donfrancesco, M.D. 1
1Division of Pediatric Oncology, Ospedale Pediatrico Bambino Gesù-IRCCS, Rome, Italy
2Division of Pathology, Ospedale Pediatrico Bambino Gesù-IRCCS, Rome, Italy
3Division of Pediatric Surgery, Ospedale Pediatrico Bambino Gesù-IRCCS, Rome, Italy
4Department of Pediatrics, La Sapienza University, Rome, Italy
email: Giuseppe Maria Milano (milano_gm@hotmail.com)

*Correspondence to Giuseppe Maria Milano, Dipartimento di Oncoematologia Pediatrica e Servizio Immunotrasfusionale, UO di Oncologia, Ospedale Pediatrico Bambino Gesù-IRCCS, Piazza Sant'Onofrio 4, Rome, 00165, Italy
Fax: (011) 396 68592242

Keywords
Ewing sarcoma family tumors • chemotherapy • dose intensification • histologic response • tumor necrosis • survival

Abstract

BACKGROUND
Ewing sarcoma (ES) and extraosseous ES/primitive neuroectodermal tumors (PNET) share histopathologic features of the ES family of tumors (ESFT). The authors report on their results from a regimen of ifosfamide, carboplatin, and etoposide (ICE) with cyclophosphamide, doxorubicin, and vincristine (CAV) dose intensification in patients with high-risk ESFT.

METHODS
Since 1990, patients with ESFT and with 1 or more of the following risk factors were reviewed: tumor volume > 200 mL, tumor site with a poor prognosis, and pulmonary and/or bone marrow metastases.

RESULTS
Thirty-six patients with ESFT who were involved in the study were divided into 2 arms of 18 patients each. One group received treatment with various regimens, and the other group received treatment with ICE plus CAV. The disease was brought under control more rapidly in the latter patients, for whom surgery was more easily feasible, and up to 90% of patients achieved a major response, with an estimated 3-year overall survival rate of 67% ± 12%.

CONCLUSIONS
The current results showed that ICE plus CAV was tolerated well and was effective in the studied subset of tumors, indicating that dose intensification correlates with better disease control, a high percentage of necrosis, and conservative surgery in patients with high-risk ESFT. Cancer 2006. © 2006 American Cancer Society.

http://www.fda.gov/bbs/topics/news/2006/NEW01316.html

Press Release

FOR IMMEDIATE RELEASE Tuesday, February 14, 2006

FDA Press Office 301-827-6242 NCI Press Office (301) 496-6641 CMS Press Office (202) 690-6145

New Federal Health Initiative to Improve Cancer Therapy
Patients will Benefit from Rapid Development and Delivery of New Cancer Treatments

The Food and Drug Administration (FDA), the National Cancer Institute (NCI), part of the National Institutes of Health, and the Centers for Medicare & Medicaid Services (CMS) today announced the Oncology Biomarker Qualification Initiative (OBQI) -- an agreement to collaborate on improving the development of cancer therapies and the outcomes for cancer patients through biomarker development and evaluation.

Biomarkers are biologic indicators of disease or therapeutic effects, which can be measured through dynamic imaging tests, as well as tests on blood, tissue and other biologic samples. This initiative is the first time these three Department of Health and Human Services (HHS) agencies have focused together on biomarkers as a way of speeding the development and evaluation of cancer therapies.

"We are excited about this effort to speed the development and delivery of new cancer treatments for patients," said Secretary of Health and Human Services Mike Leavitt. "By bringing together the scientific, regulatory and delivery expertise of these three agencies, we can bring targeted, more personalized cancer diagnostics, treatments and preventions to patients more rapidly."

The collaboration will develop scientific understanding of how biomarkers can be used to assess the impact of therapies and better match therapies to patients. For instance, OBQI will address questions such as how particular biomarkers can be used to:

• Assess after one or two treatments if a patient';s tumor is responding to treatment
• Determine more definitively if a tumor is dying, even if it is not shrinking
• Identify which cancer patients are at high risk of their tumor coming back after therapy
• Determine if a patient';s tumor is likely to respond at all to a specific treatment
• Efficiently evaluate whether an investigational therapy is effective for tumor treatment.

The goal of OBQI is to validate particular biomarkers so that they can be used to evaluate new, promising technologies in a manner that will shorten clinical trials, reduce the time and resources spent during the drug development process, improve the linkage between drug approval and drug coverage, and increase the safety and appropriateness of drug choices for cancer patients.

"Almost four years ago, NIH set out to create a "roadmap" for 21st century medical research. Programs like OBQI will be central to that vision, not only because they will lead to vital discoveries about the biology of disease, but because they will be models for scientific collaboration," said NIH Director Elias A. Zerhouni, M.D.

"An enhanced understanding of clinical biomarkers will help make the development of diagnostics and treatments more targeted, one of our most pressing goals under the Critical Path Initiative, FDA';s program to modernize the medical product development process," said FDA Acting Commissioner of Food and Drugs Andrew C. von Eschenbach, M.D. "We believe partnerships that help us standardize the use of new technologies are essential to refining the drug development process, so we can bring personalized medicines to patients more quickly and ultimately improve outcomes."

Under the OBQI, biomarker research will be focused in four key areas: standardizing and evaluating imaging technologies to see in more detail how treatments are working, developing scientific bases for diagnostic assays to enable personalized treatments, instituting new trial designs to utilize biomarkers, and pooling data to ensure that key lessons are shared from one trial to another. By working with academic and industry scientists, as well as professional organizations, the OBQI teams can foster the development of key information on biomarkers through clinical trials.

"By identifying biomarkers for specific cancers and clinically evaluating them, researchers will have an evidence base for their use in targeted drug development and to determine which therapies are likely to work for patients before treatment selection," said NCI Deputy Director Anna D. Barker, Ph.D. "Rather than waiting weeks to months to determine if a specific drug works for a patient, biomarkers could be used to monitor real-time treatment responses."

The first OBQI project to be implemented will serve to validate and standardize the use of Fluorodeoxyglucose - Positron Emission Tomography (FDG-PET) scanning. PET scans are used to characterize biochemical changes in a cancer. Under the collaboration, researchers will use FDG-PET imaging technology in trials of patients being treated for non-Hodgkin';s lymphoma, to determine if FDG-PET is a predictor of tumor response. Data resulting from this type of evidence-based study will help both FDA and CMS work with drug developers based on a common understanding of the roles of these types of assessments.

"There are many steps between a novel scientific idea with tremendous promise and a new drug reliably benefiting patients," said CMS Administrator Mark B. McClellan, M.D., Ph.D. "This collaboration will produce evidence that will help people with Medicare and Medicaid get better care more quickly, as a result of better-targeted treatment decisions for cancer patients."

Over the next several months, the OBQI team will design a number of initiatives to identify and clinically qualify other cancer biomarkers. The new initiatives will bring together scientists from many sources and address agency priorities identified through FDA';s Critical Path and NIH';s Roadmap Initiatives. The OBQI also represents the work of the NCI-FDA Interagency Oncology Task Force (IOTF). The IOTF is a collaboration between NCI and FDA to enhance the efficiency of clinical research and the scientific evaluation of new cancer treatments. The two agencies, along with CMS, share knowledge and resources to facilitate the development of new cancer drugs and diagnostics and speed their delivery to patients as safely and as cost-effectively as possible.

FDA Critical Path

Critical Path is the FDA';s premier initiative to identify and prioritize the most pressing medical product development problems and the greatest opportunities for rapid improvement in public health benefits. Its primary purpose is to ensure that basic scientific discoveries translate more rapidly into new and better medical treatments by creating new tools to find answers about how the safety and effectiveness of new medical products can be demonstrated in faster timeframes with more certainty and at lower costs.

The NIH Roadmap

The NIH Roadmap is a series of new initiatives designed to pursue major opportunities and gaps in biomedical research that no single NIH institute could tackle alone, but which the agency as a whole can address to make the biggest impact possible on the progress of medical research, and to catalyze changes that will serve to transform new scientific knowledge into tangible benefits for public health. Additional information about the NIH Roadmap can be found at its Web site, www.nihroadmap.nih.gov.

For information about the Food and Drug Administration, please visit http://www.fda.gov.
For additional information about the National Cancer Institute, please visit http://www.cancer.gov.
For information about the Centers for Medicare & Medicaid Services, please visit http://cms.hhs.gov.

FDA/NCI/CMS Memorandum of Understanding

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