Clinical trial NCT02049905
Conditions: Metastatic, Locally Advanced or Unresectable Soft Tissue Sarcoma
Keywords: soft tissue sarcoma unresectable metastatic locally advanced sarcoma
Sponsor: ImmunityBio, Inc.
Start date: 2014-01-01; Completion date: 2017-05-01
Enrollment: 433 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine the efficacy and safety of aldoxorubicin in subjects with metastatic, locally advanced, or unresectable soft tissue sarcomas.

Detailed description:

Arms: arm 1: Aldoxorubicin is administered at 350 mg/m2 (260 mg/m2 doxorubicin equivalent) intravenously on Day 1 every 21-day cycles until tumor progression or unacceptable toxicity occurs. arm 2: These treatments include:

1. Dacarbazine administered at 1000 mg/m2 by intravenous infusion (IVI), over 90±15 minutes on Day 1 every 21 days until tumor progression or unacceptable toxicity occurs;
2. Pazopanib, 800 mg orally each day until tumor progression or unacceptable toxicity occurs;
3. Gemcitabine, 900 mg/m2 by IVI over 90 minutes on Days 1 and 8, plus docetaxel, 100 mg/m2 by IVI over 1 hour on Day 8 of a 28 day cycle until tumor progression or unacceptable toxicity occurs;
4. Doxorubicin, 75 mg/m2 by IVI over 5 to 30 minutes every 21 days for a maximum cumulative dose of 550 mg/m2 or unacceptable toxicity occurs; or
5. Ifosfamide 2.0 g/m2 administered over 2 to 4 hours on Days 1-4 of a 21 day cycle + mesna per standard site administration regimen until tumor progression or unacceptable toxicity occurs.
Interventions: intervention 1: Aldoxorubicin intervention 2: Investigator's Choice Treatment (Darcabazine, Pazopanib, Gemcitabine + Docetaxel, Doxorubicin, Ifosfamide)
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
CLINICAL PROTOCOL 
TITLE: 
A Multicenter, Randomized, Open-Label Phase 3 Study 
to Investigate the Efficacy and Safety of Aldoxorubicin 
Compared to Investigator’s Choice in Subjects with 
Metastatic, Locally Advanced, or Unresectable Soft 
Tissue Sarcomas Who Either Relapsed or Were 
Refractory to Prior Non-Adjuvant Chemotherapy 
PROTOCOL NUMBER: 
ALDOXORUBICIN-P3-STS-01 
STUDY DRUG: 
Aldoxorubicin 
IND NUMBER: 
113,695 
EUDRACT NUMBER: 
2013-004103-40 
SPONSOR:  
CytRx Corporation 
11726 San Vicente Blvd 
Los Angeles, CA 90049 
(310) 826-5648
FAX: (310) 826-6139
SAFETY HOTLINE: 
Toll-free: TBD 
SAFETY FAX: 
Toll-free: TBD 
DATE OF PROTOCOL: 
April 3, 2013 
CONFIDENTIAL 
The information contained in this document is confidential and the proprietary property of CytRx 
Corporation. Any unauthorized use or disclosure of such information without the prior written 
authorization of CytRx Corporation is prohibited. 


ALDOXORUBICIN-P3..STS-01 
April 3, 2013 
PROTOCOL SIGNATURE PAGE 
A Multicenter, Randomized, Open-Label Phase 3 Study to Investigate the 
Efficacy and Safety of Aldoxorubicin Compared to Investigator's Choice in 
Subjects with Metastatic, Locally Advanced, or Unresectable Soft Tissue 
Sarcomas Who Either Relapsed or Were Refractory to Prior Non-Adjuvant 
Chemotherapy 
By signing below, the Investigator agrees to adhere to the protocol as outlined and agrees 
that any changes to the protocol must be approved by CytRx Corporation (CytRx) prior to 
seeking approval from the Institutional Review Board (IRB)/lndependent Ethics Committee 
(IEC). 
The study will be conducted in accordance with current United States (US) Food and Drug 
Administration (FDA) regulations, International Conference on Harmonization (ICH) 
guidelines, Good Clinical Practice (GCP) guidelines, the principles of the Declaration of 
Helsinki, and other applicable regulations and guidelines. 
I agree to ensure that Financial Disclosure Statements will be completed by: 
• 
me (including, if applicable, my spouse [or legal partner] and dependent children) 
• 
my subinvestigators (including, if applicable, their spouses [or legal partner] and 
dependent children) 
at the start of the study and for up to 1 year after the study is completed, if there are 
changes that affect my financial disclosure status. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of CytRx. 
Investigator's Signature:------------------
Printed Name: - --------------------
Name of Institution/Company: ----------------
Date: 
Daniel Levitt, M.D., Ph.D. 
Chief Medical Officer 
CytRx Corporation 
;J 
Date: 
31 
CytRx Corporation 
CONFIDENTIAL 
Page 2 


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Protocol Synopsis 
Name of Sponsor/Company: CytRx Corporation 
 
Protocol Number:  
ALDOXORUBICIN-P3-STS-01 
Phase of Development: 3 
 
Title of the Protocol:  
A Multicenter, Randomized, Open-Label Phase 3 Study to Investigate the Efficacy and Safety of 
Aldoxorubicin Compared to Investigator’s Choice in Subjects with Metastatic, Locally Advanced, or 
Unresectable Soft Tissue Sarcomas Who Either Relapsed or Were Refractory to Prior Non-Adjuvant 
Chemotherapy 
Primary Objective: 
The primary objective of this study is to determine the efficacy of administration of aldoxorubicin 
compared to investigator’s choice of treatment in subjects with metastatic, locally advanced, or 
unresectable soft tissue sarcomas who have relapsed or were refractory to prior non-adjuvant 
chemotherapy, as measured by progression-free survival (PFS). 
Secondary Objectives: 
The secondary objectives of this study are to evaluate the efficacy of aldoxorubicin as measured by 
OS, safety of aldoxorubicin compared to investigator’s choice in this population assessed by the 
frequency and severity of adverse events (AEs), abnormal findings on physical examination, 
laboratory tests, vital signs, echocardiogram (ECHO) evaluations, electrocardiogram (ECG) results, 
and weight, as well as disease control rate, tumor response and quality of life (quality of life 
evaluation will only be used for exploratory purposes). 
Exploratory Objectives: 
To determine the pharmacokinetics (PK) of aldoxorubicin, doxorubicin, and doxorubicinol following 
intravenous (IV) administration of aldoxorubicin, and to evaluate the exposure-response relationships 
between aldoxorubicin, doxorubicin, and/or doxorubicinol and PFS, OS, and selected safety 
parameters. 
Study Rationale and Significance: 
Aldoxorubicin (INNO-206; DOXO-EMCH) is a novel prodrug that binds covalently to albumin in the 
circulation. The drug is accumulated in tumors and doxorubicin is released in the tumor by cleaving 
the acid labile linker (EMCH) in the low pH tumor environment. This carrier-linked prodrug has 
demonstrated enhanced antitumor activity with reduced toxicity in several murine models when 
compared with free doxorubicin. 
Patients with metastatic, locally advanced, or unresectable soft tissue sarcomas who have failed prior 
chemotherapies have a poor prognosis with PFS of around 2-4.6 months and median OS of 
approximately 9-12 months. Several chemotherapy regimens have been explored as palliative 
therapy for subjects with these patients and include such agents as ifosfamide, gemcitabine, 
docetaxel, vinorelbine, dacarbazine, temozolomide, epirubicin, pazopanib and liposomal doxorubicin. 
However, these regimens can be quite toxic and have not significantly impacted either progression-
free or OS in these individuals. Pazopanib, recently approved in the US and Europe, does appear to 
extend PFS in soft tissue sarcoma patients (except liposarcomas) who have relapsed after receiving 
prior chemotherapy compared to no treatment, but does not increase OS. Aldoxorubicin may improve 
upon the activity of doxorubicin without an increase in toxicity as has been demonstrated in animal 
studies. 


ALDOXORUBICIN-P3-STS-01 
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CONFIDENTIAL 
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Name of Sponsor/Company: CytRx Corporation 
 
Protocol Number:  
ALDOXORUBICIN-P3-STS-01 
Phase of Development: 3 
 
Study Design and Methodology: 
This is a phase 3 open-label study evaluating the efficacy and safety of aldoxorubicin administered at 
350 mg/m2 (260 mg/m2 doxorubicin equivalent) intravenously on Day 1 every 21 days for up to 8 
cycles compared to investigator’s choice of treatment among 5 different therapies. These therapies 
include:  1) dacarbazine administered at 1000 mg/m2 by intravenous infusion (IVI), over 90±15 
minutes on Day 1 every 21 days for up to 8 consecutive cycles; 2) pazopanib, 800 mg orally each day 
until tumor progression or unacceptable toxicity occurs; 3) gemcitabine, 900 mg/m2 by IVI over 90 
minutes on Days 1 and 8, plus docetaxel, 100 mg/m2 by IVI over 1 hour on Day 8 of a 28 day cycle 
for up to 8 cycles; 4) doxorubicin, 75 mg/m2 by IVI over 5 to 30 minutes every 21 days for up to 8 
cycles or a maximum cumulative dose of 550 mg/m2; or 5) ifosfamide 2.0 g/m2 administered over 2 to 
4 hours on Days 1-4 of a 21 day cycle + mesna per standard site administration regimen for up to 8 
cycles. The investigative site must pre-specify their choice of treatments for the comparator arm to 
be used at their site, and no more than 3 treatment regimens may be selected for the comparator arm 
at each site which must be selected prior to the study site initiation visit. Subjects will be randomized 
1:1 to receive either aldoxorubicin or investigator’s choice of up to 3 control regimens pre-selected by 
the study site. Pretreatment with G-CSF is permitted according to ASCO Guidelines (Appendix E). 
All Screening requirements, including an ECHO exam, must be completed within 28 days of the  
Cycle 1-Day 1 visit. Subjects receiving aldoxorubicin, ifosfamide, dacarbazine or doxorubicin will  
visit the study site on Day 1 of each cycle. They will have complete blood counts (CBC) and serum 
chemistries on Day 15 and Day 21 (if Day 21 does not correspond to Day 1 of the next cycle,  
±3 days; Day 28 for subjects taking pazopanib) of each cycle as well. Subjects receiving pazopanib 
will visit the study site on Day 1 of their next cycle for monitoring, testing (same as for Day 1 for other 
treatment regimens) and to receive a new supply of study drug. Subjects receiving gemcitabine plus 
docetaxel will visit the study site on both days of their infusions (Days 1 and 8) and at Day 21 of each 
cycle. Safety monitoring, including AEs, a directed physical examination, laboratory evaluations 
(serum chemistry, CBC, and urinalysis), vital signs, weight measurements, Eastern Cooperative 
Oncology Group (ECOG) performance status (PS) and ECGs will be performed on Day 1 (for all 
subjects) of each cycle. Cardiac function will also be followed periodically (per Schedule of Treatment 
and Evaluations in Appendix A) with ECHOs for subjects receiving either aldoxorubicin or 
doxorubicin. Treatment will continue until tumor progression is observed, 8 cycles of treatment are 
completed (except for pazopanib), subject asks to withdraw, unacceptable toxicity occurs, a change 
in therapy would be in the best interest of the subject, subject becomes pregnant or fails to use 
adequate birth control, need for any treatment not allowed by the protocol, or subject is non-compliant 
with study requirements. 
Tumor response will be monitored at screening, every 6 weeks from Cycle 1-Day 1 through Week 30, 
and then every 12 weeks until disease progression using the Response Evaluation Criteria in Solid 
Tumors (RECIST) 1.1 criteria.[50] OS, PFS, and PFS at 4 and 6 months will be evaluated. Objective 
overall response rate (ORR) (complete and partial responses [PRs]), disease control rate (objective 
responses plus stable disease at 4 months) and quality of life will be assessed.  
The PK of aldoxorubicin, doxorubicin, and doxorubicinol will be evaluated using a sparse sample 
analysis. Plasma samples will be collected at Cycle 1 at the following time points: the end of the 
infusion, between 1.5 and 4 hours from the end of the infusion, and on Days 2, and 3. If necessary 
and possible, PK samples may be collected at a later cycle. 


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Name of Sponsor/Company: CytRx Corporation 
 
Protocol Number:  
ALDOXORUBICIN-P3-STS-01 
Phase of Development: 3 
 
Study Population and Main Criteria for Inclusion/Exclusion: 
Inclusion Criteria: 
Subjects must meet the following criteria to be included in the study: 
1. Has provided written informed consent prior to any study related activities. 
2. Age ≥15 years (US only), and 18-80 (rest of world (ROW)), male or female. 
3. Histological confirmation of intermediate or high grade soft-tissue sarcoma. Tissue must be sent to a 
central pathology lab for review but will not preclude entry onto the study. Final assignment of tumor 
grade and histology will be based on the designation provided by the central pathology review. 
4. An adequate tumor specimen obtained by either excisional biopsy, inclusion biopsy or core 
needle biopsy must be sent to the central pathology lab for evaluation. The material must 
measure at least 0.8 × 0.1 cm in size or contain at least 50 tumor cells. 
5. Locally advanced, unresectable, and/or metastatic soft-tissue sarcoma of intermediate or high grade 
with evidence of disease progression by either computed tomography (CT) or magnetic resonance 
imaging (MRI) scan, or clinical judgment on or after the last cancer therapy within 6 months prior to 
randomization. 
6. Relapsed or refractory (lack of response) to ≥1 course of systemic therapy regimen(s), excluding 
adjuvant or neoadjuvant chemotherapy, and is incurable by either surgery or radiation. 
7. Capable of providing informed consent and complying with trial procedures. 
8. ECOG PS 0-2. 
9. Life expectancy >12 weeks. 
10. Measurable tumor lesions according to RECIST 1.1 criteria.[50] 
11. Women must not be able to become pregnant (e.g., post-menopausal for at least 1 year, surgically 
sterile, or practicing adequate birth control methods) for the duration of the study. (Adequate 
contraception includes: oral contraception, implanted contraception, intrauterine device implanted for 
at least 3 months, or barrier method in conjunction with spermicide.) 
12. Males and their female partner(s) of child-bearing potential must use 2 forms of effective contraception 
(see Inclusion 11 plus condom or vasectomy for males) from the last menstrual period of the female 
partner during the study treatment and agree to continue use for 6 months after the final dose of study 
treatment. 
13. Women of child bearing potential must have a negative serum or urine pregnancy test at the Screening 
Visit and be non-lactating. 
14. Accessibility to the site that optimizes the subject’s ability to keep all study-related appointments.  
Exclusion Criteria: 
Subjects meeting the following criteria will not be enrolled: 
1. Prior exposure to >375 mg/m2 of doxorubicin or liposomal doxorubicin. 
2. Palliative surgery and/or radiation treatment <4 weeks prior to date of randomization. 
3. Exposure to any investigational agent within 30 days of date of randomization. 
4. Exposure to any systemic chemotherapy within 28 days of date of randomization. 
5. An inadequate tumor specimen as defined by the central pathologist. 
6. Current evidence/diagnosis of alveolar soft part sarcoma, extraskeletal myxoid chondrosarcoma, 
rhabdomyosarcoma, osteosarcoma, gastrointestinal stromal tumor (GIST), dermatofibrosarcoma 
(unless transformed to fibrosarcoma), Ewing’s sarcoma, Kaposi’s sarcoma, mixed mesodermal tumor, 
clear cell sarcomas. 
7. Evidence of central nervous system (CNS) metastasis who have not received prior definitive therapy 
for their lesions.  
8. History of other malignancies except cured basal cell carcinoma, cutaneous squamous cell carcinoma, 
melanoma in situ, superficial bladder cancer or carcinoma in situ of the cervix unless documented free 
of cancer for ≥5 years. 


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Name of Sponsor/Company: CytRx Corporation 
 
Protocol Number:  
ALDOXORUBICIN-P3-STS-01 
Phase of Development: 3 
 
9. Laboratory values: Screening serum creatinine >1.5 x upper limit of normal (ULN), alanine 
aminotransferase (ALT) >3×ULN or >5×ULN if liver metastases are present, total bilirubin >2×ULN, 
absolute neutrophil count (ANC) <1,500/mm3, platelet concentration <100,000/mm3, hemoglobin  
<9 g/dL. 
10. Clinically evident congestive heart failure (CHF) > class II of the New York Heart Association (NYHA) 
(Appendix D) guidelines.  
11. Current, serious, clinically significant cardiac arrhythmias, defined as the existence of an absolute 
arrhythmia or ventricular arrhythmias classified as Lown III, IV or V (Appendix F). 
12. Baseline QTc >470 msec and/or previous history of QT prolongation while taking other medications.  
13. Concomitant use of medications associated with a high incidence of QT prolongation is not allowed 
(Appendix G). 
14. History or signs of active coronary artery disease with or without angina pectoris within the last 6 
months. 
15. Serious myocardial dysfunction defined by ECHO as absolute left ventricular ejection fraction (LVEF) 
below the institution’s lower limit of predicted normal. 
16. Known history of HIV infection.  
17. Active, clinically significant serious infection requiring treatment with antibiotics, anti-virals or  
anti-fungals. The Medical Monitor should be contacted for any uncertainties. 
18. Major surgery within 4 weeks prior to date of randomization. 
19. Current or past substance abuse or any condition that might interfere with the subject’s participation in 
the study or in the evaluation of the study results. 
20. Any condition that is unstable and could jeopardize the subject’s participation in the study. 
Number of Subjects: 
Approximately 400 subjects with metastatic, locally advanced or unresectable soft tissue sarcomas 
who have either not responded to or have progressed after treatment with 1 or more systemic 
regimens of non-adjuvant chemotherapies will be randomized 1:1 (aldoxorubicin:investigator’s 
choice) at approximately 75 study centers in the US, Europe, China, Canada, Latin America and 
Australia. The randomization will be stratified according to their initial PS (ECOG 0-1 vs 2), whether 
they had either 1 prior systemic non-adjuvant chemotherapy regimens or >1 prior systemic  
non-adjuvant chemotherapy regimens and whether they had received prior doxorubicin 
chemotherapy.  Subjects will also be stratified by their histopathological diagnosis as determined by 
the local site.  The four stratification groups will be leiomyosarcomas, liposarcoma, synovial sarcoma, 
and all other sarcomas. 


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Name of Sponsor/Company: CytRx Corporation 
 
Protocol Number:  
ALDOXORUBICIN-P3-STS-01 
Phase of Development: 3 
 
Test Product, Dose and Mode of Administration: 
Aldoxorubicin: Lyophilized powder in vials that contain 200 mg of aldoxorubicin reconstituted by 
adding a solution of 50% ethanol: 50% sterile water, administration completed within 2 hours (of 
being reconstituted) as a 30-minute IVI Lactated Ringer’s solution. Total dose of 350 mg/m2  
(260 mg/m2 doxorubicin equivalent). 
Investigator’s Choice: Up to three treatment regimens are to be chosen by the investigator from the 
list above prior to the initiation of the study site and the treatment chosen for each subject enrolled in 
the study must be entered into the case report form. 
Dacarbazine 100 mg/vial and 200 mg/vial are reconstituted with 9.9 mL and 19.7 mL, respectively, 
Sterile Water for Injection, USP. The resulting solution contains 10 mg/mL of dacarbazine having a 
pH of 3.0 to 4.0. The calculated dose of the resulting solution is drawn into a syringe and 
administered only intravenously. The reconstituted solution may be further diluted with 5% dextrose 
injection, or sodium chloride injection (250 to 500 mL), and administered as an IVI over 90±15 
minutes. 
After reconstitution and prior to use, the solution in the vial may be stored at 4°C for up to 72 hours or 
at normal room conditions (temperature and light) for up to 8 hours. If the reconstituted solution is 
further diluted in 5% dextrose injection or sodium chloride injection, the resulting solution may be 
stored at 4°C for up to 24 hours or at normal room conditions for up to 8 hours. 
Pazopanib (Votrient®) 200 mg tablets can be stored at room temperature between 20° and 25°C; 
excursions are permitted between 15° and 30°C. Tablets are taken 1 hour before or 2 hours after a 
meal and tablets are NOT to be crushed. 
Gemcitabine 200 mg or 1 g lyophilized powder in a single use vial is reconstituted with 0.9% NaCl to 
a final concentration of ≤40 mg/mL and pH 2.7 to 3.3. The reconstituted solution may be further 
diluted with 0.9% NaCl and administered by IVI in <60 minutes. It is stable for up to 24 hours at 
controlled room temperature  
(20° to 25°C) and should not be refrigerated. 
Docetaxel 80 mg/2 mL and 20 mg/0.5 mL with diluents for both strengths (13% [w/w] ethanol in water 
for injection) is administered by IVI over approximately 60 minutes after dilution into a 250 to 500 mL 
infusion bag of either 0.9% NaCl or 5% dextrose solution to produce a final concentration of 0.3 to 
0.74 mg/mL. Docetaxel final dilution for infusion should be administered within 4 hours of preparation. 
It can be stored between 2° and 25°C. 
Doxorubicin HCl Injection is a sterile parenteral, isotonic available in 5 mL (10 mg), 10 mL (20 mg),  
25 mL (50 mg) single dose vials. Each mL contains doxorubicin HCl and the following inactive 
ingredients:  NaCl (0.9%) and water for injection q.s. Hydrochloric acid is used to adjust the pH to a 
target of pH of 3.0. The reconstituted solution is diluted in 0.9% NaCl or 5% dextrose and may be 
administered over 5 to 30 minutes. 
Ifosamide single-dose vials for constitution and administration by IVI each contain 1 gram or 3 grams 
of sterile ifosfamide, USP. Ifosfamide is a chemotherapeutic agent chemically related to the nitrogen 
mustards and a synthetic analog of cyclophosphamide. Injections are prepared for parenteral use by 
adding Sterile Water for Injection, USP, or Sterile Bacteriostatic Water for Injection, USP (benzyl 
alcohol or parabens preserved) to the vial and shaking to dissolve. The reconstituted solution is 
diluted in 0.9% NaCl or 5% dextrose solution and may be administered over 2 to 4 hours. 


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Name of Sponsor/Company: CytRx Corporation 
 
Protocol Number:  
ALDOXORUBICIN-P3-STS-01 
Phase of Development: 3 
 
Criteria for Evaluation: 
Efficacy: 
The following efficacy variables will be evaluated as noted: 
 PFS. 
 OS. 
 Objective tumor response (RECIST 1.1 criteria[50]). 
 Disease control rate (objective tumor response + stable disease at 4 months). 
 Subject Reported Outcome as measured by the European Organisation for Research and 
Treatment of Cancer (EORTC) Quality of Life Questionnaire. 
 
Safety: 
The following safety variables will be assessed over the duration of the study: 
 AEs. 
 Ability to remain on assigned treatment (tolerability). 
 Clinical and laboratory data including physical examinations, vital signs, weight, ECHO 
evaluations, ECG results and laboratory test results. 
 Use of concomitant medications. 
Pharmacokinetics: 
The following PK variables will be assessed for aldoxorubicin, doxorubicin, and doxorubicinol: 
 Maximum drug concentration (Cmax) in plasma. 
 Area under the plasma drug-concentration-time profile (AUC). 
 Clearance (CL). 
 Volume of distribution (Vd). 
 Half-life (t½). 


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Name of Sponsor/Company: CytRx Corporation 
 
Protocol Number:  
ALDOXORUBICIN-P3-STS-01 
Phase of Development: 3 
 
Statistical Methods: 
In accordance with the intention-to-treat principle, all randomized subjects will be evaluated for 
efficacy. All subjects who receive at least 1 dose of study medication will be evaluated for safety.  
Efficacy:  
The primary analysis of PFS will be carried out when approximately 191 PFS events have been 
observed (approximately 15 months following the completion of enrollment of 400 subjects). Survival 
distributions will be estimated using the Kaplan-Meier method and the two groups will be compared 
using a two-sided log rank test at the α=0.05 level of significance. 
An important secondary endpoint is overall survival (OS). The analysis of OS will be considered 
confirmatory only if the PFS analysis is statistically significant. As a result, the nominal level of 
significance for the OS analysis will be α=0.05. However, because an interim analysis of OS will be 
carried out at the time of the analysis of PFS, the levels of significance for the interim and final 
analyses of OS will be α=0.00305 and α=0.049, respectively. 
The final analysis of OS will be completed when 320 OS events have occurred. Survival distributions 
will be estimated using the Kaplan-Meier method and the two groups will be compared using a two-
sided log rank test at the α=0.049 level of significance. The same methodology will be used for the 
interim analysis, but at the α=0.00305 level of significance. 
Tumor response will be monitored at screening, every 6 weeks from Cycle 1-Day 1 through Week 30, 
and then every 12 weeks until disease progression. The percentage of subjects with complete or 
PRs, or stable disease will be evaluated and the disease control rate (CR, PR and SD at 4 months) 
will be compared using Pearson’s chi-square test, or if 20% or more of the expected cell frequencies 
are <5, Fisher’s exact test. Patient reported outcomes as assessed by the EORTC Quality of Life 
Questionnaire will be analyzed using analysis of covariance. 
Sample Size Justification: 
Power calculations and subject numbers were calculated based on the primary endpoint of PFS. 
Reviewing the literature for studies that have evaluated gemcitabine + docetaxel, pazopanib, 
ifosfamide and dacarbazine as treatment for patients that have relapsed or not responded to first line 
therapies, it is estimated that the median PFS for the investigator’s choice group will be 3.5 months 
and that the median PFS for the aldoxorubicin group will be 5.6 months. Based on the use of a two-
sided log rank test at the α=0.05 level of significance, a total of 191 PFS events will be required for 
90% power to detect this difference. Assuming an 18 month accrual period and a 15 month follow-up 
period after enrollment of the last subject, approximately 400 subjects will be needed to achieve the 
total of 191 PFS events. 
Safety:  
The safety data will be summarized by treatment group. The treatment groups will be compared with 
respect to occurrence of each AE. Total number of AEs leading to withdrawal, and abnormal 
laboratory tests will be compared between groups using Fisher’s exact test. AEs, ability to remain on 
assigned treatment (tolerability), and abnormal findings on physical examinations, vital signs, weight, 
ECG results, laboratory test results, and use of concomitant medications, will be assessed to 
characterize the safety profile of the treatment regimens. Descriptive statistics denoting the changes 
from baseline to the final assessment visit with respect to key laboratory parameters and vital signs 
will also be provided.  


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Name of Sponsor/Company: CytRx Corporation 
 
Protocol Number:  
ALDOXORUBICIN-P3-STS-01 
Phase of Development: 3 
 
Pharmacokinetics:  
All subjects who receive aldoxorubicin and provide at least one PK sample with concentrations above 
the limit of quantification will be included in the PK analysis. Sparse plasma aldoxorubicin, 
doxorubicin, and doxorubicinol concentration data will be analyzed, and aldoxorubicin, doxorubicin, 
and doxorubicinol PK parameters will be estimated based on a population PK analysis. PK 
parameters will be summarized using descriptive statistics. 
Exploratory exposure-response/exposure-safety analyses will be conducted using the primary and 
secondary efficacy endpoints, PFS and OS, and for selected AEs. 


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APPENDIX A: Schedule of Treatment and Evaluations 
 
Screening 
-28 Days 
Cycle 
1 
Cycle 
2 
Cycle 
3 
Cycle 
4 
Cycle 
5 
Cycle 
6 
Cycle 
7 
Cycle 8 
Day 15 
and 21 
each Cycle
End of 
Treatment14 
Every 6 
Weeks → 
Week 3013 
Every 
12 
Weeks13 
Follow 
Up12 
Signed informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review inclusion/exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination22 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Height (cm)2 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Weight (kg) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
BSA calculation2 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Vital signs3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
ECOG PS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
CT/ MRI scan / tumor measurements4 
X8a 
 
 
X8 
 
X8 
 
X8 
 
 
X10 
X 
X 
 
ECG20 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X11 
X 
X 
 
ECHO (with ejection fraction)21  
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
CBC w/differential & plts5 
X 
X16 
X 
X 
X 
X 
X 
X 
X 
X 
X11 
X 
X 
 
Serum chemistries 5, 6 
X 
X16 
X 
X 
X 
X 
X 
X 
X 
X 
X11 
 
 
 
Urinalysis7 
X 
 
 
 
 
 
 
 
 
 
X11 
 
 
 
Serum/urine pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Quality of Life Questionnaire 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
Randomization 
 
X15 
 
 
 
 
 
 
 
 
 
 
 
 
Aldoxorubicin, doxorubicin, ifosfamide 
or dacarbazine administration17 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Gemcitabine and docetaxel 
administration, 18 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Pazopanib administration and diary19 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
Pharmacokinetic sampling23 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
X9 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
Telephone call 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
NOTE: All assessment must be performed within 72 hours of each specified time parameter, except Cycle 1 (see Section 7 for details). 


 
CLINICAL PROTOCOL 
TITLE: 
A Multicenter, Randomized, Open-Label Phase 3 Study 
to Investigate the Efficacy and Safety of Aldoxorubicin 
Compared to Investigator’s Choice in Subjects with 
Metastatic, Locally Advanced, or Unresectable Soft 
Tissue Sarcomas Who Either Relapsed or Were 
Refractory to Prior Non-Adjuvant Chemotherapy 
 
PROTOCOL NUMBER: 
ALDOXORUBICIN-P3-STS-01 
STUDY DRUG: 
Aldoxorubicin 
IND NUMBER: 
113,695 
EUDRACT NUMBER: 
2013-004103-40 
SPONSOR:  
CytRx Corporation 
 
11726 San Vicente Blvd 
 
Los Angeles, CA 90049 
 
(310) 826-5648  
 
FAX: (310) 826-6139 
 
IMMEDIATE SAFETY ASSISTANCE: 
 
 
Region 
Hotline 
Fax 
Email 
North America 
Australia 
Asia 
1-866-326-5053 
or 
1-434-951-4082 
1-800-280-7035 
or 
1-913-307-5751 
AldoxP3STS@PRAIntl.com 
Europe 
+44 1792 52-5608 
+49 621 878-2828 
AldoxP3STS@PRAIntl.com 
 
SAE SUBMISSION: 
 
 
Region 
SAE Fax 
SAE Email 
North America 
1-888-772-6919 
CHOSafety@PRAIntl.com 
Rest of World 
+44 1792 525-720 
MHGSafety@PRAIntl.com 
 
 
 
ORIGINAL PROTOCOL:  
  April 3, 2013 
 
AMENDMENT 1: 
August 28, 2013 
 
 
 
 
CONFIDENTIAL 
The information contained in this document is confidential and the proprietary property of CytRx 
Corporation. Any unauthorized use or disclosure of such information without the prior written 
authorization of CytRx Corporation is prohibited. 


ALDOXORUBICIN-P3-STS-01 A1 
August 28, 2013 
PROTOCOL SIGNATURE PAGE 
A Multicenter, Randomized, Open-Label Phase 3 Study to Investigate the 
Efficacy and Safety of Aldoxorubicin Compared to Investigator's Choice in 
Subjects with Metastatic, Locally Advanced, or Unresectable Soft Tissue 
Sarcomas Who Either Relapsed or Were Refractory to Prior Non-Adjuvant 
Chemotherapy 
By signing below, the Investigator agrees to adhere to the protocol as outlined and agrees 
that any changes to the protocol must be approved by CytRx Corporation (CytRx) prior to 
seeking approval from the Institutional Review Board (IRB)/lndependent Ethics Committee 
(IEC). 
The study will be conducted in accordance with current United States (US) Food and Drug 
Administration (FDA) regulations, International Conference on Harmonization (ICH) 
guidelines, Good Clinical Practice (GCP) guidelines, the principles of the Declaration of 
Helsinki, and other applicable regulations and guidelines. 
I agree to ensure that Financial Disclosure Statements will be completed by: 
• 
me (including, if applicable, my spouse [or legal partner] and dependent children) 
• 
my subinvestigators (including, if applicable, their spouses [or legal partner] and 
dependent children) 
at the start of the study and for up to 1 year after the study is completed, if there are 
changes that affect my financial disclosure status. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of CytRx. 
Investigator's Signature: -----------------
Printed Name: 
Name of Institution/Company: ---------------
Date: ______________________ 
Sponsor Signature: 
Daniel Levitt, M.D., Ph.D. 
Chief Medical Officer 
CytRx Corporation 
Date: ___ 
-1_o_ .. _· 
... 
_2.._0_1_71 __ _ 
CytRx Corporation 
CONFIDENTIAL 
Page2 


ALDOXORUBICIN-P3-STS-01 A1 
August 28, 2013
CytRx Corporation 
CONFIDENTIAL 
Page 3 
Protocol Synopsis 
Name of Sponsor/Company: CytRx Corporation 
Protocol Number:  
ALDOXORUBICIN-P3-STS-01 
Phase of Development: 3 
Title of the Protocol:  
A Multicenter, Randomized, Open-Label Phase 3 Study to Investigate the Efficacy and Safety of 
Aldoxorubicin Compared to Investigator’s Choice in Subjects with Metastatic, Locally Advanced, or 
Unresectable Soft Tissue Sarcomas Who Either Relapsed or Were Refractory to Prior Non-Adjuvant 
Chemotherapy 
Primary Objective: 
The primary objective of this study is to determine the efficacy of administration of aldoxorubicin 
compared to investigator’s choice of treatment in subjects with metastatic, locally advanced, or 
unresectable soft tissue sarcomas who have relapsed or were refractory to prior non-adjuvant 
chemotherapy, as measured by progression-free survival (PFS). 
Secondary Objectives: 
The secondary objectives of this study are to evaluate the efficacy of aldoxorubicin as measured by 
OS, safety of aldoxorubicin compared to investigator’s choice in this population assessed by the 
frequency and severity of adverse events (AEs), abnormal findings on physical examination, 
laboratory tests, vital signs, echocardiogram (ECHO) evaluations, electrocardiogram (ECG) results, 
and weight, as well as disease control rate, and tumor response. 
Exploratory Objectives: 
To determine the pharmacokinetics (PK) of aldoxorubicin, doxorubicin, and doxorubicinol following 
intravenous (IV) administration of aldoxorubicin, and to evaluate the exposure-response relationships 
between aldoxorubicin, doxorubicin, and/or doxorubicinol and PFS, OS, selected safety parameters, 
and quality of life. 
Study Rationale and Significance: 
Aldoxorubicin (INNO-206; DOXO-EMCH) is a novel prodrug that binds covalently to circulating 
albumin. The drug is accumulated in tumors and doxorubicin is released in the tumor by cleaving the 
acid labile linker (EMCH) in the low pH tumor environment. This carrier-linked prodrug has 
demonstrated enhanced antitumor activity with reduced toxicity in several murine models when 
compared with free doxorubicin. 
Patients with metastatic, locally advanced, or unresectable soft tissue sarcomas who have failed prior 
chemotherapies have a poor prognosis with PFS of around 2-4.6 months and median OS of 
approximately 9-12 months. Several chemotherapy regimens have been explored as palliative 
therapy for subjects with these patients and include such agents as ifosfamide, gemcitabine, 
docetaxel, vinorelbine, dacarbazine, temozolomide, epirubicin, pazopanib and liposomal doxorubicin. 
However, these regimens can be quite toxic and have not significantly impacted either progression-
free or OS in these individuals. Pazopanib, recently approved in the US and Europe, does appear to 
extend PFS in soft tissue sarcoma patients (except liposarcomas) who have relapsed after receiving 
prior chemotherapy compared to no treatment, but does not increase OS. Aldoxorubicin may improve 
upon the activity of doxorubicin without an increase in toxicity as has been demonstrated in animal 
studies. 


ALDOXORUBICIN-P3-STS-01 A1 
August 28, 2013 
 
CytRx Corporation 
CONFIDENTIAL 
Page 4 
Name of Sponsor/Company: CytRx Corporation 
 
Protocol Number:  
ALDOXORUBICIN-P3-STS-01 
Phase of Development: 3 
 
Study Design and Methodology: 
This is a phase 3 open-label study evaluating the efficacy and safety of aldoxorubicin administered at 
350 mg/m2 (260 mg/m2 doxorubicin equivalent) intravenously on Day 1 every 21 days until tumor 
progression or unacceptable toxicity occurs compared to investigator’s choice of treatment among  
5 different therapies. These therapies include:  1) dacarbazine administered at 1000 mg/m2 by 
intravenous infusion (IVI), over 90±15 minutes on Day 1 every 21 days until tumor progression or 
unacceptable toxicity occurs; 2) pazopanib, 800 mg orally each day until tumor progression or 
unacceptable toxicity occurs; 3) gemcitabine, 900 mg/m2 by IVI over 90 minutes on Days 1 and 8, 
plus docetaxel, 100 mg/m2 by IVI over 1 hour on Day 8 of a 28 day cycle until tumor progression or 
unacceptable toxicity occurs; 4) doxorubicin, 75 mg/m2 by IVI over 5 to 30 minutes every 21 days for a 
maximum cumulative dose of 550 mg/m2 or unacceptable toxicity occurs; or 5) ifosfamide 2.0 g/m2 
administered over 2 to 4 hours on Days 1-4 of a 21 day cycle + mesna per standard site 
administration regimen until tumor progression or unacceptable toxicity occurs. The investigative site 
must pre-specify their choice of treatments for the comparator arm to be used at their site, and no 
more than 3 treatment regimens may be selected for the comparator arm at each site which must be 
selected prior to the study site initiation visit. Subjects will be randomized 1:1 to receive either 
aldoxorubicin or investigator’s choice of up to 3 control regimens pre-selected by the study site. 
Pretreatment with G-CSF is permitted according to ASCO Guidelines (Appendix E). 
All Screening requirements, including an ECHO exam, must be completed within 28 days of the  
Cycle 1-Day 1 visit. Subjects receiving aldoxorubicin, ifosfamide, dacarbazine or doxorubicin will  
visit the study site on Day 1 of each cycle. They will have complete blood counts (CBC) and serum 
chemistries on Day 15 and Day 21 (if Day 21 does not correspond to Day 1 of the next cycle,  
±3 days; Day 28 for subjects taking pazopanib) of each cycle as well. Subjects receiving pazopanib 
will visit the study site on Day 1 of their next cycle for monitoring, testing (same as for Day 1 for other 
treatment regimens) and to receive a new supply of study drug. Subjects receiving gemcitabine plus 
docetaxel will visit the study site on both days of their infusions (Days 1 and 8) and at Day 21 of each 
cycle. Safety monitoring, including AEs, a directed physical examination, laboratory evaluations 
(serum chemistry, CBC, and urinalysis), vital signs, weight measurements, Eastern Cooperative 
Oncology Group (ECOG) performance status (PS) and ECGs will be performed on Day 1 (for all 
subjects) of each cycle. Cardiac function will also be followed periodically (per Schedule of Treatment 
and Evaluations in Appendix A) with ECHOs for subjects receiving either aldoxorubicin or 
doxorubicin. Treatment will continue until tumor progression is observed, a maximum cumulative 
dose of 550 mg/m2 is reached (doxorubicin), subject asks to withdraw, unacceptable toxicity occurs,  
a change in therapy would be in the best interest of the subject, subject becomes pregnant or fails to 
use adequate birth control, need for any treatment not allowed by the protocol, or subject is  
non-compliant with study requirements. 
Tumor response will be monitored at screening, every 6 weeks from Cycle 1-Day 1 through Week 30, 
and then every 12 weeks until disease progression using the Response Evaluation Criteria in Solid 
Tumors (RECIST) 1.1 criteria.[50] OS, PFS, and PFS at 4 and 6 months will be evaluated. Objective 
overall response rate (ORR) (complete and partial responses [PRs]), disease control rate (objective 
responses plus stable disease at 4 months) and quality of life will be assessed.  
The PK of aldoxorubicin, doxorubicin, and doxorubicinol will be evaluated using a sparse sample 
analysis. Plasma samples will be collected at Cycle 1 at the following time points: the end of the 
infusion, between 1.5 and 4 hours from the end of the infusion, and on Days 2, and 3. If necessary 
and possible, PK samples may be collected at a later cycle. 


ALDOXORUBICIN-P3-STS-01 A1 
August 28, 2013 
 
CytRx Corporation 
CONFIDENTIAL 
Page 5 
Name of Sponsor/Company: CytRx Corporation 
 
Protocol Number:  
ALDOXORUBICIN-P3-STS-01 
Phase of Development: 3 
 
Study Population and Main Criteria for Inclusion/Exclusion: 
Inclusion Criteria: 
Subjects must meet the following criteria to be included in the study: 
1. Has provided written informed consent prior to any study related activities. 
2. Age ≥15 years (US only), and 18-80 (rest of world (ROW)), male or female. 
3. Histological confirmation of intermediate or high grade soft-tissue sarcoma. Tissue must be sent to a 
central pathology lab for review but will not preclude entry onto the study. Final assignment of tumor 
grade and histology will be based on the designation provided by the central pathology review. 
4. An adequate tumor specimen obtained by either excisional biopsy, incisional biopsy or core 
needle biopsy must be sent to the central pathology lab for evaluation. The material must 
measure at least 0.8 × 0.1 cm in size or contain at least 50 tumor cells. 
5. Locally advanced, unresectable, and/or metastatic soft-tissue sarcoma of intermediate or high grade 
with evidence of disease progression by either computed tomography (CT) or magnetic resonance 
imaging (MRI) scan, or clinical judgment on or after the last cancer therapy within 6 months prior to 
randomization. 
6. Relapsed or refractory (lack of response) to ≥1 course of systemic therapy regimen(s), excluding 
adjuvant or neoadjuvant chemotherapy, and is incurable by either surgery or radiation. 
7. Capable of providing informed consent and complying with trial procedures. 
8. ECOG PS 0-2. 
9. Life expectancy >12 weeks. 
10. Measurable tumor lesions according to RECIST 1.1 criteria.[50] 
11. Women must not be able to become pregnant (e.g., post-menopausal for at least 1 year, surgically 
sterile, or practicing adequate birth control methods) for the duration of the study. (Adequate 
contraception includes: oral contraception, implanted contraception, intrauterine device implanted for 
at least 3 months, or barrier method in conjunction with spermicide.) 
12. Males and their female partner(s) of child-bearing potential must use 2 forms of effective contraception 
(see Inclusion 11 plus condom or vasectomy for males) from the last menstrual period of the female 
partner during the study treatment and agree to continue use for 6 months after the final dose of study 
treatment. 
13. Women of child bearing potential must have a negative serum or urine pregnancy test at the Screening 
Visit and be non-lactating. 
14. Accessibility to the site that optimizes the subject’s ability to keep all study-related appointments.  
Exclusion Criteria: 
Subjects meeting the following criteria will not be enrolled: 
1. Prior exposure to >375 mg/m2 of doxorubicin or liposomal doxorubicin. 
2. Palliative surgery and/or radiation treatment within 30 days prior to date of randomization. 
3. Exposure to any investigational agent within 30 days of date of randomization. 
4. Exposure to any systemic chemotherapy within 30 days of date of randomization. 
5. An inadequate tumor specimen as defined by the central pathologist. 
6. Current evidence/diagnosis of alveolar soft part sarcoma, extraskeletal myxoid chondrosarcoma, 
rhabdomyosarcoma, osteosarcoma, gastrointestinal stromal tumor (GIST), dermatofibrosarcoma 
(unless transformed to fibrosarcoma), Ewing’s sarcoma, Kaposi’s sarcoma, mixed mesodermal tumor, 
clear cell sarcomas. 
7. Evidence of central nervous system (CNS) metastasis who have not received prior definitive therapy 
for their lesions.  
8. History of other malignancies except cured basal cell carcinoma, cutaneous squamous cell carcinoma, 
melanoma in situ, superficial bladder cancer or carcinoma in situ of the cervix unless documented free 
of cancer for ≥5 years. 


ALDOXORUBICIN-P3-STS-01 A1 
August 28, 2013 
 
CytRx Corporation 
CONFIDENTIAL 
Page 6 
Name of Sponsor/Company: CytRx Corporation 
 
Protocol Number:  
ALDOXORUBICIN-P3-STS-01 
Phase of Development: 3 
 
9. Laboratory values: Screening serum creatinine >1.5 x upper limit of normal (ULN), alanine 
aminotransferase (ALT) >3×ULN or >5×ULN if liver metastases are present, total bilirubin >2×ULN, 
absolute neutrophil count (ANC) <1,500/mm3, platelet concentration <100,000/mm3, hemoglobin  
<9 g/dL. 
10. Clinically evident congestive heart failure (CHF) > class II of the New York Heart Association (NYHA) 
(Appendix D) guidelines.  
11. Current, serious, clinically significant cardiac arrhythmias, defined as the existence of an absolute 
arrhythmia or ventricular arrhythmias classified as Lown III, IV or V (Appendix F). 
12. Baseline QTc >470 msec and/or previous history of QT prolongation while taking other medications.  
13. Concomitant use of medications associated with a high incidence of QT prolongation is not allowed 
(Appendix G). 
14. History or signs of active coronary artery disease with or without angina pectoris within the last 6 
months. 
15. Serious myocardial dysfunction defined by ECHO as absolute left ventricular ejection fraction (LVEF) 
below the institution’s lower limit of predicted normal. 
16. Known history of HIV infection.  
17. Active, clinically significant serious infection requiring treatment with antibiotics, anti-virals or  
anti-fungals. The Medical Monitor should be contacted for any uncertainties. 
18. Major surgery within 30 days prior to date of randomization. 
19. Current or past substance abuse or any condition that might interfere with the subject’s participation in 
the study or in the evaluation of the study results. 
20. Any condition that is unstable and could jeopardize the subject’s participation in the study. 
Number of Subjects: 
Approximately 400 subjects with metastatic, locally advanced or unresectable soft tissue sarcomas 
who have either not responded to or have progressed after treatment with 1 or more systemic 
regimens of non-adjuvant chemotherapies will be randomized 1:1 (aldoxorubicin:investigator’s 
choice) at approximately 120 study centers in the US, Europe, Canada, Latin America, Asia and 
Australia. The randomization will be stratified according to their initial PS (ECOG 0-1 vs 2), whether 
they had either 1 prior systemic non-adjuvant chemotherapy regimens or >1 prior systemic  
non-adjuvant chemotherapy regimens and whether they had received prior doxorubicin 
chemotherapy.  Subjects will also be stratified by their histopathological diagnosis as determined by 
the local site.  The four stratification groups will be leiomyosarcomas, liposarcoma, synovial sarcoma, 
and all other sarcomas. 


ALDOXORUBICIN-P3-STS-01 A1 
August 28, 2013 
 
CytRx Corporation 
CONFIDENTIAL 
Page 7 
Name of Sponsor/Company: CytRx Corporation 
 
Protocol Number:  
ALDOXORUBICIN-P3-STS-01 
Phase of Development: 3 
 
Test Product, Dose and Mode of Administration: 
Aldoxorubicin: Lyophilized powder in vials that contain 200 mg of aldoxorubicin reconstituted by 
adding a solution of 50% ethanol: 50% sterile water, administration completed within 2 hours (of 
being reconstituted) as a 30-minute IVI Lactated Ringer’s solution. Total dose of 350 mg/m2  
(260 mg/m2 doxorubicin equivalent). 
Investigator’s Choice: Up to three treatment regimens are to be chosen by the investigator from the 
list below prior to the initiation of the study site and the treatment chosen for each subject enrolled in 
the study must be entered into the case report form. 
Dacarbazine 100 mg/vial and 200 mg/vial are reconstituted with 9.9 mL and 19.7 mL, respectively, 
Sterile Water for Injection, USP. The resulting solution contains 10 mg/mL of dacarbazine having a 
pH of 3.0 to 4.0. The calculated dose of the resulting solution is drawn into a syringe and 
administered only intravenously. The reconstituted solution may be further diluted with 5% dextrose 
injection, or sodium chloride injection (250 to 500 mL), and administered as an IVI over 90±15 
minutes. 
After reconstitution and prior to use, the solution in the vial may be stored at 4°C for up to 72 hours or 
at normal room conditions (temperature and light) for up to 8 hours. If the reconstituted solution is 
further diluted in 5% dextrose injection or sodium chloride injection, the resulting solution may be 
stored at 4°C for up to 24 hours or at normal room conditions for up to 8 hours. 
Pazopanib (Votrient®) 200 mg tablets can be stored at room temperature between 20° and 25°C; 
excursions are permitted between 15° and 30°C. Tablets are taken 1 hour before or 2 hours after a 
meal and tablets are NOT to be crushed. 
Gemcitabine 200 mg or 1 g lyophilized powder in a single use vial is reconstituted with 0.9% NaCl to 
a final concentration of ≤40 mg/mL and pH 2.7 to 3.3. The reconstituted solution may be further 
diluted with 0.9% NaCl and administered by IVI in <60 minutes. It is stable for up to 24 hours at 
controlled room temperature  
(20° to 25°C) and should not be refrigerated. 
Docetaxel 80 mg/2 mL and 20 mg/0.5 mL with diluents for both strengths (13% [w/w] ethanol in water 
for injection) is administered by IVI over approximately 60 minutes after dilution into a 250 to 500 mL 
infusion bag of either 0.9% NaCl or 5% dextrose solution to produce a final concentration of 0.3 to 
0.74 mg/mL. Docetaxel final dilution for infusion should be administered within 4 hours of preparation. 
It can be stored between 2° and 25°C. 
Doxorubicin HCl Injection is a sterile parenteral, isotonic available in 5 mL (10 mg), 10 mL (20 mg),  
25 mL (50 mg) single dose vials. Each mL contains doxorubicin HCl and the following inactive 
ingredients:  NaCl (0.9%) and water for injection q.s. Hydrochloric acid is used to adjust the pH to a 
target of pH of 3.0. The reconstituted solution is diluted in 0.9% NaCl or 5% dextrose and may be 
administered over 5 to 30 minutes. 
Ifosamide single-dose vials for constitution and administration by IVI each contain 1 gram or 3 grams 
of sterile ifosfamide, USP. Ifosfamide is a chemotherapeutic agent chemically related to the nitrogen 
mustards and a synthetic analog of cyclophosphamide. Injections are prepared for parenteral use by 
adding Sterile Water for Injection, USP, or Sterile Bacteriostatic Water for Injection, USP (benzyl 
alcohol or parabens preserved) to the vial and shaking to dissolve. The reconstituted solution is 
diluted in 0.9% NaCl or 5% dextrose solution and may be administered over 2 to 4 hours. 


ALDOXORUBICIN-P3-STS-01 A1 
August 28, 2013 
 
CytRx Corporation 
CONFIDENTIAL 
Page 8 
Name of Sponsor/Company: CytRx Corporation 
 
Protocol Number:  
ALDOXORUBICIN-P3-STS-01 
Phase of Development: 3 
 
Criteria for Evaluation: 
Efficacy: 
The following efficacy variables will be evaluated as noted: 
 PFS. 
 OS. 
 Objective tumor response (RECIST 1.1 criteria[50]). 
 Disease control rate (objective tumor response + stable disease at 4 months). 
 Subject Reported Outcome as measured by the European Organisation for Research and 
Treatment of Cancer (EORTC) Quality of Life Questionnaire. 
 
Safety: 
The following safety variables will be assessed over the duration of the study: 
 AEs. 
 Ability to remain on assigned treatment (tolerability). 
 Clinical and laboratory data including physical examinations, vital signs, weight, ECHO 
evaluations, ECG results and laboratory test results. 
 Use of concomitant medications. 
Pharmacokinetics: 
The following PK variables will be assessed for aldoxorubicin, doxorubicin, and doxorubicinol: 
 Maximum drug concentration (Cmax) in plasma. 
 Area under the plasma drug-concentration-time profile (AUC). 
 Clearance (CL). 
 Volume of distribution (Vd). 
 Half-life (t½). 


ALDOXORUBICIN-P3-STS-01 A1 
August 28, 2013 
 
CytRx Corporation 
CONFIDENTIAL 
Page 9 
Name of Sponsor/Company: CytRx Corporation 
 
Protocol Number:  
ALDOXORUBICIN-P3-STS-01 
Phase of Development: 3 
 
Statistical Methods: 
In accordance with the intention-to-treat principle, all randomized subjects will be evaluated for 
efficacy. All subjects who receive at least 1 dose of study medication will be evaluated for safety.  
Efficacy:  
The primary analysis of PFS will be carried out when approximately 191 PFS events have been 
observed (approximately 15 months following the completion of enrollment of 400 subjects). Survival 
distributions will be estimated using the Kaplan-Meier method and the two groups will be compared 
using a two-sided log rank test at the α=0.05 level of significance. 
An important secondary endpoint is overall survival (OS). The analysis of OS will be considered 
confirmatory only if the PFS analysis is statistically significant. As a result, the nominal level of 
significance for the OS analysis will be α=0.05. However, because an interim analysis of OS will be 
carried out at the time of the analysis of PFS, the levels of significance for the interim and final 
analyses of OS will be α=0.00305 and α=0.049, respectively. 
The final analysis of OS will be completed when 320 OS events have occurred. Survival distributions 
will be estimated using the Kaplan-Meier method and the two groups will be compared using a two-
sided log rank test at the α=0.049 level of significance. The same methodology will be used for the 
interim analysis, but at the α=0.00305 level of significance. 
Tumor response will be monitored at screening, every 6 weeks from Cycle 1-Day 1 through Week 30, 
and then every 12 weeks until disease progression. The percentage of subjects with complete or 
PRs, or stable disease will be evaluated and the disease control rate (CR, PR and SD at 4 months) 
will be compared using Pearson’s chi-square test, or if 20% or more of the expected cell frequencies 
are <5, Fisher’s exact test. Patient reported outcomes as assessed by the EORTC Quality of Life 
Questionnaire will be analyzed using analysis of covariance. 
Sample Size Justification: 
Power calculations and subject numbers were calculated based on the primary endpoint of 
PFS. Reviewing the literature for studies that have evaluated gemcitabine + docetaxel, 
pazopanib, ifosfamide and dacarbazine as treatment for patients that have relapsed or not 
responded to first line therapies, it is estimated that the median PFS for the investigator’s 
choice group will be 3.5 months and that the median PFS for the aldoxorubicin group will be 
5.6 months. Based on the use of a two-sided log rank test at the α=0.05 level of significance, 
a total of 191 PFS events will be required for 90% power to detect this difference. Assuming 
an 18 month accrual period and a 15 month follow-up period after enrollment of the last 
subject, approximately 400 subjects will be needed to achieve the total of 191 PFS events. 
Safety:  
The safety data will be summarized by treatment group. The treatment groups will be compared with 
respect to occurrence of each AE. Total number of AEs leading to withdrawal, and abnormal 
laboratory tests will be compared between groups using Fisher’s exact test. AEs, ability to remain on 
assigned treatment (tolerability), and abnormal findings on physical examinations, vital signs, weight, 
ECG results, laboratory test results, and use of concomitant medications, will be assessed to 
characterize the safety profile of the treatment regimens. Descriptive statistics denoting the changes 
from baseline to the final assessment visit with respect to key laboratory parameters and vital signs 
will also be provided.  


ALDOXORUBICIN-P3-STS-01 A1 
August 28, 2013 
 
CytRx Corporation 
CONFIDENTIAL 
Page 10 
Name of Sponsor/Company: CytRx Corporation 
 
Protocol Number:  
ALDOXORUBICIN-P3-STS-01 
Phase of Development: 3 
 
Pharmacokinetics:  
All subjects who receive aldoxorubicin and provide at least one PK sample with concentrations above 
the limit of quantification will be included in the PK analysis. Sparse plasma aldoxorubicin, 
doxorubicin, and doxorubicinol concentration data will be analyzed, and aldoxorubicin, doxorubicin, 
and doxorubicinol PK parameters will be estimated based on a population PK analysis. PK 
parameters will be summarized using descriptive statistics. 
Exploratory exposure-response/exposure-safety analyses will be conducted using the primary and 
secondary efficacy endpoints, PFS and OS, and for selected AEs. 


ALDOXORUBICIN-P3-STS-01 A1 
August 28, 2013 
 
CytRx Corporation 
CONFIDENTIAL 
Page 68 
APPENDIX A: Schedule of Treatment and Evaluations 
 
Screening 
-28 Days 
Cycle 
1 
Cycle 
222 
Cycle 
3 
Cycle 
4 
Cycle 
5 
Cycle 
6 
Cycle 
7 
Cycle 
8, 9+ 
Day 15 
and 21 each 
Cycle 
End of 
Treatment23 
Every 6 
Weeks → 
Week 3024 
Every 
12 
Weeks24 
Follow 
Up 
GENERAL AND SAFETY 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Specimen1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X25 
X25 
X25 
 
Height (cm) 
X 
X5 
 
 
 
 
 
 
 
 
 
 
 
 
Weight (kg) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
BSA Calculation5 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Vital Signs6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Adverse Events7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
Survival Follow-Up8 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
ECOG PS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
Concomitant Medications 
X9 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
RADIOGRAPHIC ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT/ MRI Scan / Tumor 
Measurements10 
X11a 
 
 
X11 
 
X11 
 
X11 
 
 
X26 
X 
X 
 
  CARDIAC ASSESSMENTS 
ECG12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X27 
X 
X 
 
ECHO (with ejection fraction)13  
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
  CENTRAL LAB ASSESSMENTS 
CBC w/differential & Platelets14 
X 
X16 
X 
X 
X 
X 
X 
X 
X 
X 
X27 
X 
X 
 
Serum Chemistries14, 15 
X 
X16 
X 
X 
X 
X 
X 
X 
X 
X 
X27 
 
 
 
Pharmacokinetic Sampling18 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis17 
X 
 
 
 
 
 
 
 
 
 
X27 
 
 
 
Serum/Urine Pregnancy Test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


ALDOXORUBICIN-P3-STS-01 A1 
August 28, 2013
CytRx Corporation 
CONFIDENTIAL 
Page 69 
Screening 
-28 Days
Cycle 
1 
Cycle 
222 
Cycle 
3 
Cycle 
4 
Cycle 
5 
Cycle 
6 
Cycle 
7 
Cycle 
8, 9+ 
Day 15 
and 21 each 
Cycle 
End of 
Treatment23 
Every 6 
Weeks → 
Week 3024 
Every 
12 
Weeks24 
Follow 
Up
  LOCAL LAB ASSESSMENTS28 
CBC w/differential & Platelets14 
X16 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Chemistries 14, 15 
X16 
X 
X 
X 
X 
X 
X 
X 
X 
 QUALITY OF LIFE QUESTIONNAIRE 
EORTC QLQ-C30 Version 3 
X 
X 
X 
 CHEMOTHERAPY: ALDOXORUBICIN OR INVESTIGATOR’S CHOICE 
Aldoxorubicin, Doxorubicin, Ifosfamide 
or Dacarbazine Administration19 
X 
X 
X 
X 
X 
X 
X 
X 
Gemcitabine and Docetaxel 
Administration 20 
X 
X 
X 
X 
X 
X 
X 
X 
Pazopanib Administration and Diary21 
X 
X 
X 
X 
X 
X 
X 
X 
NOTE: All assessment must be performed within 72 hours of each specified time parameter, except Cycle 1 (see Section 6 for details). 


CLINICAL PROTOCOL 
TITLE: 
A Multicenter, Randomized, Open-Label Phase 3 Study 
to Investigate the Efficacy and Safety of Aldoxorubicin 
Compared to Investigator’s Choice in Subjects with 
Metastatic, Locally Advanced, or Unresectable Soft 
Tissue Sarcomas Who Either Relapsed or Were 
Refractory to Prior Non-Adjuvant Chemotherapy 
PROTOCOL NUMBER: 
ALDOXORUBICIN-P3-STS-01 
STUDY DRUG: 
Aldoxorubicin 
IND NUMBER: 
113,695 
EUDRACT NUMBER: 
2013-004103-40 
SPONSOR:  
CytRx Corporation 
11726 San Vicente Blvd 
Los Angeles, CA 90049 
(310) 826-5648
FAX: (310) 826-6139
IMMEDIATE SAFETY ASSISTANCE: 
Region 
Hotline 
Fax 
Email 
North America 
Australia 
Asia 
Latin America 
1-866-326-5053
or 
1-434-951-4082
1-800-280-7035
or 
1-913-307-5751
AldoxP3STS@PRAIntl.com 
Europe 
+44 1792 52-5608
+49 621 878-2828
AldoxP3STS@PRAIntl.com 
SAE SUBMISSION: 
Region 
SAE Fax 
SAE Email 
North America 
1-888-772-6919
CHOSafety@PRAIntl.com 
Rest of World 
+44 1792 525-720
MHGSafety@PRAIntl.com 
ORIGINAL PROTOCOL: 
April 3, 2013 
AMENDMENT 1: 
August 28, 2013 
AMENDMENT 2: 
March 21, 2014 
CONFIDENTIAL 
The information contained in this document is confidential and the proprietary property of CytRx 
Corporation. Any unauthorized use or disclosure of such information without the prior written 
authorization of CytRx Corporation is prohibited. 


ALDOXORUBICIN-P3-STS-01 A2 
March 21 2014 
PROTOCOL SIGNATURE PAGE 
A Multicenter, Randomized, Open-Label Phase 3 Study to Investigate the 
Efficacy and Safety of Aldoxorubicin Compared to Investigator's Choice in 
Subjects with Metastatic, Locally Advanced, or Unresectable Soft Tissue 
Sarcomas Who Either Relapsed or Were Refractory to Prior Non-Adjuvant 
Chemotherapy 
By signing below, the Investigator agrees to adhere to the protocol as outlined and agrees 
that any changes to the protocol must be approved by CytRx Corporation (CytRx) prior to 
seeking approval from the Institutional Review Board (IRB)/lndependent Ethics Committee 
(IEC). 
The study will be conducted in accordance with current United States (US) Food and Drug 
Administration (FDA) regulations, International Conference on Harmonization (ICH) 
guidelines, Good Clinical Practice (GCP) guidelines, the principles of the Declaration of 
Helsinki, and other applicable regulations and guidelines. 
I agree to ensure that Financial Disclosure Statements will be completed by: 
• 
me (including, if applicable, my spouse [or legal partner) and dependent children) 
• 
my subinvestigators (including, if applicable, their spouses [or legal partner] and 
dependent children) 
at the start of the study and for up to 1 year after the study is completed, if there are 
changes that affect my financial disclosure status. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of CytRx. 
Investigator's Signature:-----------------
Printed Name:---------------------
Name of Institution/Company: ---------------
Date: _______________________ _ 
Sponsor Signature: ___ QJ 
_____ · ___ C:U-
__ . _______ _ 
Daniel Levitt, M.D., Ph.D. 
Chief Medical Officer 
CytRx Corporation 
/) 
Date: 
CytRx Corporation 
CONFIDENTIAL 
Page 2 


ALDOXORUBICIN-P3-STS-01 A2 
March 21, 2014 
 
CytRx Corporation 
CONFIDENTIAL 
Page 3 
Protocol Synopsis 
Name of Sponsor/Company: CytRx Corporation 
 
Protocol Number:  
ALDOXORUBICIN-P3-STS-01 
Phase of Development: 3 
 
Title of the Protocol:  
A Multicenter, Randomized, Open-Label Phase 3 Study to Investigate the Efficacy and Safety of 
Aldoxorubicin Compared to Investigator’s Choice in Subjects with Metastatic, Locally Advanced, or 
Unresectable Soft Tissue Sarcomas Who Either Relapsed or Were Refractory to Prior Non-Adjuvant 
Chemotherapy 
Primary Objective: 
The primary objective of this study is to determine the efficacy of administration of aldoxorubicin 
compared to investigator’s choice of treatment in subjects with metastatic, locally advanced, or 
unresectable soft tissue sarcomas who have relapsed or were refractory to prior non-adjuvant 
chemotherapy, as measured by progression-free survival (PFS). 
Secondary Objectives: 
The secondary objectives of this study are to evaluate the efficacy of aldoxorubicin as measured by 
OS, safety of aldoxorubicin compared to investigator’s choice in this population assessed by the 
frequency and severity of adverse events (AEs), abnormal findings on physical examination, 
laboratory tests, vital signs, echocardiogram (ECHO) evaluations, electrocardiogram (ECG) results, 
and weight, as well as disease control rate, and tumor response. 
Exploratory Objectives: 
To determine the pharmacokinetics (PK) of aldoxorubicin, doxorubicin, and doxorubicinol following 
intravenous (IV) administration of aldoxorubicin, and to evaluate the exposure-response relationships 
between aldoxorubicin, doxorubicin, and/or doxorubicinol and PFS, OS, selected safety parameters, 
and quality of life. 
Study Rationale and Significance: 
Aldoxorubicin (INNO-206; DOXO-EMCH) is a novel prodrug that binds covalently to circulating 
albumin. The drug is accumulated in tumors and doxorubicin is released in the tumor by cleaving the 
acid labile linker (EMCH) in the low pH tumor environment. This carrier-linked prodrug has 
demonstrated enhanced antitumor activity with reduced toxicity in several murine models when 
compared with free doxorubicin. 
Patients with metastatic, locally advanced, or unresectable soft tissue sarcomas who have failed prior 
chemotherapies have a poor prognosis with PFS of around 2-4.6 months and median OS of 
approximately 9-12 months. Several chemotherapy regimens have been explored as palliative 
therapy for subjects with these patients and include such agents as ifosfamide, gemcitabine, 
docetaxel, vinorelbine, dacarbazine, temozolomide, epirubicin, pazopanib and liposomal doxorubicin. 
However, these regimens can be quite toxic and have not significantly impacted either progression-
free or OS in these individuals. Pazopanib, recently approved in the US and Europe, does appear to 
extend PFS in soft tissue sarcoma patients (except liposarcomas) who have relapsed after receiving 
prior chemotherapy compared to no treatment, but does not increase OS. Aldoxorubicin may improve 
upon the activity of doxorubicin without an increase in toxicity as has been demonstrated in animal 
studies. 


ALDOXORUBICIN-P3-STS-01 A2 
March 21, 2014 
 
CytRx Corporation 
CONFIDENTIAL 
Page 4 
Name of Sponsor/Company: CytRx Corporation 
 
Protocol Number:  
ALDOXORUBICIN-P3-STS-01 
Phase of Development: 3 
 
Study Design and Methodology: 
This is a phase 3 open-label study evaluating the efficacy and safety of aldoxorubicin administered at 
350 mg/m2 (260 mg/m2 doxorubicin equivalent) intravenously on Day 1 every 21 days until tumor 
progression or unacceptable toxicity occurs compared to investigator’s choice of treatment among  
5 different therapies. These therapies include:  1) dacarbazine administered at 1000 mg/m2 by 
intravenous infusion (IVI), over 90±15 minutes on Day 1 every 21 days until tumor progression or 
unacceptable toxicity occurs; 2) pazopanib, 800 mg orally each day until tumor progression or 
unacceptable toxicity occurs; 3) gemcitabine, 900 mg/m2 by IVI in less than 60 minutes on Days 1 
and 8, plus docetaxel, 100 mg/m2 by IVI over 1 hour on Day 8 of a 21 day cycle until tumor 
progression or unacceptable toxicity occurs; 4) doxorubicin, 75 mg/m2 by IVI over 5 to 30 minutes 
every 21 days for a maximum cumulative dose of 550 mg/m2 or unacceptable toxicity occurs; or 5) 
ifosfamide 2.0 g/m2 administered over 2 to 4 hours on Days 1-4 of a 21 day cycle + mesna per 
standard site administration regimen until tumor progression or unacceptable toxicity occurs. The 
investigative site must pre-specify their choice of treatments for the comparator arm to be used at 
their site, and no more than 3 treatment regimens may be selected for the comparator arm at each 
site which must be selected prior to the study site initiation visit. Subjects will be randomized 1:1 to 
receive either aldoxorubicin or investigator’s choice of up to 3 control regimens pre-selected by the 
study site. Pretreatment with G-CSF is permitted according to ASCO Guidelines (Appendix E). 
All Screening requirements, including an ECHO exam, must be completed within 28 days of the  
Cycle 1-Day 1 visit. Subjects receiving aldoxorubicin, ifosfamide, dacarbazine or doxorubicin will  
visit the study site on Day 1 of each cycle. They will have complete blood counts (CBC) and serum 
chemistries on Day 15 and Day 21 (if Day 21 does not correspond to Day 1 of the next cycle,  
±3 days) of each cycle as well. Subjects receiving pazopanib will visit the study site on Day 1 of their 
next cycle for monitoring, testing (same as for Day 1 for other treatment regimens) and to receive a 
new supply of study drug. Subjects receiving pazopanib will also have CBC and serum chemistry on 
Day 15 and Day 28 (if Day 28 does not correspond to Day 1 of the next cycle, ±2 days). Subjects 
receiving gemcitabine plus docetaxel will visit the study site on both days of their infusions (Days 1 
and 8) and at Days 15 and 21 of each cycle. Safety monitoring, including AEs, a directed physical 
examination, laboratory evaluations (serum chemistry, CBC, and urinalysis), vital signs, weight 
measurements, Eastern Cooperative Oncology Group (ECOG) performance status (PS) and ECGs 
will be performed on Day 1 (for all subjects) of each cycle. Cardiac function will also be followed 
periodically (per Schedule of Treatment and Evaluations in Appendix A) with ECHOs for subjects 
receiving either aldoxorubicin or doxorubicin. Treatment will continue until tumor progression is 
observed, a maximum cumulative dose of 550 mg/m2 is reached (doxorubicin), subject asks to 
withdraw, unacceptable toxicity occurs, a change in therapy would be in the best interest of the 
subject, subject becomes pregnant or fails to use adequate birth control, need for any treatment not 
allowed by the protocol, or subject is non-compliant with study requirements. 
Tumor response will be monitored at screening, every 6 weeks from Cycle 1-Day 1 through Week 30, 
and then every 12 weeks until disease progression using the Response Evaluation Criteria in Solid 
Tumors (RECIST) 1.1 criteria.[50] OS, PFS, and PFS at 4 and 6 months will be evaluated. Objective 
overall response rate (ORR) (complete and partial responses [PRs]), disease control rate (objective 
responses plus stable disease at 4 months) and quality of life will be assessed.  
The PK of aldoxorubicin, doxorubicin, and doxorubicinol will be evaluated using a sparse sample 
analysis. Plasma samples will be collected at Cycle 1 at the following time points: the end of the 
infusion, between 1.5 and 4 hours from the end of the infusion, and on Days 2, and 3. If necessary 
and possible, PK samples may be collected at a later cycle. 


ALDOXORUBICIN-P3-STS-01 A2 
March 21, 2014 
 
CytRx Corporation 
CONFIDENTIAL 
Page 5 
Name of Sponsor/Company: CytRx Corporation 
 
Protocol Number:  
ALDOXORUBICIN-P3-STS-01 
Phase of Development: 3 
 
Study Population and Main Criteria for Inclusion/Exclusion: 
Inclusion Criteria: 
Subjects must meet the following criteria to be included in the study: 
1. Has provided written informed consent prior to any study related activities. 
2. Age ≥15 years (US only), and 18-80 (rest of world (ROW)), male or female. 
3. Histological confirmation of intermediate or high grade soft-tissue sarcoma. Tissue must be sent to a 
central pathology lab for review but will not preclude entry onto the study. Final assignment of tumor 
grade and histology will be based on the designation provided by the central pathology review. 
4. An adequate tumor specimen obtained by either excisional biopsy, incisional biopsy or core 
needle biopsy must be sent to the central pathology lab for evaluation. The material must 
measure at least 0.8 × 0.1 cm in size or contain at least 50 tumor cells. 
5. Locally advanced, unresectable, and/or metastatic soft-tissue sarcoma of intermediate or high grade 
with evidence of disease progression by either computed tomography (CT) or magnetic resonance 
imaging (MRI) scan, or clinical judgment on or after the last cancer therapy within 6 months prior to 
randomization. 
6. Relapsed or refractory (lack of response) to ≥1 course of systemic therapy regimen(s), excluding 
adjuvant or neoadjuvant chemotherapy, and is incurable by either surgery or radiation. 
7. Capable of providing informed consent and complying with trial procedures. 
8. ECOG PS 0-2. 
9. Life expectancy >12 weeks. 
10. Measurable tumor lesions according to RECIST 1.1 criteria.[50] 
11. Women must not be able to become pregnant (e.g., post-menopausal for at least 1 year, surgically 
sterile, or practicing adequate birth control methods) for the duration of the study. (Adequate 
contraception includes: oral contraception, implanted contraception, intrauterine device implanted for 
at least 3 months, or barrier method in conjunction with spermicide.) 
12. Males and their female partner(s) of child-bearing potential must use 2 forms of effective contraception 
(see Inclusion 11 plus condom or vasectomy for males) from the last menstrual period of the female 
partner during the study treatment and agree to continue use for 6 months after the final dose of study 
treatment. 
13. Women of child bearing potential must have a negative serum or urine pregnancy test at the Screening 
Visit and be non-lactating. 
14. Accessibility to the site that optimizes the subject’s ability to keep all study-related appointments.  
Exclusion Criteria: 
Subjects meeting the following criteria will not be enrolled: 
1. Prior exposure to >375 mg/m2 of doxorubicin or liposomal doxorubicin. 
2. Palliative surgery and/or radiation treatment within 30 days prior to date of randomization. 
3. Exposure to any investigational agent within 30 days of date of randomization. 
4. Exposure to any systemic chemotherapy within 30 days of date of randomization. 
5. An inadequate tumor specimen as defined by the central pathologist. 
6. Current evidence/diagnosis of alveolar soft part sarcoma, extraskeletal myxoid chondrosarcoma, 
rhabdomyosarcoma, osteosarcoma, gastrointestinal stromal tumor (GIST), dermatofibrosarcoma 
(unless transformed to fibrosarcoma), Ewing’s sarcoma, Kaposi’s sarcoma, mixed mesodermal tumor, 
clear cell sarcomas. 
7. Evidence of central nervous system (CNS) metastasis who have not received prior definitive therapy 
for their lesions.  
8. History of other malignancies except cured basal cell carcinoma, cutaneous squamous cell carcinoma, 
melanoma in situ, superficial bladder cancer or carcinoma in situ of the cervix unless documented free 
of cancer for ≥5 years. 


ALDOXORUBICIN-P3-STS-01 A2 
March 21, 2014 
 
CytRx Corporation 
CONFIDENTIAL 
Page 6 
Name of Sponsor/Company: CytRx Corporation 
 
Protocol Number:  
ALDOXORUBICIN-P3-STS-01 
Phase of Development: 3 
 
9. Laboratory values: Screening serum creatinine >1.5 x upper limit of normal (ULN), alanine 
aminotransferase (ALT) >3×ULN or >5×ULN if liver metastases are present, total bilirubin >2×ULN, 
absolute neutrophil count (ANC) <1,500/mm3, platelet concentration <100,000/mm3, hemoglobin  
<9 g/dL. 
10. Clinically evident congestive heart failure (CHF) > class II of the New York Heart Association (NYHA) 
(Appendix D) guidelines.  
11. Current, serious, clinically significant cardiac arrhythmias, defined as the existence of an absolute 
arrhythmia or ventricular arrhythmias classified as Lown III, IV or V (Appendix F). 
12. Baseline QTc >470 msec and/or previous history of QT prolongation while taking other medications.  
13. Concomitant use of medications associated with a high incidence of QT prolongation is not allowed 
(Appendix G). 
14. History or signs of active coronary artery disease with or without angina pectoris within the last 6 
months. 
15. Serious myocardial dysfunction defined by ECHO as absolute left ventricular ejection fraction (LVEF) 
below the institution’s lower limit of predicted normal. 
16. Known history of HIV infection.  
17. Active, clinically significant serious infection requiring treatment with antibiotics, anti-virals or  
anti-fungals. The Medical Monitor should be contacted for any uncertainties. 
18. Major surgery within 30 days prior to date of randomization. 
19. Current or past substance abuse or any condition that might interfere with the subject’s participation in 
the study or in the evaluation of the study results. 
20. Any condition that is unstable and could jeopardize the subject’s participation in the study. 
Number of Subjects: 
Approximately 400 subjects with metastatic, locally advanced or unresectable soft tissue sarcomas 
who have either not responded to or have progressed after treatment with 1 or more systemic 
regimens of non-adjuvant chemotherapies will be randomized 1:1 (aldoxorubicin:investigator’s 
choice) at approximately 120 study centers in the US, Europe, Canada, Latin America, Asia and 
Australia. The randomization will be stratified according to their initial PS (ECOG 0-1 vs 2), whether 
they had either 1 prior systemic non-adjuvant chemotherapy regimens or >1 prior systemic  
non-adjuvant chemotherapy regimens and whether they had received prior doxorubicin 
chemotherapy.  Subjects will also be stratified by their histopathological diagnosis as determined by 
the local site.  The four stratification groups will be leiomyosarcomas, liposarcoma, synovial sarcoma, 
and all other sarcomas. 


ALDOXORUBICIN-P3-STS-01 A2 
March 21, 2014 
 
CytRx Corporation 
CONFIDENTIAL 
Page 7 
Name of Sponsor/Company: CytRx Corporation 
 
Protocol Number:  
ALDOXORUBICIN-P3-STS-01 
Phase of Development: 3 
 
Test Product, Dose and Mode of Administration: 
Aldoxorubicin: Lyophilized powder in vials that contain 200 mg of aldoxorubicin reconstituted by 
adding a solution of 50% ethanol: 50% sterile water, administration completed within 2 hours (of 
being reconstituted) as a 30-minute IVI Lactated Ringer’s solution. Total dose of 350 mg/m2  
(260 mg/m2 doxorubicin equivalent). 
Investigator’s Choice: Up to three treatment regimens are to be chosen by the investigator from the 
list below prior to the initiation of the study site and the treatment chosen for each subject enrolled in 
the study must be entered into the case report form. 
Dacarbazine 100 mg/vial and 200 mg/vial are reconstituted with 9.9 mL and 19.7 mL, respectively, 
Sterile Water for Injection, USP. The resulting solution contains 10 mg/mL of dacarbazine having a 
pH of 3.0 to 4.0. The calculated dose of the resulting solution is drawn into a syringe and 
administered only intravenously. The reconstituted solution may be further diluted with 5% dextrose 
injection, or sodium chloride injection (250 to 500 mL), and administered as an IVI over 90±15 
minutes. 
After reconstitution and prior to use, the solution in the vial may be stored at 4°C for up to 72 hours or 
at normal room conditions (temperature and light) for up to 8 hours. If the reconstituted solution is 
further diluted in 5% dextrose injection or sodium chloride injection, the resulting solution may be 
stored at 4°C for up to 24 hours or at normal room conditions for up to 8 hours. 
Pazopanib (Votrient®) 200 mg tablets can be stored at room temperature between 20° and 25°C; 
excursions are permitted between 15° and 30°C. Tablets are taken 1 hour before or 2 hours after a 
meal and tablets are NOT to be crushed. 
Gemcitabine 200 mg or 1 g lyophilized powder in a single use vial is reconstituted with 0.9% NaCl to 
a final concentration of ≤40 mg/mL and pH 2.7 to 3.3. The reconstituted solution may be further 
diluted with 0.9% NaCl and administered by IVI in <60 minutes. It is stable for up to 24 hours at 
controlled room temperature (20° to 25°C) and should not be refrigerated. 
Docetaxel 80 mg/2 mL and 20 mg/0.5 mL with diluents for both strengths (13% [w/w] ethanol in water 
for injection) is administered by IVI over approximately 60 minutes after dilution into a 250 to 500 mL 
infusion bag of either 0.9% NaCl or 5% dextrose solution to produce a final concentration of 0.3 to 
0.74 mg/mL. Docetaxel final dilution for infusion should be administered within 4 hours of preparation. 
It can be stored between 2° and 25°C. 
Doxorubicin HCl Injection is a sterile parenteral, isotonic available in 5 mL (10 mg), 10 mL (20 mg),  
25 mL (50 mg) single dose vials. Each mL contains doxorubicin HCl and the following inactive 
ingredients:  NaCl (0.9%) and water for injection q.s. Hydrochloric acid is used to adjust the pH to a 
target of pH of 3.0. The reconstituted solution is diluted in 0.9% NaCl or 5% dextrose and may be 
administered over 5 to 30 minutes. 
Ifosamide single-dose vials for constitution and administration by IVI each contain 1 gram or 3 grams 
of sterile ifosfamide, USP. Ifosfamide is a chemotherapeutic agent chemically related to the nitrogen 
mustards and a synthetic analog of cyclophosphamide. Injections are prepared for parenteral use by 
adding Sterile Water for Injection, USP, or Sterile Bacteriostatic Water for Injection, USP (benzyl 
alcohol or parabens preserved) to the vial and shaking to dissolve. The reconstituted solution is 
diluted in 0.9% NaCl or 5% dextrose solution and may be administered over 2 to 4 hours. 
See Section 5.2 for additional investigator’s choice treatment concentrations and preparation 
instructions as per package inserts. 


ALDOXORUBICIN-P3-STS-01 A2 
March 21, 2014 
 
CytRx Corporation 
CONFIDENTIAL 
Page 8 
Name of Sponsor/Company: CytRx Corporation 
 
Protocol Number:  
ALDOXORUBICIN-P3-STS-01 
Phase of Development: 3 
 
Criteria for Evaluation: 
Efficacy: 
The following efficacy variables will be evaluated as noted: 
 PFS. 
 OS. 
 Objective tumor response (RECIST 1.1 criteria[50]). 
 Disease control rate (objective tumor response + stable disease at 4 months). 
 Subject Reported Outcome as measured by the European Organisation for Research and 
Treatment of Cancer (EORTC) Quality of Life Questionnaire. 
 
Safety: 
The following safety variables will be assessed over the duration of the study: 
 AEs. 
 Ability to remain on assigned treatment (tolerability). 
 Clinical and laboratory data including physical examinations, vital signs, weight, ECHO 
evaluations, ECG results and laboratory test results. 
 Use of concomitant medications. 
Pharmacokinetics: 
The following PK variables will be assessed for aldoxorubicin, doxorubicin, and doxorubicinol: 
 Maximum drug concentration (Cmax) in plasma. 
 Area under the plasma drug-concentration-time profile (AUC). 
 Clearance (CL). 
 Volume of distribution (Vd). 
 Half-life (t½). 


ALDOXORUBICIN-P3-STS-01 A2 
March 21, 2014 
 
CytRx Corporation 
CONFIDENTIAL 
Page 9 
Name of Sponsor/Company: CytRx Corporation 
 
Protocol Number:  
ALDOXORUBICIN-P3-STS-01 
Phase of Development: 3 
 
Statistical Methods: 
In accordance with the intention-to-treat principle, all randomized subjects will be evaluated for 
efficacy. All subjects who receive at least 1 dose of study medication will be evaluated for safety.  
Efficacy:  
The primary analysis of PFS will be carried out when approximately 191 PFS events have been 
observed (approximately 15 months following the completion of enrollment of 400 subjects). Survival 
distributions will be estimated using the Kaplan-Meier method and the two groups will be compared 
using a two-sided log rank test at the α=0.05 level of significance. 
An important secondary endpoint is overall survival (OS). The analysis of OS will be considered 
confirmatory only if the PFS analysis is statistically significant. As a result, the nominal level of 
significance for the OS analysis will be α=0.05. However, because an interim analysis of OS will be 
carried out at the time of the analysis of PFS, the levels of significance for the interim and final 
analyses of OS will be α=0.00305 and α=0.049, respectively. 
The final analysis of OS will be completed when 320 OS events have occurred. Survival distributions 
will be estimated using the Kaplan-Meier method and the two groups will be compared using a two-
sided log rank test at the α=0.049 level of significance. The same methodology will be used for the 
interim analysis, but at the α=0.00305 level of significance. 
Tumor response will be monitored at screening, every 6 weeks from Cycle 1-Day 1 through Week 30, 
and then every 12 weeks until disease progression. The percentage of subjects with complete or 
PRs, or stable disease will be evaluated and the disease control rate (CR, PR and SD at 4 months) 
will be compared using Pearson’s chi-square test, or if 20% or more of the expected cell frequencies 
are <5, Fisher’s exact test. Patient reported outcomes as assessed by the EORTC Quality of Life 
Questionnaire will be analyzed using analysis of covariance. 
Sample Size Justification: 
Power calculations and subject numbers were calculated based on the primary endpoint of PFS. 
Reviewing the literature for studies that have evaluated gemcitabine + docetaxel, pazopanib, 
ifosfamide and dacarbazine as treatment for patients that have relapsed or not responded to first line 
therapies, it is estimated that the median PFS for the investigator’s choice group will be 3.5 months 
and that the median PFS for the aldoxorubicin group will be 5.6 months. Based on the use of a two-
sided log rank test at the α=0.05 level of significance, a total of 191 PFS events will be required for 
90% power to detect this difference. Assuming an 18 month accrual period and a 15 month follow-up 
period after enrollment of the last subject, approximately 400 subjects will be needed to achieve the 
total of 191 PFS events. 
Safety:  
The safety data will be summarized by treatment group. The treatment groups will be compared with 
respect to occurrence of each AE. Total number of AEs leading to withdrawal, and abnormal 
laboratory tests will be compared between groups using Fisher’s exact test. AEs, ability to remain on 
assigned treatment (tolerability), and abnormal findings on physical examinations, vital signs, weight, 
ECG results, laboratory test results, and use of concomitant medications, will be assessed to 
characterize the safety profile of the treatment regimens. Descriptive statistics denoting the changes 
from baseline to the final assessment visit with respect to key laboratory parameters and vital signs 
will also be provided.  


ALDOXORUBICIN-P3-STS-01 A2 
March 21, 2014 
 
CytRx Corporation 
CONFIDENTIAL 
Page 10 
Name of Sponsor/Company: CytRx Corporation 
 
Protocol Number:  
ALDOXORUBICIN-P3-STS-01 
Phase of Development: 3 
 
Pharmacokinetics:  
All subjects who receive aldoxorubicin and provide at least one PK sample with concentrations above 
the limit of quantification will be included in the PK analysis. Sparse plasma aldoxorubicin, 
doxorubicin, and doxorubicinol concentration data will be analyzed, and aldoxorubicin, doxorubicin, 
and doxorubicinol PK parameters will be estimated based on a population PK analysis. PK 
parameters will be summarized using descriptive statistics. 
Exploratory exposure-response/exposure-safety analyses will be conducted using the primary and 
secondary efficacy endpoints, PFS and OS, and for selected AEs. 


ALDOXORUBICIN-P3-STS-01 A2 
March 21, 2014 
 
CytRx Corporation 
CONFIDENTIAL 
Page 68 
APPENDIX A: Schedule of Treatment and Evaluations 
 
Screening 
-28 Days 
Cycle 
1 
Cycle 
222 
Cycle 
3 
Cycle 
4 
Cycle 
5 
Cycle 
6 
Cycle 
7 
Cycle 
8, 9+ 
Day 15 and 21 
(28 for pazopanib) 
each Cycle 
End of 
Treatment23 
Every 6 
Weeks → 
Week 3024 
Every 
12 
Weeks24 
Follow 
Up 
GENERAL AND SAFETY 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Specimen1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X25 
X25 
X25 
 
Height (cm) 
X 
X5 
 
 
 
 
 
 
 
 
 
 
 
 
Weight (kg) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
BSA Calculation5 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Vital Signs6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Adverse Events7 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
Survival Follow-Up8 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
ECOG PS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
Concomitant Medications 
X9 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
RADIOGRAPHIC ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT/ MRI Scan / Tumor 
Measurements10 
X11a 
 
 
X11 
 
X11 
 
X11 
 
 
X26 
X 
X 
 
  CARDIAC ASSESSMENTS 
ECG12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X27 
X 
X 
 
ECHO (with ejection fraction)13  
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
  CENTRAL LAB ASSESSMENTS 
CBC w/differential & Platelets14 
X 
X16 
X 
X 
X 
X 
X 
X 
X 
X 
X27 
X 
X 
 
Serum Chemistries14, 15 
X 
X16 
X 
X 
X 
X 
X 
X 
X 
X 
X27 
 
 
 
Pharmacokinetic Sampling18 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis17 
X 
 
 
 
 
 
 
 
 
 
X27 
 
 
 
Serum/Urine Pregnancy Test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


ALDOXORUBICIN-P3-STS-01 A2 
March 21, 2014 
 
CytRx Corporation 
CONFIDENTIAL 
Page 69 
 
Screening 
-28 Days 
Cycle 
1 
Cycle 
222 
Cycle 
3 
Cycle 
4 
Cycle 
5 
Cycle 
6 
Cycle 
7 
Cycle 
8, 9+ 
Day 15 and 21 
(28 for pazopanib) 
each Cycle 
End of 
Treatment23 
Every 6 
Weeks → 
Week 3024 
Every 
12 
Weeks24 
Follow 
Up 
  LOCAL LAB ASSESSMENTS28 
CBC w/differential & Platelets14 
 
X16 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Serum Chemistries 14, 15 
 
X16 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
  QUALITY OF LIFE QUESTIONNAIRE 
EORTC QLQ-C30 Version 3 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
  CHEMOTHERAPY: ALDOXORUBICIN OR INVESTIGATOR’S CHOICE 
Aldoxorubicin, Doxorubicin, Ifosfamide 
or Dacarbazine Administration19 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Gemcitabine and Docetaxel 
Administration 20 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Pazopanib Administration and Diary21 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
NOTE: All assessment must be performed within 72 hours of each specified time parameter (48 hours for pazopanib treated subjects), except Cycle 1 (see 
Section 6 for details). 


CLINICAL PROTOCOL 
TITLE: 
A Multicenter, Randomized, Open-Label Phase 3 Study to Investigate 
the Efficacy and Safety of Aldoxorubicin Compared to Investigator’s 
Choice in Subjects with Metastatic, Locally Advanced, or Unresectable 
Soft Tissue Sarcomas Who Either Relapsed or Were Refractory to Prior 
Non-Adjuvant Chemotherapy 
PROTOCOL NUMBER: 
ALDOXORUBICIN-P3-STS-01 
STUDY DRUG: 
Aldoxorubicin 
IND NUMBER: 
113,695 
EUDRACT NUMBER: 
2013-004103-40 
SPONSOR:  
CytRx Corporation 
11726 San Vicente Blvd 
Los Angeles, CA 90049 
(310) 826-5648
FAX: (310) 826-6139
IMMEDIATE SAFETY ASSISTANCE: 
Region 
Hotline 
Fax 
Email 
North America 
Australia 
Latin America 
1-866-326-5053
or 
1-434-951-4082
1-800-280-7035
or 
1-913-307-5751
AldoxP3STS@PRAIntl.com 
Europe 
+44 1792 52-5608
+49 621 878-2828
AldoxP3STS@PRAIntl.com 
SAE SUBMISSION: 
Region 
SAE Fax 
SAE Email 
North America 
1-888-772-6919
CHOSafety@PRAIntl.com 
Rest of World 
+44 1792 525-720
MHGSafety@PRAIntl.com 
ORIGINAL PROTOCOL: 
April 3, 2013 
AMENDMENT 1: 
August 28, 2013 
AMENDMENT 2: 
March 21, 2014 
AMENDMENT 3: 
January 13, 2015 
CONFIDENTIAL 
The information contained in this document is confidential and the proprietary property of CytRx 
Corporation. Any unauthorized use or disclosure of such information without the prior written 
authorization of CytRx Corporation is prohibited. 


ALDOXORUBICIN-P3-STS-01 A3 
January 13, 2015 
PROTOCOL SIGNATURE PAGE 
A Multicenter, Randomized, Open-Label Phase 3 Study to Investigate the 
Efficacy and Safety of Aldoxorubicin Compared to Investigator's Choice in 
Subjects with Metastatic, Locally Advanced, or Unresectable Soft Tissue 
Sarcomas Who Either Relapsed or Were Refractory to Prior Non-Adjuvant 
Chemotherapy 
By signing below, the Investigator agrees to adhere to the protocol as outlined and agrees 
that any changes to the protocol must be approved by CytRx Corporation (CytRx) prior to 
seeking approval from the Institutional Review Board (IRB)/lndependent Ethics Committee 
(IEC). 
The study will be conducted in accordance with current United States (US) Food and Drug 
Administration (FDA) regulations, International Conference on Harmonization (ICH) 
guidelines, Good Clinical Practice (GCP) guidelines, the principles of the Declaration of 
Helsinki, and other applicable regulations and guidelines. 
I agree to ensure that Financial Disclosure Statements will be completed by: 
• 
me (including, if applicable, my spouse [or legal partner] and dependent children) 
• 
my subinvestigators (including, if applicable, their spouses [or legal partner] and 
dependent children) 
at the start of the study and for up to 1 year after the study is completed, if there are 
changes that affect my financial disclosure status. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of CytRx. 
Investigator's Signature: ------------------
Printed Name:---------------------
Name of Institution/Company: ---------------
Date: 
Sponsor Signature: ___ Q 
__ 
_____ _ 
Daniel Levitt, M.D., Ph.D. 
Chief Medical Officer 
CytRx Corporation 
Date: ______ 
:::,=--------
CytRx Corporation 
CONFIDENTIAL 
Page2 


ALDOXORUBICIN-P3-STS-01 A3 
January 13, 2015 
 
CytRx Corporation 
CONFIDENTIAL 
Page 3 
Protocol Synopsis 
Name of Sponsor/Company: CytRx Corporation 
 
Protocol Number:  
ALDOXORUBICIN-P3-STS-01 
Phase of Development: 3 
 
Title of the Protocol:  
A Multicenter, Randomized, Open-Label Phase 3 Study to Investigate the Efficacy and Safety of 
Aldoxorubicin Compared to Investigator’s Choice in Subjects with Metastatic, Locally Advanced, or 
Unresectable Soft Tissue Sarcomas Who Either Relapsed or Were Refractory to Prior Non-Adjuvant 
Chemotherapy 
Primary Objective: 
The primary objective of this study is to determine the efficacy of administration of aldoxorubicin 
compared to investigator’s choice of treatment in subjects with metastatic, locally advanced, or 
unresectable soft tissue sarcomas who have relapsed or were refractory to prior non-adjuvant 
chemotherapy, as measured by progression-free survival (PFS). 
Secondary Objectives: 
The secondary objectives of this study are to evaluate the efficacy of aldoxorubicin as measured by 
OS, safety of aldoxorubicin compared to investigator’s choice in this population assessed by the 
frequency and severity of adverse events (AEs), abnormal findings on physical examination, 
laboratory tests, vital signs, echocardiogram (ECHO) evaluations, electrocardiogram (ECG) results, 
and weight, as well as disease control rate, and tumor response. 
Exploratory Objectives: 
To determine the pharmacokinetics (PK) of aldoxorubicin, doxorubicin, and doxorubicinol following 
intravenous (IV) administration of aldoxorubicin, and to evaluate the exposure-response relationships 
between aldoxorubicin, doxorubicin, and/or doxorubicinol and PFS, OS, selected safety parameters, 
and quality of life. 
Study Rationale and Significance: 
Aldoxorubicin (INNO-206; DOXO-EMCH) is a novel prodrug that binds covalently to circulating 
albumin. The drug is accumulated in tumors and doxorubicin is released in the tumor by cleaving the 
acid labile linker (EMCH) in the low pH tumor environment. This carrier-linked prodrug has 
demonstrated enhanced antitumor activity with reduced toxicity in several murine models when 
compared with free doxorubicin. 
Patients with metastatic, locally advanced, or unresectable soft tissue sarcomas who have failed prior 
chemotherapies have a poor prognosis with PFS of around 2-4.6 months and median OS of 
approximately 9-12 months. Several chemotherapy regimens have been explored as palliative 
therapy for subjects with these patients and include such agents as ifosfamide, gemcitabine, 
docetaxel, vinorelbine, dacarbazine, temozolomide, epirubicin, pazopanib and liposomal doxorubicin. 
However, these regimens can be quite toxic and have not significantly impacted either progression-
free or OS in these individuals. Pazopanib, recently approved in the US and Europe, does appear to 
extend PFS in soft tissue sarcoma patients (except liposarcomas) who have relapsed after receiving 
prior chemotherapy compared to no treatment, but does not increase OS. Aldoxorubicin may improve 
upon the activity of doxorubicin without an increase in toxicity as has been demonstrated in animal 
studies. 


ALDOXORUBICIN-P3-STS-01 A3 
January 13, 2015 
 
CytRx Corporation 
CONFIDENTIAL 
Page 4 
Name of Sponsor/Company: CytRx Corporation 
 
Protocol Number:  
ALDOXORUBICIN-P3-STS-01 
Phase of Development: 3 
 
Study Design and Methodology: 
This is a phase 3 open-label study evaluating the efficacy and safety of aldoxorubicin administered at 350 
mg/m2 (260 mg/m2 doxorubicin equivalent) intravenously on Day 1 every 21 days until tumor progression 
or unacceptable toxicity occurs compared to investigator’s choice of treatment among  
5 different therapies. These therapies include (dosages should follow the institutional standard of care, 
package insert (SPCs), or the following suggestions based on the US package inserts and the literature):  
1) dacarbazine administered at 1000 mg/m2 by intravenous infusion (IVI), over 90±15 minutes on Day 1 
every 21 days until tumor progression or unacceptable toxicity occurs; 2) pazopanib, 800 mg orally each 
day until tumor progression or unacceptable toxicity occurs; 3) gemcitabine, 900 mg/m2 by IVI in less than 
60 minutes on Days 1 and 8, plus docetaxel, 100 mg/m2 by IVI over 1 hour on Day 8 of a 21 day cycle until 
tumor progression or unacceptable toxicity occurs; 4) doxorubicin, 75 mg/m2 by IVI over 5 to 30 minutes 
every 21 days for a maximum cumulative dose of 550 mg/m2 or unacceptable toxicity occurs; or 5) 
ifosfamide 2.0 g/m2 administered over 2 to 4 hours on Days 1-4 of a 21 day cycle + mesna per standard 
site administration regimen until tumor progression or unacceptable toxicity occurs. The investigative site 
must pre-specify their choice of treatments for the comparator arm to be used at their site, and no more 
than 3 treatment regimens may be selected for the comparator arm at each site which must be selected 
prior to the study site initiation visit. Subjects will be randomized 1:1 to receive either aldoxorubicin or 
investigator’s choice of up to 3 control regimens pre-selected by the study site. Treatment with G-CSF 
should be administered to all subjects as per investigator’s clinical judgment or according to ASCO 
Guidelines (Appendix E). Note:  aldoxorubicin has been associated with >20% incidence of grade 3 
or 4 neutropenia. Therefore, the administration of G-CSF should occur even during Cycle 1. 
All Screening requirements, including an ECHO exam, must be completed within 28 days of the  
Cycle 1-Day 1 visit. Subjects receiving aldoxorubicin, ifosfamide, dacarbazine or doxorubicin will  
visit the study site on Day 1 of each cycle. They will have complete blood counts (CBC) and serum 
chemistries on Day 15 and Day 21 (if Day 21 does not correspond to Day 1 of the next cycle,  
±3 days) of each cycle as well. Subjects receiving pazopanib will visit the study site on Day 1 of their next 
cycle for monitoring, testing (same as for Day 1 for other treatment regimens) and to receive a new supply 
of study drug. Subjects receiving pazopanib will also have CBC and serum chemistry on Day 15 and Day 
28 (if Day 28 does not correspond to Day 1 of the next cycle, ±2 days). Subjects receiving gemcitabine 
plus docetaxel will visit the study site on both days of their infusions (Days 1 and 8) and at Days 15 and 21 
of each cycle. Safety monitoring, including AEs, a directed physical examination, laboratory evaluations 
(serum chemistry, CBC, and urinalysis), vital signs, weight measurements, Eastern Cooperative Oncology 
Group (ECOG) performance status (PS) and ECGs will be performed on Day 1 (for all subjects) of each 
cycle. Subjects receiving aldoxorubicin will have blood drawn for serum electrolytes to evaluate the anion 
gap prior to each drug administration. Cardiac function will also be followed periodically (per Schedule of 
Treatment and Evaluations in Appendix A) with ECHOs for subjects receiving either aldoxorubicin or 
doxorubicin. Treatment will continue until tumor progression is observed, a maximum cumulative dose of 
550 mg/m2 is reached (doxorubicin), subject asks to withdraw, unacceptable toxicity occurs, a change in 
therapy would be in the best interest of the subject, subject becomes pregnant or fails to use adequate 
birth control, need for any treatment not allowed by the protocol, or subject is non-compliant with study 
requirements. 
Tumor response will be monitored at screening, every 6 weeks from Cycle 1-Day 1 through Week 30, and 
then every 12 weeks until disease progression using the Response Evaluation Criteria in Solid Tumors 
(RECIST) 1.1 criteria.[50] OS, PFS, and PFS at 4 and 6 months will be evaluated. Objective overall 
response rate (ORR) (complete and partial responses [PRs]), disease control rate (objective responses 
plus stable disease at 4 months) and quality of life will be assessed.  
The PK of aldoxorubicin, doxorubicin, and doxorubicinol will be evaluated using a sparse sample analysis. 
Plasma samples will be collected at Cycle 1 at the following time points: the end of the infusion, between 
1.5 and 4 hours from the end of the infusion, and on Days 2, and 3. If necessary and possible, PK samples 
may be collected at a later cycle. 


ALDOXORUBICIN-P3-STS-01 A3 
January 13, 2015 
 
CytRx Corporation 
CONFIDENTIAL 
Page 5 
Name of Sponsor/Company: CytRx Corporation 
 
Protocol Number:  
ALDOXORUBICIN-P3-STS-01 
Phase of Development: 3 
 
Study Population and Main Criteria for Inclusion/Exclusion: 
Inclusion Criteria: 
Subjects must meet the following criteria to be included in the study: 
1. Has provided written informed consent prior to any study related activities. 
2. Age ≥15 years (US only), and 18-80 (rest of world (ROW)), male or female. 
3. Histological confirmation of intermediate or high grade soft-tissue sarcoma as determined by the local 
pathology report.  Archival tissue must be sent to a central pathology lab for review but will not 
preclude entry onto the study (study-specific biopsies are not allowed). Final assignment of tumor 
grade and histology will be based on the designation provided by the central pathology review. 
4. An adequate tumor specimen obtained by either excisional biopsy, incisional biopsy or core 
needle biopsy must be sent to the central pathology lab for evaluation.  
5. Locally advanced, unresectable, and/or metastatic soft-tissue sarcoma of intermediate or high grade 
with evidence of disease progression by either computed tomography (CT) or magnetic resonance 
imaging (MRI) scan, or clinical judgment on or after the last cancer therapy within 6 months prior to 
randomization. 
6. Relapsed or refractory (lack of response) to ≥1 course of systemic therapy regimen(s), excluding 
adjuvant or neoadjuvant chemotherapy, and is incurable by either surgery or radiation. 
7. Capable of providing informed consent and complying with trial procedures. 
8. ECOG PS 0-2. 
9. Life expectancy >12 weeks. 
10. Measurable tumor lesions according to RECIST 1.1 criteria.[50] 
11. Women must not be able to become pregnant (e.g., post-menopausal for at least 1 year, surgically 
sterile, or practicing adequate birth control methods) for the duration of the study. (Adequate 
contraception includes: oral contraception, implanted contraception, intrauterine device implanted for 
at least 3 months, or barrier method in conjunction with spermicide.) 
12. Males and their female partner(s) of child-bearing potential must use 2 forms of effective contraception 
(see Inclusion 11 plus condom or vasectomy for males) from the last menstrual period of the female 
partner during the study treatment and agree to continue use for 6 months after the final dose of study 
treatment. 
13. Women of child bearing potential must have a negative serum or urine pregnancy test at the Screening 
Visit and be non-lactating. 
14. Accessibility to the site that optimizes the subject’s ability to keep all study-related appointments.  
Exclusion Criteria: 
Subjects meeting the following criteria will not be enrolled: 
1. Prior exposure to >375 mg/m2 of doxorubicin or liposomal doxorubicin. 
2. Palliative surgery and/or radiation treatment within 30 days prior to date of randomization. 
3. Exposure to any investigational agent within 30 days of date of randomization. 
4. Exposure to any systemic chemotherapy within 30 days of date of randomization. 
5. An inadequate tumor specimen as defined by the central pathologist. 
6. Current evidence/diagnosis of alveolar soft part sarcoma, extraskeletal myxoid chondrosarcoma, 
rhabdomyosarcoma, osteosarcoma, gastrointestinal stromal tumor (GIST), dermatofibrosarcoma 
(unless transformed to fibrosarcoma), Ewing’s sarcoma, Kaposi’s sarcoma, mixed mesodermal tumor, 
clear cell sarcomas. 
7. Evidence of central nervous system (CNS) metastasis who have not received prior definitive therapy 
for their lesions.  
8. History of other malignancies except cured basal cell carcinoma, cutaneous squamous cell carcinoma, 
melanoma in situ, superficial bladder cancer or carcinoma in situ of the cervix unless documented free 
of cancer for ≥5 years. 


ALDOXORUBICIN-P3-STS-01 A3 
January 13, 2015 
 
CytRx Corporation 
CONFIDENTIAL 
Page 6 
Name of Sponsor/Company: CytRx Corporation 
 
Protocol Number:  
ALDOXORUBICIN-P3-STS-01 
Phase of Development: 3 
 
9. Laboratory values: Screening serum creatinine >1.5 x upper limit of normal (ULN), alanine 
aminotransferase (ALT) >3×ULN or >5×ULN if liver metastases are present, total bilirubin >2×ULN, 
absolute neutrophil count (ANC) <1,500/mm3, platelet concentration <100,000/mm3, hemoglobin  
<9 g/dL. 
10. Anion gap > 16 meq/L (Central Laboratory) or arterial blood pH < 7.30 (as determined by the Local 
Laboratory). 
11. Clinically evident congestive heart failure (CHF) > class II of the New York Heart Association (NYHA) 
(Appendix D) guidelines.  
12. Current, serious, clinically significant cardiac arrhythmias, defined as the existence of an absolute 
arrhythmia or ventricular arrhythmias classified as Lown III, IV or V (Appendix F). 
13. Baseline QTc >470 msec and/or previous history of QT prolongation while taking other medications.  
14. Concomitant use of medications associated with a high incidence of QT prolongation is not allowed 
(Appendix G). 
15. History or signs of active coronary artery disease with or without angina pectoris within the last 6 
months. 
16. Serious myocardial dysfunction defined by ECHO as absolute left ventricular ejection fraction (LVEF) 
below the institution’s lower limit of predicted normal. 
17. Known history of HIV infection.  
18. Active, clinically significant serious infection requiring treatment with antibiotics, anti-virals or  
anti-fungals. The Medical Monitor should be contacted for any uncertainties. 
19. Major surgery within 30 days prior to date of randomization. 
20. Current or past substance abuse or any condition that might interfere with the subject’s participation in 
the study or in the evaluation of the study results. 
21. Any condition that is unstable and could jeopardize the subject’s participation in the study. 
Number of Subjects: 
Approximately 400 subjects with metastatic, locally advanced or unresectable soft tissue sarcomas 
who have either not responded to or have progressed after treatment with 1 or more systemic 
regimens of non-adjuvant chemotherapies will be randomized 1:1 (aldoxorubicin:investigator’s 
choice) at approximately 120 study centers in the US, Europe, Canada, Latin America, and Australia. 
The randomization will be stratified according to their initial PS (ECOG 0-1 vs 2), whether they had 
either 1 prior systemic non-adjuvant chemotherapy regimens or >1 prior systemic non-adjuvant 
chemotherapy regimens and whether they had received prior doxorubicin chemotherapy.  Subjects 
will also be stratified by their histopathological diagnosis as determined by the local site.  The four 
stratification groups will be leiomyosarcomas, liposarcoma, synovial sarcoma, and all other sarcomas. 


ALDOXORUBICIN-P3-STS-01 A3 
January 13, 2015 
 
CytRx Corporation 
CONFIDENTIAL 
Page 7 
Name of Sponsor/Company: CytRx Corporation 
 
Protocol Number:  
ALDOXORUBICIN-P3-STS-01 
Phase of Development: 3 
 
Test Product, Dose and Mode of Administration: 
Aldoxorubicin: Lyophilized powder in vials that contain 200 mg of aldoxorubicin reconstituted by 
adding a solution of 50% ethanol: 50% sterile water, administration completed within 2 hours (of 
being reconstituted) as a 30-minute IVI Lactated Ringer’s solution. Total dose of 350 mg/m2  
(260 mg/m2 doxorubicin equivalent). Aldoxorubicin infusion may exceed 30 minutes if deemed 
necessary by the investigative site but the total time from the completion of reconstitution of 
aldoxorubicin to completion of infusion must not be more than 2 hours. 
Investigator’s Choice: Up to three treatment regimens are to be chosen by the investigator from the 
list below prior to the initiation of the study site and the treatment chosen for each subject enrolled in 
the study must be entered into the case report form.  Directions for dosage and reconstitution should 
follow institutional standard of care, package inserts (SPCs), or the suggestions below based on the 
US package inserts and the literature.  
Dacarbazine 100 mg/vial and 200 mg/vial are reconstituted with 9.9 mL and 19.7 mL, respectively, 
Sterile Water for Injection, USP. The resulting solution contains 10 mg/mL of dacarbazine having a 
pH of 3.0 to 4.0. The calculated dose of the resulting solution is drawn into a syringe and 
administered only intravenously. The reconstituted solution may be further diluted with 5% dextrose 
injection, or sodium chloride injection (250 to 500 mL), and administered as an IVI over 90±15 
minutes. 
After reconstitution and prior to use, the solution in the vial may be stored at 4°C for up to 72 hours or 
at normal room conditions (temperature and light) for up to 8 hours. If the reconstituted solution is 
further diluted in 5% dextrose injection or sodium chloride injection, the resulting solution may be 
stored at 4°C for up to 24 hours or at normal room conditions for up to 8 hours. 
Pazopanib (Votrient®) 200 mg tablets can be stored at room temperature between 20° and 25°C; 
excursions are permitted between 15° and 30°C. Tablets are taken 1 hour before or 2 hours after a 
meal and tablets are NOT to be crushed. 
Gemcitabine 200 mg or 1 g lyophilized powder in a single use vial is reconstituted with 0.9% NaCl to 
a final concentration of ≤40 mg/mL and pH 2.7 to 3.3. The reconstituted solution may be further 
diluted with 0.9% NaCl and administered by IVI in <60 minutes. It is stable for up to 24 hours at 
controlled room temperature (20° to 25°C) and should not be refrigerated. 
Docetaxel 80 mg/8 mL and 20 mg/2 mL is administered by IVI over approximately 60 minutes after 
dilution into a 250 to 500 mL infusion bag of either 0.9% NaCl or 5% dextrose solution to produce a 
final concentration of 0.3 to 0.74 mg/mL. Docetaxel final dilution for infusion should be administered 
within 4 hours of preparation. It can be stored between 2° and 25°C. 
Doxorubicin HCl Injection is a sterile parenteral, isotonic available in 5 mL (10 mg), 10 mL (20 mg),  
25 mL (50 mg) single dose vials. Each mL contains doxorubicin HCl and the following inactive 
ingredients:  NaCl (0.9%) and water for injection q.s. Hydrochloric acid is used to adjust the pH to a 
target of pH of 3.0. The reconstituted solution is diluted in 0.9% NaCl or 5% dextrose and may be 
administered over 5 to 30 minutes. 
Ifosamide single-dose vials for constitution and administration by IVI each contain 1 gram or 3 grams 
of sterile ifosfamide, USP. Ifosfamide is a chemotherapeutic agent chemically related to the nitrogen 
mustards and a synthetic analog of cyclophosphamide. Injections are prepared for parenteral use by 
adding Sterile Water for Injection, USP, or Sterile Bacteriostatic Water for Injection, USP (benzyl 
alcohol or parabens preserved) to the vial and shaking to dissolve. The reconstituted solution is 
diluted in 0.9% NaCl or 5% dextrose solution and may be administered over 2 to 4 hours. 
See Section 5.2 for additional investigator’s choice treatment concentrations and preparation 
instructions as per package inserts. 


ALDOXORUBICIN-P3-STS-01 A3 
January 13, 2015 
 
CytRx Corporation 
CONFIDENTIAL 
Page 8 
Name of Sponsor/Company: CytRx Corporation 
 
Protocol Number:  
ALDOXORUBICIN-P3-STS-01 
Phase of Development: 3 
 
Criteria for Evaluation: 
Efficacy: 
The following efficacy variables will be evaluated as noted: 
 PFS. 
 OS. 
 Objective tumor response (RECIST 1.1 criteria[50]). 
 Disease control rate (objective tumor response + stable disease at 4 months). 
 Subject Reported Outcome as measured by the European Organisation for Research and 
Treatment of Cancer (EORTC) Quality of Life Questionnaire. 
 
Safety: 
The following safety variables will be assessed over the duration of the study: 
 AEs. 
 Ability to remain on assigned treatment (tolerability). 
 Clinical and laboratory data including physical examinations, vital signs, weight, ECHO 
evaluations, ECG results and laboratory test results. 
 Use of concomitant medications. 
Pharmacokinetics: 
The following PK variables will be assessed for aldoxorubicin, doxorubicin, and doxorubicinol: 
 Maximum drug concentration (Cmax) in plasma. 
 Area under the plasma drug-concentration-time profile (AUC). 
 Clearance (CL). 
 Volume of distribution (Vd). 
 Half-life (t½). 


ALDOXORUBICIN-P3-STS-01 A3 
January 13, 2015 
 
CytRx Corporation 
CONFIDENTIAL 
Page 9 
Name of Sponsor/Company: CytRx Corporation 
 
Protocol Number:  
ALDOXORUBICIN-P3-STS-01 
Phase of Development: 3 
 
Statistical Methods: 
In accordance with the intention-to-treat principle, all randomized subjects will be evaluated for 
efficacy. All subjects who receive at least 1 dose of study medication will be evaluated for safety.  
Efficacy:  
The primary analysis of PFS will be carried out when approximately 191 PFS events have been 
observed by the blinded Central Imaging Research Organization (approximately 15 months following 
the completion of enrollment of 400 subjects). Survival distributions will be estimated using the 
Kaplan-Meier method and the two groups will be compared using a two-sided log rank test at the 
α=0.05 level of significance. 
An important secondary endpoint is overall survival (OS). The analysis of OS will be considered 
confirmatory only if the PFS analysis is statistically significant. As a result, the nominal level of 
significance for the OS analysis will be α=0.05. However, because an interim analysis of OS will be 
carried out at the time of the analysis of PFS, the levels of significance for the interim and final 
analyses of OS will be α=0.00305 and α=0.049, respectively. 
The final analysis of OS will be completed when 320 OS events have occurred. Survival distributions 
will be estimated using the Kaplan-Meier method and the two groups will be compared using a two-
sided log rank test at the α=0.049 level of significance. The same methodology will be used for the 
interim analysis, but at the α=0.00305 level of significance. 
Tumor response will be monitored at screening, every 6 weeks from Cycle 1-Day 1 through Week 30, 
and then every 12 weeks until disease progression. The percentage of subjects with complete or 
PRs, or stable disease will be evaluated and the disease control rate (CR, PR and SD at 4 months) 
will be compared using Pearson’s chi-square test, or if 20% or more of the expected cell frequencies 
are <5, Fisher’s exact test. Patient reported outcomes as assessed by the EORTC Quality of Life 
Questionnaire will be analyzed using analysis of covariance. 
Sample Size Justification: 
Power calculations and subject numbers were calculated based on the primary endpoint of PFS.  
Reviewing the literature for studies that have evaluated gemcitabine + docetaxel, pazopanib, 
ifosfamide and dacarbazine as treatment for patients that have relapsed or not responded to first line 
therapies, it is estimated that the median PFS for the investigator’s choice group will be 3.5 months 
and that the median PFS for the aldoxorubicin group will be 5.6 months.  Based on the use of a two-
sided log rank test at the α=0.05 level of significance, a total of 191 events will be required for 90% 
power to detect this difference.  Assuming an 18 month accrual period and a 15 month follow-up 
period after enrollment of the last subject, approximately 400 subjects will be needed to achieve the 
total of 191 events. 
Safety:  
The safety data will be summarized by treatment group. The treatment groups will be compared with 
respect to occurrence of each AE. Total number of AEs leading to withdrawal, and abnormal 
laboratory tests will be compared between groups using Fisher’s exact test. AEs, ability to remain on 
assigned treatment (tolerability), and abnormal findings on physical examinations, vital signs, weight, 
ECG results, laboratory test results, and use of concomitant medications, will be assessed to 
characterize the safety profile of the treatment regimens. Descriptive statistics denoting the changes 
from baseline to the final assessment visit with respect to key laboratory parameters and vital signs 
will also be provided.  


ALDOXORUBICIN-P3-STS-01 A3 
January 13, 2015 
 
CytRx Corporation 
CONFIDENTIAL 
Page 10 
Name of Sponsor/Company: CytRx Corporation 
 
Protocol Number:  
ALDOXORUBICIN-P3-STS-01 
Phase of Development: 3 
 
Pharmacokinetics:  
All subjects who receive aldoxorubicin and provide at least one PK sample with concentrations above 
the limit of quantification will be included in the PK analysis. Sparse plasma aldoxorubicin, 
doxorubicin, and doxorubicinol concentration data will be analyzed, and aldoxorubicin, doxorubicin, 
and doxorubicinol PK parameters will be estimated based on a population PK analysis. PK 
parameters will be summarized using descriptive statistics. 
Exploratory exposure-response/exposure-safety analyses will be conducted using the primary and 
secondary efficacy endpoints, PFS and OS, and for selected AEs. 


ALDOXORUBICIN-P3-STS-01 A3 
January 13, 2015 
 
CytRx Corporation 
CONFIDENTIAL 
Page 70 
APPENDIX A: Schedule of Treatment and Evaluations 
 
Screening 
-28 Days 
Cycle 
1 
Cycle 
222 
Cycle 
322 
Cycle 
422 
Cycle 
522 
Cycle 
622 
Cycle 
722 
Cycle 
822, 
9+22 
Day 15 and 21 
(28 for pazopanib) 
each Cycle 
End of 
Treatment23 
Every 6 
Weeks → 
Week 3024 
Every 
12 
Weeks24 
Follow 
Up 
GENERAL AND SAFETY 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Specimen1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X25 
X25 
X25 
 
Height (cm) 
X 
X5 
 
 
 
 
 
 
 
 
 
 
 
 
Weight (kg) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
BSA Calculation5 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Vital Signs6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Adverse Events7 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
Survival Follow-Up8 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
ECOG PS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
Concomitant Medications 
X9 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
RADIOGRAPHIC ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT/ MRI Scan / Tumor 
Measurements10 
X11a 
 
 
X11 
 
X11 
 
X11 
 
 
 
X 
X 
 
  CARDIAC ASSESSMENTS 
ECG12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X26 
X 
X 
 
ECHO (with ejection fraction)13  
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
  CENTRAL LAB ASSESSMENTS 
CBC w/differential & Platelets14 
X 
X16 
X 
X 
X 
X 
X 
X 
X 
X 
X26 
X 
X 
 
Serum Chemistries14, 15 
X 
X16 
X 
X 
X 
X 
X 
X 
X 
X 
X26 
 
 
 
Pharmacokinetic Sampling18 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis17 
X 
 
 
 
 
 
 
 
 
 
X26 
 
 
 
Serum/Urine Pregnancy Test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


ALDOXORUBICIN-P3-STS-01 A3 
January 13, 2015 
 
CytRx Corporation 
CONFIDENTIAL 
Page 71 
 
Screening 
-28 Days 
Cycle 
1 
Cycle 
222 
Cycle 
322 
Cycle 
422 
Cycle 
522 
Cycle 
622 
Cycle 
722 
Cycle 
822, 
9+22 
Day 15 and 21 
(28 for pazopanib) 
each Cycle 
End of 
Treatment23 
Every 6 
Weeks → 
Week 3024 
Every 
12 
Weeks24 
Follow 
Up 
  LOCAL LAB ASSESSMENTS27 
CBC w/differential & Platelets14 
X* 
X16 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Serum Chemistries 14, 15 
 
X16 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
  QUALITY OF LIFE QUESTIONNAIRE 
EORTC QLQ-C30 Version 3 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
  CHEMOTHERAPY: ALDOXORUBICIN OR INVESTIGATOR’S CHOICE 
Aldoxorubicin, Doxorubicin, Ifosfamide 
or Dacarbazine Administration19 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Gemcitabine and Docetaxel 
Administration 20 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Pazopanib Administration and Diary21 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
NOTE: All assessment must be performed within 72 hours of each specified time parameter (48 hours for pazopanib treated subjects), except Cycle 1 (see 
Section 6 for details). 
*Arterial blood gas test, if needed, to confirm acid levels. 


CLINICAL PROTOCOL 
TITLE: 
A Multicenter, Randomized, Open-Label Phase 3 Study to Investigate 
the Efficacy and Safety of Aldoxorubicin Compared to Investigator’s 
Choice in Subjects with Metastatic, Locally Advanced, or Unresectable 
Soft Tissue Sarcomas Who Either Relapsed or Were Refractory to Prior 
Non-Adjuvant Chemotherapy 
PROTOCOL NUMBER: 
ALDOXORUBICIN-P3-STS-01 
STUDY DRUG: 
Aldoxorubicin 
IND NUMBER: 
113,695 
EUDRACT NUMBER: 
2013-004103-40 
SPONSOR:  
CytRx Corporation 
11726 San Vicente Blvd 
Los Angeles, CA 90049 
(310) 826-5648
FAX: (310) 826-6139
IMMEDIATE SAFETY ASSISTANCE: 
Region 
Hotline 
Fax 
Email 
North America 
Australia 
Latin America 
1-866-326-5053
or 
1-434-951-4082
1-800-280-7035
or 
1-913-307-5751
AldoxP3STS@PRAIntl.com 
Europe 
+44 1792 52-5608
+49 621 878-2828
AldoxP3STS@PRAIntl.com 
SAE SUBMISSION: 
Region 
SAE Fax 
SAE Email 
North America 
1-888-772-6919
CHOSafety@PRAIntl.com 
Rest of World 
+44 1792 525-720
MHGSafety@PRAIntl.com 
ORIGINAL PROTOCOL: 
April 3, 2013 
AMENDMENT 1: 
August 28, 2013 
AMENDMENT 2: 
March 21, 2014 
AMENDMENT 3: 
January 13, 2015 
AMENDMENT 4: 
April 13, 2015 
CONFIDENTIAL
The information contained in this document is confidential and the proprietary property of CytRx 
Corporation. Any unauthorized use or disclosure of such information without the prior written 
authorization of CytRx Corporation is prohibited. 


ALDOXORUBICIN-P3-STS-01 A4 
April 13. 2015 
PROTOCOL SIGNATURE PAGE 
A Multicenter, Randomized, Open-Label Phase 3 Study to Investigate the 
Efficacy and Safety of Aldoxorubicin Compared to Investigator's Choice in 
Subjects with Metastatic, Locally Advanced, or Unresectable Soft Tissue 
Sarcomas Who Either Relapsed or Were Refractory to Prior Non-Adjuvant 
Chemotherapy 
By signing below, the Investigator agrees to adhere to the protocol as outlined and agrees 
that any changes to the protocol must be approved by CytRx Corporation (CytRx) prior to 
seeking approval from the Institutional Review Board (IRB)/lndependent Ethics Committee 
(IEC). 
The study will be conducted in accordance with current United States (US) Food and Drug 
Administration (FDA) regulations, International Conference on Harmonization (ICH) 
guidelines, Good Clinical Practice (GCP) guidelines, the principles of the Declaration of 
Helsinki, and other applicable regulations and guidelines. 
I agree to ensure that Financial Disclosure Statements will be completed by: 
• 
me (including, if applicable, my spouse [or legal partner) and dependent children) 
• 
my subinvestigators (including, if applicable, their spouses [or legal partner) and 
dependent children) 
at the start of the study and for up to 1 year after the study is completed, if there are 
changes that affect my financial disclosure status. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of CytRx. 
Investigator's Signature: ------------------
Printed Name: 
Name of Institution/Company: ----------------
Date: _______________________ 
Sponsor Signature: _ 
____ 
_,.__ ___ _ 
Daniel Levitt, M.D., Ph.D. 
Chief Medical Officer 
CytRx 
:.-& 
Date: 
Y 
CytRx Corporation 
CONFIDENTIAL 
-----·------ -
-
-- -------
Page 2 


ALDOXORUBICIN-P3-STS-01 A4 
April 13, 2015 
 
CytRx Corporation 
CONFIDENTIAL 
Page 3 
Protocol Synopsis 
Name of Sponsor/Company: CytRx Corporation 
 
Protocol Number:  
ALDOXORUBICIN-P3-STS-01 
Phase of Development: 3 
 
Title of the Protocol:  
A Multicenter, Randomized, Open-Label Phase 3 Study to Investigate the Efficacy and Safety of 
Aldoxorubicin Compared to Investigator’s Choice in Subjects with Metastatic, Locally Advanced, or 
Unresectable Soft Tissue Sarcomas Who Either Relapsed or Were Refractory to Prior Non-Adjuvant 
Chemotherapy 
Primary Objective: 
The primary objective of this study is to determine the efficacy of administration of aldoxorubicin 
compared to investigator’s choice of treatment in subjects with metastatic, locally advanced, or 
unresectable soft tissue sarcomas who have relapsed or were refractory to prior non-adjuvant 
chemotherapy, as measured by progression-free survival (PFS). 
Secondary Objectives: 
The secondary objectives of this study are to evaluate the efficacy of aldoxorubicin as measured by 
OS, safety of aldoxorubicin compared to investigator’s choice in this population assessed by the 
frequency and severity of adverse events (AEs), abnormal findings on physical examination, 
laboratory tests, vital signs, echocardiogram (ECHO) evaluations, electrocardiogram (ECG) results, 
and weight, as well as disease control rate, and tumor response. 
Exploratory Objectives: 
To determine the pharmacokinetics (PK) of aldoxorubicin, doxorubicin, and doxorubicinol following 
intravenous (IV) administration of aldoxorubicin, and to evaluate the exposure-response relationships 
between aldoxorubicin, doxorubicin, and/or doxorubicinol and PFS, OS, selected safety parameters, 
and quality of life. 
Study Rationale and Significance: 
Aldoxorubicin (INNO-206; DOXO-EMCH) is a novel prodrug that binds covalently to circulating 
albumin. The drug is accumulated in tumors and doxorubicin is released in the tumor by cleaving the 
acid labile linker (EMCH) in the low pH tumor environment. This carrier-linked prodrug has 
demonstrated enhanced antitumor activity with reduced toxicity in several murine models when 
compared with free doxorubicin. 
Patients with metastatic, locally advanced, or unresectable soft tissue sarcomas who have failed prior 
chemotherapies have a poor prognosis with PFS of around 2-4.6 months and median OS of 
approximately 9-12 months. Several chemotherapy regimens have been explored as palliative 
therapy for subjects with these patients and include such agents as ifosfamide, gemcitabine, 
docetaxel, vinorelbine, dacarbazine, temozolomide, epirubicin, pazopanib and liposomal doxorubicin. 
However, these regimens can be quite toxic and have not significantly impacted either progression-
free or OS in these individuals. Pazopanib, recently approved in the US and Europe, does appear to 
extend PFS in soft tissue sarcoma patients (except liposarcomas) who have relapsed after receiving 
prior chemotherapy compared to no treatment, but does not increase OS. Aldoxorubicin may improve 
upon the activity of doxorubicin without an increase in toxicity as has been demonstrated in animal 
studies. 


ALDOXORUBICIN-P3-STS-01 A4 
April 13, 2015 
 
CytRx Corporation 
CONFIDENTIAL 
Page 4 
Name of Sponsor/Company: CytRx Corporation 
 
Protocol Number:  
ALDOXORUBICIN-P3-STS-01 
Phase of Development: 3 
 
Study Design and Methodology: 
This is a phase 3 open-label study evaluating the efficacy and safety of aldoxorubicin administered at 350 
mg/m2 (260 mg/m2 doxorubicin equivalent) intravenously on Day 1 every 21 days until tumor progression 
or unacceptable toxicity occurs compared to investigator’s choice of treatment among  
5 different therapies. These therapies include (dosages should follow the institutional standard of care, 
package insert (SPCs), or the following suggestions based on the US package inserts and the literature):  
1) dacarbazine administered at 1000 mg/m2 by intravenous infusion (IVI), over 90±15 minutes on Day 1 
every 21 days until tumor progression or unacceptable toxicity occurs; 2) pazopanib, 800 mg orally each 
day until tumor progression or unacceptable toxicity occurs; 3) gemcitabine, 900 mg/m2 by IVI in less than 
60 minutes on Days 1 and 8, plus docetaxel, 100 mg/m2 by IVI over 1 hour on Day 8 of a 21 day cycle until 
tumor progression or unacceptable toxicity occurs; 4) doxorubicin, 75 mg/m2 by IVI over 5 to 30 minutes 
every 21 days for a maximum cumulative dose of 550 mg/m2 or unacceptable toxicity occurs; or 5) 
ifosfamide 2.0 g/m2 administered over 2 to 4 hours on Days 1-4 of a 21 day cycle + mesna per standard 
site administration regimen until tumor progression or unacceptable toxicity occurs. The investigative site 
must pre-specify their choice of treatments for the comparator arm to be used at their site, and no more 
than 3 treatment regimens may be selected for the comparator arm at each site which must be selected 
prior to the study site initiation visit. Subjects will be randomized 1:1 to receive either aldoxorubicin or 
investigator’s choice of up to 3 control regimens pre-selected by the study site. Treatment with G-CSF 
should be administered to all subjects as per investigator’s clinical judgment or according to ASCO 
Guidelines (Appendix E). Note:  aldoxorubicin has been associated with >20% incidence of grade 3 
or 4 neutropenia. Therefore, the administration of G-CSF should occur even during Cycle 1. 
All Screening requirements, including an ECHO exam, must be completed within 28 days of the  
Cycle 1-Day 1 visit. Subjects receiving aldoxorubicin, ifosfamide, dacarbazine or doxorubicin will  
visit the study site on Day 1 of each cycle. They will have complete blood counts (CBC) and serum 
chemistries on Day 15 and Day 21 (if Day 21 does not correspond to Day 1 of the next cycle,  
±3 days) of each cycle as well. Subjects receiving pazopanib will visit the study site on Day 1 of their next 
cycle for monitoring, testing (same as for Day 1 for other treatment regimens) and to receive a new supply 
of study drug. Subjects receiving pazopanib will also have CBC and serum chemistry on Day 15 and Day 
28 (if Day 28 does not correspond to Day 1 of the next cycle, ±2 days). Subjects receiving gemcitabine 
plus docetaxel will visit the study site on both days of their infusions (Days 1 and 8) and at Days 15 and 21 
of each cycle. Safety monitoring, including AEs, a directed physical examination, laboratory evaluations 
(serum chemistry, CBC, and urinalysis), vital signs, weight measurements, Eastern Cooperative Oncology 
Group (ECOG) performance status (PS) and ECGs will be performed on Day 1 (for all subjects) of each 
cycle. Subjects receiving aldoxorubicin will have blood drawn for serum electrolytes to evaluate the anion 
gap prior to each drug administration. Cardiac function will also be followed periodically (per Schedule of 
Treatment and Evaluations in Appendix A) with ECHOs for subjects receiving either aldoxorubicin or 
doxorubicin. Treatment will continue until tumor progression is observed, a maximum cumulative dose of 
550 mg/m2 is reached (doxorubicin), subject asks to withdraw, unacceptable toxicity occurs, a change in 
therapy would be in the best interest of the subject, subject becomes pregnant or fails to use adequate 
birth control, need for any treatment not allowed by the protocol, or subject is non-compliant with study 
requirements. 
Tumor response will be monitored at screening, every 6 weeks from Cycle 1-Day 1 through Week 30, and 
then every 12 weeks until disease progression using the Response Evaluation Criteria in Solid Tumors 
(RECIST) 1.1 criteria.[50] OS, PFS, and PFS at 4 and 6 months will be evaluated. Objective overall 
response rate (ORR) (complete and partial responses [PRs]), disease control rate (objective responses 
plus stable disease at 4 months) and quality of life will be assessed.  
The PK of aldoxorubicin, doxorubicin, and doxorubicinol will be evaluated using a sparse sample analysis. 
Plasma samples will be collected at Cycle 1 at the following time points: the end of the infusion, between 
1.5 and 4 hours from the end of the infusion, and on Days 2, and 3. If necessary and possible, PK samples 
may be collected at a later cycle. 


ALDOXORUBICIN-P3-STS-01 A4 
April 13, 2015 
 
CytRx Corporation 
CONFIDENTIAL 
Page 5 
Name of Sponsor/Company: CytRx Corporation 
 
Protocol Number:  
ALDOXORUBICIN-P3-STS-01 
Phase of Development: 3 
 
Study Population and Main Criteria for Inclusion/Exclusion: 
Inclusion Criteria: 
Subjects must meet the following criteria to be included in the study: 
1. Has provided written informed consent prior to any study related activities. 
2. Age ≥15 years (US only), and 18-80 (rest of world (ROW)), male or female. 
3. Histological confirmation of intermediate or high grade soft-tissue sarcoma as determined by the local 
pathology report.  Archival tissue must be sent to a central pathology lab for review but will not 
preclude entry onto the study (study-specific biopsies are not allowed). Final assignment of tumor 
grade and histology will be based on the designation provided by the central pathology review. 
4. An adequate tumor specimen obtained by either excisional biopsy, incisional biopsy or core 
needle biopsy must be sent to the central pathology lab for evaluation.  
5. Locally advanced, unresectable, and/or metastatic soft-tissue sarcoma of intermediate or high grade 
with evidence of disease progression by either computed tomography (CT) or magnetic resonance 
imaging (MRI) scan, or clinical judgment on or after the last cancer therapy within 6 months prior to 
randomization. 
6. Relapsed or refractory (lack of response) to ≥1 course of systemic therapy regimen(s), excluding 
adjuvant or neoadjuvant chemotherapy, and is incurable by either surgery or radiation. 
7. Capable of providing informed consent and complying with trial procedures. 
8. ECOG PS 0-2. 
9. Life expectancy >12 weeks. 
10. Measurable tumor lesions according to RECIST 1.1 criteria.[50] 
11. Women must not be able to become pregnant (e.g., post-menopausal for at least 1 year, surgically 
sterile, or practicing adequate birth control methods) for the duration of the study. (Adequate 
contraception includes: oral contraception, implanted contraception, intrauterine device implanted for 
at least 3 months, or barrier method in conjunction with spermicide.) 
12. Males and their female partner(s) of child-bearing potential must use 2 forms of effective contraception 
(see Inclusion 11 plus condom or vasectomy for males) from the last menstrual period of the female 
partner during the study treatment and agree to continue use for 6 months after the final dose of study 
treatment. 
13. Women of child bearing potential must have a negative serum or urine pregnancy test at the Screening 
Visit and be non-lactating. 
14. Accessibility to the site that optimizes the subject’s ability to keep all study-related appointments.  
Exclusion Criteria: 
Subjects meeting the following criteria will not be enrolled: 
1. Prior exposure to >375 mg/m2 of doxorubicin or liposomal doxorubicin. 
2. Palliative surgery and/or radiation treatment within 30 days prior to date of randomization. 
3. Exposure to any investigational agent within 30 days of date of randomization. 
4. Exposure to any systemic chemotherapy within 30 days of date of randomization. 
5. An inadequate tumor specimen as defined by the central pathologist. 
6. Current evidence/diagnosis of alveolar soft part sarcoma, extraskeletal myxoid chondrosarcoma, 
rhabdomyosarcoma, osteosarcoma, gastrointestinal stromal tumor (GIST), dermatofibrosarcoma 
(unless transformed to fibrosarcoma), Ewing’s sarcoma, Kaposi’s sarcoma, mixed mesodermal tumor, 
clear cell sarcomas. 
7. Evidence of central nervous system (CNS) metastasis who have not received prior definitive therapy 
for their lesions.  
8. History of other malignancies except cured basal cell carcinoma, cutaneous squamous cell carcinoma, 
melanoma in situ, superficial bladder cancer or carcinoma in situ of the cervix unless documented free 
of cancer for ≥5 years. 


ALDOXORUBICIN-P3-STS-01 A4 
April 13, 2015 
 
CytRx Corporation 
CONFIDENTIAL 
Page 6 
Name of Sponsor/Company: CytRx Corporation 
 
Protocol Number:  
ALDOXORUBICIN-P3-STS-01 
Phase of Development: 3 
 
9. Laboratory values: Screening serum creatinine >1.5 x upper limit of normal (ULN), alanine 
aminotransferase (ALT) >3×ULN or >5×ULN if liver metastases are present, total bilirubin >2×ULN, 
absolute neutrophil count (ANC) <1,500/mm3, platelet concentration <100,000/mm3, hemoglobin  
<9 g/dL. 
10. Anion gap > 16 meq/L (Central Laboratory) or arterial blood pH < 7.30 (as determined by the Local 
Laboratory). 
11. Clinically evident congestive heart failure (CHF) > class II of the New York Heart Association (NYHA) 
(Appendix D) guidelines.  
12. Current, serious, clinically significant cardiac arrhythmias, defined as the existence of an absolute 
arrhythmia or ventricular arrhythmias classified as Lown III, IV or V (Appendix F). 
13. Baseline QTc >470 msec and/or previous history of QT prolongation while taking other medications.  
14. Concomitant use of medications associated with a high incidence of QT prolongation is not allowed 
(Appendix G). 
15. History or signs of active coronary artery disease with or without angina pectoris within the last 6 
months. 
16. Serious myocardial dysfunction defined by ECHO as absolute left ventricular ejection fraction (LVEF) 
below the institution’s lower limit of predicted normal. 
17. Known history of HIV infection.  
18. Active, clinically significant serious infection requiring treatment with antibiotics, anti-virals or  
anti-fungals. The Medical Monitor should be contacted for any uncertainties. 
19. Major surgery within 30 days prior to date of randomization. 
20. Current or past substance abuse or any condition that might interfere with the subject’s participation in 
the study or in the evaluation of the study results. 
21. Any condition that is unstable and could jeopardize the subject’s participation in the study. 
Number of Subjects: 
Approximately 400 subjects with metastatic, locally advanced or unresectable soft tissue sarcomas 
who have either not responded to or have progressed after treatment with 1 or more systemic 
regimens of non-adjuvant chemotherapies will be randomized 1:1 (aldoxorubicin:investigator’s 
choice) at approximately 120 study centers in the US, Europe, Canada, Latin America, and Australia. 
The randomization will be stratified according to their initial PS (ECOG 0-1 vs 2), whether they had 
either 1 prior systemic non-adjuvant chemotherapy regimens or >1 prior systemic non-adjuvant 
chemotherapy regimens and whether they had received prior doxorubicin chemotherapy.  Subjects 
will also be stratified by their histopathological diagnosis as determined by the local site.  The four 
stratification groups will be leiomyosarcomas, liposarcoma, synovial sarcoma, and all other sarcomas.


ALDOXORUBICIN-P3-STS-01 A4 
April 13, 2015 
 
CytRx Corporation 
CONFIDENTIAL 
Page 7 
Name of Sponsor/Company: CytRx Corporation 
 
Protocol Number:  
ALDOXORUBICIN-P3-STS-01 
Phase of Development: 3 
 
Test Product, Dose and Mode of Administration: 
Aldoxorubicin: Lyophilized powder in vials that contain 200 mg of aldoxorubicin reconstituted by 
adding a solution of 50% ethanol: 50% sterile water, administration completed within 2 hours (of 
being reconstituted) as a 30-minute IVI Lactated Ringer’s solution. Total dose of 350 mg/m2  
(260 mg/m2 doxorubicin equivalent). Aldoxorubicin infusion may exceed 30 minutes if deemed 
necessary by the investigative site but the total time from the completion of reconstitution of 
aldoxorubicin to completion of infusion must not be more than 2 hours. 
Investigator’s Choice: Up to three treatment regimens are to be chosen by the investigator from the 
list below prior to the initiation of the study site and the treatment chosen for each subject enrolled in 
the study must be entered into the case report form.  Directions for dosage and reconstitution should 
follow institutional standard of care, package inserts (SPCs), or the suggestions below based on the 
US package inserts and the literature.  
Dacarbazine 100 mg/vial and 200 mg/vial are reconstituted with 9.9 mL and 19.7 mL, respectively, 
Sterile Water for Injection, USP. The resulting solution contains 10 mg/mL of dacarbazine having a 
pH of 3.0 to 4.0. The calculated dose of the resulting solution is drawn into a syringe and 
administered only intravenously. The reconstituted solution may be further diluted with 5% dextrose 
injection, or sodium chloride injection (250 to 500 mL), and administered as an IVI over 90±15 
minutes. 
After reconstitution and prior to use, the solution in the vial may be stored at 4°C for up to 72 hours or 
at normal room conditions (temperature and light) for up to 8 hours. If the reconstituted solution is 
further diluted in 5% dextrose injection or sodium chloride injection, the resulting solution may be 
stored at 4°C for up to 24 hours or at normal room conditions for up to 8 hours. 
Pazopanib (Votrient®) 200 mg tablets can be stored at room temperature between 20° and 25°C; 
excursions are permitted between 15° and 30°C. Tablets are taken 1 hour before or 2 hours after a 
meal and tablets are NOT to be crushed. 
Gemcitabine 200 mg or 1 g lyophilized powder in a single use vial is reconstituted with 0.9% NaCl to 
a final concentration of ≤40 mg/mL and pH 2.7 to 3.3. The reconstituted solution may be further 
diluted with 0.9% NaCl and administered by IVI in <60 minutes. It is stable for up to 24 hours at 
controlled room temperature (20° to 25°C) and should not be refrigerated. 
Docetaxel 80 mg/8 mL and 20 mg/2 mL is administered by IVI over approximately 60 minutes after 
dilution into a 250 to 500 mL infusion bag of either 0.9% NaCl or 5% dextrose solution to produce a 
final concentration of 0.3 to 0.74 mg/mL. Docetaxel final dilution for infusion should be administered 
within 4 hours of preparation. It can be stored between 2° and 25°C. 
Doxorubicin HCl Injection is a sterile parenteral, isotonic available in 5 mL (10 mg), 10 mL (20 mg),  
25 mL (50 mg) single dose vials. Each mL contains doxorubicin HCl and the following inactive 
ingredients:  NaCl (0.9%) and water for injection q.s. Hydrochloric acid is used to adjust the pH to a 
target of pH of 3.0. The reconstituted solution is diluted in 0.9% NaCl or 5% dextrose and may be 
administered over 5 to 30 minutes. 
Ifosamide single-dose vials for constitution and administration by IVI each contain 1 gram or 3 grams 
of sterile ifosfamide, USP. Ifosfamide is a chemotherapeutic agent chemically related to the nitrogen 
mustards and a synthetic analog of cyclophosphamide. Injections are prepared for parenteral use by 
adding Sterile Water for Injection, USP, or Sterile Bacteriostatic Water for Injection, USP (benzyl 
alcohol or parabens preserved) to the vial and shaking to dissolve. The reconstituted solution is 
diluted in 0.9% NaCl or 5% dextrose solution and may be administered over 2 to 4 hours. 
See Section 5.2 for additional investigator’s choice treatment concentrations and preparation 
instructions as per package inserts. 


ALDOXORUBICIN-P3-STS-01 A4 
April 13, 2015 
 
CytRx Corporation 
CONFIDENTIAL 
Page 8 
Name of Sponsor/Company: CytRx Corporation 
 
Protocol Number:  
ALDOXORUBICIN-P3-STS-01 
Phase of Development: 3 
 
Criteria for Evaluation: 
Efficacy: 
The following efficacy variables will be evaluated as noted: 
 PFS. 
 OS. 
 Objective tumor response (RECIST 1.1 criteria[50]). 
 Disease control rate (objective tumor response + stable disease at 4 months). 
 Subject Reported Outcome as measured by the European Organisation for Research and 
Treatment of Cancer (EORTC) Quality of Life Questionnaire. 
 
Safety: 
The following safety variables will be assessed over the duration of the study: 
 AEs. 
 Ability to remain on assigned treatment (tolerability). 
 Clinical and laboratory data including physical examinations, vital signs, weight, ECHO 
evaluations, ECG results and laboratory test results. 
 Use of concomitant medications. 
Pharmacokinetics: 
The following PK variables will be assessed for aldoxorubicin, doxorubicin, and doxorubicinol: 
 Maximum drug concentration (Cmax) in plasma. 
 Area under the plasma drug-concentration-time profile (AUC). 
 Clearance (CL). 
 Volume of distribution (Vd). 
 Half-life (t½). 


ALDOXORUBICIN-P3-STS-01 A4 
April 13, 2015 
 
CytRx Corporation 
CONFIDENTIAL 
Page 9 
Name of Sponsor/Company: CytRx Corporation 
 
Protocol Number:  
ALDOXORUBICIN-P3-STS-01 
Phase of Development: 3 
 
Statistical Methods: 
In accordance with the intention-to-treat principle, all randomized subjects will be evaluated for 
efficacy. All subjects who receive at least 1 dose of study medication will be evaluated for safety.  
Efficacy:  
The primary analysis of PFS will be carried out when approximately 191 PFS events have been 
observed by the blinded Central Imaging Research Organization (approximately 15 months following 
the completion of enrollment of 400 subjects). Survival distributions will be estimated using the 
Kaplan-Meier method and the two groups will be compared using a two-sided log rank test at the 
α=0.05 level of significance. 
An important secondary endpoint is overall survival (OS). The analysis of OS will be considered 
confirmatory only if the PFS analysis is statistically significant. As a result, the nominal level of 
significance for the OS analysis will be α=0.05. However, because an interim analysis of OS will be 
carried out at the time of the analysis of PFS, the levels of significance for the interim and final 
analyses of OS will be α=0.00305 and α=0.049, respectively. 
The final analysis of OS will be completed when 320 OS events have occurred. Survival distributions 
will be estimated using the Kaplan-Meier method and the two groups will be compared using a two-
sided log rank test at the α=0.049 level of significance. The same methodology will be used for the 
interim analysis, but at the α=0.00305 level of significance. 
Tumor response will be monitored at screening, every 6 weeks from Cycle 1-Day 1 through Week 30, 
and then every 12 weeks until disease progression. The percentage of subjects with complete or 
PRs, or stable disease will be evaluated and the disease control rate (CR, PR and SD at 4 months) 
will be compared using Pearson’s chi-square test, or if 20% or more of the expected cell frequencies 
are <5, Fisher’s exact test. Patient reported outcomes as assessed by the EORTC Quality of Life 
Questionnaire will be analyzed using analysis of covariance. 
Sample Size Justification: 
Power calculations and subject numbers were calculated based on the primary endpoint of PFS.  
Reviewing the literature for studies that have evaluated gemcitabine + docetaxel, pazopanib, 
ifosfamide and dacarbazine as treatment for patients that have relapsed or not responded to first line 
therapies, it is estimated that the median PFS for the investigator’s choice group will be 3.5 months 
and that the median PFS for the aldoxorubicin group will be 5.6 months.  Based on the use of a two-
sided log rank test at the α=0.05 level of significance, a total of 191 events will be required for 90% 
power to detect this difference.  Assuming an 18 month accrual period and a 15 month follow-up 
period after enrollment of the last subject, approximately 400 subjects will be needed to achieve the 
total of 191 events. 
Safety:  
The safety data will be summarized by treatment group. The treatment groups will be compared with 
respect to occurrence of each AE. Total number of AEs leading to withdrawal, and abnormal 
laboratory tests will be compared between groups using Fisher’s exact test. AEs, ability to remain on 
assigned treatment (tolerability), and abnormal findings on physical examinations, vital signs, weight, 
ECG results, laboratory test results, and use of concomitant medications, will be assessed to 
characterize the safety profile of the treatment regimens. Descriptive statistics denoting the changes 
from baseline to the final assessment visit with respect to key laboratory parameters and vital signs 
will also be provided.  


ALDOXORUBICIN-P3-STS-01 A4 
April 13, 2015 
 
CytRx Corporation 
CONFIDENTIAL 
Page 10 
Name of Sponsor/Company: CytRx Corporation 
 
Protocol Number:  
ALDOXORUBICIN-P3-STS-01 
Phase of Development: 3 
 
Pharmacokinetics:  
All subjects who receive aldoxorubicin and provide at least one PK sample with concentrations above 
the limit of quantification will be included in the PK analysis. Sparse plasma aldoxorubicin, 
doxorubicin, and doxorubicinol concentration data will be analyzed, and aldoxorubicin, doxorubicin, 
and doxorubicinol PK parameters will be estimated based on a population PK analysis. PK 
parameters will be summarized using descriptive statistics. 
Exploratory exposure-response/exposure-safety analyses will be conducted using the primary and 
secondary efficacy endpoints, PFS and OS, and for selected AEs. 


ALDOXORUBICIN-P3-STS-01 A4 
April 13, 2015 
 
CytRx Corporation 
CONFIDENTIAL 
Page 70 
APPENDIX A: Schedule of Treatment and Evaluations 
 
Screening 
-28 Days 
Cycle 
1 
Cycle 
222 
Cycle 
322 
Cycle 
422 
Cycle 
522 
Cycle 
622 
Cycle 
722 
Cycle 
822, 
9+22 
Day 15 and 21 
(28 for pazopanib) 
each Cycle 
End of 
Treatment23 
Every 6 
Weeks → 
Week 3024 
Every 
12 
Weeks24 
Follow 
Up 
GENERAL AND SAFETY 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Specimen1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X25 
X25 
X25 
 
Height (cm) 
X 
X5 
 
 
 
 
 
 
 
 
 
 
 
 
Weight (kg) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
BSA Calculation5 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Vital Signs6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Adverse Events7 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
Survival Follow-Up8 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
ECOG PS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
Concomitant Medications 
X9 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
RADIOGRAPHIC ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT/ MRI Scan / Tumor 
Measurements10 
X11a 
 
 
X11 
 
X11 
 
X11 
 
 
 
X 
X 
 
  CARDIAC ASSESSMENTS 
ECG12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X26 
X 
X 
 
ECHO (with ejection fraction)13  
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
  CENTRAL LAB ASSESSMENTS 
CBC w/differential & Platelets14 
X 
X16 
X 
X 
X 
X 
X 
X 
X 
X 
X26 
X 
X 
 
Serum Chemistries14, 15 
X 
X16 
X 
X 
X 
X 
X 
X 
X 
X 
X26 
 
 
 
Pharmacokinetic Sampling18 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis17 
X 
 
 
 
 
 
 
 
 
 
X26 
 
 
 
Serum/Urine Pregnancy Test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


ALDOXORUBICIN-P3-STS-01 A4 
April 13, 2015 
 
CytRx Corporation 
CONFIDENTIAL 
Page 71 
 
Screening 
-28 Days 
Cycle 
1 
Cycle 
222 
Cycle 
322 
Cycle 
422 
Cycle 
522 
Cycle 
622 
Cycle 
722 
Cycle 
822, 
9+22 
Day 15 and 21 
(28 for pazopanib) 
each Cycle 
End of 
Treatment23 
Every 6 
Weeks → 
Week 3024 
Every 
12 
Weeks24 
Follow 
Up 
  LOCAL LAB ASSESSMENTS27 
CBC w/differential & Platelets14 
X* 
X16 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Serum Chemistries 14, 15 
 
X16 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
  QUALITY OF LIFE QUESTIONNAIRE 
EORTC QLQ-C30 Version 3 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
  CHEMOTHERAPY: ALDOXORUBICIN OR INVESTIGATOR’S CHOICE 
Aldoxorubicin, Doxorubicin, Ifosfamide 
or Dacarbazine Administration19 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Gemcitabine and Docetaxel 
Administration 20 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Pazopanib Administration and Diary21 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
NOTE: All assessment must be performed within 72 hours of each specified time parameter (48 hours for pazopanib treated subjects), except Cycle 1 (see 
Section 6 for details). 
*Arterial blood gas test, if needed, to confirm acid levels. 


CLINICAL PROTOCOL 
TITLE: 
A Multicenter, Randomized, Open-Label Phase 3 Study to Investigate 
the Efficacy and Safety of Aldoxorubicin Compared to Investigator’s 
Choice in Subjects with Metastatic, Locally Advanced, or Unresectable 
Soft Tissue Sarcomas Who Either Relapsed or Were Refractory to Prior 
Non-Adjuvant Chemotherapy 
PROTOCOL NUMBER: 
ALDOXORUBICIN-P3-STS-01 
STUDY DRUG: 
Aldoxorubicin 
IND NUMBER: 
113,695 
EUDRACT NUMBER: 
2013-004103-40 
SPONSOR:  
CytRx Corporation 
11726 San Vicente Blvd 
Los Angeles, CA 90049 
(310) 826-5648
FAX: (310) 826-6139
IMMEDIATE SAFETY ASSISTANCE: 
Region 
Hotline 
Fax 
Email 
North America 
Australia 
Latin America 
1-866-326-5053
or 
1-434-951-4082
1-800-280-7035
or 
1-913-307-5751
AldoxP3STS@PRAIntl.com 
Europe 
+44 1792 52-5608
+49 621 878-2828
AldoxP3STS@PRAIntl.com 
SAE SUBMISSION: 
Region 
SAE Fax 
SAE Email 
North America 
1-888-772-6919
CHOSafety@PRAIntl.com 
Rest of World 
+44 1792 525-720
MHGSafety@PRAIntl.com 
ORIGINAL PROTOCOL: 
April 3, 2013 
AMENDMENT 1: 
August 28, 2013 
AMENDMENT 2: 
March 21, 2014 
AMENDMENT 3: 
January 13, 2015 
AMENDMENT 4: 
April 13, 2015 
AMENDMENT 5: 
January 21, 2016 
CONFIDENTIAL 
The information contained in this document is confidential and the proprietary property of CytRx 
Corporation. Any unauthorized use or disclosure of such information without the prior written 
authorization of CytRx Corporation is prohibited. 


ALDOXORUBICIN-PJ-STS-01 AS 
January 21, 2016 
PROTOCOL SIGNATURE PAGE 
A Multicenter, Randomized, Open-Label Phase 3 Study to Investigate the 
Efficacy and Safety of Aldoxorubicin Compared to Investigator's Choice in 
Subjects with Metastatic, Locally Advanced, or Unresectable Soft Tissue 
Sarcomas Who Either Relapsed or Were Refractory to Prior Non-Adjuvant 
Chemotherapy 
By signing below, the Investigator agrees to adhere to the protocol as outlined and agrees 
that any changes to the protocol must be approved by CytRx Corporation (CytRx) prior to 
seeking approval from the Institutional Review Board (IRB)/lndependent Ethics Committee 
(IEC). 
The study will be conducted in accordance with current United States (US) Food and Drug 
Administration (FDA) regulations, International Conference on Harmonization (ICH) 
guidelines, Good Clinical Practice (GCP) guidelines, the principles of the Declaration of 
Helsinki, and other applicable regulations and guidelines. 
I agree to ensure that Financial Disclosure Statements will be completed by: 
• 
me (including, if applicable, my spouse [or legal partner] and dependent children) 
• 
my subinvestigators (including, if applicable, their spouses [or legal partner] and 
dependent children) 
at the start of the study and for up to 1 year after the study is completed, if there are 
changes that affect my financial disclosure status. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of CytRx. 
Investigator's Signature: ------------------
Printed Name: 
Name of Institution/Company: ---------------
Date: _______________________ 
Sponsor Signature: 
.... : ... 
____ _ 
Daniel Levitt, M.D., Ph.D. 
Chief Medical Officer 
CytRx Corporation 
Date: __ 
___..fVl 
__ 
____ _ 
CytRx Corporation 
CONFIDENTIAL 
Page 2 


ALDOXORUBICIN-P3-STS-01 A5 
January 21, 2016 
 
CytRx Corporation 
CONFIDENTIAL 
Page 3 
Protocol Synopsis 
Name of Sponsor/Company: CytRx Corporation 
 
Protocol Number:  
ALDOXORUBICIN-P3-STS-01 
Phase of Development: 3 
 
Title of the Protocol:  
A Multicenter, Randomized, Open-Label Phase 3 Study to Investigate the Efficacy and Safety of 
Aldoxorubicin Compared to Investigator’s Choice in Subjects with Metastatic, Locally Advanced, or 
Unresectable Soft Tissue Sarcomas Who Either Relapsed or Were Refractory to Prior Non-Adjuvant 
Chemotherapy 
Primary Objective: 
The primary objective of this study is to determine the efficacy of administration of aldoxorubicin 
compared to investigator’s choice of treatment in subjects with metastatic, locally advanced, or 
unresectable soft tissue sarcomas who have relapsed or were refractory to prior non-adjuvant 
chemotherapy, as measured by progression-free survival (PFS). 
Secondary Objectives: 
The secondary objectives of this study are to evaluate the efficacy of aldoxorubicin as measured by 
overall survival (OS), overall response rate (ORR), disease control rate (ORR + SD at 4 months), 
PFS at 4 and 6 months, safety of aldoxorubicin compared to investigator’s choice in this population 
assessed by the frequency and severity of adverse events (AEs), abnormal findings on physical 
examination, laboratory tests, vital signs, echocardiogram (ECHO) evaluations, electrocardiogram 
(ECG) results, and weight. 
Exploratory Objectives: 
To determine the sparse pharmacokinetics (PK) of aldoxorubicin, doxorubicin, and doxorubicinol 
following intravenous (IV) administration of aldoxorubicin, and to evaluate the exposure-response 
relationships between aldoxorubicin, doxorubicin, and/or doxorubicinol and PFS, OS, selected safety 
parameters, and quality of life (EORTC QLQ-C30). 
Study Rationale and Significance: 
Aldoxorubicin (INNO-206; DOXO-EMCH) is a novel prodrug that binds covalently to circulating 
albumin. The drug is accumulated in tumors and doxorubicin is released in the tumor by cleaving the 
acid labile linker (EMCH) in the low pH tumor environment. This carrier-linked prodrug has 
demonstrated enhanced antitumor activity with reduced toxicity in several murine models when 
compared with free doxorubicin. 
Patients with metastatic, locally advanced, or unresectable soft tissue sarcomas who have failed prior 
chemotherapies have a poor prognosis with PFS of around 2-4.6 months and median OS of 
approximately 9-12 months. Several chemotherapy regimens have been explored as palliative 
therapy for subjects with these patients and include such agents as ifosfamide, gemcitabine, 
docetaxel, vinorelbine, dacarbazine, temozolomide, epirubicin, pazopanib and liposomal doxorubicin. 
However, these regimens can be quite toxic and have not significantly impacted either progression-
free or OS in these individuals. Pazopanib, recently approved in the US and Europe, does appear to 
extend PFS in soft tissue sarcoma patients (except liposarcomas) who have relapsed after receiving 
prior chemotherapy compared to no treatment, but does not increase OS. Aldoxorubicin may improve 
upon the activity of doxorubicin without an increase in toxicity as has been demonstrated in animal 
studies. 


ALDOXORUBICIN-P3-STS-01 A5 
January 21, 2016 
 
CytRx Corporation 
CONFIDENTIAL 
Page 4 
Name of Sponsor/Company: CytRx Corporation 
 
Protocol Number:  
ALDOXORUBICIN-P3-STS-01 
Phase of Development: 3 
 
Study Design and Methodology: 
This is a phase 3 open-label study evaluating the efficacy and safety of aldoxorubicin administered at 350 
mg/m2 (260 mg/m2 doxorubicin equivalent) intravenously on Day 1 every 21 days until tumor progression 
or unacceptable toxicity occurs compared to investigator’s choice of treatment among  
5 different therapies. These therapies include (dosages should follow the institutional standard of care, 
package insert (SPCs), or the following suggestions based on the US package inserts and the literature):  
1) dacarbazine administered at 1000 mg/m2 by intravenous infusion (IVI), over 90±15 minutes on Day 1 
every 21 days until tumor progression or unacceptable toxicity occurs; 2) pazopanib, 800 mg orally each 
day until tumor progression or unacceptable toxicity occurs; 3) gemcitabine, 900 mg/m2 by IVI in less than 
60 minutes on Days 1 and 8, plus docetaxel, 100 mg/m2 by IVI over 1 hour on Day 8 of a 21 day cycle until 
tumor progression or unacceptable toxicity occurs; 4) doxorubicin, 75 mg/m2 by IVI over 5 to 30 minutes 
every 21 days for a maximum cumulative dose of 550 mg/m2 or unacceptable toxicity occurs; or 5) 
ifosfamide 2.0 g/m2 administered over 2 to 4 hours on Days 1-4 of a 21 day cycle + mesna per standard 
site administration regimen until tumor progression or unacceptable toxicity occurs. The investigative site 
must pre-specify their choice of treatments for the comparator arm to be used at their site, and no more 
than 3 treatment regimens may be selected for the comparator arm at each site which must be selected 
prior to the study site initiation visit. Subjects will be randomized 1:1 to receive either aldoxorubicin or 
investigator’s choice of up to 3 control regimens pre-selected by the study site. Treatment with G-CSF 
should be administered to all subjects as per investigator’s clinical judgment or according to ASCO 
Guidelines (Appendix E). Note:  aldoxorubicin has been associated with >20% incidence of grade 3 
or 4 neutropenia. Therefore, the administration of G-CSF should occur even during Cycle 1. 
All Screening requirements, including an ECHO exam, must be completed within 28 days of the  
Cycle 1-Day 1 visit. Subjects receiving aldoxorubicin, ifosfamide, dacarbazine or doxorubicin will  
visit the study site on Day 1 of each cycle. They will have complete blood counts (CBC) and serum 
chemistries on Day 15 and Day 21 (if Day 21 does not correspond to Day 1 of the next cycle,  
±3 days) of each cycle as well. Subjects receiving pazopanib will visit the study site on Day 1 of their next 
cycle for monitoring, testing (same as for Day 1 for other treatment regimens) and to receive a new supply 
of study drug. Subjects receiving pazopanib will also have CBC and serum chemistry on Day 15 and Day 
28 (if Day 28 does not correspond to Day 1 of the next cycle, ±2 days). Subjects receiving gemcitabine 
plus docetaxel will visit the study site on both days of their infusions (Days 1 and 8) and at Days 15 and 21 
of each cycle. Safety monitoring, including AEs, a directed physical examination, laboratory evaluations 
(serum chemistry, CBC, and urinalysis), vital signs, weight measurements, Eastern Cooperative Oncology 
Group (ECOG) performance status (PS) and ECGs will be performed on Day 1 (for all subjects) of each 
cycle. Subjects receiving aldoxorubicin will have blood drawn for serum electrolytes to evaluate the anion 
gap prior to each drug administration. Cardiac function will also be followed periodically (per Schedule of 
Treatment and Evaluations in Appendix A) with ECHOs for subjects receiving either aldoxorubicin or 
doxorubicin. Treatment will continue until tumor progression is observed, a maximum cumulative dose of 
550 mg/m2 is reached (doxorubicin), subject asks to withdraw, unacceptable toxicity occurs, a change in 
therapy would be in the best interest of the subject, subject becomes pregnant or fails to use adequate 
birth control, need for any treatment not allowed by the protocol, or subject is non-compliant with study 
requirements. 
Tumor response will be monitored at screening, every 6 weeks from Cycle 1-Day 1 through Week 30, and 
then every 12 weeks until disease progression using the Response Evaluation Criteria in Solid Tumors 
(RECIST) 1.1 criteria.[50] OS, PFS, and PFS at 4 and 6 months will be evaluated. Objective overall 
response rate (ORR) (complete and partial responses [PRs]), disease control rate (objective responses 
plus stable disease at 4 months) and quality of life will be assessed.  
The PK of aldoxorubicin, doxorubicin, and doxorubicinol will be evaluated using a sparse sample analysis. 
Plasma samples will be collected from subjects receiving aldoxorubicin at Cycle 1 at the following time 
points: the end of the infusion, between 1.5 and 4 hours from the end of the infusion, and on Days 2, and 3. 
If necessary and possible, PK samples may be collected at a later cycle along with collecting a predose 
blood sample. 


ALDOXORUBICIN-P3-STS-01 A5 
January 21, 2016 
 
CytRx Corporation 
CONFIDENTIAL 
Page 5 
Name of Sponsor/Company: CytRx Corporation 
 
Protocol Number:  
ALDOXORUBICIN-P3-STS-01 
Phase of Development: 3 
 
Study Population and Main Criteria for Inclusion/Exclusion: 
Inclusion Criteria: 
Subjects must meet the following criteria to be included in the study: 
1. Has provided written informed consent prior to any study related activities. 
2. Age ≥15 years (US only), and 18-80 (rest of world (ROW)), male or female. 
3. Histological confirmation of intermediate or high grade soft-tissue sarcoma as determined by the local 
pathology report.  Archival tissue must be sent to a central pathology lab for review but will not 
preclude entry onto the study (study-specific biopsies are not allowed). Final assignment of tumor 
grade and histology will be based on the designation provided by the central pathology review. 
4. An adequate tumor specimen obtained by either excisional biopsy, incisional biopsy or core 
needle biopsy must be sent to the central pathology lab for evaluation.  
5. Locally advanced, unresectable, and/or metastatic soft-tissue sarcoma of intermediate or high grade 
with evidence of disease progression by either computed tomography (CT) or magnetic resonance 
imaging (MRI) scan, or clinical judgment on or after the last cancer therapy within 6 months prior to 
randomization. 
6. Relapsed or refractory (lack of response) to ≥1 course of systemic therapy regimen(s), excluding 
adjuvant or neoadjuvant chemotherapy, and is incurable by either surgery or radiation. 
7. Capable of providing informed consent and complying with trial procedures. 
8. ECOG PS 0-2. 
9. Life expectancy >12 weeks. 
10. Measurable tumor lesions according to RECIST 1.1 criteria.[50] 
11. Women must not be able to become pregnant (e.g., post-menopausal for at least 1 year, surgically 
sterile, or practicing adequate birth control methods) for the duration of the study. (Adequate 
contraception includes: oral contraception, implanted contraception, intrauterine device implanted for 
at least 3 months, or barrier method in conjunction with spermicide.) 
12. Males and their female partner(s) of child-bearing potential must use 2 forms of effective contraception 
(see Inclusion 11 plus condom or vasectomy for males) from the last menstrual period of the female 
partner during the study treatment and agree to continue use for 6 months after the final dose of study 
treatment. 
13. Women of child bearing potential must have a negative serum or urine pregnancy test at the Screening 
Visit and be non-lactating. 
14. Accessibility to the site that optimizes the subject’s ability to keep all study-related appointments.  
Exclusion Criteria: 
Subjects meeting the following criteria will not be enrolled: 
1. Prior exposure to >375 mg/m2 of doxorubicin or liposomal doxorubicin. 
2. Palliative surgery and/or radiation treatment within 30 days prior to date of randomization. 
3. Exposure to any investigational agent within 30 days of date of randomization. 
4. Exposure to any systemic chemotherapy within 30 days of date of randomization. 
5. An inadequate tumor specimen as defined by the central pathologist. 
6. Current evidence/diagnosis of alveolar soft part sarcoma, extraskeletal myxoid chondrosarcoma, 
rhabdomyosarcoma, osteosarcoma, gastrointestinal stromal tumor (GIST), dermatofibrosarcoma 
(unless transformed to fibrosarcoma), Ewing’s sarcoma, Kaposi’s sarcoma, mixed mesodermal tumor, 
clear cell sarcomas. 
7. Evidence of central nervous system (CNS) metastasis who have not received prior definitive therapy 
for their lesions.  
8. History of other malignancies except cured basal cell carcinoma, cutaneous squamous cell carcinoma, 
melanoma in situ, superficial bladder cancer or carcinoma in situ of the cervix unless documented free 
of cancer for ≥5 years. 


ALDOXORUBICIN-P3-STS-01 A5 
January 21, 2016 
 
CytRx Corporation 
CONFIDENTIAL 
Page 6 
Name of Sponsor/Company: CytRx Corporation 
 
Protocol Number:  
ALDOXORUBICIN-P3-STS-01 
Phase of Development: 3 
 
9. Laboratory values: Screening serum creatinine >1.5 x upper limit of normal (ULN), alanine 
aminotransferase (ALT) >3×ULN or >5×ULN if liver metastases are present, total bilirubin >2×ULN, 
absolute neutrophil count (ANC) <1,500/mm3, platelet concentration <100,000/mm3, hemoglobin  
<9 g/dL. 
10. Anion gap > 16 meq/L (Central Laboratory) or arterial blood pH < 7.30 (as determined by the Local 
Laboratory). 
11. Clinically evident congestive heart failure (CHF) > class II of the New York Heart Association (NYHA) 
(Appendix D) guidelines.  
12. Current, serious, clinically significant cardiac arrhythmias, defined as the existence of an absolute 
arrhythmia or ventricular arrhythmias classified as Lown III, IV or V (Appendix F). 
13. Baseline QTc >470 msec and/or previous history of QT prolongation while taking other medications.  
14. Concomitant use of medications associated with a high incidence of QT prolongation is not allowed 
(Appendix G). 
15. History or signs of active coronary artery disease with or without angina pectoris within the last 6 
months. 
16. Serious myocardial dysfunction defined by ECHO as absolute left ventricular ejection fraction (LVEF) 
below the institution’s lower limit of predicted normal. 
17. Known history of HIV infection.  
18. Active, clinically significant serious infection requiring treatment with antibiotics, anti-virals or  
anti-fungals. The Medical Monitor should be contacted for any uncertainties. 
19. Major surgery within 30 days prior to date of randomization. 
20. Current or past substance abuse or any condition that might interfere with the subject’s participation in 
the study or in the evaluation of the study results. 
21. Any condition that is unstable and could jeopardize the subject’s participation in the study. 
Number of Subjects: 
Approximately 400 subjects with metastatic, locally advanced or unresectable soft tissue sarcomas 
who have either not responded to or have progressed after treatment with 1 or more systemic 
regimens of non-adjuvant chemotherapies will be randomized 1:1 (aldoxorubicin:investigator’s 
choice) at approximately 79 study centers in the US, Europe, Canada, Latin America, and Australia. 
The randomization will be stratified according to their initial PS (ECOG 0-1 vs 2), whether they had 
either 1 prior systemic non-adjuvant chemotherapy regimens or >1 prior systemic non-adjuvant 
chemotherapy regimens and whether they had received prior doxorubicin chemotherapy.  Subjects 
will also be stratified by their histopathological diagnosis as determined by the local site.  The four 
stratification groups will be leiomyosarcomas, liposarcoma, synovial sarcoma, and all other sarcomas. 


ALDOXORUBICIN-P3-STS-01 A5 
January 21, 2016 
 
CytRx Corporation 
CONFIDENTIAL 
Page 7 
Name of Sponsor/Company: CytRx Corporation 
 
Protocol Number:  
ALDOXORUBICIN-P3-STS-01 
Phase of Development: 3 
 
Test Product, Dose and Mode of Administration: 
Aldoxorubicin: Lyophilized powder in vials that contain 200 mg of aldoxorubicin reconstituted by 
adding a solution of 50% ethanol: 50% sterile water, administration completed within 2 hours (of 
being reconstituted) as a 30-minute IVI Lactated Ringer’s solution. Total dose of 350 mg/m2  
(260 mg/m2 doxorubicin equivalent). Aldoxorubicin infusion may exceed 30 minutes if deemed 
necessary by the investigative site but the total time from the completion of reconstitution of 
aldoxorubicin to completion of infusion must not be more than 2 hours. 
Investigator’s Choice: Up to three treatment regimens are to be chosen by the investigator from the 
list below prior to the initiation of the study site and the treatment chosen for each subject enrolled in 
the study must be entered into the case report form.  Directions for dosage and reconstitution should 
follow institutional standard of care, package inserts (SPCs), or the suggestions below based on the 
US package inserts and the literature.  
Dacarbazine 100 mg/vial and 200 mg/vial are reconstituted with 9.9 mL and 19.7 mL, respectively, 
Sterile Water for Injection, USP. The resulting solution contains 10 mg/mL of dacarbazine having a 
pH of 3.0 to 4.0. The calculated dose of the resulting solution is drawn into a syringe and 
administered only intravenously. The reconstituted solution may be further diluted with 5% dextrose 
injection, or sodium chloride injection (250 to 500 mL), and administered as an IVI over 90±15 
minutes. 
After reconstitution and prior to use, the solution in the vial may be stored at 4°C for up to 72 hours or 
at normal room conditions (temperature and light) for up to 8 hours. If the reconstituted solution is 
further diluted in 5% dextrose injection or sodium chloride injection, the resulting solution may be 
stored at 4°C for up to 24 hours or at normal room conditions for up to 8 hours. 
Pazopanib (Votrient®) 200 mg tablets can be stored at room temperature between 20° and 25°C; 
excursions are permitted between 15° and 30°C. Tablets are taken 1 hour before or 2 hours after a 
meal and tablets are NOT to be crushed. 
Gemcitabine 200 mg or 1 g lyophilized powder in a single use vial is reconstituted with 0.9% NaCl to 
a final concentration of ≤40 mg/mL and pH 2.7 to 3.3. The reconstituted solution may be further 
diluted with 0.9% NaCl and administered by IVI in <60 minutes. It is stable for up to 24 hours at 
controlled room temperature (20° to 25°C) and should not be refrigerated. 
Docetaxel 80 mg/8 mL and 20 mg/2 mL is administered by IVI over approximately 60 minutes after 
dilution into a 250 to 500 mL infusion bag of either 0.9% NaCl or 5% dextrose solution to produce a 
final concentration of 0.3 to 0.74 mg/mL. Docetaxel final dilution for infusion should be administered 
within 4 hours of preparation. It can be stored between 2° and 25°C. 
Doxorubicin HCl Injection is a sterile parenteral, isotonic available in 5 mL (10 mg), 10 mL (20 mg),  
25 mL (50 mg) single dose vials. Each mL contains doxorubicin HCl and the following inactive 
ingredients:  NaCl (0.9%) and water for injection q.s. Hydrochloric acid is used to adjust the pH to a 
target of pH of 3.0. The reconstituted solution is diluted in 0.9% NaCl or 5% dextrose and may be 
administered over 5 to 30 minutes. 
Ifosamide single-dose vials for constitution and administration by IVI each contain 1 gram or 3 grams 
of sterile ifosfamide, USP. Ifosfamide is a chemotherapeutic agent chemically related to the nitrogen 
mustards and a synthetic analog of cyclophosphamide. Injections are prepared for parenteral use by 
adding Sterile Water for Injection, USP, or Sterile Bacteriostatic Water for Injection, USP (benzyl 
alcohol or parabens preserved) to the vial and shaking to dissolve. The reconstituted solution is 
diluted in 0.9% NaCl or 5% dextrose solution and may be administered over 2 to 4 hours. 
See Section 5.2 for additional investigator’s choice treatment concentrations and preparation 
instructions as per package inserts. 


ALDOXORUBICIN-P3-STS-01 A5 
January 21, 2016 
 
CytRx Corporation 
CONFIDENTIAL 
Page 8 
Name of Sponsor/Company: CytRx Corporation 
 
Protocol Number:  
ALDOXORUBICIN-P3-STS-01 
Phase of Development: 3 
 
Criteria for Evaluation: 
Efficacy: 
The following efficacy variables will be evaluated as noted: 
 PFS. 
 OS. 
 Objective tumor response (RECIST 1.1 criteria[50]). 
 Disease control rate (objective tumor response + stable disease at 4 months). 
 PFS at 4 and 6 months. 
 Subject Reported Outcome as measured by the European Organisation for Research and 
Treatment of Cancer (EORTC) Quality of Life Questionnaire. 
 
Safety: 
The following safety variables will be assessed over the duration of the study: 
 AEs. 
 Ability to remain on assigned treatment (tolerability). 
 Clinical and laboratory data including physical examinations, vital signs, weight, ECHO 
evaluations, ECG results and laboratory test results. 
 Use of concomitant medications. 
Pharmacokinetics: 
The following PK variables will be assessed for aldoxorubicin, doxorubicin, and doxorubicinol: 
 Maximum drug concentration (Cmax) in plasma. 
 Area under the plasma drug-concentration-time profile (AUC0-inf). 
 Clearance (CL). 
 Volume of distribution (Vd). 
 Half-life (t½). 


ALDOXORUBICIN-P3-STS-01 A5 
January 21, 2016 
 
CytRx Corporation 
CONFIDENTIAL 
Page 9 
Name of Sponsor/Company: CytRx Corporation 
 
Protocol Number:  
ALDOXORUBICIN-P3-STS-01 
Phase of Development: 3 
 
Statistical Methods: 
In accordance with the intention-to-treat principle, all randomized subjects will be evaluated for 
efficacy. All subjects who receive at least 1 dose of study medication will be evaluated for safety.  
Efficacy:  
The primary analysis of PFS will be carried out when approximately 191 PFS events have been 
observed by the blinded Central Imaging Research Organization (approximately 15 months following 
the completion of enrollment of 400 subjects). Survival distributions will be estimated using the 
Kaplan-Meier method and the two groups will be compared using a two-sided unstratified log rank 
test at the α=0.05 level of significance. 
An important secondary endpoint is overall survival (OS). The analysis of OS will be considered 
confirmatory only if the PFS analysis is statistically significant. As a result, the nominal level of 
significance for the OS analysis will be α=0.05. However, because an interim analysis of OS will be 
carried out at the time of the analysis of PFS, the levels of significance for the interim and final 
analyses of OS will be α=0.00305 and α=0.049, respectively. 
The final analysis of OS will be completed when 320 OS events have occurred. Survival distributions 
will be estimated using the Kaplan-Meier method and the two groups will be compared using a two-
sided unstratified log rank test at the α=0.049 level of significance. The same methodology will be 
used for the interim analysis, but at the α=0.00305 level of significance. 
Tumor response will be monitored at screening, every 6 weeks from Cycle 1-Day 1 through Week 30, 
and then every 12 weeks until disease progression. The percentage of subjects with complete or 
PRs, or stable disease will be evaluated and the disease control rate (CR, PR and SD at 4 months) 
will be compared using Pearson’s chi-square test, or if 20% or more of the expected cell frequencies 
are <5, Fisher’s exact test. Patient reported outcomes as assessed by the EORTC Quality of Life 
Questionnaire will be analyzed using analysis of covariance. 
Sample Size Justification: 
Power calculations and subject numbers were calculated based on the primary endpoint of PFS.  
Reviewing the literature for studies that have evaluated gemcitabine + docetaxel, pazopanib, 
ifosfamide and dacarbazine as treatment for patients that have relapsed or not responded to first line 
therapies, it is estimated that the median PFS for the investigator’s choice group will be 3.5 months 
and that the median PFS for the aldoxorubicin group will be 5.6 months.  Based on the use of a two-
sided log rank test at the α=0.05 level of significance, a total of 191 events will be required for 90% 
power to detect this difference.  Assuming an 18 month accrual period and a 15 month follow-up 
period after enrollment of the last subject, approximately 400 subjects will be needed to achieve the 
total of 191 events. 
Safety:  
The safety data will be summarized by treatment group. The treatment groups will be compared with 
respect to occurrence of each AE. Total number of AEs leading to withdrawal, and abnormal 
laboratory tests will be compared between groups using Fisher’s exact test. AEs, ability to remain on 
assigned treatment (tolerability), and abnormal findings on physical examinations, vital signs, weight, 
ECG results, laboratory test results, and use of concomitant medications, will be assessed to 
characterize the safety profile of the treatment regimens. Descriptive statistics denoting the changes 
from baseline to the final assessment visit with respect to key laboratory parameters and vital signs 
will also be provided.  


ALDOXORUBICIN-P3-STS-01 A5 
January 21, 2016 
 
CytRx Corporation 
CONFIDENTIAL 
Page 10 
Name of Sponsor/Company: CytRx Corporation 
 
Protocol Number:  
ALDOXORUBICIN-P3-STS-01 
Phase of Development: 3 
 
Pharmacokinetics:  
All subjects who receive aldoxorubicin and provide at least one PK sample with concentrations above 
the limit of quantification will be included in the PK analysis. Sparse plasma aldoxorubicin, 
doxorubicin, and doxorubicinol concentration data will be analyzed, and aldoxorubicin, doxorubicin, 
and doxorubicinol PK parameters will be estimated based on a population PK analysis. PK 
parameters will be summarized using descriptive statistics. 
Exploratory exposure-response/exposure-safety analyses will be conducted using the primary and 
secondary efficacy endpoints, PFS and OS, and for selected AEs. 


ALDOXORUBICIN-P3-STS-01 A5 
January 21, 2016 
 
CytRx Corporation 
CONFIDENTIAL 
Page 70 
APPENDIX A: Schedule of Treatment and Evaluations 
 
Screening 
-28 Days 
Cycle 
1 
Cycle 
222 
Cycle 
322 
Cycle 
422 
Cycle 
522 
Cycle 
622 
Cycle 
722 
Cycle 
822, 
9+22 
Day 15 and 21 
(28 for pazopanib) 
each Cycle 
End of 
Treatment23 
Every 6 
Weeks → 
Week 3024 
Every 
12 
Weeks24 
Follow 
Up 
GENERAL AND SAFETY 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Specimen1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X25 
X25 
X25 
 
Height (cm) 
X 
X5 
 
 
 
 
 
 
 
 
 
 
 
 
Weight (kg) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
BSA Calculation5 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Vital Signs6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Adverse Events7 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
Survival Follow-Up8 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
ECOG PS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
Concomitant Medications 
X9 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
RADIOGRAPHIC ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT/ MRI Scan / Tumor 
Measurements10 
X11a 
 
 
X11 
 
X11 
 
X11 
 
 
 
X 
X 
 
  CARDIAC ASSESSMENTS 
ECG12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X26 
X 
X 
 
ECHO (with ejection fraction)13  
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
  CENTRAL LAB ASSESSMENTS 
CBC w/differential & Platelets14 
X 
X16 
X 
X 
X 
X 
X 
X 
X 
X 
X26 
X 
X 
 
Serum Chemistries14, 15 
X 
X16 
X 
X 
X 
X 
X 
X 
X 
X 
X26 
 
 
 
Pharmacokinetic Sampling18 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis17 
X 
 
 
 
 
 
 
 
 
 
X26 
 
 
 
Serum/Urine Pregnancy Test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


ALDOXORUBICIN-P3-STS-01 A5 
January 21, 2016 
 
CytRx Corporation 
CONFIDENTIAL 
Page 71 
 
Screening 
-28 Days 
Cycle 
1 
Cycle 
222 
Cycle 
322 
Cycle 
422 
Cycle 
522 
Cycle 
622 
Cycle 
722 
Cycle 
822, 
9+22 
Day 15 and 21 
(28 for pazopanib) 
each Cycle 
End of 
Treatment23 
Every 6 
Weeks → 
Week 3024 
Every 
12 
Weeks24 
Follow 
Up 
  LOCAL LAB ASSESSMENTS27 
CBC w/differential & Platelets14 
X* 
X16 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Serum Chemistries 14, 15 
 
X16 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
  QUALITY OF LIFE QUESTIONNAIRE 
EORTC QLQ-C30 Version 3 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
  CHEMOTHERAPY: ALDOXORUBICIN OR INVESTIGATOR’S CHOICE 
Aldoxorubicin, Doxorubicin, Ifosfamide 
or Dacarbazine Administration19 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Gemcitabine and Docetaxel 
Administration 20 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Pazopanib Administration and Diary21 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
NOTE: All assessment must be performed within 72 hours of each specified time parameter (48 hours for pazopanib treated subjects), except Cycle 1 (see 
Section 6 for details). 
*Arterial blood gas test, if needed, to confirm acid levels.