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Therapeutic Trial for Patients With Ewing Sarcoma Family of Tumor and Desmoplastic Small Round Cell Tumors

Primary Purpose

Desmoplastic Small Round Cell Tumor, Ewing Sarcoma of Bone or Soft Tissue, Localized Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor

Status

Active

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

vincristine

doxorubicin

cyclophosphamide

ifosfamide

etoposide

temozolomide

temsirolimus

bevacizumab

sorafenib

surgery

radiation

About this trial

This is an interventional treatment trial for Desmoplastic Small Round Cell Tumor

Eligibility Criteria

undefined - 25 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Group A participants must be <14 years of age at time of diagnosis of histologically proven non-pelvic localized Ewing sarcoma family of tumor (ESFT) involving the bone or soft tissue.
Group B participants must have newly diagnosed of histologically proven ESFT involving the bone or soft tissue and at least one of the following: metastatic disease (must be biopsy proven), or pelvic primary, or ≥14 years of age at the time of diagnosis.
OR Group B participants must be newly diagnosed with intra-abdominal, unresectable or metastatic desmoplastic small round cell tumor. Metastatic site must be biopsy proven.
Age must be ≤25 years.
Adequate bone marrow function defined as a peripheral absolute neutrophil count (ANC) ≥750/m^3 and platelet count ≥75,000/m^3 (no transfusion within 7 days of study enrollment). Patients with Ewing sarcoma metastatic to the bone marrow are not required to meet bone marrow criteria for study eligibility and are not evaluable for hematologic toxicity.
Must have adequate renal function based on age.
Must not have had prior chemotherapy or radiation therapy. Emergent radiotherapy to preserve vital organ function is permitted. Participants who receive emergent radiation will not be eligible for window therapy.
Must have adequate hepatic function defined as total bilirubin ≤3.0 mg/dL.
Must have adequate cardiac function defined as shortening fraction ≥28%.
Females of childbearing potential and males able to father a child must be willing to practice acceptable methods of birth control to prevent pregnancy.
Additional criteria for Group B participants who will receive upfront window therapy (does not apply to participants who opt out of window therapy):
- Cytochrome P450 CYP3A4 active agents: Must not be taking any of the following potent CYP3A4 inducers or inhibitors within 1 week prior to study entry: azole antifungals (such as fluconazole, voriconazole, itraconazole, ketoconazole), rifampin, phenytoin, phenobarbitol, carbamazepine, grapefruit juice and St. John's wort.
- Must have measurable disease.
- Must not have received emergent radiation therapy.
- Serum triglyceride level ≤ 300 mg/dL and serum cholesterol ≤ 300 mg/dL.
- Random or fasting glucose within the upper limits of normal for age. If random glucose is elevated, fasting glucose must be within normal range.
- SGOT (AST) and SGPT (ALT) ≤3.0 x upper limit of normal for age.

Exclusion Criteria:

Participant is pregnant or breastfeeding.
Inability or unwillingness of research participant or legal guardian/representative to give written informed consent.
Participant has a prior history of malignancy, with the exception of non-melanoma skin cancer. Participants with history of skin cancer must have 5 years elapse since that diagnosis, be in remission, and must not have received chemotherapy, immunotherapy, or radiation therapy.

Sites / Locations

St. Jude Children's Research Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Arm Label

Group A (Standard Risk)

Group B (High Risk)

Arm Description

Participants will receive vincristine, doxorubicin, cyclophosphamide, ifosfamide and etoposide. Doxorubicin will be omitted following a total cumulative dose of 375 mg/m^2. Depending on the size and location of the participant's tumor, they will have surgery alone, radiation alone, or surgery followed by radiation. Local control measures (surgery and/or radiation therapy) will be instituted after 6 courses of chemotherapy. Total duration of treatment is approximately 29 weeks.

Participants will receive vincristine, doxorubicin, cyclophosphamide, ifosfamide, etoposide, irinotecan, temozolomide, temsirolimus, bevacizumab, and sorafenib. Depending on the size and location of the participant's tumor, they will have surgery alone, radiation alone or surgery followed by radiation.

Outcomes

Primary Outcome Measures

Response to Window Therapy (2 Courses) for Group B (High-risk) - ESFT Participants

Response rate will be defined as the proportion of patients who achieved complete response or partial response (CR+PR) using the World Health Organization (WHO) criteria evaluated after two initial courses of temsirolimus, temozolomide and irinotecan in previously untreated patients with high risk Ewing Sarcoma Family of Tumor (ESFT). Participants who are treated in Group B with Desmoplastic Small Round Cell Tumor (DSRCT) or those who do not receive window therapy will not be included in this analysis.

Secondary Outcome Measures

Overall Survival

Overall survival (OS) is defined as the time interval from the date on study to the date of death or the date of last follow-up. OS will be estimated using the method of Kaplan-Meier for group A and B participants, respectively.

Progression-free Survival

Progression free survival (PFS) is defined as the time interval from the date on study to the date of disease progression or death or the date if last follow-up. PFS will be estimated using the method of Kaplan-Meier for group A and B participants, respectively.

Time to Progression

Median time to progression of group B patients will be estimated from the Kaplan-Meier curve.

Local Failure Rate

Loco-regional failure is defined as the time interval from date of start of local therapy to date of loco-regional failure. Distant failure or death prior to loco-regional failure will be considered competing events in the analyses. The cumulative incidence of loco-regional failure will be estimated using methods described in Kalbfleisch and Prentice.

Full Information

NCT ID

NCT01946529

First Posted

September 16, 2013

Last Updated

July 31, 2023

Sponsor

St. Jude Children's Research Hospital

Collaborators

University of Tennessee, University of Florida, Nemours Children's Clinic

1. Study Identification

Unique Protocol Identification Number

NCT01946529

Brief Title

Therapeutic Trial for Patients With Ewing Sarcoma Family of Tumor and Desmoplastic Small Round Cell Tumors

Official Title

Therapeutic Trial for Patients With Ewing Sarcoma Family of Tumor and Desmoplastic Small Round Cell Tumors

Study Type

Interventional

2. Study Status

Record Verification Date

July 2023

Overall Recruitment Status

Active, not recruiting

Study Start Date

December 27, 2013 (Actual)

Primary Completion Date

August 2015 (Actual)

Study Completion Date

July 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

St. Jude Children's Research Hospital

Collaborators

University of Tennessee, University of Florida, Nemours Children's Clinic

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

This protocol will study treatment for Ewing sarcoma family of tumors (ESFT) and desmoplastic small round cell tumor (DSRCT). Participants with ESFT will be divided into two treatment groups, A or B, based on tumor characteristics. Group A (standard risk) participants have tumor that is not in the pelvis, has not spread to other parts of the body, and are less than 14 years of age. Because previous clinical trials have shown that standard treatment is very effective for children whose tumors have these characteristics, these participants will receive standard treatment. Group B (high risk) participants are 14 years of age or older or have tumor in the pelvis, or the tumor has spread to other parts of the body. Participants with DSRCT in the abdomen and/or pelvis or with tumor that cannot be removed by surgery alone or has spread to other parts of the body will be included in Group B. Participants in this group are considered high risk because there is a greater chance of tumor recurring following standard treatments currently in use. All participants will be followed and evaluated for 10 years following completion of therapy.

Detailed Description

PRIMARY OBJECTIVE: To estimate the response rate to two initial courses of temsirolimus, temozolomide and irinotecan in previously untreated patients with high-risk Ewing sarcoma family of tumors (ESFT). SECONDARY OBJECTIVES: To estimate the overall survival and progression-free survival in participants with ESFT treated with these approaches. To estimate the time to progression in participants with ESFT treated in Group B (high risk). To estimate the cumulative incidence of local failure following local control paradigm in this trial. Group A: Participants will receive interval compressed (every 2 weeks) alternating courses of chemotherapy with vincristine, doxorubicin, and cyclophosphamide (VDC) and with ifosfamide and etoposide (IE). Doxorubicin will be omitted following a total cumulative dose of 375 mg/m^2. Local control measures (surgery and/or radiation therapy) will be instituted after 6 courses of chemotherapy. Total duration of treatment is approximately 29 weeks. Group B: Participants eligible for the window therapy will receive two courses (21 days duration each) of mTOR inhibitor, temsirolimus, in combination with temozolomide and irinotecan. Irinotecan (20 mg/m^2) will be administered IV on a protracted schedule of daily for 5 days, 2 days off, repeated daily x 5 [(qdx5)x2], temozolomide (100 mg/m^2) PO daily x 5 days and temsirolimus 35 mg/m^2 IV weekly on day 1 and 8. Following window treatment (weeks 1 - 6), participants will proceed to induction chemotherapy (weeks 7 - 33) consisting of interval compressed (every 2 weeks) alternating courses of chemotherapy with vincristine, doxorubicin, and cyclophosphamide (VDC) with ifosfamide and etoposide (IE). Doxorubicin will be omitted following a total cumulative dose of 375 mg/m^2. Local control measures (surgery and/or radiation therapy) will be instituted after 6 courses of induction chemotherapy (week 19). Participants whose tumors respond to window therapy will receive temsirolimus, temozolomide and irinotecan at weeks 29 and 31 in place of ifosfamide and etoposide. Following induction therapy, participants will receive six 21-day courses of maintenance therapy consisting of bevacizumab IV on day 1 and daily oral sorafenib and low-dose cyclophosphamide day 1 through day 21.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Desmoplastic Small Round Cell Tumor, Ewing Sarcoma of Bone or Soft Tissue, Localized Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor, Metastatic Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

24 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Group A (Standard Risk)

Arm Type

Active Comparator

Arm Description

Arm Title

Group B (High Risk)

Arm Type

Active Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

vincristine

Other Intervention Name(s)

Oncovin(R)

Intervention Description

Dosage and route of administration: Infants < 12 months of age: 0.05 mg/kg IV day 1; participants ≥ 12 months of age: 1.5 mg/m^2 IV day 1 (max. dose 2 mg).

Intervention Type

Drug

Intervention Name(s)

doxorubicin

Other Intervention Name(s)

Adriamycin(R)

Intervention Description

Dosage and route of administration: Infants < 1 year 2.5 mg/kg continuous infusion (CI) over 48 hours, days 1-2; participants > 1 year of age 75 mg/m^2 CI over 48 hours, days 1-2.

Intervention Type

Drug

Intervention Name(s)

cyclophosphamide

Other Intervention Name(s)

Cytoxan(R)

Intervention Description

Dosage and route of administration: The dose and route are different in neo-adjuvant/adjuvant chemotherapy and maintenance therapy. Please see the Detailed Description for further information.

Intervention Type

Drug

Intervention Name(s)

ifosfamide

Other Intervention Name(s)

Ifex(R)

Intervention Description

Dosage and route of administration: Infants < 1 year of age 60 mg/kg/day IV over 60 minutes days 1-5; participants > 12 months of age 1800 mg/m^2 IV over 60 minutes x 5 days, days 1-5.

Intervention Type

Drug

Intervention Name(s)

etoposide

Other Intervention Name(s)

VP-16, Vepesid(R)

Intervention Description

Dosage and route of administration: Infants < 1 year of age 3.3 mg/kg/day IV over 60 minutes days 1-5; children > 1 year 100 mg/m^2 daily IV over 60 minutes days 1-5.

Intervention Type

Drug

Intervention Name(s)

temozolomide

Other Intervention Name(s)

Temodar(R)

Intervention Description

Dosage and route of administration: Temozolomide 100 mg/m^2 PO once daily, days 1-5.

Intervention Type

Drug

Intervention Name(s)

temsirolimus

Other Intervention Name(s)

CCI-779, Torisel^TM

Intervention Description

Dosage and route of administration: Temsirolimus 35 mg/m^2 IV once day 1 and day 8.

Intervention Type

Drug

Intervention Name(s)

bevacizumab

Other Intervention Name(s)

rhumab VEGF, Avastin(R)

Intervention Description

Dosage and route of administration: Bevacizumab 15 mg/kg IV on day 1 every 3 weeks.

Intervention Type

Drug

Intervention Name(s)

sorafenib

Other Intervention Name(s)

BAY-43-9006, Nexavar(R)

Intervention Description

Dosage and route of administration: 90 mg/m^2/dose PO BID

Intervention Type

Procedure

Intervention Name(s)

surgery

Other Intervention Name(s)

therapeutic conventional surgery

Intervention Description

If participant meets the criteria, they will have surgical resection of their tumor.

Intervention Type

Radiation

Intervention Name(s)

radiation

Other Intervention Name(s)

proton beam radiation therapy, external beam radiation therapy, brachytherapy

Intervention Description

If the participant meets the criteria, participants will receive radiation therapy. Chemotherapy will continue during radiation.

Primary Outcome Measure Information:

Title

Response to Window Therapy (2 Courses) for Group B (High-risk) - ESFT Participants

Description

Time Frame

at 6 weeks after start of therapy (after 2 initial courses)

Secondary Outcome Measure Information:

Title

Overall Survival

Description

Time Frame

Maximum of 11 years after the start of therapy

Title

Progression-free Survival

Description

Time Frame

Maximum of 11 years after the start of therapy

Title

Time to Progression

Description

Median time to progression of group B patients will be estimated from the Kaplan-Meier curve.

Time Frame

Maximum of 11 years after the start of therapy

Title

Local Failure Rate

Description

Time Frame

Maximum of 11 years after the start of therapy

10. Eligibility

Sex

All

Maximum Age & Unit of Time

25 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Group A participants must be <14 years of age at time of diagnosis of histologically proven non-pelvic localized Ewing sarcoma family of tumor (ESFT) involving the bone or soft tissue. Group B participants must have newly diagnosed of histologically proven ESFT involving the bone or soft tissue and at least one of the following: metastatic disease (must be biopsy proven), or pelvic primary, or ≥14 years of age at the time of diagnosis. OR Group B participants must be newly diagnosed with intra-abdominal, unresectable or metastatic desmoplastic small round cell tumor. Metastatic site must be biopsy proven. Age must be ≤25 years. Adequate bone marrow function defined as a peripheral absolute neutrophil count (ANC) ≥750/m^3 and platelet count ≥75,000/m^3 (no transfusion within 7 days of study enrollment). Patients with Ewing sarcoma metastatic to the bone marrow are not required to meet bone marrow criteria for study eligibility and are not evaluable for hematologic toxicity. Must have adequate renal function based on age. Must not have had prior chemotherapy or radiation therapy. Emergent radiotherapy to preserve vital organ function is permitted. Participants who receive emergent radiation will not be eligible for window therapy. Must have adequate hepatic function defined as total bilirubin ≤3.0 mg/dL. Must have adequate cardiac function defined as shortening fraction ≥28%. Females of childbearing potential and males able to father a child must be willing to practice acceptable methods of birth control to prevent pregnancy. Additional criteria for Group B participants who will receive upfront window therapy (does not apply to participants who opt out of window therapy): Cytochrome P450 CYP3A4 active agents: Must not be taking any of the following potent CYP3A4 inducers or inhibitors within 1 week prior to study entry: azole antifungals (such as fluconazole, voriconazole, itraconazole, ketoconazole), rifampin, phenytoin, phenobarbitol, carbamazepine, grapefruit juice and St. John's wort. Must have measurable disease. Must not have received emergent radiation therapy. Serum triglyceride level ≤ 300 mg/dL and serum cholesterol ≤ 300 mg/dL. Random or fasting glucose within the upper limits of normal for age. If random glucose is elevated, fasting glucose must be within normal range. SGOT (AST) and SGPT (ALT) ≤3.0 x upper limit of normal for age. Exclusion Criteria: Participant is pregnant or breastfeeding. Inability or unwillingness of research participant or legal guardian/representative to give written informed consent. Participant has a prior history of malignancy, with the exception of non-melanoma skin cancer. Participants with history of skin cancer must have 5 years elapse since that diagnosis, be in remission, and must not have received chemotherapy, immunotherapy, or radiation therapy.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Sara M. Federico, MD

Organizational Affiliation

St. Jude Children's Research Hospital

Official's Role

Principal Investigator

Facility Information:

Facility Name

St. Jude Children's Research Hospital

City

Memphis

State/Province

Tennessee

ZIP/Postal Code

38105

Country

United States

12. IPD Sharing Statement

Links:

URL

http://www.stjude.org

Description

St. Jude Children's Research Hospital

URL

http://www.stjude.org/protocols

Description

Clinical Trials Open at St. Jude

Learn more about this trial

Therapeutic Trial for Patients With Ewing Sarcoma Family of Tumor and Desmoplastic Small Round Cell Tumors

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