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Doxorubicin With Upfront Dexrazoxane for the Treatment of Advanced or Metastatic Soft Tissue Sarcoma

Primary Purpose

Sarcoma, Soft Tissue, Soft Tissue Sarcoma, Undifferentiated Pleomorphic Sarcoma

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Dexrazoxane
Doxorubicin
Sponsored by
Washington University School of Medicine
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Sarcoma, Soft Tissue

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Histologically confirmed grade 2 or 3 soft tissue sarcoma that is unresectable or metastatic. Surgery for primary or metastatic disease after chemotherapy following a response is allowed. Patients with the following tumor types are eligible:

    • Undifferentiated pleomorphic sarcoma
    • Leiomyosarcoma
    • Malignant fibrous histiocytoma
    • Liposarcoma (myxoid/round cell, pleomorphic or dedifferentiated)
    • Synovial sarcoma
    • Myxofibrosarcoma
    • Angiosarcoma
    • Fibrosarcoma
    • Malignant peripheral nerve sheath tumor
    • Epithelioid sarcoma
    • Unclassified high-grade sarcoma (not otherwise specified)
    • Soft tissue sarcoma for which treatment with an anthracycline is appropriate at the approval of the Principal Investigator (PI)
  • Measurable disease according to RECIST 1.1; that is, measurable disease defined as lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 10 mm with CT scan, as ≥ 20 mm by chest x-ray, or ≥ 10 mm with calipers by clinical exam.
  • Planning to initiate treatment with doxorubicin (starting dose 75 mg/m2) as routine care.
  • Prior adjuvant chemotherapy with gemcitabine and/or docetaxel/paclitaxel is allowed.
  • At least 18 years of age.
  • ECOG performance status of 0 or 1

  • Adequate organ function defined as:

    • Leukocytes ≥ 3,000/mcL
    • Absolute neutrophil count ≥ 1,500/mcl
    • Platelets ≥ 100,000/mcl
    • Total bilirubin ≤ 1.5 x IULN
    • AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN
    • Creatinine ≤ IULN OR Creatinine clearance ≥ 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal. Creatinine clearance should be calculated using the actual weight from day 1 of cycle
  • Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately.
  • Able to understand and willing to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).

Exclusion Criteria:

  • Myocardial infarction within the past 12 months, or stable or unstable angina.
  • Systolic heart failure defined as left ventricular ejection fraction ≤ 45%.
  • Symptomatic valvular heart disease.
  • Prior chemotherapy for advanced or metastatic disease.
  • Known brain metastases.
  • Prior or second primary malignancies within the last two years (except carcinoma in situ of the cervix, non-metastatic prostate cancer, or basal cell or squamous cell carcinoma of the skin which were treated with local resection only; prior adjuvant androgen deprivation therapy in the case of prostate cancer is permitted, but current adjuvant androgen deprivation therapy is not).
  • Currently receiving any investigational agents.
  • A history of allergic reactions attributed to compounds of similar chemical or biologic composition to dexrazoxane or other agents used in the study.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, or psychiatric illness/social situations that would limit compliance with study requirements.
  • Pregnant and/or breastfeeding. Patient must have a negative pregnancy test within 14 days of study entry.
  • Known HIV-positivity on combination antiretroviral therapy because of the potential for pharmacokinetic interactions with dexrazoxane. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.
  • Prior treatment with anthracyclines.

Sites / Locations

  • Washington University School of Medicine

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Arm 1: dexrazoxane & standard of care doxorubicin

Arm 2: control (standard of care doxorubicin)

Arm Description

Dexrazoxane will be given intravenously on an outpatient basis over 15 minutes on each day that doxorubicin is given. Dexrazoxane should be given no more than 30 minutes prior to administration of doxorubicin, which is typically given on Day 1 of a 21-day cycle. Dosing is a 10:1 ratio of dexrazoxane to doxorubicin; doxorubicin is typically given at 75 mg/m2, so dexrazoxane dosing would be 750 mg/m2. In the event of a national shortage of dexrazoxane, 72-hour infusional doxorubicin can be used instead of dexrazoxane and bolus doxorubicin..

Doxorubicin is given as standard of care. Doxorubicin is typically given at 75 mg/m2 on Day 1 of a 21-day cycle. The last 10 patients enrolled after completion of enrollment to Arm 1 (dexrazoxane & standard of care doxorubicin) will be enrolled to Arm 2 (control arm - standard of care doxorubicin only)

Outcomes

Primary Outcome Measures

Progression-free survival (PFS) (Arm 1 only)
PFS is defined as the time from randomization to the first occurrence of progression or death, whichever occurs first. If no event exists, the PFS will be censored at the last scheduled disease assessment on study. Progressive disease - At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions).

Secondary Outcome Measures

Cardiac-related mortality
Measured using CTCAE Version 4.0
Incidence of heart failure or cardiomyopathy
Measured using CTCAE Version 4.0
Ability of 3D echocardiogram to serve as an early marker of cardiac dysfunction by measuring echocardiogram parameters of left ventricular ejection fraction by comparing to 2D echocardiogram modified Simpson's biplane method of LVEF
Left ventricular ejection fraction (LVEF) will be evaluated by 2D echocardiogram by modified Simpson's biplane method. Left ventricular systolic function will also be evaluated by 3D echocardiogram.
Ability of 3D echocardiogram to serve as an early marker of cardiac dysfunction by measuring echocardiogram parameters of ventricular strain by comparing to 2D echocardiogram modified Simpson's biplane method of LVEF
Left ventricular strain will be evaluated by 2D echocardiogram by evaluating the degree of shortening of the ventricular myocardium. Left ventricular strain will also be evaluated by 3D echocardiogram.

Full Information

First Posted
October 12, 2015
Last Updated
May 5, 2023
Sponsor
Washington University School of Medicine
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1. Study Identification

Unique Protocol Identification Number
NCT02584309
Brief Title
Doxorubicin With Upfront Dexrazoxane for the Treatment of Advanced or Metastatic Soft Tissue Sarcoma
Official Title
A Non-Inferiority Study of Doxorubicin With Upfront Dexrazoxane for the Treatment of Advanced or Metastatic Soft Tissue Sarcoma
Study Type
Interventional

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Completed
Study Start Date
February 22, 2016 (Actual)
Primary Completion Date
July 17, 2022 (Actual)
Study Completion Date
July 17, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Washington University School of Medicine

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this research study is to look at whether giving a drug called dexrazoxane with standard of care doxorubicin affects the progression of the disease. Dexrazoxane is often given at the same time as doxorubicin to help reduce the incidence and severity of disease of the heart muscle (which can be caused by doxorubicin). In January 2019 Eli Lilly and Company reported that the results of the Phase 3 study of olaratumab (Lartruvo), in combination with doxorubicin in patients with advanced or metastatic soft tissue sarcoma, did not confirm the clinical benefit of olaratumab in combination with doxorubicin as compared to doxorubicin alone. Therefore olaratumab is being removed from the front line standard of care regimen. Amendment #9 was made to the protocol to reflect these changes to the standard of care treatment.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Sarcoma, Soft Tissue, Soft Tissue Sarcoma, Undifferentiated Pleomorphic Sarcoma, Leiomyosarcoma, Liposarcoma, Synovial Sarcoma, Myxofibrosarcoma, Angiosarcoma, Fibrosarcoma, Malignant Peripheral Nerve Sheath Tumor, Epithelioid Sarcoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
73 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Arm 1: dexrazoxane & standard of care doxorubicin
Arm Type
Experimental
Arm Description
Dexrazoxane will be given intravenously on an outpatient basis over 15 minutes on each day that doxorubicin is given. Dexrazoxane should be given no more than 30 minutes prior to administration of doxorubicin, which is typically given on Day 1 of a 21-day cycle. Dosing is a 10:1 ratio of dexrazoxane to doxorubicin; doxorubicin is typically given at 75 mg/m2, so dexrazoxane dosing would be 750 mg/m2. In the event of a national shortage of dexrazoxane, 72-hour infusional doxorubicin can be used instead of dexrazoxane and bolus doxorubicin..
Arm Title
Arm 2: control (standard of care doxorubicin)
Arm Type
Active Comparator
Arm Description
Doxorubicin is given as standard of care. Doxorubicin is typically given at 75 mg/m2 on Day 1 of a 21-day cycle. The last 10 patients enrolled after completion of enrollment to Arm 1 (dexrazoxane & standard of care doxorubicin) will be enrolled to Arm 2 (control arm - standard of care doxorubicin only)
Intervention Type
Drug
Intervention Name(s)
Dexrazoxane
Other Intervention Name(s)
Zinecard®, Totect®
Intervention Type
Drug
Intervention Name(s)
Doxorubicin
Other Intervention Name(s)
Adriamycin, Hydroxydaunomycin Hydrochloride, Hydroxydoxorubicin Hydrochloride, Rubex
Primary Outcome Measure Information:
Title
Progression-free survival (PFS) (Arm 1 only)
Description
PFS is defined as the time from randomization to the first occurrence of progression or death, whichever occurs first. If no event exists, the PFS will be censored at the last scheduled disease assessment on study. Progressive disease - At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions).
Time Frame
Up to 5 years
Secondary Outcome Measure Information:
Title
Cardiac-related mortality
Description
Measured using CTCAE Version 4.0
Time Frame
Up to 12 months
Title
Incidence of heart failure or cardiomyopathy
Description
Measured using CTCAE Version 4.0
Time Frame
Up to 12 months
Title
Ability of 3D echocardiogram to serve as an early marker of cardiac dysfunction by measuring echocardiogram parameters of left ventricular ejection fraction by comparing to 2D echocardiogram modified Simpson's biplane method of LVEF
Description
Left ventricular ejection fraction (LVEF) will be evaluated by 2D echocardiogram by modified Simpson's biplane method. Left ventricular systolic function will also be evaluated by 3D echocardiogram.
Time Frame
Day 1 of each odd numbered cycle (estimated median of 4 cycles)
Title
Ability of 3D echocardiogram to serve as an early marker of cardiac dysfunction by measuring echocardiogram parameters of ventricular strain by comparing to 2D echocardiogram modified Simpson's biplane method of LVEF
Description
Left ventricular strain will be evaluated by 2D echocardiogram by evaluating the degree of shortening of the ventricular myocardium. Left ventricular strain will also be evaluated by 3D echocardiogram.
Time Frame
Day 1 of each odd numbered cycle (estimated median of 4 cycles)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Histologically confirmed grade 2 or 3 soft tissue sarcoma that is unresectable or metastatic. Surgery for primary or metastatic disease after chemotherapy following a response is allowed. Patients with the following tumor types are eligible: Undifferentiated pleomorphic sarcoma Leiomyosarcoma Malignant fibrous histiocytoma Liposarcoma (myxoid/round cell, pleomorphic or dedifferentiated) Synovial sarcoma Myxofibrosarcoma Angiosarcoma Fibrosarcoma Malignant peripheral nerve sheath tumor Epithelioid sarcoma Unclassified high-grade sarcoma (not otherwise specified) Soft tissue sarcoma for which treatment with an anthracycline is appropriate at the approval of the Principal Investigator (PI) Measurable disease according to RECIST 1.1; that is, measurable disease defined as lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 10 mm with CT scan, as ≥ 20 mm by chest x-ray, or ≥ 10 mm with calipers by clinical exam. Planning to initiate treatment with doxorubicin (starting dose 75 mg/m2) as routine care. Prior adjuvant chemotherapy with gemcitabine and/or docetaxel/paclitaxel is allowed. At least 18 years of age. ECOG performance status of 0 or 1 Adequate organ function defined as: Leukocytes ≥ 3,000/mcL Absolute neutrophil count ≥ 1,500/mcl Platelets ≥ 100,000/mcl Total bilirubin ≤ 1.5 x IULN AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN Creatinine ≤ IULN OR Creatinine clearance ≥ 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal. Creatinine clearance should be calculated using the actual weight from day 1 of cycle Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. Able to understand and willing to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable). Exclusion Criteria: Myocardial infarction within the past 12 months, or stable or unstable angina. Systolic heart failure defined as left ventricular ejection fraction ≤ 45%. Symptomatic valvular heart disease. Prior chemotherapy for advanced or metastatic disease. Known brain metastases. Prior or second primary malignancies within the last two years (except carcinoma in situ of the cervix, non-metastatic prostate cancer, or basal cell or squamous cell carcinoma of the skin which were treated with local resection only; prior adjuvant androgen deprivation therapy in the case of prostate cancer is permitted, but current adjuvant androgen deprivation therapy is not). Currently receiving any investigational agents. A history of allergic reactions attributed to compounds of similar chemical or biologic composition to dexrazoxane or other agents used in the study. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, or psychiatric illness/social situations that would limit compliance with study requirements. Pregnant and/or breastfeeding. Patient must have a negative pregnancy test within 14 days of study entry. Known HIV-positivity on combination antiretroviral therapy because of the potential for pharmacokinetic interactions with dexrazoxane. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated. Prior treatment with anthracyclines.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Brian A Van Tine, M.D., Ph.D.
Organizational Affiliation
Washington University School of Medicine
Official's Role
Principal Investigator
Facility Information:
Facility Name
Washington University School of Medicine
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Links:
URL
http://www.siteman.wustl.edu
Description
Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Learn more about this trial

Doxorubicin With Upfront Dexrazoxane for the Treatment of Advanced or Metastatic Soft Tissue Sarcoma

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