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

Study Overview
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Brief Summary
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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.

Official Title
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A Non-Inferiority Study of Doxorubicin With Upfront Dexrazoxane for the Treatment of Advanced or Metastatic Soft Tissue Sarcoma

Conditions
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Malignant Peripheral Nerve Sheath Tumor, Sarcoma, Soft Tissue, Soft Tissue Sarcoma, Undifferentiated Pleomorphic Sarcoma, Leiomyosarcoma, Liposarcoma, Synovial Sarcoma, Myxofibrosarcoma, Angiosarcoma, Fibrosarcoma, Epithelioid Sarcoma

Intervention / Treatment
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* Drug: Dexrazoxane
* Drug: Doxorubicin


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: Doxorubicin and Upfront Dexrazoxane<br>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.. | Drug: Dexrazoxane<br> <br> * Other names: Totect®;Drug: Doxorubicin<br> <br> * Other names: Rubex;|
| Active Comparator: Arm 2: control (Doxorubicin and Standard of Care Dexrazoxane)<br>Doxorubicin is given as standard of care. Doxorubicin is typically given at 75 mg/m2 on Day 1 of a 21-day cycle. Starting with cycle 5, standard of care dexrazoxane (75 mg/m2) will be given for 4 cycles. The last 10 patients enrolled after completion of enrollment to Arm 1 will be enrolled to Arm 2. | Drug: Dexrazoxane<br> <br> * Other names: Totect®;Drug: Doxorubicin<br> <br> * Other names: Rubex;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) (Arm 1 Only) | PFS is defined as the time from on study to the first occurrence of progression or death, whichever occurs first. If no event exists, the PFS will be censored at the last follow-up. 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). | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cardiac-related Mortality | Death due to cardiovascular while on study (heart failure, myocardial infarction, fatal arrhythmia). | Up to 12 months | 
| Percentage of Patients With Heart Failure or Cardiomyopathy | Cardiomyopathy is now referred to as cancer therapy related cardiac dysfunction (CTRCD) by the recent consensus statement of the International Cardio-Oncology Society. Moderate CTRCD is defined as >10% ejection fraction drop to <50%. Mild CTRCD is defined as drop in ≥15% ventricular strain or if no ventricular strain, a drop in ejection fraction of ≥50%. Heart failure is defined according to the recent Universal Definition and Classification of Heart Failure: A Report of the Heart Failure Society of America, Heart Failure Association of the European Society of Cardiology, Japanese Heart Failure Society and Writing Committee of the Universal Definition of Heart Failure. | Up to 12 months | 
| Ability of 3D Echocardiogram to Serve as an Early Marker of Cardiac Dysfunction Compared to 2D Echocardiogram Modified Simpson's Biplane Method of LVEF | Cardiac dysfunction for this outcome measure is defined as moderate cancer therapy related cardiac dysfunction (CTRCD) as assessed by 2D Echocardiogram Modified Simpson's Biplane Method of LVEF. Moderate CTRCD is defined as >10% ejection fraction drop to <50%. 3D echocardiograms were reviewed for evidence of cardiac dysfunction prior to onset of Moderate CTRCD by 2D echocardiogram. Dysfunction on 3D Echo was defined as >10% ejection fraction drop to <50%. | Baseline and day 1 of each odd numbered cycle (each cycle is 21 days) up to 1 year | 
| Early Detection of Cardiac Dysfunction by 2D Echocardiography Ventricular Strain Compared to 2D Echocardiography Ejection Fraction | Cardiac dysfunction for this outcome measure is defined as moderate cancer therapy related cardiac dysfunction (CTRCD) by 2D Echocardiogram Modified Simpson's Biplane Method of LVEF. Moderate CTRCD is defined as >10% ejection fraction drop to <50%. Patients were assessed for early evidence of dysfunction by strain defined as a relative drop in global longitudinal strain (GLS) by 15% and GLS > -17%. | Baseline and day 1 of each odd numbered cycle (each cycle is 21 days) up to 1 year |