Conditions: Sarcoma, Soft Tissue Soft Tissue Sarcoma Undifferentiated Pleomorphic Sarcoma Leiomyosarcoma Liposarcoma Synovial Sarcoma Myxofibrosarcoma Angiosarcoma Fibrosarcoma Malignant Peripheral Nerve Sheath Tumor Epithelioid Sarcoma
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 73
Healthy volunteers: no

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.

Detailed description:

Arms:
arm 1: * 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 2: * 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.

Interventions: intervention 1: Dexrazoxane intervention 2: Doxorubicin
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_SAP_000.pdf: 
Protocol Version: 11/01/19 
 
Page 1 of 41 
 
 
 
A Non-Inferiority Study of Doxorubicin with Upfront Dexrazoxane for the Treatment of 
Advanced or Metastatic Soft Tissue Sarcoma 
 
Washington University School of Medicine 
Division of Oncology 
660 South Euclid Avenue, Campus Box 8056 
St. Louis, MO  63110 
 
Protocol #: 201510049  
Version Date: 11/01/19 
 
Principal Investigator: 
 
Brian A. Van Tine, M.D., Ph.D. 
Phone:  (314) 747-8475 
E-mail:  bvantine@wustl.edu 
 
 
 
 
. 
 
Sub-Investigators 
 
 
Modality 
Ashley E. Frith, M.D.  
 
Medical Oncology 
Douglas R. Adkins, M.D. 
 
Medical Oncology 
Peter Oppelt, M.D.  
 
 
Medical Oncology 
Caron Rigden, M.D.   
 
Medical Oncology 
Angela Hirbe, M.D.   
 
Medical Oncology 
 
Jose Alvarez-Cardona, M.D.  
Cardiology 
John Gorcsan, M.D.  
 
Cardiology 
George Heberton, M.D. 
 
Cardiology 
Ronald J. Krone, M.D. 
 
Cardiology  
Daniel Lenihan, M.D   
 
Cardiology 
Joshua Mitchell M.D.  
 
Cardiology 
Justin Vader, M.D. 
 
 
Cardiology 
Kathleen Zhang, M.D.  
 
Cardiology 
Mitchell G. Scott PhD 
 
Pathology and Immunology  
Fei Wan, Ph.D. 
 
 
Biostatistics 
 
Study Drug(s): 
 
Dexrazoxane (Zinecard) 
 
ClinicalTrials.gov#: 
NCT02584309 
 
 
 
 
 


Protocol Version: 11/01/19 
 
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CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the extent necessary to 
obtain informed consent, may not be disclosed to another party unless law or regulations require such 
disclosure.  Persons to whom the information is disclosed must be informed that the information is 
confidential and may not be further disclosed by themA Non-Inferiority Study of Doxorubicin with 
Upfront Dexrazoxane for the Treatment of Advanced or Metastatic Soft Tissue Sarcoma 
 
Protocol Revision History 
 
Initial Approval Version 
 
 
 
 
 
 
08/28/15 
Amendment #1 Version 
 
 
 
 
 
 
12/22/15 
Amendment #2 Version 
 
 
 
 
 
 
06/21/16 
Amendment #3 Version 
 
 
 
 
 
 
10/17/16 
Amendment #4 Version 
 
 
 
 
 
 
12/22/16 
Amendment #5 Version 
 
 
 
 
 
 
06/26/17 
Amendment #6 Version 
 
 
 
 
 
 
08/01/17 
Amendment #7 Version 
 
 
 
 
 
 
01/26/18 
Amendment #8 Version 
 
 
 
 
 
 
10/04/18 
Amendment #9 Version 
 
 
 
 
 
 
02/04/19 
Amendment #10 Version 
 
 
 
 
 
 
11/01/19 


Protocol Version: 11/01/19 
 
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A Non-Inferiority Study of Doxorubicin with Upfront Dexrazoxane for the Treatment of 
Advanced or Metastatic Soft Tissue Sarcoma   
 
 
 
 


Protocol Version: 11/01/19 
 
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Glossary of Abbreviations 
AE 
Adverse event 
ALT (SGPT) 
Alanine transaminase (serum glutamate pyruvic transaminase) 
AST (SGOT) 
Aspartate transaminase (serum glutamic oxaloacetic transaminase) 
B-HCG 
Beta human chorionic gonadotropin  
BNP 
B-type natriuretic peptide 
CBC 
Complete blood count 
CMP 
Complete metabolic panel 
CR 
Complete response 
CRF 
Case report form 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
DNA 
deoxyribonucleic acid 
DSM 
Data and Safety Monitoring  
ECOG 
Eastern Cooperative Oncology Group 
EDTA 
ethylenediaminetetraacetic acid 
EORTC 
European Organisation for Research and Treatment of Cancer 
FDA 
Food and Drug Administration 
HIV 
Human Immunodeficiency Virus 
HRPO 
Human Research Protection Office (IRB) 
HRV 
Heart rate variability 
IRB 
Institutional Review Board 
IULN 
Institutional upper limit of normal 
LIIF 
Load independent index of filling 
LVEF 
Left ventricular ejection fraction 
MRI 
Magnetic resonance imaging 
NCI 
National Cancer Institute 
OHRP 
Office of Human Research Protections  
OS 
Overall survival 
PD 
Progressive disease 
PFS 
Progression-free survival 
PI 
Principal investigator 
PR 
Partial response 
QASMC 
Quality Assurance and Safety Monitoring Committee 
RECIST 
Response Evaluation Criteria in Solid Tumors (Committee) 
RNA 
Ribonucleic acid 
RR 
Response rate 
SAE 
Serious adverse event 
SD 
Stable disease 
UPN 
Unique patient number 
 


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Table of Contents 
 
1.0 
BACKGROUND AND RATIONALE ................................................................................ 7 
1.1 
Sarcoma ............................................................................................................................ 7 
1.2 
Treatment of Metastatic Sarcoma .................................................................................... 7 
1.3 
Anthracyclines .................................................................................................................. 7 
1.4 
Dexrazoxane (Zinecard) ................................................................................................... 8 
1.5 
Measurement of Cardiac Toxicity .................................................................................... 9 
1.6 
Amendment #3 – Addition of Olaratumab ..................................................................... 11 
1.7 
Amendment #9—Removal of Olaratumab .................................................................... 11 
2.0 
OBJECTIVES .................................................................................................................... 11 
2.1 
Primary Objective .......................................................................................................... 11 
2.2 
Secondary Objectives ..................................................................................................... 12 
3.0 
PATIENT SELECTION .................................................................................................... 12 
3.1 
Inclusion Criteria ............................................................................................................ 12 
3.2 
Exclusion Criteria ........................................................................................................... 13 
3.3 
Inclusion of Women and Minorities............................................................................... 14 
4.0 
REGISTRATION PROCEDURES ................................................................................... 14 
4.1 
Confirmation of Patient Eligibility ................................................................................. 14 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database ........................... 14 
4.3 
Assignment of UPN ....................................................................................................... 14 
5.0 
TREATMENT PLAN ........................................................................................................ 14 
5.1 
Agent Administration ..................................................................................................... 14 
5.2 
General Concomitant Medication and Supportive Care Guidelines .............................. 15 
5.3 
Women of Childbearing Potential .................................................................................. 15 
5.4 
Duration of Therapy ....................................................................................................... 15 
5.5 
Duration of Follow-up .................................................................................................... 16 
6.0 
DOSE DELAYS/DOSE MODIFICATIONS .................................................................... 16 
7.0 
REGULATORY AND REPORTING REQUIREMENTS ............................................... 16 
7.1 
Definitions ...................................................................................................................... 17 
7.2 
Reporting to the Human Research Protection Office (HRPO) at Washington University
 
18 
7.3 
Reporting to the Quality Assurance and Safety Monitoring Committee (QASMC) at 
Washington University .............................................................................................................. 19 
7.4 
Timeframe for Reporting Required Events .................................................................... 19 
8.0 
PHARMACEUTICAL INFORMATION .......................................................................... 19 
8.1 
Dexrazoxane (Zinecard) ................................................................................................. 19 
9.0 
CORRELATIVE STUDIES .............................................................................................. 21 
9.1 
Evaluation of Cardiac Function with Echocardiogram .................................................. 21 
9.2 
Measurement of High Sensitivity Troponin-I (hscTnI) and Galectin-3 ......................... 22 
9.3 
Measurement of Brain-type Natriuretic Peptide (BNP) ................................................. 22 
9.4 
Measurement of Topoisomerase II α and β ..................... Error! Bookmark not defined. 
9.5 
Heart Rate Variability .................................................................................................... 22 
10.0 STUDY CALENDAR ....................................................................................................... 23 
11.0 DATA SUBMISSION SCHEDULE ................................................................................. 23 
12.0 MEASUREMENT OF EFFECT........................................................................................ 26 


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12.1 Antitumor Effect – Solid Tumors................................................................................... 26 
12.2 Disease Parameters ......................................................................................................... 26 
12.3 Methods for Evaluation of Measurable Disease ............................................................ 27 
12.4 Response Criteria ........................................................................................................... 30 
13.0 DATA AND SAFETY MONITORING ............................................................................ 32 
14.0 STATISTICAL CONSIDERATIONS............................................................................... 33 
14.1 Study Design .................................................................................................................. 33 
14.2 Primary Endpoint ........................................................................................................... 33 
14.3 Secondary Endpoints ...................................................................................................... 34 
15.0 REFERENCES .................................................................................................................. 38 
APPENDIX A: ECOG Performance Status Scale ........................................................................ 41 
 
 


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1.0 
BACKGROUND AND RATIONALE 
 
1.1 
Sarcoma 
 
Sarcomas are a heterogeneous group of rare cancers that share a common mesenchymal 
origin.  Mesenchymal cells are derived from pluripotent embryonic connective tissue that 
differentiates into one or several lineages such as muscle, adipose, cartilage, nerves, 
vascular tissue, etc.  They are broadly divided into bone sarcomas and soft tissue sarcomas.  
The incidence of bone and soft tissue sarcomas in 2013 was 11,410 and 3,010, respectively 
1.  There are more than 50 histologic subtypes of soft tissue sarcomas, each with a 
distinctive clinical profile, response to treatment, and prognosis. 
 
1.2 
Treatment of Metastatic Sarcoma 
 
Generally, localized sarcoma is treated with surgery when feasible and adjuvant radiation 
with or without chemotherapy.  Like any other cancer, sarcomas have the ability for 
hematogenous spread to develop distant metastases.  For the majority of patients with 
metastatic soft tissue sarcoma, their cancer is incurable. Therefore, the goal of treatment is 
to reduce cancer bulk, minimize cancer related symptoms, improve quality of life, and 
increase overall survival.  Despite our best efforts, the median survival of patients with 
distant metastases is 11 to 15 months with approximately 20-25% of patients being alive 
at three years 2.   
 
Most cases of advanced soft tissue sarcoma are treated with conventional chemotherapy 
for palliation.  A common treatment regimen is single agent doxorubicin.  There have been 
many attempts to improve upon this treatment approach with dose intensification and 
combination therapies.  A randomized trial by EORTC Soft Tissue and Bone Sarcoma 
Group compared doxorubicin alone, doxorubicin plus ifosfamide, and a four-drug regimen 
of cyclophosphamide, vincristine, doxorubicin, and dacarbazine.  The combination 
treatment did not significantly improve overall survival (OS), progression-free survival 
(PFS), or response rate (RR), and these combination regimens were significantly more 
toxic 3.  Another randomized phase III trial evaluated single agent doxorubicin compared 
to doxorubicin plus ifosfamide in advanced or metastatic soft tissue sarcoma.  There was 
no significant difference in OS between the two treatment groups (median OS 12.8 months 
vs. 14.3 months, p=0.076).  The combination chemotherapy group had a significantly 
higher PFS (7.4 months vs. 4.6 months, p 0.003) and there was a higher overall response 
rate in the combination treatment arm (26% vs. 14%) 4.   
 
1.3 
Anthracyclines 
 
Doxorubicin is a commonly used chemotherapy classified as an anthracycline.  It is a 
natural product of a fungus, Streptomycoces peucetius var. caseius, with antitumor 
properties.  Anthracyclines have a tetracyclic ring structure attaches to a sugar and have 
quinone and hydroquinone moieties on adjacent rings that permit the gain and loss of 
electrons.   


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Anthracyclines have several mechanisms of antitumor activity.  They bind to DNA through 
intercalation to block the synthesis of DNA and RNA.  This leads to DNA strand scission.  
Another mechanism of cytotoxicity includes inhibiting topoisomerase II, resulting in 
impaired DNA repair.  Other major cellular enzymes affected by anthracyclines include 
DNA and RNA polymerase.  Another mechanism of cellular destruction is the generation 
of semiquinone free radicals and oxygen-free radical through an iron-dependent reductive 
process.  The presence of quinone group is to allow free radical to form and accumulate in 
normal and malignant cells.  These free radicals will not only damage malignant cells but 
is also thought to contribute to toxicity of normal tissue 5, 6.    
 
1.3.1 Cardiotoxicity and Anthracyclines 
 
The most concerning toxicity of anthracyclines is cardiotoxicity.  Anthracycline-
induced cardiotoxicity ranges from subclinical left ventricular dysfunction to 
severe cardiomyopathy with heart failure.  Cardiotoxicity may occur acutely within 
the first week of treatment, early within one year of completing therapy, or late after 
one year of completing anthracycline treatment.   
 
The cardiotoxic effects of doxorubicin have been well established in studies dating 
back decades 7, 8, 9. The estimated incidence of heart failure for patients on 
doxorubicin receiving a cumulative dose of 400-550 mg/m2 range widely from a 
relatively low 3-7% by Von Hoff et al 1979 to a significantly higher 27% by Speyer 
et al 1992. At higher doses around 1000 mg/m2 as many of half of patients may 
experience the cardiotoxic effects 10. 
 
The exact mechanism of anthracycline-induced cardiotoxicity is not entirely 
known.  It has traditionally been believed that the cardiotoxic effects of have been 
mediated by redox cycling and the generation of reactive oxygen species; newer 
evidence suggests that it may be specifically mediated by topoisomerase-IIβ in 
cardiac myocytes 11.  An additional mechanism may include accumulation of 
mitochondrial iron leading to increased reactive oxygen species inside the cardiac 
myocyte 12.   
 
1.4 
Dexrazoxane (Zinecard) 
 
Dexrazoxane is a derivative of ethylenediaminetetraacetic acid (EDTA) and acts as a free-
radical scavenger.  It chelates iron, reducing anthracycline-metal iron complexes and thus 
the formation of superoxide radicals 13, 14. It has been shown to drastically reduce the 
incidence of anthracycline-induced cardiomyopathy in breast cancer 15, 16, 17, 18 and 
sarcoma 19, 20. The use of dexrazoxane has gained widespread currency and is now 
considered standard of care in several treatment regimens for sarcoma and breast cancer.  
 
The effect of dexrazoxane on the efficacy of the chemotherapy regimen remains a topic of 
debate. Some studies of breast cancer patients undergoing the a multi-agent chemotherapy 
regimen known as FAC (a combination of 5-fluorouracil, doxorubicin, and 


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cyclophosphamide) have shown lower response rates in patients receiving dexrazoxane 17, 
prompting the FDA to limit its labeling to patients who have already received a cumulative 
dose of doxorubicin of 300 mg/m2. However, others have demonstrated no difference 17, 
21, and while a recent Cochrane review by Val Dalen et al have shown a non-significant 
trend towards decreased RR (p=0.08) there was virtually no difference in PFS (p=0.89) or 
OS (p=0.65) 22. Furthermore, other studies suggest that dexrazoxane may actually limit the 
development of resistance 23 and allow patients to receive greater total doses of doxorubicin 
16, 17. This has led some 24 to propose the initiation of dexrazoxane at doses of doxorubicin 
as low as 150 mg/m2. Nonetheless this has not been adopted by any of the major guideline 
writing groups. 
 
The overwhelming majority of these trials have been conducted in breast cancer patients, 
and there is little evidence either for or against its early use in sarcoma patients. Moreover, 
in most of the breast cancer trials, coadministration of doxorubicin and dexrazoxane with 
cyclophosphamide and 5-fluorouracil is common, creating a possible confounder not 
present in standard sarcoma regimens. As such, clinical trials are needed comparing the 
outcomes of early versus late administration of dexrazoxane in sarcoma patients. 
 
1.5 
Measurement of Cardiac Toxicity 
 
1.5.1 Decrease in Left Ventricular Ejection Fraction 
 
The use of echocardiography to measure left ventricular dysfunction is an evolving 
science. Currently the ejection fraction, measured on a 2D echocardiogram using 
echogenic contrast is commonly used to monitor cardiotoxicity. However, the 
interoperator variability is wide and the ejection fraction actually measures a late 
deterioration of LV function. In most cases of anthracycline cardiotoxicity, there 
are permanent changes in the myocardium structure before it is reflected in a 
reduced ejection fraction.  
 
There are three commonly used modalities for the measurement of left ventricular 
(LV) function by echocardiography, the modified Simpson’s biplane method, strain 
measures, and 3D echocardiography.  Of these, the oldest and most widely used in 
the Simpson’s biplane estimate. This method relies on the areas of elliptical discs 
drawn on the apical four chamber and apical two chamber views. The difference 
between the end-diastolic and end-systolic volumes is then used to calculate the 
ejection fraction. However, this method is imperfect and does not account for 
changes such as left ventricular hypertrophy which may see paradoxically elevated 
ejection fractions even in the presence of significant systolic dysfunction.  
 
In single center studies, calculating the ejection fraction using 3D 
echocardiography has been recommended to be a more consistent measure of LV 
function.  3D echocardiography has been around for decades, but only recently have 
advances in technology made this modality available for routine clinical use 25, 26. 
Several studies have demonstrated improved accuracy and reproducibility of 
ejection fractions calculated by the 3D echo compared to the traditional Simpson’s 


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biplane method 14, 27, 28. However, owing to its widespread use and common 
acceptance use as a standard measurement in most facilities, we propose a primary 
endpoint of LVEF by the modified Simpson’s biplane method.   
 
A more recently developed method measures left ventricular strain, strain rate, and 
peak myocardial velocity 29, 30, 31. This method uses 2D echocardiography to 
evaluate the degree of shortening of the ventricular myocardium using the apical 2-
, 3- and 4- chamber views. A recent systematic review by Thavendiranathan et al 
showed the efficacy of stain measurements as an early marker of LV dysfunction 
in patients undergoing anthracycline-based chemotherapy 32. 
 
Left ventricular diastolic dysfunction is a relatively recently identified clinical 
entity affecting nearly half of all patients with cardiac dysfunction. It is 
characterized by abnormal relaxation of the ventricle even in the presence of a 
preserved ejection fraction. Traditional methods of measuring diastolic function, 
including mitral inflow pulsed wave Doppler and pulmonary vein Doppler, are 
classified as load dependent, meaning that the measurements are dependent on and 
will vary with the filling pressure of the heart. More recently developed methods, 
including tissue Doppler imaging of the mitral annulus and color M-mode, are 
independent of this parameter and may vary less based on patient’s fluid status. 
These parameters will be measured and evaluated against the Ejection fraction 
endpoint again to determine if changes in diastolic function will be an early marker 
of depressed ejection fraction. 
 
In order to quality control these measurements, carried out in our clinical 
echocardiographic laboratory, the echocardiographic images will be also evaluated 
in our core echocardiographic laboratory. The clinical decisions will be based on 
the clinically obtained echocardiograms in consultation with a cardio-oncologist 
 
A separate measure of diastolic function, Load Independent Index of Filling, has 
been developed at Washington University 33, 34. This can be measured using a 
standard echocardiogram. We propose measuring this parameter on all 
echocardiograms obtained during the study and evaluating whether changes in the 
LIIF can be an early marker of LV systolic dysfunction. 
 
These more recent echogenic measures of LV function will be monitored to 
determine if they can predict LV deterioration as measured on the ejection fraction. 
 
1.5.2 Biomarkers as Measures of Cardiotoxicity 
 
Serum B-type natriuretic peptide (BNP), an endogenous hormone released in 
response to increased preload is established as a surrogate maker for heart failure 
35, 36.  
 
Cardiac troponin I, a cardiac myocyte protein and a marker for cardiac damage has 
long been used as marker for coronary ischemia 37, 38. A more recently developed 


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high sensitivity troponin I assay has the potential to reveal myocardial damage at a 
lower threshold than the current clinically used troponin.  It may also have the 
potential to detect patients at risk for developing cardiotoxicity long before it is 
manifested as a decrease in left ventricular ejection fraction on echocardiography. 
 
Galectin-3 (Gal-3), a soluble B-galactosidase-binding lectin, is produced by 
activated macrophages and induces cardiac fibroblasts to deposit type 1 
collagen.   Galectin-3 production is increased prior to and after the onset of heart 
failure (HF) and is believed to play a role in cardiac fibrosis.  Several studies have 
shown that elevated Galectin-3 serum concentrations are associated with an 
increased two year risk of HF following acute coronary syndrome, cumulative ten 
year incidence of HF in the Framingham Offspring Cohort, and 18 month survival 
among HF patients. 
 
Heart rate variability (HRV) is well known to provide information about the 
autonomic status of a patient, segregating patients with excessive sympathetic tone 
from those with excessive vagal tone 39. A reduced HRV has been shown to be 
correlated to autonomic dysfunction and increased overall mortality 40. It has also 
been used for prognostic purposes in some cancers 41, 42, 43. 
 
 
1.6 
Amendment #3 – Addition of Olaratumab 
 
In October 2016, olaratumab (Lartruvo) was approved by the FDA to be given in 
combination with doxorubicin for the treatment of soft tissue sarcomas with a histologic 
subtype for which an anthracycline-containing regimen is appropriate and which is not 
amenable to curative treatment with radiotherapy or surgery.  Amendment #3 was made to 
the protocol to allow patients to receive this new standard of care treatment. 
 
1.7 
Amendment #9—Removal of Olaratumab 
 
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.  Section 9.1 was also 
updated to clarfiy 9.1 the evaluation of cardiac function using echocardiogram and the 
addition of 10 sarcoma banking protocol #201203042 participants to be used as controls in 
the secondary objectives analysis. 
  
 
 
2.0 
OBJECTIVES 
 
2.1 
Primary Objective 


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To determine progression-free survival (PFS) in patients with metastatic soft tissue 
sarcoma who are treated with doxorubicin in combination with dexrazoxane. 
 
2.2 
Secondary Objectives 
 
1. To determine cardiac-related mortality in patients with metastatic soft tissue sarcoma 
who are treated with doxorubicin in combination with dexrazoxane. 
 
2. To determine incidence of heart failure or cardiomyopathy in patients with metastatic 
soft tissue sarcoma who are treated with doxorubicin in combination with dexrazoxane. 
 
3. To evaluate additional echocardiogram parameters of left ventricular ejection fraction 
to determine if either 3D echocardiogram or ventricular strain is able to serve as an 
early marker of cardiac dysfunction compared to 2d echocardiogram modified 
Simpson’s biplane method of LVEF. 
 
 
3.0 
PATIENT SELECTION 
 
At least 57 but up to 65 patients will be enrolled in this study to receive dexrazoxane concurrently 
with standard of care doxorubicin.  At the completion of accrual, an additional 10 patients meeting 
the eligibility criteria below will be enrolled as a control group for the correlative studies as there 
is no baseline data for these tests; these patients will receive institutional standard of care therapy. 
 
3.1 
Inclusion Criteria 
 
1. 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: 
a. Undifferentiated pleomorphic sarcoma  
b. Leiomyosarcoma 
c. Malignant fibrous histiocytoma 
d. Liposarcoma (myxoid/round cell, pleomorphic or dedifferentiated) 
e. Synovial sarcoma 
f. Myxofibrosarcoma 
g. Angiosarcoma 
h. Fibrosarcoma 
i. Malignant peripheral nerve sheath tumor 
j. Epithelioid sarcoma 
k. Unclassified high-grade sarcoma (not otherwise specified) 
l. Soft tissue sarcoma for which treatment with an anthracycline is appropriate at the 
approval of the PI 
2. 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 


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be recorded) as ≥ 10 mm with CT scan, as ≥ 20 mm by chest x-ray, or ≥ 10 mm with 
calipers by clinical exam. 
3. Planning to initiate treatment with doxorubicin (starting dose of 75 mg/m2) as routine 
care. 
4. Prior adjuvant chemotherapy with gemcitabine and/or docetaxel/paclitaxel is allowed.  
5. At least 18 years of age. 
6. ECOG performance status of 0 or 1 (see Appendix A). 
7. Adequate organ function defined as:  
a. Leukocytes ≥ 3,000/mcL 
b. Absolute neutrophil count ≥ 1,500/mcl 
c. Platelets ≥ 100,000/mcl 
d. Total bilirubin ≤ 1.5 x IULN 
e. AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN 
f. Creatinine ≤ IULN OR creatinine clearance ≥ 60 mL/min/1.73 m2 for patients 
with creatinine levels above institutional normal. Creatinine clearance should 
be calculated using the actual weight from day 1 of the cycle 
8. 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. 
9. Able to understand and willing to sign an IRB approved written informed consent 
document (or that of legally authorized representative, if applicable). 
 
3.2 
Exclusion Criteria 
 
1. Myocardial infarction within the past 12 months, or stable or unstable angina. 
2. Systolic heart failure defined as left ventricular ejection fraction ≤ 45%. 
3. Symptomatic valvular heart disease. 
4. Prior chemotherapy for advanced or metastatic disease. 
5. Known brain metastases.   
6. 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). 
7. Currently receiving any investigational agents. 
8. A history of allergic reactions attributed to compounds of similar chemical or biologic 
composition to dexrazoxane or other agents used in the study. 
9. 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. 
10. Pregnant and/or breastfeeding.  Patient must have a negative pregnancy test within 14 
days of study entry. 
11. Known HIV-positivity on combination antiretroviral therapy because of the potential 
for pharmacokinetic interactions with dexrazoxane.  In addition, these patients are at 


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increased risk of lethal infections when treated with marrow-suppressive therapy.  
Appropriate studies will be undertaken in patients receiving combination antiretroviral 
therapy when indicated. 
12. Prior treatment with anthracyclines. 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this trial. 
 
 
4.0 
REGISTRATION PROCEDURES 
 
Patients must not start any protocol intervention prior to registration through the Siteman 
Cancer Center. 
 
The following steps must be taken before registering patients to this study: 
 
1. Confirmation of patient eligibility 
2. Registration of patient in the Siteman Cancer Center OnCore database 
3. Assignment of unique patient number (UPN) 
 
4.1 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility by collecting the information listed below: 
 
1. Registering MD’s name 
2. Patient’s race, sex, and DOB 
3. Three letters (or two letters and a dash) for the patient’s initials 
4. Copy of signed consent form 
5. Completed eligibility checklist, signed and dated by a member of the study team 
6. Copy of appropriate source documentation confirming patient eligibility 
 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database 
 
All patients must be registered through the Siteman Cancer Center OnCore database. 
 
4.3 
Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study.  All data 
will be recorded with this identification number on the appropriate CRFs. 
 
 
5.0 
TREATMENT PLAN 
 
5.1 
Agent Administration 
 


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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 will be started at 75 
mg/m2, so dexrazoxane dosing would be 750 mg/m2.  Doxorubicin is being given as routine 
care; the administration is not dictated per protocol.  Patients who are enrolled in the control 
group will receive institutional standard of care therapy. 
 
In the event of a national shortage of dexrazoxane, 72-hour infusional doxorubicin can be 
used instead of dexrazoxane and bolus doxorubicin. 
 
5.2 
General Concomitant Medication and Supportive Care Guidelines 
 
Premedications and supportive care may be given routinely as needed to prevent or treat 
doxorubicin-related toxicities or adverse reactions. 
 
5.3 
Women of Childbearing Potential 
 
Women of childbearing potential (defined as women with regular menses, women with 
amenorrhea, women with irregular cycles, women using a contraceptive method that 
precludes withdrawal bleeding, and women who have had a tubal ligation) are required to 
have a negative pregnancy test within 14 days prior to the first dose of study treatment.   
 
Female and male patients (along with their female partners) are required to use two forms 
of acceptable contraception, including one barrier method, during participation in the study 
and for one month following the last dose of study treatment.  
 
If a patient is suspected to be pregnant, study treatment should be immediately 
discontinued.  In addition a positive urine test must be confirmed by a serum pregnancy 
test.  If it is confirmed that the patient is not pregnant, the patient may resume dosing. 
 
If a female patient or female partner of a male patient becomes pregnant during therapy or 
within one month after the last dose of study treatment, the investigator must be notified in 
order to facilitate outcome follow-up. 
 
5.4 
Duration of Therapy 
 
If at any time the constraints of this protocol are considered to be detrimental to the 
patient’s health and/or the patient no longer wishes to continue protocol therapy, the 
protocol therapy should be discontinued and the reason(s) for discontinuation documented 
in the case report forms. 
 
In the absence of treatment delays due to adverse events, treatment with dexrazoxane may 
continue as long as treatment with doxorubicin continues or until one of the following 
criteria applies: 
 


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• Documented and confirmed disease progression 
• Death 
• Adverse event(s) that, in the judgment of the investigator, may cause severe or 
permanent harm or which rule out continuation of study drug 
• General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator 
• Suspected pregnancy 
• Serious non-compliance with the study protocol 
• Lost to follow-up 
• Patient withdraws consent 
• Investigator removes the patient from study 
• The Siteman Cancer Center decides to close the study 
 
Patients who prematurely discontinue treatment for any reason will be followed as 
indicated in the study calendar. 
 
5.5 
Duration of Follow-up 
 
Patients will be followed every 3 months for up to five years or until death, whichever 
occurs first.  Patients removed from study for unacceptable adverse events will be followed 
until resolution or stabilization of the adverse event. Patients who go off study due to 
toxicities will be followed until progression of their disease. 
 
 
6.0 
DOSE DELAYS/DOSE MODIFICATIONS 
 
Dosing of dexrazoxane should be consistent with dosing of doxorubicin to maintain the 10:1 ratio; 
if dosing of doxorubicin is reduced as part of the patient’s routine care, dosing of dexrazoxane 
should be reduced proportionally. 
 
Dosing of dexrazoxane should be reduced in patients with moderate to severe renal impairment 
(creatinine clearance levels < 40 mL/min) by 50%, i.e., reducing the dexrazoxane to doxorubicin 
ratio from 10:1 to 5:1. 
 
In the event of a national shortage of dexrazoxane, 72-hour infusional doxorubicin can be used in 
place of dexrazoxane and bolus doxorubicin. 
 
All dose reductions should be discussed with the Principal Investigator.  
 
 
 
7.0 
REGULATORY AND REPORTING REQUIREMENTS 
 
The entities providing oversight of safety and compliance with the protocol require reporting as 
outlined below. 
 


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The Washington University Human Research Protection Office (HRPO) requires that all events 
meeting the definition of unanticipated problem or serious noncompliance be reported as outlined 
in Section 7.2. 
 
7.1 
Definitions 
 
7.1.1 Adverse Events (AEs) 
 
Definition: any unfavorable medical occurrence in a human subject including any 
abnormal sign, symptom, or disease.  For the purposes of this study, adverse events 
related to doxorubicin are not considered reportable. However, all AEs will be 
tracked in OnCore. For purposes of data collection, the study drug is dexrazoxane.   
 
Grading: the descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for 
all toxicity reporting.  A copy of the CTCAE version 4.0 can be downloaded from 
the CTEP website. 
 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for the 
terms listed that should be used are those provided by the Department of Health 
and Human Services’ Office for Human Research Protections (OHRP).  A copy of 
this guidance can be found on OHRP’s website: 
http://www.hhs.gov/ohrp/policy/advevntguid.html 
 
7.1.2 Serious Adverse Event (SAE) 
 
Definition:  any adverse drug experience occurring at any dose that results in any 
of the following outcomes: 
 Death 
 A life-threatening adverse drug experience 
 Inpatient hospitalization or prolongation of existing hospitalization 
 A persistent or significant disability/incapacity (i.e., a substantial disruption 
of a person’s ability to conduct normal life functions) 
 A congenital anomaly/birth defect 
 Any other experience which, based upon appropriate medical judgment, 
may jeopardize the subject and may require medical or surgical intervention 
to prevent one of the outcomes listed above 
 
7.1.3 Unexpected Adverse Experience 
 
Definition: any adverse drug experience, the specificity or severity of which is not 
consistent with the current investigator brochure (or risk information, if an IB is not 
required or available). 
 
7.1.4 Life-Threatening Adverse Experience  
 


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Definition: any adverse drug experience that places the subject (in the view of the 
investigator) at immediate risk of death from the reaction as it occurred, i.e., it does 
not include a reaction that, had it occurred in a more severe form, might have caused 
death. 
 
7.1.5 Unanticipated Problems 
 
Definition: 
 
• unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
• related or possibly related to participation in the research (“possibly related” 
means there is a reasonable possibility that the incident, experience, or outcome 
may have been caused by the procedures involved in the research); and 
• suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
 
7.1.6 Noncompliance 
 
Definition: failure to follow any applicable regulation or institutional policies that 
govern human subjects research or failure to follow the determinations of the 
IRB.  Noncompliance may occur due to lack of knowledge or due to deliberate 
choice to ignore regulations, institutional policies, or determinations of the IRB. 
 
7.1.7 Serious Noncompliance 
 
Definition: noncompliance that materially increases risks, that results in substantial 
harm to subjects or others, or that materially compromises the rights or welfare of 
participants. 
 
7.1.8 Protocol Exceptions 
 
Definition: A planned deviation from the approved protocol that are under the 
research team’s control. Exceptions apply only to a single participant or a singular 
situation. 
 
Pre-approval of all protocol exceptions must be obtained prior to the event. 
 
7.2 
Reporting to the Human Research Protection Office (HRPO) at Washington 
University 
 
The PI is required to promptly notify the IRB of the following events: 
 


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• Any unanticipated problems involving risks to participants or others which occur 
at WU, any BJH or SLCH institution, or that impacts participants or the conduct of 
the study. 
• Noncompliance with federal regulations or the requirements or determinations of 
the IRB. 
• Receipt of new information that may impact the willingness of participants to 
participate or continue participation in the research study. 
 
These events must be reported to the IRB within 10 working days of the occurrence of the 
event or notification to the PI of the event.  The death of a research participant that qualifies 
as a reportable event should be reported within 1 working day of the occurrence of the 
event or notification to the PI of the event. 
 
7.3 
Reporting to the Quality Assurance and Safety Monitoring Committee 
(QASMC) at Washington University 
 
The PI is required to notify the QASMC of any unanticipated problem occurring at WU or 
any BJH or SLCH institution that has been reported to and acknowledged by HRPO as 
reportable.  (Unanticipated problems reported to HRPO and withdrawn during the review 
process need not be reported to QASMC). 
 
QASMC must be notified within 10 days of receipt of IRB acknowledgment via email to 
a QASMC auditor. 
 
7.4 
Timeframe for Reporting Required Events  
 
Adverse events will be tracked for 30 days following the last day of study treatment.  For 
the purposes of this protocol, adverse events considered possibly, probably, or definitely 
related to doxorubicin are not reportable. 
 
 
8.0 
PHARMACEUTICAL INFORMATION 
 
8.1 
Dexrazoxane (Zinecard) 
 
In the event of a national shortage of dexrazoxane, 72-hour infusional doxorubicin can be 
used in place of dexrazoxane and bolus doxorubicin. 
 
8.1.1 Dexrazoxane Description 
 
Dexrazoxane is a cardioprotective agent for use in conjunction with doxorubicin.  
Chemically, 
dexrazoxane 
is 
(S)-4,4’-(1-methyl-1,2-ethanediyl)bis-2,6-
piperazinedione.  The molecular formula is C11H16N4O4, and its molecular weight 
is 268.28. 
 
8.1.2 Clinical Pharmacology 


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The mechanism by which dexrazoxane exerts its cytoprotective activity is not fully 
understood.  Dexrazoxane is a cyclic derivative of EDTA that penetrates cell 
membranes.  Results of laboratory studies suggest that dexrazoxane is converted 
intracellularly to a ring-opened chelating agent that interferes with iron-mediated 
free radical generation thought to be responsible, in part, for anthracycline-induced 
cardiomyopathy. 
 
8.1.3 Pharmacokinetics and Drug Metabolism 
 
The pharmacokinetics of dexrazoxane can be adequately described by a two-
compartment open model with first-order elimination.  The mean peak plasma 
concentration of dexrazoxane was 36.5 µg/mL at 15 minutes after intravenous 
administration of 500 mg/m2 of dexrazoxane. 
 
Qualitative metabolism studies have confirmed the presence of unchanged drug, a 
diacid-diamide cleavage product, and two monoacid-monoamide ring products in 
the urine of animals and man. 
 
8.1.4 Supplier(s) 
 
Dexrazoxane is available commercially and will be billed as standard of care. 
 
8.1.5 Dosage Form and Preparation 
 
Dexrazoxane is available as 250 mg or 500 mg single dose vials as sterile, pyrogen-
free lyophilizates. 
 
Reconstitute dexrazoxane with Sterile Water for Injection, USP. Reconstitute with 
25 mL for a dexrazoxane 250 mg vial and 50 mL for a dexrazoxane 500 mg vial to 
give a concentration of 10 mg/mL. Dilute the reconstituted solution further with 
Lactated Ringer’s Injection, USP to a concentration of 1.3 to 3.0 mg/mL in 
intravenous infusion bags for intravenous infusion. 
 
Parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration, whenever solution and container permit. 
Solutions containing a precipitate should be discarded. 
 
8.1.6 Storage and Stability 
 
Reconstituted dexrazoxane for injection, when transferred to an empty infusion 
bag, is stable for 6 hours from the time of reconstitution when stored at controlled 
room temperature, 20° to 25°C (68° to 77°F) or under refrigeration, 2° to 8°C (36° 
to 46°F). DISCARD UNUSED SOLUTIONS. The reconstituted dexrazoxane for 
injection solution may be diluted with either 0.9% Sodium Chloride Injection, USP 
or 5% Dextrose Injection, USP to a concentration range of 1.3 to 5 mg/mL in 


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intravenous infusion bags. The resultant solutions are stable for 6 hours when stored 
at controlled room temperature, 20° to 25°C (68° to 77°F) or under refrigeration, 
2° to 8°C (36° to 46°F). DISCARD UNUSED SOLUTIONS. 
 
8.1.7 Administration 
 
Administer the final diluted solution of dexrazoxane by intravenous infusion over 
15 minutes before the administration of doxorubicin. DO NOT ADMINISTER VIA 
AN INTRAVENOUS PUSH. Administer doxorubicin within 30 minutes after the 
completion of dexrazoxane infusion. 
 
8.1.8 Special Handling Instructions 
 
Use caution when handling and preparing the reconstituted solution. The use of 
gloves is recommended. If dexrazoxane powder or solutions contact the skin or 
mucosae, wash exposed area immediately and thoroughly with soap and water. 
Follow special handling and disposal procedures. 
 
 
9.0 
CORRELATIVE STUDIES 
 
9.1 
Evaluation of Cardiac Function with Echocardiogram 
 
Patients receiving dexrazoxane will undergo cardiac evaluation with echocardiograms 
every six weeks to evaluate for cardiac function.   
 
Left ventricular ejection fraction (LVEF) will be evaluated by 2D echocardiogram by 
modified Simpson’s biplane method will be provided to investigators within two days of 
the evaluation.  Treatment decisions regarding cardiac safety will be determined by a 
decrease in LVEF by 2D echocardiogram (modified Simpson’s biplane method) based on 
the clinical reading. 
 
In addition, cardiac function will be evaluated using these images and interpreted by offline 
research echocardiographic laboratory and this interpretation will not be made available to 
the treating physicians, however the PI will have access for non-clinical purposes.  Left 
ventricular systolic function will also be evaluated by 3D echocardiogram when technically 
possible.     
 
Left ventricular diastolic function will be evaluated by mitral inflow pulsed wave Doppler 
to evaluate the mitral E velocity, mitral E deceleration time and mitral A velocity.  Tissue 
Doppler imaging of the mitral annulus will also be evaluated.  Load Independent Index of 
Filling (LIIF) will be measured. It should be noted that this has never been done outside a 
research laboratory. This measurement in this part of the protocol is experimental. 
 
Right ventricular systolic function will be measured and cardiac valves will be evaluated. 
The additional cardiac measurements, specifically 3D echocardiogram calculated ejection 


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fraction, left ventricular strain, will be used to evaluate for an early or more precise 
measurement of cardiac dysfunction.    
 
Additional controls for these analyses will be collected from the sarcoma banking study 
(HRPO #201203042) under a waiver of consent. Identifiers will be collected in order to 
perform the chart review. The chart review will be performed to assess for cardiac function 
and symptomatic heart failure. 
   
9.2 
Measurement of High Sensitivity Troponin-I (hscTnI) and Galectin-3 
 
Blood will be drawn with pre-clinic blood work and 4 hours after doxorubicin exposure 
with each cycle of chemotherapy (collected at baseline and Day 1 of every cycle for control 
group up to Cycle 6). Ten mL of whole blood should be drawn into an EDTA tube.  Blood 
samples will be sent to the lab of Mitchell Scott in pathology to be run in large batches.          
 
9.3 
Measurement of Brain-type Natriuretic Peptide (BNP) 
 
Patients receiving dexrazoxane will have blood drawn to measure BNP.  Blood will be 
drawn in an EDTA (lavender top) tube as a baseline measurement before Cycle 1 and then 
after a cumulative dose of 300mg/m2 of doxorubicin. In patients continuing to receive 
doxorubicin after a cumulative dose of 300mg/m2, a BNP will be measured every 6 weeks.  
A total of 2mL of blood needs to be collected in each EDTA tube or the lab may be added 
onto a basic metabolic panel or complete metabolic panel if done prior to chemotherapy.  
BNPs will be performed as a clinical test to evaluate early appearance of cardiac toxicity 
and clinically relevant LV systolic deterioration. An increase of BNP above normal or 
baseline will trigger additional evaluation of cardiac function (another echocardiogram) 
and possibly evaluation by cardiology per treating oncologist’s discretion.   
 
 
9.4 
Heart Rate Variability 
 
All patients receiving dexrazoxane will be wear a small, 3-channel Holter monitor 
(MyPatch,® DMS Holter, Stateside, CA) to record their continuous 24 hour 
electrocardiogram in order to examine their cardiac rhythm and measure heart rate 
variability (HRV). The patch recorder will be placed at the time of the baseline, 6 week 
and subsequent clinical echocardiograms by a cardiac tech in the north CDL. Patients will 
be instructed to remove the myPatch recorder after 24 hours.  It should then be placed in 
an envelope provided by the study and FedEx pick-up.  Once the HRV devices have been 
returned to the Washington University Cardiology Department, recordings will be scanned 
by the research technician at the HRV Lab and then overread for scanning accuracy by Dr. 
Phyllis Stein, Director of the HRV Lab.  If any clinical abnormalities are seen on the Holter 
recording, Dr. Ron Krone will be notified and a copy of the Holter report provided to him.   
 
 
 


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10.0 
STUDY CALENDAR 
 
 
10.1 
DEXRAZOXANE ARM 
 
Baseline/screening procedures may take place up to 14 days prior to the start of treatment, except 
consent and scans (including the echocardiogram and Holter monitor), which may take place up 
to 28 days prior to the start of treatment.   
 
 
Baseline / 
Screening 
Day 1 of 
Each Cycle 
Day 1 of Each 
Odd-Numbered 
Cycle6 
End of Each 
Even-Numbered 
Cycle 
EOT F/U3 
Informed consent 
X 
 
 
 
 
 
H&P, ECOG PS 
X 
 
 
 
X 
X 
CBC 
X 
 
 
 
 
 
CMP 
X 
 
 
 
 
 
β-hCG1 
X 
 
 
 
 
 
2D and 3D echocardiogram 
X 
 
X7 
 
 
 
CT C/A/P 
X 
 
 
X 
X 
 
Dexrazoxane4 
 
X 
 
 
 
 
Blood for hscTnI and galectin-3 
 
X5 
 
 
 
 
Blood for BNP2 
X 
After cumulative dose of 300 mg/m2 of doxorubicin, 
and then every 6 weeks thereafter 
 
 
24-hour Holter monitor 
X 
 
X 
 
 
 
AE assessment 
X ------------------------------------------------------------------------ X 
 
1. Women of childbearing potential only 
2. Can be drawn with a BMP or CMP if being drawn for routine pre-doxorubicin labs 
3. Every 3 months for up to 5 years; Patients who are removed for reasons other than progression will be followed 
until standard of care imaging shows progression per RECIST 1.1.  
4. No more than 30 minutes before SOC doxorubicin 
5. With SOC pre-treatment bloodwork and 4 hours post-doxorubicin 
6. Except Cycle 1 
7. -3 day window to allow for the echo to be read prior to the start of the next cycle 
 
 
 
 


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10.2 
CONTROL ARM 
Baseline/screening procedures may take place up to 14 days prior to the start of treatment, except 
consent and scans (including the echocardiogram and Holter monitor), which may take place up 
to 28 days prior to the start of treatment.   
 
 
 
Baseline / 
Screening 
Day 1 of 
Each Cycle 
Day 1 of Each 
Odd-Numbered 
Cycle6 
End of Each 
Even-Numbered 
Cycle 
EOT F/U3 
Informed consent 
X 
 
 
 
 
 
H&P, ECOG PS 
X 
 
 
 
X 
X 
CBC 
X 
 
 
 
 
 
CMP 
X 
 
 
 
 
 
β-hCG1 
X 
 
 
 
 
 
2D and 3D echocardiogram 
X 
 
X7 
 
 
 
CT C/A/P 
X 
 
 
X 
X 
 
Dexrazoxane4 
Given as SOC at cycle 5 or a cumulative dose of 350 mg/m2 
Blood for hscTnI and galectin-3 
X 
X5 
 
 
 
 
Blood for BNP2 
X 
After cumulative dose of 300 mg/m2 of doxorubicin, 
and then every 6 weeks thereafter 
 
 
24-hour Holter monitor 
X 
 
X 
 
 
 
AE assessment 
X ------------------------------------------------------------------------ X 
 
1. Women of childbearing potential only 
2. Can be drawn with a BMP or CMP if being drawn for routine pre-doxorubicin labs 
3. Every 3 months for up to 5 years. Patients who are removed for reasons other than progression will be followed 
until standard of care imaging shows progression per RECIST 1.1.  
4. No more than 30 minutes before SOC doxorubicin 
5. With SOC pre-treatment bloodwork and 4 hours post-doxorubicin up until cycle 6 
6. Except Cycle 1 
7. -3 day window to allow for the echo to be read prior to the start of the next cycle 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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11.0 
DATA SUBMISSION SCHEDULE 
 
Case report forms with appropriate source documentation will be completed according to the 
schedule listed in this section. 
 
Case Report Form 
Submission Schedule 
Original Consent Form 
Prior to registration 
On-Study Form 
Prior to starting treatment 
Treatment Form 
Every cycle 
Toxicity Form 
Continuous 
Treatment Summary Form 
Completion of treatment 
Follow Up Form 
Every 3 months for up to 5 years 
Tumor Measurement Form 
Baseline, end of every even numbered cycles, EOT, and for all 
standard of care disease assessments done during follow up 
until documented progression. 
Echocardiogram & Holter 
Monitor Form 
Baseline, and Day 1 of every odd-numbered cycle starting with 
Cycle 3 
hscTNI & Galectin-3 Form 
Day 1 of every cycle 
BNP Form 
Baseline and Day 1 of every odd-numbered cycle starting with 
Cycle 5 
 
 
 
 
12.0 
MEASUREMENT OF EFFECT 
 
12.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every 6 weeks.  
In addition to a baseline scan, confirmatory scans should also be obtained not less than 4 
weeks following initial documentation of objective response. 
 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) 
guideline (version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter 
(unidimensional measurement) of the tumor lesions and the shortest diameter in the case 
of malignant lymph nodes are used in the RECIST criteria. 
 
12.2 
Disease Parameters 
 
Measurable disease:  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as >20 mm by chest 
x-ray, as >10 mm with CT scan, or >10 mm with calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Malignant lymph nodes:  To be considered pathologically enlarged and measurable, a 


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lymph node must be >15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed. 
 
Non-measurable disease:  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-measurable) since 
they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 
Target lesions:  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target lesions 
and recorded and measured at baseline.  Target lesions should be selected on the basis of 
their size (lesions with the longest diameter), be representative of all involved organs, but 
in addition should be those that lend themselves to reproducible repeated measurements.  
It may be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion which can be measured 
reproducibly should be selected.  A sum of the diameters (longest for non-nodal lesions, 
short axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters.  If lymph nodes are to be included in the sum, then only the short 
axis is added into the sum.  The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease. 
 
Non-target lesions:  All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should 
also be recorded at baseline.  Measurements of these lesions are not required, but the 
presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 
12.3 
Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 


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evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions:  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed 
using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI:  This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less.  If CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.  MRI is also acceptable in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the evaluation of the 
type and site of disease.  Furthermore, as with CT, the modality used at follow-up should 
be the same as was used at baseline and the lesions should be measured/assessed on the 
same pulse sequence.  It is beyond the scope of the RECIST guidelines to prescribe specific 
MRI pulse sequence parameters for all scanners, body parts, and diseases.  Ideally, the 
same type of scanner should be used and the image acquisition protocol should be followed 
as closely as possible to prior scans.  Body scans should be performed with breath-hold 
scanning techniques, if possible. 
 
PET-CT:  At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a PET-
CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then 
the CT portion of the PET-CT can be used for RECIST measurements and can be used 
interchangeably with conventional CT in accurately measuring cancer lesions over time.  
Note, however, that the PET portion of the CT introduces additional data which may bias 
an investigator if it is not routinely or serially performed.   
 
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement.  Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next.  If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised.  If there is concern about radiation exposure 
at CT, MRI may be used instead of CT in selected instances. 
 


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Endoscopy, Laparoscopy:  The utilization of these techniques for objective tumor 
evaluation is not advised.  However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers:  Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered 
in complete clinical response.  Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and PSA response (in recurrent prostate cancer) have been published [JNCI 
96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008].  
In addition, the Gynecologic Cancer Intergroup has developed CA-125 progression criteria 
which are to be integrated with objective tumor assessment for use in first-line trials in 
ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology:  These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or stable 
disease is mandatory to differentiate between response or stable disease (an effusion may 
be a side effect of the treatment) and progressive disease. 
 
FDG-PET:  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm:  
 
• Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
• No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this 
is PD.  If the positive FDG-PET at follow-up is not confirmed as a new site of 
disease on CT, additional follow-up CT  scans are needed to determine if there is 
truly progression occurring at that site (if so, the date of PD will be the date of the 
initial abnormal FDG-PET scan).  If the positive FDG-PET at follow-up 
corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD. 
• FDG-PET may be used to upgrade a response to a CR in a manner similar to a 
biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring.  The use of FDG-PET in this circumstance should be 
prospectively described in the protocol and supported by disease-specific medical 
literature for the indication.  However, it must be acknowledged that both 
approaches may lead to false positive CR due to limitations of FDG-PET and 
biopsy resolution/sensitivity. 
  


Protocol Version: 11/01/19 
 
Page 30 of 41 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
12.4 
Response Criteria 
 
12.4.1 Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm. 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  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). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
12.4.2 Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph nodes must be non-pathological 
in size (<10 mm short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the 
opinion of the treating physician should prevail in such circumstances, and the 
progression status should be confirmed at a later time by the review panel (or 
Principal Investigator). 
 


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12.4.3 Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started).  The 
patient's best response assignment will depend on the achievement of both 
measurement and confirmation criteria. 
    
For Patients with Measurable Disease (i.e., Target Disease) 
Target Lesions Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
Note: Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be reported 
as “symptomatic deterioration.”  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
                                      For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since 
SD is increasingly used as an endpoint for assessment of efficacy in some trials so to 
assign this category when no lesions can be measured is not advised 
 
 
 
 


Protocol Version: 11/01/19 
 
Page 32 of 41 
 
12.4.4 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements recorded 
since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first 
met for CR until the first date that progressive disease is objectively documented.  
 
Duration of stable disease:  Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the smallest 
measurements recorded since the treatment started, including the baseline 
measurements.  
 
12.4.5 Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of progression 
or death, whichever occurs first. 
 
12.4.6 Response Review 
 
It is strongly recommended that all responses be reviewed by an expert(s) 
independent of the study at the study’s completion. 
 
 
13.0 
DATA AND SAFETY MONITORING 
 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, the 
Principal Investigator will provide a Data and Safety Monitoring (DSM) report to the Washington 
University Quality Assurance and Safety Monitoring Committee (QASMC) semi-annually 
beginning six months after accrual has opened (if at least five patients have been enrolled) or one 
year after accrual has opened (if fewer than five patients have been enrolled at the six-month mark). 
 
The Principal Investigator will review all patient data at least every six months, and provide a 
semi-annual report to the QASMC. This report will include: 
• HRPO protocol number, protocol title, Principal Investigator name, data coordinator name, 
regulatory coordinator name, and statistician 
• Date of initial HRPO approval, date of most recent consent HRPO approval/revision, date 
of HRPO expiration, date of most recent QA audit, study status, and phase of study 
• History of study including summary of substantive amendments; summary of accrual 
suspensions including start/stop dates and reason; and summary of protocol exceptions, 
error, or breach of confidentiality including start/stop dates and reason 
• Study-wide target accrual and study-wide actual accrual 


Protocol Version: 11/01/19 
 
Page 33 of 41 
• Protocol activation date 
• Average rate of accrual observed in year 1, year 2, and subsequent years 
• Expected accrual end date and accrual by cohort 
• Objectives of protocol with supporting data and list the number of participants who have 
met each objective 
• Measures of efficacy  
• Early stopping rules with supporting data and list the number of participants who have met 
the early stopping rules 
• Summary of toxicities separated by cohorts 
• Abstract submissions/publications 
• Summary of any recent literature that may affect the safety or ethics of the study  
 
The study principal investigator and Research Patient Coordinator will monitor for serious 
toxicities on an ongoing basis. Once the principal investigator or Research Patient Coordinator 
becomes aware of an adverse event, the AE will be reported to the HRPO and QASMC according 
to institutional guidelines. All adverse events are tracked in the OnCore database. 
 
 
14.0 
STATISTICAL CONSIDERATIONS 
 
14.1 
Study Design 
 
This is a two cohort, open label, nonrandomized study with a noninferiority primary 
endpoint. The last ten patients enrolled after accrual to the dexrazoxane treatment group 
has been completed will be considered a control group; the purpose of this group is to 
obtain control samples for some of the correlative studies.  The primary endpoint will be 
tested only in the active treatment cohort. Toxicity and cardiac function biomarkers will be 
documented in both cohorts.  
 
14.2 
Primary Endpoint 
 
We are comparing the progression-free survival (PFS) rate of patients being treated with 
doxorubicin in combination with dexrazoxane to a historic control established by Judson 
et al in 2014.  PFS is defined as the time from randomization to the first occurrence of 
progression or death due to any cause.  If no event exists, the PFS will be censored at the 
last scheduled disease assessment on study.  Patients who have reached their maximum 
follow-up and have remained progression-free will be censored for progression at the date 
of their last disease assessment. Intention to treat principles will be used for analyzing the 
primary endpoint.  The primary endpoint will be tested using estimates of median PFS and 
95% confidence intervals derived from Kaplan-Meier models. 
 
 


Protocol Version: 11/01/19 
 
Page 34 of 41 
 
14.3 
Secondary Endpoints 
 
Cardiac-specific mortality will be analyzed using Kaplan-Meier models to estimate median 
times to these events, as well as the proportion experiencing an event at 3, 6, 9 and 12 
months. 
 
Agreement between 3D and 2d echocardiogram biomarkers will be described using Bland-
Altman plots, which plot the mean of two measurements on the same individual against 
the difference of those measurements. If the values are reasonably Gaussian, the standard 
± 2 standard deviations will be used as the limits of agreement. If the values are non-
Gaussian, bootstrap estimates will be used to define the limits of agreement.  
 
14.3.1 Sample Size and Statistical Power 
 
The historic control used for comparison is based on data published by Judson et 
al.  Patients with advanced or metastatic soft tissue sarcoma treated with single 
agent doxorubicin had a median PFS of 4.6 months.  We consider a median PFS of 
3.7 months (safety margin of 20%) to be non-inferior to the PFS seen in patients 
treated with doxorubicin alone.  We will be using a one-sided log-rank test at an 
alpha level of 0.05 with a power of 0.80 to determine if treatment of doxorubicin 
with upfront dexrazoxane is non-inferior to doxorubicin alone.   
 
A maximum of 65 patients may be enrolled to allow for a 10% dropout rate, 
resulting in at least 57 patients for testing of the primary endpoint. Using 57 
patients, we have 0.80 power at a 1-sided significance level of 0.05 to detect a 
median PFS 3.7 months compared to this historic control’s PFS of 4.6 months.   
 
14.3.2 Continuous Monitoring Rule to Evaluate for Early Progression 
 
The expected rate is 50%, maximum allowable rate is 70%. Total number of 
patients is 63, including 10% for withdrawal or loss to follow up.  The desired 
probability of stopping at a rate of 50% (incorrect early stopping) is ≤ 0.05. The 
desired probability of stopping at a rate of 70% (correct early stopping) is 0.80.  
 
If the true rate is 50%, then the calculated probability of incorrect early stopping is 
0.05. If the true rate is as high as 70%, the calculated probability of correct early 
stopping is 0.88. 
 


Protocol Version: 11/01/19 
 
Page 35 of 41 
 
A table and reference are on the following page. 
 
0
3
6
9
12
15
18
21
24
27
30
33
36
39
42
0
3
6
9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63
Total Number of Early Progressions and Deaths
Total Number of Enrolled Patients
Continuous monitoring of early progression and death
SUSPEND IF # CASES 
FALLS ABOVE THE 
LINE 
CONTINUE IF # 
CASES ON OR 
BELOW THE LINE 


Protocol Version: 11/01/19 
 
Page 36 of 41 
Suspend for review if # early 
progression events or deaths 
EXCEEDS: 
In the first ___ 
patients: 
2 
2 
3 
3 
4 
4 
5 
5 
6 
7 
7 
8 
8 
10 
9 
11 
10 
13 
11 
14 
12 
16 
13 
17 
14 
19 
15 
20 
16 
22 
17 
23 
18 
25 
19 
27 
20 
28 
21 
30 
22 
32 
23 
33 
24 
35 
25 
37 
26 
38 
27 
40 
28 
42 
29 
43 
30 
45 
31 
47 
32 
49 
33 
50 
34 
52 
35 
54 
36 
56 
37 
57 
38 
59 
39 
61 
40 
63 
 
Reference: 
Ivanova A, Qaqish BF and Schell MJ. (2005). Continuous Toxicity Monitoring in Phase II Trials in 
Oncology. Biometrics 61, 540-545. 


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Page 37 of 41 
 
14.3.3 Maximum Accrual 
 
Maximum accrual in the treatment group is 63 patients, which includes 10% over 
the accrual to replace those patients deemed ineligible due to improper histology 
having been determined on the basis of information available prior to 
randomization.   Accrual to the control group is 10. 
 
   
 
 
 
 


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Page 38 of 41 
 
15.0 
REFERENCES 
 
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4. 
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6. 
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29. 
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APPENDIX A: ECOG Performance Status Scale 
 
 
Grade 
 
 
Description 
0 
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time.  Ambulatory and capable of all self-care, but 
unable to carry out any work activities.  Up and about more than 50% 
of waking hours. 
3 
 
In bed >50% of the time.  Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair. 
5 
 
Dead.