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Neoplasms, Connective and Soft Tissue

Neoplasms by Histologic Type

Neoplasms, Fibrous Tissue

Neoplasms, Connective Tissue

Soft Tissue Sarcoma

Undifferentiated Pleomorphic Sarcoma

Synovial Sarcoma

Malignant Peripheral Nerve Sheath Tumor

Epithelioid Sarcoma

Alveolar Soft Part Sarcoma

Dermatofibrosarcoma Protuberans

Antineoplastic Agents

All Drugs and Chemicals

Anti-Infective Agents

Doxorubicin

Liposomal doxorubicin

Ifosfamide

Isophosphamide mustard

Anti-Bacterial Agents

Antibiotics, Antitubercular

Enzyme Inhibitors

Antineoplastic Agents, Alkylating

Alkylating Agents

doxorubicin hydrochloride

ifosfamide

adjuvant therapy

conventional surgery

neoadjuvant therapy

radiation therapy

Ruth Ladenstein, MD

Nadine Francotte, MD

Catherine Rechnitzer, MD, PhD

Daniel Orbach, MD

Anne O'Meara, MD

Soledad Gallego, MD, PhD

Gustaf Ljungman, MD

Felix Niggli, MD

David Hobin, MD

M. C. G. Stevens, MD

Denise Williams, MD

Adam Glaser, MD

Johann Visser, MD

Heather P. McDowell, MD

Ananth Shankar, MD

Julia Chisholm, MD

Bernadette Brennan, MD

Juliet Hale, MD

Martin Hewitt, MD, BSc, FRCP, FRCPCH

Kate Wheeler, MD

Mary P. Gerrard, MBChB, FRCP, FRCPCH

Janice A. Kohler, MD, FRCP

Kathy Pritchard-Jones, MD

Anthony McCarthy, MD

Derek King, MD

W. Hamish Wallace, MD

Milind D. Ronghe, MD

Heidi Traunecker, MD, PhD

Andrea Ferrari, MD

Modesto Carli, MD

Joern Treuner, MD

Max Van Noesel, MD, PhD

RATIONALE: Drugs used in chemotherapy, such as ifosfamide and doxorubicin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving combination chemotherapy with or without radiation therapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving radiation therapy after surgery may kill any tumor cells that remain after surgery.

PURPOSE: This phase III trial is studying how well giving ifosfamide and doxorubicin, radiation therapy, and/or surgery works in treating young patients with localized soft tissue sarcoma.

OBJECTIVES:

Primary

* Determine survival rates (event-free survival and overall survival \[OS\]) and the pattern of treatment failure in patients with synovial sarcoma or adult-type soft tissue sarcoma treated with ifosfamide and doxorubicin hydrochloride, radiotherapy, and/or surgery.
* Determine the role of ifosfamide and doxorubicin hydrochloride in improving the response rate in patients with unresectable synovial sarcoma or adult-type soft tissue sarcoma.

Secondary

* Evaluate clinical/pathological prognostic factors, particularly tumor grade and radiological and pathological response to neoadjuvant treatment.
* Determine the impact of omitting adjuvant chemotherapy in patients with low-risk synovial sarcoma (tumor \< 5 cm).
* Determine the role of adjuvant chemotherapy in improving the metastases-free survival and OS in patients with adult-type soft tissue sarcoma (Intergroup Rhabdomyosarcoma Study \[IRS\] postsurgical grouping system I-II, tumor grade 3, tumor size \> 5 cm).

OUTLINE: This is a nonrandomized, prospective, historically controlled, multicenter study. Patients with synovial sarcoma are stratified according to the Intergroup Rhabdomyosarcoma Study (IRS) postsurgical grouping system (I vs II vs III) and tumor size ( ≤ 5 cm vs \> 5 cm). Patients with adult-type soft tissue sarcoma are stratified according to the IRS postsurgical grouping system (I vs II vs III), tumor size ( ≤ 5 cm vs \> 5 cm), and tumor grade (G1 vs G2 vs G3). Patients are assigned to 1 of 9 treatment groups according to disease and stratification.

Synovial sarcoma

* Group 1 (IRS group I, tumor ≤ 5 cm): Patients undergo surgical resection of tumor.
* Group 2 (IRS group I, tumor \> 5 cm): Patients receive ifosfamide IV over 3 hours on days 1-3 and doxorubicin hydrochloride IV over 4-6 hours on days 1 and 2 (IFO-DOX). Treatment repeats every 21 days for 4 courses.
* Group 3 (IRS group II, tumor ≤ 5 cm): Patients receive 3 courses of IFO-DOX. After the completion of chemotherapy, patients undergo radiotherapy 5 days a week for 5-6 weeks.
* Group 4 (IRS group II, tumor \> 5 cm): Patients receive 3 courses of IFO-DOX. Patients then receive ifosfamide alone IV over 3 hours on days 1-3. Treatment with ifosfamide repeats every 21 days for 2 courses. Patients also receive concurrent radiotherapy (concurrently with ifosfamide) 5 days a week for 5-6 weeks. After completion of radiotherapy, patients receive 1 additional course of IFO-DOX.
* Group 5 (IRS group III, N1): Patients receive 3 courses of IFO-DOX. Patients with no response to chemotherapy receive 1 of the following local therapies:

  * Delayed complete resection\*
  * Radiotherapy (as in group 3) followed by surgery\*
  * Delayed complete resection\* followed by radiotherapy\*\* (as in group 3)
  * Delayed incomplete resection\* followed by radiotherapy\*\* (as in group 3)
  * Radiotherapy (as in group 3) Patients with major or minor response to chemotherapy receive 2 courses of ifosfamide with concurrent radiotherapy followed by 1 additional course of IFO-DOX (as in group 4, above).

NOTE: \* Patients undergo surgery 5 weeks after completion of chemotherapy and/or radiotherapy.

NOTE: \*\*Patients undergo radiotherapy beginning \< 21 days after surgery.

Adult-type soft tissue sarcoma

* Group 1 (IRS group I, tumor ≤ 5 cm): Patients undergo surgical resection of tumor.
* Group 2 (IRS group I, tumor \> 5 cm): Patients receive therapy according to tumor grade:

  * G1 disease: Patients undergo surgical resection.
  * G2 disease: Patients undergo radiotherapy 5 days a week for 5-6 weeks.
  * G3 disease: Patients receive the following sequential treatment: 3 courses of IFO-DOX followed by 2 courses of ifosfamide with concurrent radiotherapy followed by 1 course of IFO-DOX.
* Group 3 (IRS group II, N0): Patients receive therapy according to tumor grade:

  * G1 disease: Patients undergo surgical resection.
  * G2-3 disease (≤ 5 cm) and G2 disease (\> 5 cm): Patients undergo radiotherapy 5 days a week for 5-6 weeks.
  * G3 disease (\> 5 cm): Patients undergo sequential treatment (as in group 2, adult-type soft tissue sarcoma).
* Group 4 (IRS group III, N1): Patients receive 3 courses of IFO-DOX. Patients with no response to chemotherapy receive local therapy (as in group 5 synovial sarcoma). Patients with major or minor response to chemotherapy receive 2 courses of ifosfamide with concurrent radiotherapy followed by 2 additional courses of IFO-DOX (as in group 4, synovial sarcoma).

After completion of study therapy, patients are followed periodically for up to 10 years.

PROJECTED ACCRUAL: A total of 250 patients will be accrued for this study.

Ifosfamide and Doxorubicin, Radiation Therapy, and/or Surgery in Treating Young Patients With Localized Soft Tissue Sarcoma

Localized Non-Rhabdomyosarcoma Soft Tissue Sarcomas

Italian Association for Pediatric Hematology Oncology

Cooperative Weichteilsarkom Studie

Children's Cancer and Leukaemia Group

Dutch Childhood Oncology Group

European Paediatric Soft Tissue Sarcoma Study Group

Symptoms and General Pathology

Recurrence

Amino Acids

Imatinib Mesylate

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Tyrosine

Patients receive oral imatinib mesylate once daily on days 1-56. Treatment repeats every 56 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients with documented tumor progression and no serious side effects may continue therapy at a higher dose for another 6 courses.

imatinib mesylate

laboratory biomarker analysis

Scott Schuetze

This phase II trial is studying how well imatinib mesylate works in treating patients with locally recurrent or metastatic dermatofibrosarcoma protuberans (DFSP) or transformed fibrosarcomatous DFSP (a type of soft tissue sarcoma). Imatinib mesylate may stop the growth of tumor cells by blocking the enzymes necessary for their growth

PRIMARY OBJECTIVES:

I. To assess the response rate (confirmed complete and confirmed partial response) in patients with locally advanced or metastatic dermatofibrosarcoma protuberans (DFSP) treated with imatinib.

II. To estimate the one-year progression-free survival probability in this population when treated with imatinib.

III. To evaluate the frequency and severity of toxicities associated with this treatment.

IV. To measure the presence of PDGFB gene rearrangement in DFSP detectable by RT-PCR (for COL1A1-PDGFB fusions) and/or FISH (PDGFB rearrangements with unknown partners) and explore relationships between these measures and survival and tumor response in a preliminary manner.

V. To investigate in a preliminary fashion the correlation of plasma levels of imatinib after 1 month of treatment with the response of DFSP.

VI. To obtain tumor material for additional future correlative studies of the activity of intracellular kinases, cDNA microarray analyses and PDGFB receptor gene sequence analyses.

OUTLINE:

Patients receive oral imatinib mesylate once daily on days 1-56. Treatment repeats every 56 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients with documented tumor progression and no serious side effects may continue therapy at a higher dose for another 6 courses.

Patients are followed every 6 months for 2 years and then annually for 3 years.

Imatinib Mesylate in Treating Patients With Locally Recurrent or Metastatic Dermatofibrosarcoma Protuberans

A Phase II Study of Imatinib (NSC-716051) in Patients With Locally Advanced or Metastatic Dermatofibrosarcoma Protuberans

National Cancer Institute (NCI)

Patients who have their dermatofibrosarcoma protuberans excised with MOHS surgery.

Mohs surgery is a precise surgical technique used to treat skin cancer. Thin layers of cancer-containing skin are progressively removed and examined microscopically until only cancer-free tissue remains.

MOHS micrographic surgery

A surgical technique in which the skin cancer is excised along with 2-3 cm of clinically normal appearing surrounding tissue.

Wide local excision

Randall K Roenigk

The purpose of this proposed study is to assess effectiveness of MOHS micrographic surgery as a form of treatment for dermatofibrosarcoma protuberans in patients who are 10 years of age or younger through review of the patients at Mayo Clinic treated from 1988-2017, and to explore the challenges that providers face which may prevent them performing this potentially superior treatment. This study will provide a comparison of outcomes and recurrence rates in pediatric patients treated by MOHS versus traditional excision.

Treatment of Dermatofibrosarcoma Protuberans in Patients 10 Years and Younger

Developing an additional dermatofibrosarcoma protuberans at any location, but particularly noting local recurrence (defined as being within or contiguous to the field of the previous excision.

Death which is directly related to the dermatofibrosarcoma or complications related to it as judged by clinical investigators

Will be measured by the area of tissue removed and any functional or physical impairment which resulted from the surgical procedure such as limited range of motion, resulting reported pain, or any reported complications.

Mayo Clinic

Professor of Dermatology

Osteosarcoma

Rhabdomyosarcoma

Mesenchymoma

Malignant Mesenchymoma

pre-operative radiation + surgery PTV will receive a total dose of 50 Gy in 25 fractions, 2 Gy per fraction, 5 fractions per week, over approximately 5 weeks. Concurrently, the GTV2, if present, will receive 54 Gy in 25 fraction. Dose will be prescribed to the isodose volume that encompasses the PTV. All patients will be treated by 6 MV photon beam.

gene expression analysis

polymerase chain reaction

western blotting

therapeutic conventional surgery

intensity-modulated radiation therapy

Richard D. Pezner, MD

RATIONALE: Specialized radiation therapy that delivers a high dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue. Giving radiation therapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.

PURPOSE: This phase II trial is studying the side effects of intensity-modulated radiation therapy and to see how well it works in treating patients undergoing surgery for stage IB, stage II, or stage III soft tissue sarcoma.

OBJECTIVES:

Primary

* Estimate the wound complication rate in patients with stage IB-III soft tissue sarcoma (STS) treated with neoadjuvant intensity-modulated radiotherapy (IMRT).

Secondary

* Assess local control rate in patients treated with this regimen.
* Assess metastatic failure rate in patients treated with this regimen.
* Assess disease-free survival of patients treated with this regimen.
* Assess overall survival of patients treated with this regimen.
* Assess function and general health in these patients using the Musculoskeletal Tumor Society rating scale, Toronto Extremity Salvage Score, and the Short-Form 36.
* Determine changes in STS gene expression after IMRT by microarray analyses.
* Correlate, preliminarily, changes in STS gene expression with pathological and clinical outcomes.

OUTLINE: Patients undergo intensity-modulated radiotherapy (IMRT) once daily 5 days a week for 5 weeks in the absence of disease progression or unacceptable toxicity. Patients then undergo surgery \> 1 month after completion of IMRT.

Tumor tissue samples are collected at baseline and at the time of surgery for correlative laboratory studies. Samples are analyzed for gene expression by RNA microarray, real-time polymerase chain reaction, and western blotting.

After completion of study treatment, patients are followed periodically for 2 years.

Intensity-Modulated Radiation Therapy in Treating Patients Undergoing Surgery for Stage IB, Stage II, or Stage III Soft Tissue Sarcoma

Phase II Study of Preoperative Intensity-Modulated Radiation Therapy for Soft-Tissue Sarcomas

Major wound complications up to 4 months post surgery include:

Complications requiring a secondary operation under general or regional anesthesia for wound care.

Seroma aspiration. Drain placement. Minor wound debridement and wound care. Readmission for wound care such as intravenous antibiotics. Persistent wound deep packing or wound vacuum assisted closure for greater than 120 days.

City of Hope Medical Center

Only one patients was on treatment for 5 days with no adverse events to report.

Arm 1

Age, Categorical

Sex: Female, Male

Study closed 05/12/2010 (opened 7/25/2008): No patients were accrued and treated per protocol in nearly two years (2 patients were screened). The study was terminated by the IRB when the PI decided not to continue. Protocol objectives were not met.

Paul Frankel, Ph.D.

The one patient accrued to the study stopped treatment prior to completing treatment due to insurance denial.

Wound Complication Rate

Overall Study

400 mg orally twice a day for 10 - 14 days

Scott Schuetze, MD, PhD

The purpose of this study is to examine the effect of imatinib on dermatofibrosarcoma protuberan tumors.

Neoadjuvant Imatinib in Dermatofibrosarcoma Protuberans

Study of a Short Course of Neoadjuvant Gleevec (Imatinib Mesylate) in Dermatofibrosarcoma Protuberans

To obtain matched tumor tissue samples of trial participants dermatofibrosarcoma protuberans (DFSP)for the purpose of determining whether imatinib mesylate affects autocrine/paracrine stimulated signal transduction through the platelet-derived growth factor receptor pathway in DFSP by comparing the level of phosphorylated platelet-derived growth factor receptor beta (PDGFRB) in DFSP after up to 2 weeks of treatment with imatinib to the level of phosphorylated PDGFRB pre-treatment.

Sarcoma Alliance for Research through Collaboration

Imatinib

Age Continuous

United States

Region of Enrollment

Dermatofibrosarcoma protuberans (DFSP)is a rare tumor type. During the the trial the drug manufacturer obtained approval for DSFP indication.The other limitation is limited funding; SARC is actively seeking funding for secondary outcome goal 12/2012.

SARC, Chief Operating Officer

Population of paired tissue samples collected from patients with confirmed diagnosis of dermatofibrosarcoma protuberans. Tissue sample will be considered evaluable if there is adequate pre-treatment and on-treatment tumor tissue available for the proposed molecular studies, and resection of DFSP was completed after receiving imatinib.

To Collect Matched Tumor Tissue of Trial Participants With Dermatofibrosarcoma Protuberans Before and After Treatment With Imatinib for Future Use in cDNA Microarray and Tissue Array Studies.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Ifosfamide and Doxorubicin, Radiation Therapy, and/or Surgery in Treating Young Patients With Localized Soft Tissue Sarcoma	NCT00334854	Childhood Malig... Sarcoma	doxorubicin hyd... ifosfamide adjuvant therap... conventional su... neoadjuvant the... radiation thera...	- 20 Years	National Cancer Institute (NCI)
Imatinib Mesylate in Treating Patients With Locally Recurrent or Metastatic Dermatofibrosarcoma Protuberans	NCT00084630	Adult Fibrosarc... Dermatofibrosar... Recurrent Adult... Stage IV Adult ...	imatinib mesyla... laboratory biom...	18 Years -	National Cancer Institute (NCI)
Treatment of Dermatofibrosarcoma Protuberans in Patients 10 Years and Younger	NCT03381846	Dermatofibrosar...	MOHS micrograph... Wide local exci...	1 Year - 10 Years	Mayo Clinic
Intensity-Modulated Radiation Therapy in Treating Patients Undergoing Surgery for Stage IB, Stage II, or Stage III Soft Tissue Sarcoma	NCT00740597	Sarcoma	gene expression... polymerase chai... western blottin... neoadjuvant the... therapeutic con... intensity-modul...	18 Years -	City of Hope Medical Center
Ifosfamide and Doxorubicin, Radiation Therapy, and/or Surgery in Treating Young Patients With Localized Soft Tissue Sarcoma	NCT00334854	Childhood Malig... Sarcoma	doxorubicin hyd... ifosfamide adjuvant therap... conventional su... neoadjuvant the... radiation thera...	- 20 Years	National Cancer Institute (NCI)
Neoadjuvant Imatinib in Dermatofibrosarcoma Protuberans	NCT00243191	Dermatofibrosar...	imatinib mesyla...	18 Years -	Sarcoma Alliance for Research through Collaboration

Spots Global Cancer Trial Database for dermatofibrosarcoma protuberans