Phase II Study of Nab-Paclitaxel in Combination With Gemcitabine for Treatment of Recurrent/Refractory Sarcoma in Teenagers and Young Adults
Phase: PHASE2
Conditions: Osteosarcoma, Ewing Sarcoma, Rhabdomyosarcoma, Soft Tissue Sarcoma
Sponsor: H. Lee Moffitt Cancer Center and Research Institute

1 
 
MCC Protocol #: 18613 
 
 
ClinicalTrials.gov Identifier:  NCT02945800 
 
Title:  Phase II Study of nab-Paclitaxel in Combination with Gemcitabine for Treatment of 
Recurrent/Refractory Sarcoma in Teenagers and Young Adults 
 
 
 
Corresponding Organization: Moffitt Cancer Center 
12902 Magnolia Drive 
Tampa, FL 33612 
Email: SunshineProject@moffitt.org 
 
 
Coordinating Center:                Sunshine Project at Moffitt Cancer Center 
     12902 Magnolia Drive 
     Tampa, FL 33612 
     Email: SunshineProject@moffitt.org 
 
 
Principal Investigator: 
Javier E. Oesterheld, MD 
 
Carolinas Medical Center 
 
Levine Cancer Institute 
 
Pediatric Hematology/Oncology 
 
100 Blyth Blvd 
 
Charlotte, NC 28303 
 
T: 704-381-9900 
 
F: 704-381-9901 
 
Email: 23TUJavier.oesterheld@atriumhealth.org 
 
 
 
Co- Investigators: 
Tom Badgett, MD 
University of Kentucky 
 
 
Lexington, KY 
 
 
 
Damon Reed, MD 
Moffitt Cancer Center 
 
Tampa, FL 
 
Eric Sandler, MD 
Nemours Children’s Hospital 
Jacksonville, FL  
 
 
       
Julio Barredo, MD  
Holtz Children’s Hospital at the University of Miami 
Miami, FL 
 
 
 

2 
Joanne Lagmay, MD 
Shand’s Hospital for Children at the University of Florida 
Gainesville, FL 
 
Leo Mascarhenas, MD 
Children’s Hospital of Los Angeles 
Los Angeles, CA 
 
Michael Isakoff, MD 
Connecticut Children’s Medical Center 
Hartford, CT 
 
Emi Caywood, MD 
Alfred I DuPont Hospital for Children 
Wilmington, DE 
 
Bhuvana Setty, MD  
Nationwide Children’s Hospital 
Columbus, OH 
 
 
Christine Pratilas, MD 
 
Johns Hopkins University 
 
Baltimore, MD 
 
 
Lars Wagner, MD 
 
Duke Health 
 
Durham, NC 
 
 
Scott Borinstein, MD 
 
Vanderbilt-Ingram Cancer Center 
 
Nashville, TN  
 
Hong Yin, MD 
Children’s Healthcare of Atlanta Department of Pathology 
Atlanta, GA 
 
 
Rikesh Makanji, MD, Natarajan Raghunand, PhD,  
 
& Olya Stringfield, PhD 
 
Moffitt Cancer Center 
 
Tampa, FL 
 
 
Masanori Hayashi, MD 
 
University of Colorado Denver 
 
Denver, CO 
 
 
Patrick Thompson, MD 
 
University of North Carolina 
 
Chapel Hill, NC 
 
 

3 
Elizabeth Alva, MD  
Children’s of Alabama at UAB 
 Birmingham, AL 
 
 
 
Statistician: 
Brooke Fridley, PhD  
 
 
Moffitt Cancer Center 
 
 
 
12902 Magnolia Dr., MRC-Bio2  
 
 
Tampa, FL, 33612 
 
 
 
T: 813-745-1461 
 
 
 
Email: Brooke.Fridley@moffitt.org 
 
 
Image Data Management:  
Melissa Cochran, MSPH, CCRP 
 
 
IRAT Core & Radiology Research Project Manager 
 
 
Moffitt Cancer Center 
 
 
12902 Magnolia Dr., MCC-CRU 
 
 
Tampa, FL, 33612 
 
 
T: 813-745-2836 
 
  
Email: 23TUMelissa.Cochran@moffitt.orgU23T 
 
 
Sponsor: 
National Pediatric Cancer Foundation 
 
NCI-Supplied Agent(s):   
Not applicable 
 
Other Agent(s):   
nab-Paclitaxel (Abraxane) NSC # 
 
Gemcitabine (Gemzar), NSC # 
 
 
 
Protocol Type / Version # / Version Date: 
Original/ Version 1/ Version Date: March 1, 2016 
 
 
 
 
Amendment/ Version 2/ Version Date: April 12, 2016 
 
 
 
 
Amendment/ Version 3/ Version Date: June 01, 2016 
 
 
 
 
Amendment/Version 4/Version Date: July 27, 2016 
 
 
 
 
Amendment/Version 5.1/Version Date: September 27, 2017 
 
 
 
 
Amendment/Version 6/Version Date: June 27, 2019 
 
 
 
 
Amendment/Version 7/Version Date: November 17, 2020 
 
 
 
 
Amendment/Version 8/Version Date: February 25, 2021 
 
 
 
 
Amendment/Version 9/Version Date: March 3, 2023 
 
 
 
 
 
 
 
 
 
 
 
 

4 
SCHEMA 
 
The combination of gemcitabine and docetaxel is widely used for recurrent pediatric bone and soft tissue sarcoma, 
although efficacy is suboptimal. Nab-Paclitaxel (AbraxaneP®
P) is a nanoparticle albumin-bound preparation of 
paclitaxel that is more active and less toxic than either paclitaxel or docetaxel in breast cancer patients. 
Compelling activity has been seen with nab-paclitaxel against the Pediatric Preclinical Testing Program panel of 
sarcoma xenografts, including maintained complete responses in multiple models of Ewing sarcoma and 
rhabdomyosarcoma. In addition, the combination of gemcitabine and nab-paclitaxel is now approved by the US 
Food and Drug Administration for treating pancreatic cancer, based on preclinical models and clinical trials 
showing potential synergy with these drugs. Taken together, these findings suggest nab-paclitaxel may be a better 
taxane for the treatment of pediatric sarcoma. To test this hypothesis, we will conduct a single-arm, multi-strata, 
open-label Phase II study to assess the activity of gemcitabine and nab-paclitaxel in teenagers and young adults 
with sarcoma. Following the schema below, patients age >12 years with recurrent or refractory Ewing sarcoma, 
osteosarcoma, rhabdomyosarcoma, or other soft tissue sarcoma will receive the previously established regimen 
of gemcitabine 1,000 mg/mP2
P together with nab-paclitaxel 125 mg/mP2
P on days 1, 8, and 15 of every 4-week cycle. 
A two-stage Simon design will be used, with up to 18 total patients enrolled in each of the four disease cohorts. 
The combination will be of sufficient interest for further study if the estimated rate of partial + complete responses 
is > 35% for patients with Ewing and soft tissue sarcoma, and if the estimated 4-month progression-free survival 
is > 35% for patients with osteosarcoma. 
 
 
 
Nab-paclitaxel 
(125 mg/mP2
P iv over 30 min) 
Gemcitabine 
(1,000 mg/mP2
P iv over 90 min) 
Myeloid Growth Factor 
Day 1 
X 
X 
 
Day 8 
X 
X 
 
Day 15 
X 
X 
 
Day 16-18 
 
 
X 
Day 16-28 
                                            REST 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

5 
TABLE OF CONTENTS 
23TSCHEMA23T .........................................................................................................................................4 
23T1.23T 
23TOBJECTIVES23T ......................................................................................................................7 
23T1.023T 
23TPrimary Objectives23T...................................................................................................7 
23T1.123T 
23TSecondary Objectives23T...............................................................................................7 
23T2.23T 
23TBACKGROUND23T .................................................................................................................7 
23T2.023T 
23TRecurrent or Refractory Sarcomas in Adolescent and Young Adult Patients23T .........7 
23T2.123T 
23TUse of nab-Paclitaxel23T ...............................................................................................8 
23T2.23T 
23TRationale23T ................................................................................................................12 
23T2.323T 
23TPatient Population23T ..................................................................................................12 
23T2.423T 
23TDose and Schedule of Administration23T ...................................................................12 
23T2.523T 
23TStudy Design23T ..........................................................................................................13 
23T2.623T 
23TCorrelative Studies23T .................................................................................................14 
23T3.23T 
23TPATIENT SELECTION23T ....................................................................................................15 
23T3.023T 
23TEligibility Criteria23T ..................................................................................................15 
23T3.123T 
23TExclusion Criteria23T ..................................................................................................16 
23T3.23T 
23TInclusion of Women and Minorities23T ......................................................................17 
23T3.323T 
23TInformed Consent Process23T .....................................................................................17 
23T4.23T 
23TREGISTRATION 
 PROCEDURES23T.............................................................................................................................18 
23T4.023T 
23TSite and Investigator Registration with Moffitt Cancer Center23T .............................18 
23T4.123T 
23TPatient Registration23T ................................................................................................18 
23T4.23T 
23TGeneral Guidelines23T.................................................................................................18 
23T5.23T 
23TTREATMENT PLAN23T ........................................................................................................18 
23T5.023T 
23TAgent Administration23T.............................................................................................18 
23T5.123T 
23TGeneral Concomitant Medication and Supportive Care Guidelines23T ......................19 
23T5.23T 
23TDuration of Therapy23T ...............................................................................................20 
23T5.323T 
23TDuration of Follow Up23T ...........................................................................................21 
23T5.423T 
23TCriteria for Removal from Study23T ...........................................................................21 
23T5.523T 
23TCriteria for Being Considered Evaluable23T ...............................................................21 
23T5.623T 
23TReplacement23T ...........................................................................................................22 
23T6.23T 
23TDOSING DELAYS/DOSE MODIFICATIONS23T ...............................................................22 
23T7.23T 
23TADVERSE EVENTS: DEFINITIONS AND REPORTING REQUIREMENTS23T .............23 
23T7.023T 
23TAdverse Event Characteristics23T ...............................................................................24 
23T7.123T 
23TExpedited Adverse Event Reporting (Serious Adverse Event)23T .............................24 
23T7.23T 
23TRoutine Adverse Event Reporting23T .........................................................................26 
23T7.323T 
23TSecond Malignancy23T ................................................................................................27 
23T8.23T 
23TPHARMACEUTICAL INFORMATION23T ..........................................................................27 
23T8.023T 
23TNab-Paclitaxel (Abraxane®)23T..................................................................................27 
23T8.123T 
23TGemcitabine23T ...........................................................................................................28 
 

6 
23T9.23T 
23TBIOMARKER, CORRELATIVE AND SPECIAL STUDIES23T .........................................30 
23T9.023T 
23TImmunohistochemical Expression of SPARC and Cav-123T .....................................30 
23T9.123T 
23TRadiomic Analysis of Diagnostic CT Images23T ........................................................30 
 
9.2 
Biomarkers of Minimal Residual Disease………………………………………..29 
23T10.23T 
23TSTUDY CALENDAR23T .......................................................................................................32 
23T10.023T 
23TDemographics23T ........................................................................................................33 
23T10.123T 
23TMedical History23T .....................................................................................................33 
23T10.23T 
23TPhysical Measurements23T ..........................................................................................33 
23T10.323T 
23TPhysical Exam23T ........................................................................................................33 
23T10.423T 
23TAdverse Events23T ......................................................................................................33 
23T10.523T 
23TRadiologic Evaluations23T ..........................................................................................33 
23T11.23T 
23TMEASUREMENT OF EFFECT23T........................................................................................34 
23T11.023T 
23TAntitumor Effect – Solid Tumors23T ..........................................................................34 
23T12.23T 
23TDATA REPORTING/REGULATORY REQUIREMENTS23T .............................................39 
23T12.023T 
23TData Reporting23T .......................................................................................................39 
23T12.123T 
23TMoffitt Cancer Center Guidelines23T ..........................................................................41 
23T13.23T 
23TSTATISICAL CONSIDERATIONS23T .................................................................................42 
23T13.023T 
23TStudy Design/Endpoints23T.........................................................................................42 
23T13.123T 
23TSample Size/Accrual Rate23T ......................................................................................43 
23T13.23T 
23TAnalysis of Other Secondary Endpoints23T ................................................................44 
23T14.23T 
23TREFERENCES23T ..................................................................................................................44 
23TAPPENDIX A23T 
23TPERFORMANCE STATUS CRITERIA23T ..................................................47 
 APPENDIX B   
Letter for Insurance Coverage for Gemcitabine and nab-Paclitaxel……..47  
 

7 
1. OBJECTIVES 
 
1.0 
Primary Objectives 
 
1. To assess the antitumor activity of nab-paclitaxel combined with gemcitabine in patients with relapsed 
or refractory osteosarcoma, Ewing sarcoma, rhabdomyosarcoma and other soft tissue sarcoma using 
RECIST 1.1 criteria and progression-free survival 
 
1.1 
Secondary Objectives 
 
1. To describe the toxicities of the combination in adolescents and young adults with relapsed/refractory 
sarcoma 
2. To assess the immunohistochemical expression of SPARC, CAV-1, and hENT1 in archival tumor 
tissue, and compare results with treatment response 
3. To evaluate a set of radiomic biomarkers calculated from baseline and post-therapy CT scans, and 
compare results with treatment response. 
4. To quantify circulating tumor cells (CTC) in patients with recurrent or refractory sarcomas, and 
determine if CTC changes reflect response to therapy or predict risk of progression. 
 
 
2. BACKGROUND 
 
2.0 
Recurrent or Refractory Sarcomas in Adolescent and Young Adult Patients 
Although many adolescent and young adults with localized bone or soft tissue sarcoma can become long-
term survivors, more effective therapies are needed for patients who present with metastatic disease or 
whose tumors recur after completing therapy. For all the major subtypes of sarcoma seen in this age group, 
less than one-third of patients with metastatic or recurrent disease are cured, and new therapeutic strategies 
are clearly required. Attractive treatment options include those using commercially available drugs for 
which there is preclinical synergy and biologic rationale, as well as previously established well-tolerated 
outpatient regimens for administration. 
 
Over the past decade, the combination of gemcitabine and docetaxel has been widely used as salvage 
therapy for relapsed or refractory pediatric-type sarcomas such as osteosarcoma, Ewing sarcoma, and 
rhabdomyosarcoma.  As seen in Table 1 below, over 100 patients with such sarcomas have been treated 
in at least 6 published studies of this regimen in which gemcitabine is administered on days 1 and 8, and 
docetaxel is given on day 8 of the 3-week cycle. While single-institution retrospective series have reported 
complete or partial responses in as many as 24-50% of patients [1-3], the response rate in a prospective 
multi-institutional trial was < 15% [6]. These findings suggest that modifications to this treatment are 
necessary in order to improve activity to a sufficient level to justify investigation in clinical trials of newly-
diagnosed patients. 
  
Adolescents and young adults may also develop non-rhabdomyosarcomatous soft tissue sarcomas, which 
are termed adult-type sarcomas because of the frequency in older patients. Such histologies include 
synovial sarcoma, malignant peripheral nerve sheath tumor, high-grade undifferentiated sarcoma, and a 
wide variety of other sarcoma subtypes. Collectively these tumors make up 3-4% of all pediatric cancers. 
The combination of gemcitabine and docetaxel has been commonly used to treat adult-type soft tissue 
sarcoma, as shown in Table II. Though responses and prolonged event-free survival have routinely been 
observed in patients receiving this therapy, the issues of toxicity and suboptimal activity have kept this 
regimen from being used frontline in most adult sarcoma patients.  
 
 

8 
 
 
Table 1. Key Trials Using Gemcitabine and Docetaxel for Recurrent Pediatric-Type Sarcoma 
 
Author 
(ref) 
Evaluable 
Patients 
Population 
Gemcitabine 
(mg/mP2
P) 
Days 1,8 
Docetaxel 
(mg/mP2
P) 
Day 8 
 
Response Rate 
(CR + PR) 
Comments 
Song 
(1) 
17 
OS 
675-900 
100 
24% 
Retrospective 
analysis 
Navid 
(2) 
14 
OS (10), ES (2), 
others 
675 
75-100 
29% all 
evaluable 
RR 30% in OS 
Mora 
(3) 
10 
ES (6), SS (2), OS 
(1) 
1,000 
100 
50% 
RR 67% in ES; 50% 
in synovial sarcoma 
Rapkin 
(4) 
18 
OS (6), RMS (5), 
ES (2), others 
675 
75 
11% for RMS 
No objective 
responses in OS or 
ES 
Qi 
(5) 
18 
OS 
675 
75-100 
6% 
Retrospective 
analysis 
Fox 
(6) 
28 
OS (14), ES (14) 
675 
75 
7% for OS 
14% for ES 
Prospective multi-
institutional trial 
OS, osteosarcoma; ES Ewing sarcoma; SS, synovial sarcoma; RMS, rhabdomyosarcoma; RR, response rate  
 
 
Table II. Key Trials Using Gemcitabine and Docetaxel for Advanced/Metastatic Adult-Type Soft Tissue Sarcoma (STS) 
 
Author 
(ref) 
Evaluable 
Patients 
Population 
Gemcitabine 
(mg/mP2
P) 
Days 1,8 
Docetaxel 
(mg/mP2
P) 
Day 8 
Response 
Rate (CR + 
PR) 
Comments 
Maki 
(7) 
73 
Metastatic 
900 
100 
16% 
Superior survival 
compared to GEM alone 
Davis 
(8) 
29 
Localized, 
resectable 
900 
100 
3% 
Longer disease-free 
survival compared to 
doxo/ifos (p = 0.08) 
Seddon 
(9) 
128 
Advanced 
unresectable 
or metastatic 
675 
75 
PFR at 24 
weeks was 
46% 
Similar PFR-24 as 
doxorubicin, but more 
toxic 
PFR, progression-free rate; GEM, gemcitabine; doxo/ifos, doxorubicin/ifosfamide 
 
2.1 
Use of nab-Paclitaxel 
Paclitaxel is an antimitotic agent that stabilizes tubulin by preventing depolymerization. Although 
paclitaxel is widely used in adult oncology to treat breast, lung, and ovarian cancer, toxicity can limit its 
use and require change to a different chemotherapy regimen. Conventional paclitaxel (Taxol®) is 
emulsified with the solvent Cremphor EL and ethanol, and this preparation is associated with 
hypersensitivity reactions and prolonged neuropathy related to the carrier vehicle. Another factor 
contributing to paclitaxel toxicity is its slow clearance rate, which leads to prolonged systemic exposure 
and resulting neutropenia.  
 
Reformulation of paclitaxel appears to circumvent these drug delivery and pharmacokinetic limitations. 
Advances in nanotechnology have allowed such insoluble hydrophobic agents to become encapsulated 
using albumin nanoparticles. This new formulation, called nanoparticle albumin-bound paclitaxel (nab-
paclitaxel, Abraxane®), is created through a proprietary high-pressure homogenization process in which 
nab-paclitaxel is non-covalently bound to albumin to create a 130 nM albumin particle form of paclitaxel 
[reviewed in 10]. The biochemical nature of this compound has important implications regarding its 
distribution into tissue, pharmacokinetics, and tolerance. For example, the albumin nanoparticle can bind 
to the endothelial cell receptor gp60, which induces caveolin-1 (CAV-1) to assist with internalization of 

9 
the albumin-substrate complex into caveolae and subsequently into the interstitial space. Once there, nab-
paclitaxel gains entry into the tumor cell through the binding protein SPARC (secreted protein, acidic and 
rich in cysteine). This mechanism of drug transport into the tumor cell suggests that either CAV-1 and/or 
SPARC may be potential biomarkers to predict sensitivity to nab-paclitaxel, as discussed further in Section 
2.3.4. Further, preclinical experiments suggest that nab-paclitaxel delivery to xenografted tumor cell is 
33% greater compared to similar doses of paclitaxel [11], which contributes to the improved efficacy of 
this new agent as described below.  
 
Because the carrier vehicle for nab-paclitaxel is albumin rather than Cremaphor XL, the incidence of 
hypersensitivity reactions is dramatically reduced, and obviates the need for the steroid and antihistamine 
premedication that is required with conventional paclitaxel. Nab-paclitaxel can also be given in a 30-
minute infusion rather than the typical 180-minute infusion of paclitaxel, and no special tubing or filters 
are required for intravenous administration. The absence of Cremaphor and ethanol may also be related 
to the more rapid resolution of neuropathy when nab-paclitaxel is compared to carrier-based paclitaxel, as 
both Cremaphor and ethanol have been shown to have direct toxic effects on neurons such as axonal 
degeneration that can be long-lasting. 
 
Finally, nab-paclitaxel has more predictable first-order pharmacokinetics, with rapid clearance and a large 
volume of distribution consistent with more widespread tissue penetration. This is in contrast to carrier-
based paclitaxel, in which clearance is prolonged and may be related to myelosuppression caused by 
extended exposure of low-level paclitaxel [12]. The reduction in toxicity with this new formulation allows 
for 50% higher paclitaxel doses to be given, resulting in activity in preclinical models and patients whose 
tumors were resistant to paclitaxel [reviewed in 10, 11].  
 
2.1.1 Clinical Experience with nab-Paclitaxel in Adults 
In the initial phase I study of adults with melanoma or breast cancer, the maximum tolerated dose (MTD) 
of nab-paclitaxel was 300 mg/m2 when given as a 30-minute intravenous infusion every three weeks 
[13]. Dose-limiting toxicities (DLT) were sensory neuropathy, stomatitis, and superficial keratopathy, 
with only one patient having DLT (neuropathy) at the MTD. Other side effects included modest 
myelosuppression and nausea. Importantly, there were no hypersensitivity reactions reported when 
using a 30-minute infusion with no steroid or antihistamine premedication.  
 
Linear pharmacokinetics were observed following nab-paclitaxel administration, with a rapid decrease 
in plasma levels as drug is distributed to peripheral tissues, followed by slower second phase of drug 
elimination. In a comparison study of nab-paclitaxel 260 mg/m2 over 30 min vs paclitaxel 175 mg/m2 
over 180 min, the maximum exposure to unbound paclitaxel was nearly 3-fold higher for nab-paclitaxel 
[14]. Although the elimination half-lives were similar (approximately 21 hours), nab-paclitaxel had 
greater clearance from plasma and greater volume of distribution, suggesting improved tissue binding. 
The metabolism and excretion of nab-paclitaxel is the same as the conventional formulation, with drug 
metabolized by the liver into the primary metabolite 6-alpha-hydroxypaclitaxel.  
 
Subsequent clinical trials have examined different administration schedules for nab-paclitaxel, and in 
direct comparison the greatest activity has been seen when it is given weekly for 3 weeks followed by 
one week of rest [15]. The MTD using this 3-of-4 schedule has ranged from 100 to 150 mg/mP2
P, 
depending on the extent of patient pretreatment [16]. The toxicity profile does not appear to be different 
with this schedule compared to administration once every three weeks. The grade 3-4 toxicities most 
commonly encountered with once-weekly nab-paclitaxel administration at the MTD are neutropenia 
(44%), and neuropathy (14%). When nab-paclitaxel was compared to single-agent docetaxel 100 mg/mP2
P 
q 3 weeks in a phase III trial, docetaxel had much greater myelosuppression and similar neurotoxicity, 
with grade 3-4 neutropenia in 94% and grade 3 neuropathy in 12% of patients [15]. Of note, the grade 
3 neuropathy encountered with nab-paclitaxel resolved to < grade 2 faster than for patients receiving 

10 
docetaxel (22 vs. 37 days), and was readily managed with dose reduction. The incidence of febrile 
neutropenia and grade 3 fatigue in this study was 8% and 19% for docetaxel vs. 1% and 3% for nab-
paclitaxel, respectively. Important for the consideration of heavily-pretreated sarcoma patients, grade 4 
thrombocytopenia with single-agent ABX is unusual, and has been reported to occur in < 5% of adult 
patients [10].  
 
Table III. Comparison of toxicities in adults with metastatic breast cancer receiving either nab-paclitaxel 150 
mg/mP2
P weekly or docetaxel 100 mg/mP2
P q 3 weeks 
 
 
Nab-paclitaxel 
 
Docetaxel 
Grade 4 neutropenia 
9% 
75% 
Grade 3 neuropathy* 
14% 
12% 
Grade 3 fatigue 
3% 
19% 
Febrile neutropenia 
1% 
8% 
Median progression-free survival 
12.9 mo 
7.5 mo (p=0.0065) 
*resolved to < grade 2 in 22 days (nab) vs 37 days (paclitaxel) 
 
In terms of efficacy assessed in randomized phase III trials, single-agent nab-paclitaxel showed superior 
response rates and disease control in breast cancer patients compared to either docetaxel [15] or paclitaxel 
[17]. When nab-paclitaxel was combined with carboplatin in a phase III trial of lung cancer patients, that 
combination showed greater efficacy and less toxicity than carboplatin + paclitaxel [18]. These studies 
led to FDA approval of nab-paclitaxel as a single agent for metastatic breast cancer, and in combination 
with carboplatin for non-small cell lung cancer.  
 
2.1.2 Preclinical Experience with nab-Paclitaxel in the Treatment of Pediatric Tumors 
Early preclinical studies using mouse models of adult cancers demonstrated that at equivalent doses, 
nab-paclitaxel had 33% greater intratumoral accumulation of drug compared to conventional paclitaxel 
[11]. As with humans, mice are able to tolerate higher doses of nab-paclitaxel compared to conventional 
paclitaxel, and studies comparing equitoxic doses show nab-paclitaxel has superior activity in mouse 
models of adult carcinomas [11] as well as in rhabdomyosarcoma [19] and osteosarcoma [20]. Also 
noted was tumor regression when nab-pacitaxel therapy was substituted in mice whose xenografted 
rhabdomyosarcoma tumors were progressing on paclitaxel [19].  
 
The most comprehensive and impressive demonstration of activity of single-agent nab-paclitaxel has 
been reported by the National Cancer Institute’s Pediatric Preclinical Testing Program. They 
demonstrated “high” activity in 5 of 8 Ewing sarcoma models tested, including 4 models with 
maintained complete responses [21]. Similar responses were seen in the rhabdomyosarcoma panel, in 
which 5 of 8 models also had “high” activity, with 5 maintained complete responses. To date, 4 different 
laboratories have now reported on the activity of nab-paclitaxel in a total of 9 models of Ewing sarcoma, 
10 rhabdomyosarcoma, and 4 osteosarcoma, with notable activity being seen in the majority of these 
models [19-22]. These results have led to an ongoing pediatric Phase I trial of single-agent nab-paclitaxel 
in children with recurrent solid tumors [clinicaltrials.gov identifier NCT01962103].  
 
2.1.3 Nab-Paclitaxel in Combination with Gemcitabine 
The modest toxicity profile of nab-paclitaxel makes it an excellent drug to consider for combination 
chemotherapy, as demonstrated by the success seen when given together with carboplatin in lung cancer 
patients [18]. In this regard, gemcitabine may also be a suitable partner for nab-paclitaxel. Gemcitabine 
is a nucleoside analog which inhibits DNA replication by blocking DNA synthesis and disrupting usual 
repair mechanisms. Gemcitabine is FDA approved for the treatment of ovarian, breast, lung, and 
pancreatic cancer, and a wide variety of combination therapies have been investigated. In adults, the 
most common toxicities include mild-to-moderate myelosuppression, nausea, fever, rash, flu-like 

11 
symptoms, and swelling of the legs. 
 
In a phase I trial of children with refractory solid tumors, gemcitabine was administered once weekly 
for three weeks followed by a one-week rest [23]. Seventeen evaluable patients were treated on this 
schedule, and the MTD was 1,200 mg/m2. At this dose, only one of eight patients experiencing DLT 
(grade 3 transaminitis that did not resolve within one week). At the higher dose of 1500 mg/m2, 
myelosuppression was dose-limiting. The pediatric MTD of 1,200 mg/m2 in heavily pretreated children 
compares with a MTD of 790 mg/m2 established in a phase I trial of heavily pretreated adults receiving 
a similar schedule [24].  
 
 
In a phase II study of twenty pediatric patients (median age 15 years) with recurrent solid tumors who 
were treated for three consecutive weeks, myelosuppression was the prominent toxicity [25]. The study 
design called for dose reductions with any grade 3 or 4 toxicity, and approximately one-third of total 
doses were reduced. Only one patient had fever, one had grade 3 nausea, and none had grade 3-4 
transaminitis. A second phase II study of relapsed sarcoma patients using gemcitabine 1,000 mg/m2 
weekly for 7 weeks before transitioning to a weekly x3 schedule also demonstrated that gemcitabine is 
well tolerated in relapsed sarcoma patients, with no grade 4 hematologic toxicity and only 17% of 
patients experiencing grade 3 neutropenia or thrombocytopenia [26]. 
 
Preclinical studies suggest that gemcitabine may be synergistic with nab-paclitaxel. Possible 
mechanisms for this include increased intracellular concentrations of gemcitabine via changes in the 
tumor stroma and vasculature [27], and/or reduction of the primary gemcitabine metabolizing enzyme, 
cytidine deaminase [28]. These mechanisms may be responsible for the 2.8-fold increase in intracellular 
gemcitabine concentrations seen with this combination compared to treatment with gemcitabine alone 
[27]. Consistent with the synergy seen with adult tumors, combining nab-paclitaxel and gemcitabine 
showed improved activity in a mouse model of osteosarcoma when compared to treatment with each 
individual agent [22].   
 
The combination of gemcitabine and nab-paclitaxel has been most thoroughly evaluated in pancreatic 
cancer. In a phase I/II trial of adults with untreated advanced pancreatic cancer, the MTD was 1,000 
mg/m2 of gemcitabine plus 125 mg/m2 of nab-paclitaxel given once weekly for 3 weeks, followed by 
one week of rest [27]. For the 44 patients treated at this dose, grade 4 neutropenia was seen in 49% of 
patients, although only one patient experienced febrile neutropenia. Only 9% of patients had grade 4 
thrombocytopenia, and 20% had grade 3 neuropathy. 
 
In a larger phase III trial of adults with newly-diagnosed metastatic pancreatic cancer, the combination 
of gemcitabine and nab-paclitaxel on the above schedule was compared with gemcitabine alone weekly 
for 7 of 8 weeks [29]. Key toxicities and use of growth factor, done at the treating physician’s discretion, 
are reported in Table IV. Although the rates of peripheral neuropathy and myelosuppression were 
somewhat higher with the combination, there was significant improvement in the progression-free and 
overall survival. These findings led to US FDA approval of the combination for this patient population. 
 
Table IV. Comparison of toxicities and growth factor use in adults with advanced pancreatic cancer receiving gemcitabine +/- 
nab-paclitaxel in a phase III trial 
 
 
Nab + Gem 
(n=421) 
Gem Alone 
(n = 402) 
Grade > 3 neutropenia 
38% 
27% 
Grade > 3 thrombocytopenia 
13% 
9% 
Febrile neutropenia 
3% 
1% 
Grade > 3 fatigue 
17% 
7% 
Grade > 3 neuropathy 
17% 
1% 

12 
Received growth factor 
26% 
15% 
Response rate 
23% 
7% (p < .001) 
1-year survival 
35% 
22% (p < .001) 
 
2.2 
Rationale  
Given the preclinical activity of nab-paclitaxel against pediatric sarcoma xenografts, as well as the 
tolerance and activity of gemcitabine and nab-paclitaxel seen in pancreatic cancer patients, nab-paclitaxel 
may be a superior partner for gemcitabine in treating adolescents and young adults with sarcoma. We 
hypothesize that this combination will be more tolerable and efficacious than the gemcitabine + docetaxel 
regimen widely being used, and that sufficient response rates and progression-free survival will be seen 
in these high-risk patients to justify further investigation in larger trials of newly-diagnosed patients. There 
currently is an ongoing phase I/II trial of single-agent nab-paclitaxel for pediatric patients with recurrent 
solid tumors. However, that trial is not expected to complete accrual until 2018, and experience would 
suggest that single-agent activity is unlikely to be as efficacious as combination cytotoxic chemotherapy 
for pediatric sarcoma. If the combination has the desired degree of activity, then additional studies could 
be performed to determine whether the gemcitabine is needed. If activity on this study is poor, it is unlikely 
that further studies with single-agent nab-paclitaxel will be performed for sarcoma. We therefore feel it is 
appropriate to move ahead with this phase II proposal, using the dosing and schedule of administration 
employed that has been previously approved by the FDA for pancreatic cancer. 
 
2.3 
Patient Population 
Patients who have recurrent or progressive disease following frontline treatment for osteosarcoma or 
Ewing sarcoma have a dismal prognosis, with less than one-fifth of patients achieving long-term cure. 
Outcomes are also poor for those with recurrent or refractory rhabdomyosarcoma, especially in those with 
the aggressive alveolar subtype. The majority of patients with these particularly high-risk bone or soft 
tissue sarcomas are teenagers or young adults.  Given the established tolerability of the proposed drug 
combination in adults, it seems reasonable to directly extend this treatment to patients of age > 12 years 
with recurrent/refractory OS, ES, or RMS. A similar approach has been employed before by the Children’s 
Oncology Group, in which the adult recommended Phase II dosage of the FDA-approved agent eribulin 
is being used in teenagers with recurrent osteosarcoma without first performing a phase I dose-finding 
trial (clinical trials.gov identifier number NCT02097238).  
 
2.4 
Dose and Schedule of Administration 
We plan to use the standard doses (gemcitabine 1,000 mg/mP2
P; nab-paclitaxel 125 mg/mP2
P) and schedule of 
administration (both drugs weekly for 3 of 4 weeks) that are approved by the FDA for combination use. 
This scheduled is detailed below: 
 
 
Nab-paclitaxel 
(125 mg/mP2
P iv over 30 
min) 
Gemcitabine 
(1,000 mg/mP2
P iv over 90 
min) 
 
Myeloid Growth Factor 
 
Day 1 
X 
X 
 
Day 8 
X 
X 
 
Day 15 
X 
X 
 
Day 16-18 
 
 
X 
Day 16-28 
                                            REST 
 
Maintaining dose intensity is reasonable given there is some suggestion of higher response rates when 
higher doses of gemcitabine and taxanes are used [1,3]. However, in order to balance the potential benefit 
of intensive therapy with safety concerns, the day 15 chemotherapy will be held in any patient who 
experiences grade 4 neutropenia (absolute neutrophil count < 500/mcL) on or before that day of the cycle. 
In that situation, patients will be subject to dose de-escalation with additional cycles as detailed in Section 
6. Similarly, patients who experience grade 3 neuropathy will have nab-paclitaxel held for the remainder 

13 
of the cycle. Other dose modifications may be made based on toxicities, and are detailed in Section 6. 
 
Additional data collected from three patients treated on study suggest that removal from study because of 
the occurrence of dose-modifying hematologic toxicity as defined in Section 6 may not be necessary. 
These patients all experienced dose-modifying hematologic toxicity despite the planned use of 
pegfilgrastim and dose modifications. They were therefore removed from study, but since their physicians 
felt they were deriving clinical benefit from the treatment and the drugs are commercially available, they 
simply continued with therapy using gemcitabine and nab-paclitaxel. These patients tolerated continued 
therapy using reduced doses (gemcitabine 675 mg/m2/dose; nab-paclitaxel 100 mg/m2/dose) for 1-9 
additional cycles, with no treatment delays or infectious toxicity noted. Importantly, one of the patients 
went on to experience a partial response with this extended off-protocol therapy. That patient used a 
modified schedule in which drugs are administered on days 1 and 8 in 21-day cycles, with pegfilgrastim 
given on day 9. This treatment regimen has been studied in a phase II trial for patients with metastatic 
breast cancer, with response rates similar to historical controls treated on the standard 28-day schedule. 
This 21-day schedule reduces the overall intensity by 11%, and is similar to the schedule of gemcitabine 
+ docetaxel used previously for recurrent sarcoma [43]. Given this information, patients on this study with 
stable or responding disease who experience a dose-modifying hematologic toxicity after dose reduction 
may continue on study using the 21-day schedule described above and detailed in Section 6. 
 
2.5 
Study Design 
This is a single-arm, multi-strata, open-label phase II study to assess the activity of nab-paclitaxel and 
gemcitabine in 4 disease types: osteosarcoma (OS), Ewing sarcoma (ES), rhabdomyosarcoma (RMS), and 
non-rhabdomyosarcoma soft tissue sarcoma (NRSTS). Osteosarcoma tumors are often composed of 
calcium, which historically in previous studies has confounded the assessment of response in some 
patients as calcified tumors are less likely to change in size even when anti-tumor therapy is effective. 
This particular feature of osteosarcoma has led the Children’s Oncology Group (COG) to use progression-
free survival (PFS) at 4 months as the preferred endpoint for phase II studies of relapsed osteosarcoma, as 
demonstrated in the most recent study [clinical trials.gov identifier number NCT02097238]. In a review 
of seven past COG phase II studies involving 95 evaluable patients, the median PFS was 12% at four 
months. Assessment of 4-month PFS therefore will be used in this study, with the threshold of > 35% 
being the level of interest for further study.  
 
For the other disease cohorts (ES, RMS, and NRSTS), the more traditional partial + complete response 
rate using RECIST 1.1 will be used. The threshold for further interest will also be a response rate ofU >U 
35%, as used in previous COG studies for these tumor types [NCT01614795]. In contrast, the combination 
will be of insufficient interest if the 4-month PFS is <10% for OS patients, or the response rate is < 10% 
for patients with ES, RMS, or NRSTS.  
 
Secondary endpoints include toxicity assessment using Common Terminology Criteria for Adverse Events 
(CTCAE) Version 4.0, and immunohistochemical assessment of putative biomarker expression in archival 
tumor tissue for patients who consent to have this testing performed. We will also perform Radiomic 
analysis of the baseline and follow-up CT scans of patients. 
 
A Simon two-stage design will be used to enroll patients to each of the four cohorts. As detailed in Section 
13, eleven patients from each cohort will be enrolled in Stage 1, and seven additional patients may be 
added to the cohort if at least 2 responses are seen in the first 11 patients of that cohort. If the combination 
has a true response rate (or 4-month PFS for OS patients) of 10%, the two-stage design described above 
will identify it of sufficient activity for further study with probability 0.10 (type I error). If the combination 
has a true response rate (or 4-month PFS for OS patients) of 35%, the probability of identifying it of 
sufficient activity for further study with probability 0.91 (power against the alternative hypothesis P = 
.35). 

14 
 
2.6 
Correlative Studies 
 
2.6.1 Immunohistochemical Expression of Putative Biomarkers in Archival Tumor Tissue 
As described above, caveolin-1 (CAV-1) facilitates the passage of nab-paclitaxel across the endothelial 
cell membrane and into the tumor interstitium. From there, drug enters the tumor cell via the adhesion 
protein SPARC (secreted protein, acidic and rich in cysteine), which normally mediates the passage of 
albumin. In some tumor types, SPARC expression in either tumor cells or stroma correlates with the 
activity of nab-paclitaxel [27,30,31], although this association has not always been consistently 
identified [32]. SPARC expression is nearly universal in osteosarcoma [33], and high expression is 
correlated with worse prognosis [19]. SPARC expression has also been reported in tumor samples of 
patients with recurrent or metastatic Ewing sarcoma [22,34]. In addition, CAV-1 is expressed in both 
osteosarcoma as well as Ewing sarcoma, especially in patients with metastatic disease [33,34]. These 
findings suggest the possibility that expression of one or both of these proteins may be correlated with 
the activity of nab-paclitaxel regimens in pediatric sarcoma. In this study, protein expression of these 
putative markers will be assessed by immunohistochemistry analysis of archival tumor samples, using 
the most recent tumor sample already available. In addition, we will also assess the immunohistochemical 
expression of hENT1, which has been reported to be associated with improved outcomes in patients with 
pancreatic cancer [41] and sarcoma [42] receiving gemcitabine. This testing will be conducted by Dr. Hong 
Yin at Children’s Healthcare of Atlanta, using previously validated immunohistochemical assays [22]. 
 
   Please see lab manual for shipping instructions of correlative studies. 
 
2.6.2 Radiomic Analysis of Diagnostic CT Images 
Radiology has traditionally been a qualitative and subjective science. Advances in medical imaging and 
image analysis technologies now permit the high-throughput extraction of quantitative image features 
and conversion of digital medical images into mineable high-dimensional data. This process, known as 
radiomics, is motivated by the concept that biomedical images contain information that reflects 
underlying pathophysiology and that these relationships can be revealed via quantitative image analyses 
[35]. Quantitative radiomic features extracted from diagnostic CT scans show promise in predicting 
patient survival in NSCLC [36]. In a study of 1019 patients with lung or head-and-neck cancer, Aerts, 
Gillies, and colleagues analyzed 440 radiomic features to quantify tumor phenotypic differences based 
on image intensity, image texture and lesion shape, and identified a large number of features with 
prognostic power [37]. In a sub-study of 20 patients with histopathologically proven, measurable, 
primary STS or isolated local recurrence of STS after previous surgery, but without metastatic disease, 
who were treated with bevacizumab, radiotherapy and surgical resection, CT image texture features 
were associated with tumor angiogenesis and overall survival [38,39]. In this study, quantitative image 
features will be extracted from baseline and follow-up diagnostic CT scans, and the radiomic features 
at baseline, as well as changes in radiomic features between baseline and follow-up scans, will be 
compared with treatment response. Lesion delineation and RECIST 1.1 measurements will be performed 
by Dr. Rikesh Makanji at the Moffitt Cancer Center using the recently FDA-approved HealthMyne® 
PACS (www.healthmyne.com). Radiomic analysis of delineated lesions will be performed by Dr. 
Natarajan Raghunand and Dr. Olya Stringfield in the IRAT Core at the Moffitt Cancer Center, also using 
the HealthMyne platform to which radiomics capabilities have been added in an ongoing collaboration 
between HealthMyne and Dr. Gillies and other radiomics researchers at the Moffitt Cancer Center. 
 
2.6.3 Minimal Residual Disease Studies 
In addition, we will use this study population to gather preliminary data regarding biomarkers of 
Minimal Residual Disease (MRD) in sarcoma patients.  MRD studies in sarcoma remain in their infancy, 
and it remains unclear if molecular studies, such as quantification of plasma tumor DNA (ptDNA) or 
circulating tumor cells (CTC), will provide superior results to imaging, including early evidence of 

15 
response and early hints of impending relapse.  In this study, blood will be collected from subjects at 
the time of enrollment, after their first cycle of therapy, and in conjunction with each imaging event, and 
will be shipped to the laboratory of Dr. Masanori Hayashi at University of Colorado.  CTC analysis will 
be performed in real time, while plasma will be cryopreserved in aliquots and analyzed in batches. 
 
For plasma analysis, we will assess aberrations in genomic, epigenomic, and transcriptional profiles, as 
well as variations defined by future technologies. Circulating tumor profiling data at baseline and all 
timepoints will be compared.  When available, we will utilize the same archival tissue as described in 
section 2.6.1 for additional comparisons to circulating tumor material.  
 
 
Please see the study lab manual for instructions on submitting the following: archival tumor tissue, CT 
images, and biomarker specimens. Section 10.5 provides instructions for standardized diagnostic CT 
acquisition parameters. 
 
 
3. PATIENT SELECTION 
 
3.0 
Eligibility Criteria  
 
3.0.1 Patients must be age ≥U3 years and ≤30 years, and have had a histologic diagnosis of osteosarcoma, 
Ewing sarcoma, or rhabdomyosarcoma or non-rhabdomyosarcoma soft tissue sarcoma either at 
diagnosis or relapse. 
 
PATIENTS MUST HAVE EXPERIENCED RELAPSE AFTER FRONT-LINE THERAPY, OR HAVE 
HAD DOCUMENTED DISEASE PROGRESSION DURING FRONT-LINE THERAPY. 
 
3.0.2 All patients must have measurable disease that can be assessed using RECIST 1.1 criteria, which is 
defined as the presence of at least one lesion on MRI or CT scan that can be accurately measured with 
the longest diameter of 10 mm in at least one dimension. For this phase II trial, patients with disease 
limited to bone or marrow metastases are NOT eligible, as disease at these sites cannot be assessed by 
RECIST 1.1 criteria. 
  
3.0.3 Patients must have relapsed or refractory cancers for which there is no known curative option.  
 
3.0.4 Prior Therapy for Treatment of Cancer: There is no limit to the number of prior therapies provided all 
eligibility criteria are met. However, patients must have recovered from the acute toxic effects of all 
prior treatment.  
 
a. Patients must not have received prior therapy with either gemcitabine or nab-paclitaxel. 
b. 
UMyelosuppressive chemotherapyU: Patients must not have received myelosuppressive 
chemotherapy within 3 weeks of protocol therapy on this study.  
c. 
UHematopoietic growth factors:U 7 days must have elapsed from the start of protocol therapy since 
the completion of therapy with filgrastim, and 14 days must have elapsed from the start of protocol 
therapy after receiving pegfilgrastim.  
d. 
UBiologic (anti-neoplastic agent):U 7 day must have elapsed from the start of protocol therapy since 
the completion of therapy with a biologic agent.  
e. 
UMonoclonal Antibodies or Antibody Drug Conjugates:U 3 half-lives or 28 days from the last dose, 
whichever is shorter, provided all toxicities have resolved, must have elapsed prior to the start of 
protocol therapy. 

16 
f. 
URadiotherapy:U 2 weeks must have elapsed from the start of protocol therapy since local palliative 
XRT (small port); 3 months must have elapsed if 50% radiation of pelvis; 6 weeks must have 
elapsed if other substantial bone marrow irradiation was given.  
g. 
UStem Cell Transplant or Rescue:U No evidence of active graft vs. host disease and 2 months must 
have elapsed from the start of protocol therapy since transplant.  
 
3.0.5 Karnofsky performance score must be ≥ 60 (see Appendix A) 
 
3.0.6 Patients must have organ and marrow function as defined below: 
 
• absolute neutrophil count ≥ 1,000/mcL 
• platelets ≥ 100,000/mcL 
• total bilirubin within normal institutional limits 
• AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional upper limit of normal 
• Serum creatinine within upper institutional limits 
 
 
 
OR 
• creatinine clearance ≥ 60 mL/min/1.73 mP2
P for patients with creatinine levels above institutional 
 
normal. 
 
3.0.7 Neuropathy: Patients must have < grade 1 neuropathy at enrollment. 
 
3.0.8 CNS Metastases: Patients with known central nervous system metastases are excluded unless treated 
surgically or with radiotherapy and stable with no recurrent lesions for at least 3 months from the start 
of protocol therapy. 
 
3.0.9 Contraception: The effects of gemcitabine and nab-paclitaxel on the developing human fetus are 
unknown.  For this reason and because these agents may be teratogenic, women of child-bearing 
potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; 
abstinence) prior to study entry and for the duration of study participation.  Should a woman become 
pregnant or suspect she is pregnant while she or her partner is participating in this study, she should 
inform her treating physician immediately.  Men treated or enrolled on this protocol must also agree to 
use adequate contraception prior to the study, for the duration of study participation, and 4 months after 
completion of gemcitabine and nab-paclitaxel administration. 
 
3.0.10 Consent: Patients must have the ability to understand and the willingness to sign a written informed 
consent or assent document. 
 
3.1 
Exclusion Criteria 
 
3.1.1 Patients who are receiving any other investigational agents are ineligible. 
 
3.1.2 Patients must not be receiving any additional medicines being given for the specific purpose of treating 
cancer. 
 
3.1.3 Patients with a history of allergic reactions attributed to docetaxel or paclitaxel are ineligible. 
 

17 
3.1.4 Concomitant Medications: The metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4. The 
following medicines should be avoided on this study because of their ability to inhibit or induce with 
CYP2C8 or CYP3A4: 
 
Inhibitors: 
ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, 
gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir 
 
Inducers: 
Rifampicin, carbamazepine, phenytoin, efavirenz, and nevirapine 
 
Patients receiving any of the above medications are ineligible.   
 
3.1.5 Patients are ineligible if they have uncontrolled intercurrent illness including, but not limited to: 
• ongoing or active infection 
• symptomatic congestive heart failure 
• unstable angina pectoris 
• cardiac arrhythmia 
• psychiatric illness/social situations that would limit compliance with study requirements 
 
3.1.6 Pregnancy and Breastfeeding: Pregnant women are excluded from this study because nab-paclitaxel and 
gemcitabine are agents with the potential for teratogenic or abortifacient effects.  Because there is an 
unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother 
with these drugs, breastfeeding should be discontinued if the mother is treated on this study.   
 
3.1.7 HIV Infection: HIV-positive patients on combination antiretroviral therapy are ineligible because of the 
potential for pharmacokinetic interactions with the study medications. In addition, these patients are at 
increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies 
will be undertaken in patients receiving combination antiretroviral therapy when indicated. 
 
3.1.8 Patients who in the opinion of the investigator may not be able to comply with the safety monitoring 
requirements of the study are not eligible.  
 
3.2 
Inclusion of Women and Minorities 
NIH policy requires that women and members of minority groups and their subpopulations be included in 
all NIH-supported biomedical and behavioral research projects involving NIH-defined clinical research 
unless a clear and compelling rationale and justification establishes to the satisfaction of the funding 
Institute & Center (IC) Director that inclusion is inappropriate with respect to the health of the subjects or 
the purpose of the research.  Exclusion under other circumstances must be designated by the Director, 
NIH, upon the recommendation of an IC Director based on a compelling rationale and justification.  Cost 
is not an acceptable reason for exclusion except when the study would duplicate data from other sources.  
Women of childbearing potential should not be routinely excluded from participation in clinical research.  
Please see  23TUhttp://grants.nih.gov/grants/funding/phs398/phs398.pdfU23T. 
 
3.3 
Informed Consent Process  
Eligible patients will be evaluated by a multi-disciplinary team at the site. During their visit, either a 
physician or a research coordinator will explain the study to the patient. Informed consent form will be 
provided to the patient, who will be given time to read over and ask questions of the study team. If the 
patient agrees to participate, a signed consent form will be obtained prior to participation and a copy of 
the signed consent will be provided to the patient. 
 

18 
4. REGISTRATION PROCEDURES 
 
4.0 
Site and Investigator Registration with Moffitt Cancer Center 
Only those members of the Sunshine Project Consortium registered with Moffitt Cancer Center may participate 
and enroll patients on this trial. Sunshine Project Consortium Member sites are defined as those centers who 
have established financial agreements with Moffitt Cancer Center and who have designated a local Principal 
Investigator who will assume the responsibility of conduct of the trial according to MCRN procedure and 
Federal and State regulations (Policy MRI-P.CRO. 41). Additionally, Consortium member sites are those sites 
that have agreed to, and signed, the Site Responsibility page located in the Sunshine Project Handbook. 
 
All patients intended to be enrolled on this trial must be registered with the Moffitt Cancer Center Clinical 
Research Network office and the Sunshine Project Coordinator (Coordinator) prior to being enrolled at the 
local level. Patients may not be treated with any agent without registration with Moffitt staff and an associated 
sequence number confirmed in the Moffitt Cancer Center electronic database OnCore.  
 
4.1 
Patient Registration 
When a potential patient presents to a participating site, the local investigator will confirm that the patient 
is a candidate for screening by reviewing known inclusion and exclusion criteria. The participating site 
must notify the coordinating center to confirm slots are available for participation, and then discuss the 
protocol with the patient.  
 
Before any patient can be enrolled, it is the responsibility of the institutional investigator to verify, sign, 
and date a completed Moffitt Cancer Center Eligibility Checklist and Moffitt Cancer Center Registration 
sheet. 
 
The local investigator will confirm all eligibility criteria are met. A signed copy of the Checklist and 
Registration sheet must be faxed, with supporting source documentation verifying inclusion and exclusion 
criteria and signed consent form, to the Sunshine Project Coordinator prior to a patient being enrolled and 
receiving drug.  
 
The source documentation and registration sheets must be faxed to the Sunshine Project Coordinator at 
Moffitt Cancer Center via email at SunshineProject@moffitt.org . 
 
Please note: No study therapy may be initiated before confirmation that the subject has been enrolled on 
therapy.  
 
4.2 
General Guidelines 
Following registration, patient information must be placed in the OnCore system within 24 hours of receipt 
of Subject Sequence Number (OnCore CRF pages: demographics, consent, eligibility, on-study, and 
treatment).  
 
Additionally, treatment should begin within 5 days of registration. Issues that would cause treatment 
delays must be discussed with the Principal Investigator and Coordinator.  If a patient does not receive 
protocol therapy following registration, the patient’s registration on the study may be canceled.   
 
5. TREATMENT PLAN 
 
5.0 
Agent Administration 
Treatment will be administered in 4-week cycles, in which patients will receive both nab-paclitaxel and 
gemcitabine on days 1, 8, and 15. Treatment may be given either in the outpatient clinic or in the hospital.  
For holidays and other schedule flexibility, doses can be moved +/- 2 days. 

19 
 
Following premedication with an antiemetic agent such as ondansetron or related agent, nab-paclitaxel 
will be given as a 30-minute infusion at the dose of 125 mg/mP2
P. 
 
This will be immediately followed by gemcitabine 1,000 mg/mP2
P, given as a 90-minute infusion. 
 
The following treatment schema will be used: 
 
 
Nab-paclitaxel 
(125 mg/mP2
P iv over 30 min) 
Gemcitabine 
(1,000 mg/mP2
P iv over 90 min) 
 
Myeloid Growth Factor 
Day 1 
X 
X 
 
Day 8 
X 
X 
 
Day 15 
X 
X 
 
Day 16-18 
 
 
X 
Day 16-28 
                                            Myeloid growth factor, REST 
 
              
 
Patients will receive a course of myeloid growth factor beginning on day 16-18 of each cycle. Both 
chemotherapy agents will be held on day 15 if the patient experiences grade 4 neutropenia (absolute 
neutrophil count < 500/mcL) during the cycle on or prior to that day and be subject to dose de-escalation 
with additional cycles as detailed in Section 6. If grade 4 neutropenia is present at the day 8 visit, patients 
will still receive therapy on day 8.  
 
Myeloid growth factor may consist of either a single dose of pegfilgrastim, or daily doses of filgrastim 
until the absolute neutrophil count is at least > 1,000/mcL.  
 
Patients who experience grade 3 neuropathy will have nab-paclitaxel held for the remainder of the cycle. 
Held or missed doses will not be made up. 
 
 
A complete list of dose modifications is included in Section 6. Patients with stable or responding disease 
who experience a dose-modifying hematologic toxicity despite dose reductions and pegfilgrastim, may 
continue treatment on study using an altered schedule of administration described in Section 6. 
                                                                                                                                                                                    
Reported adverse events and potential risks are described in Section 7. 
 
Although antiemetic medications such as ondansetron or a related agent should be given prior to 
chemotherapy administration, antihistamine or steroid premedication is not required with nab-paclitaxel, 
nor is a special filter for intravenous administration.  
 
5.0.1 Criteria for Starting Subsequent Cycles 
A cycle may be repeated every 28 days if the patient has no clinical or radiographic evidence of 
progressive disease, and has again met laboratory parameters as defined by the eligibility section. 
Specifically, this means that platelets must be > 100,000/mcL unsupported, and the absolute 
neutrophil count > 1,000/mcL.  In addition, other toxicities must have resolved to eligibility criteria 
prior to starting subsequent cycles. 
 
5.1 
General Concomitant Medication and Supportive Care Guidelines 
Standard institutional guidelines should be followed for febrile illness, use of blood products, antiemetics, 
fluids and general supportive care.  
 

20 
This therapy is expected to cause lymphopenia and put patients at risk of developing Pneumocystis 
pneumonia. Therefore, prophylaxis with trimethoprim-sulfamethoxazole, pentamadine, or some other 
appropriate medication is indicated. Because there is a potential for interaction of nab-paclitaxel and/or 
gemcitabine with other concomitantly administered drugs, all concomitant medications will undergo a 
standard concomitant medication review at each study visit without data capture in the OnCore system. 
Please note: sites must be able to provide appropriate documentation for monitoring and review of all 
medications given while on study.  
 
The Principal Investigator should be alerted if the patient is taking any agent known to affect or with the 
potential to affect selected CYP450 isoenzymes as described in Section 3.2.4.   
 
5.2 
Duration of Therapy  
Patients may receive up to 12 cycles of protocol therapy (=52 weeks, 1 year) provided none of the following 
occur: 
  
• 
Disease progression 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 
• 
Patient decides to withdraw from the study 
• 
General or specific changes in the patient's condition render the patient unacceptable for further 
treatment in the judgment of the investigator 
• 
Patient non-compliance with treatment or trial requirements: defined as any deviation from the 
protocol without prior agreement of the principal investigator 
• 
Investigator non-compliance: defined as any significant medical or non-medical deviation from 
the protocol without agreement of the principal investigator 
• 
Loss to follow-up 
 
5.2.1 Patient Withdrawal  
Patients may withdraw at any time or be dropped from the study at the discretion of investigator should 
untoward effects occur. In addition, a patient may be withdrawn by the investigator if he/she violates the 
study plan or for administrative and/or other safety reasons. The investigator or study coordinator must notify 
Moffitt immediately when a patient has been discontinued/withdrawn due to a serious adverse experience. 
All trial treatment-related toxicities and SAEs at the time of discontinuation/withdrawal should be followed 
until resolution or stabilization. Patients who are discontinued from the study will still be followed for disease 
progression.  
 
5.2.2 Patient Death  
All deaths that occur within the trial period or within 30 days after administration of the last dose of trial 
drug, regardless of relatedness, must be reported to Moffitt via the OnCore system for the purposes of serious 
adverse event (SAE) reporting.  
 
Patients who discontinue from the study for reasons unrelated to the study (e.g., personal reasons, or adverse 
events after registration but prior to receiving study therapy) may be replaced as required for the study to 
meet its objective. The replacement will generally receive the same treatment or treatment sequence (as 
appropriate) as the allocation number replaced. 
 
5.2.3 Off Protocol Treatment Criteria 
For the purposes of this trial, “Off protocol treatment” and “Off Arm” date will be the day the decision 
was made to remove the patient from protocol therapy. The End of Therapy visit will be conducted at the time 
the decision was made to remove the patient from protocol therapy +/- 3 days. 
 

21 
5.2.4 Off Study Criteria 
A patient is considered “Off study” after the follow period is completed. The “off study” date is 
considered the last day of Follow Up. 
 
5.3 
Duration of Follow Up 
Patients that come off treatment due to progression of disease will be followed for 30 days (+/- 3 days) 
after end of treatment or until death, whichever occurs first. Patients that are removed due to an adverse 
event or they have completed all cycles of treatment, will be followed for progression free survival 
every 3 months until they have disease progression or they start a new treatment. 
 
 
Patients that are removed due to an adverse event or they have completed all cycles of treatment, will be 
followed for  survival every 3 months for 2 years or until death, whichever occurs first. Additionally, if 
the patients remain on gemcitabine and nabpaclitaxel therapy but off protocol, disease (SD, PR, CR, or 
PD) and survival status will be collected at these 3 month timepoints.  Additional systemic therapies will 
not be collected.  Any surgical resections or radiation therapy will also be collected qualitatively. 
 
Additional testing may be performed as clinically necessary. All ongoing toxicities and adverse events 
will be followed until resolution, return to baseline or death within the 30 day follow up period. If the 
subject begins another line of therapy or is enrolled on another therapeutic trial, no new adverse events 
that may be attributed to that line of therapy will be collected during the 30 day follow-up period.     
 
Serious adverse events are to be collected from the time the patient initiates protocol therapy until 30 days 
following discontinuation of protocol therapy    
 
Follow-up data will be required unless consent is withdrawn. In all cases, the reason for withdrawal 
must be recorded in the CRF and in the subject's medical records. 
   
5.4 
Criteria for Removal from Study 
Patients will be removed from study when any of the criteria listed in Section 5.3 applies.  The reason and 
date for the removal from treatment and study must be captured in the OnCore eCRF.  
 
5.5 
Criteria for Being Considered Evaluable   
 
5.5.1 Toxicity 
Any patient who receives at least one dose of nab-paclitaxel or gemcitabine will be considered evaluable 
for toxicity. 
 
5.5.2 Response 
Any patient who is enrolled and receives at least one dose of nab-paclitaxel and gemcitabine will be 
considered evaluable for response provided: (1) the patient demonstrates progressive disease or death 
while on protocol therapy; (2) the patient is observed on protocol therapy for at least one cycle and the 
tumor is not removed surgically prior to the time complete response or partial response is confirmed; or 
(3) the patient demonstrates a complete or partial response according to protocol criteria. This definition 
excludes patients who stop therapy because of toxicity before the first disease evaluation, and such 
patients will be replaced for the purpose of assessing the primary objective of the study. 
 
The evaluation period for determination of the best response will be 6 treatment cycles. All other patients 
will be considered non-responders.  
 
5.5.3 Progression-Free Interval  
Eligible patients who receive at least one dose of nab-paclitaxel and gemcitabine will be included in 

22 
analysis of progression-free survival. Progression-free interval (PFI) will be calculated as the date of 
enrollment until the end PFI date, where that date is calculated as the date of disease progression, date 
of death, date of removal of all tumor by surgery or last patient contact, whichever occurs first. Patients 
whose end PFI date is disease progression or death will be considered to have experienced an event. 
Patients whose end PFI date is date of removal of all tumor by surgery and this occurs prior to the 4 
month time point will be considered removed from the analytic set at that time by a competing event 
and replaced.  Patients whose end PFI date is date of removal of all tumor by surgery and this occurs 
after the 4 month time point will be considered to have met the primary endpoint.  Patients whose end 
PFI date is the date of last patient contact will be considered censored for PFI analysis. The probability 
of remaining progression-free as a function of days since enrollment will be calculated according to the 
method of Gray, accounting for censoring and the competing events. The data from the osteosarcoma, 
Ewing sarcoma, rhabdomyosarcoma and non- rhabdomyosarcoma soft tissue sarcoma strata obtained 
from this study will be compared with a dataset of patients with the appropriate diagnosis from the 
cohort of patients treated on various previously reported studies for similar patients, using the method 
of Gray. 
 
5.6 
Replacement 
If a patient is withdrawn from protocol therapy prior to receiving at least one dose of nab-paclitaxel and 
gemcitabine, a replacement patient will be enrolled in that cohort.  
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
All toxicities should be graded according to the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0, which is located on the CTEP website at 23TUhttp://ctep.cancer.govU23T. All appropriate 
treatment areas should have access to a copy of the CTCAE version 4.0. 
 
Hematologic and non-hematologic dose-modifying toxicities will be defined differently and will be based on 
events that occur any time during the study period following initiation of chemotherapy. In order to be 
declared as a dose-modifying toxicity, an adverse event must be possibly, probably, or definitely attributed to 
study therapy.  
 
 

23 
Dose-modifying toxicities and their required modifications are described in the table below: 
 
Toxicity 
Gemcitabine 
Dose Change 
Nab-paclitaxel 
Dose Change 
Febrile neutropenia 
U 
U Reduce to 675 mg/mP2 
U 
Reduce to 100 mg/mP2 
ANC < 1,000/mcL 
by day 29 of cycle 
U 
 
U Reduce to 675 mg/mP2 
U 
 
Reduceuce to 100 mg/mP2 
ANC <500/mcL by day 15 
Hold treatment on day 15, 
AND reduce to 675 mg/mP2 for 
all subsequent cycles 
Hold treatment on day 15, AND 
reduce to 100 mg/mP2 for all 
subsequent cycles 
Platelet count < 20,000/mcL on 2 
separate days during a cycle, UORU  
requiring platelet transfusions on 2 
separate days within a 7-day period 
 
675 mg/mP2 
100 mg/mP2 
Platelet count < 100,000/mcL by day 
29 of cycle 
 
675 mg/mP2 
100 mg/mP2 
Grade 3 or greater neuropathy 
 
No change 
Immediately hold for duration of 
cycle, then resume next cycle at 100 
mg/mP2 
Other grade 3-4 non-hematologic 
toxicities (*excluding those listed 
below) 
675 mg/mP2 
100 mg/mP2 
*excludes grade 3 nausea or vomiting of < 3 days duration, grade 3 ALT/AST that resolves to eligibility criteria by the start of 
the next cycle and does not recur, grade 3 fatigue < 3 days, or grade 3 electrolyte deficiencies that respond to supplementation 
 
Patients who experience the same dose-modifying toxicities defined above even AFTER the appropriate dose 
reductions will be withdrawn from protocol therapy, with the EXCEPTION OF patients 
who have stable or responding disease and the dose-modifying toxicity is hematologic. Patient’s meeting this 
criteria may continue to receive treatment on study using the following dose schedule [43]. 
 
 
Nab-paclitaxel 
(100 mg/mP2
P iv over 30 min) 
Gemcitabine 
(675 mg/mP2
P iv over 90 min) 
Myeloid Growth Factor 
Day 1 
X 
X 
 
Day 8 
X 
X 
 
Days 9-21 
 
 
X 
Days 9-21 
REST 
 
Patients treated on the 28-day schedule who do not meet eligibility criteria to start subsequent cycles by Day 
43 will be removed from protocol therapy. Similarly, patients treated on the 21-day schedule who do not meet 
eligibility criteria by Day 36 will be removed from protocol therapy. 
 
7. ADVERSE EVENTS: DEFINITIONS AND REPORTING REQUIREMENTS 
Adverse event data collection and reporting, which are required as part of every clinical trial, are done to 
ensure the safety of patients enrolled in the studies as well as those who will enroll in future studies using 
similar agents. Adverse events are reported in a routine manner at scheduled times during a trial (See section 

24 
7.3).  
 
Additionally, certain adverse events must be reported in an expedited manner for more timely monitoring of 
patient safety and care. The following sections provide information about expedited reporting. The 
characteristics of an observed AE will determine whether the event requires expedited reporting via a 
Medwatch form and OnCore SAE eCRF to the Coordinating center in addition to routine reporting. 
 
7.0 
Adverse Event Characteristics  
Characteristics of an Adverse Event must be characterized as follows:  
 
• 
CTCAE term (AE description) and grade:  The descriptions and grading scales found in the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be 
utilized for AE reporting.  All appropriate treatment areas should have access to a copy of the 
CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be downloaded from the CTEP web 
site: 23TUhttp://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htmU23T. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.1 
Expedited Adverse Event Reporting (Serious Adverse Event) 
 
7.1.1 Determination of Reporting Requirements:  
Reporting requirements should include the following considerations: 1) whether the patient has received 
the investigational or commercial agent; 2) the characteristics of the adverse event including the grade 
(severity), the relationship to the study therapy (attribution), and the prior experience (expectedness) of 
the adverse event; and 4) whether or not hospitalization or prolongation of hospitalization was associated 
with the event. 
 
7.1.2 Steps to Determine if an Adverse Event is to be Reported in an Expedited Manner  
 
Step 1: Identify the type of event: The descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0.  
 
Step 2: Grade the event using the NCI CTCAE version 4.0.  
 
Step 3: Determine whether the adverse event is related to the protocol therapy (investigational or 
commercial). Attribution can only be determined by the Investigator. Attribution categories are as 
follows: Unrelated, Unlikely, Possible, Probable, and Definite.  
 
Step 4: Determine the prior experience of the adverse event. Expected events are those that have been 
previously identified as resulting from administration of the agent. An adverse event is considered 
unexpected, for expedited reporting purposes only, when either the type of event or the severity of the 
event is NOT listed in the investigational brochure or package insert for the investigational agent.  
 
If any of the following criteria are met, the Adverse Event should be reported in an expedited 
manner and will qualify as a Serious Adverse Event on this trial.  
 

25 
A Serious Adverse Event is defined as any untoward medical occurrence that, at any dose, meets any of 
the following criteria: 
• 
Results in death. 
• 
Is life-threatening: The term ‘life-threatening’ in the definition refers to an event in which 
the patient was at risk of death at the time of the event, it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization: A 
hospitalization or prolongation of hospitalization will not be regarded as an SAE if at least 
one of the following exceptions is met: 
o The admission results in a hospital stay of less than 24 hours. 
o The admission is pre-planned. (i.e. elective or scheduled surgery arranged prior 
to the start of the study) 
• 
The admission is not associated with an AE. (e.g. social hospitalization for purposes of 
respite care). 
• 
Disability or Permanent Damage 
• 
Congenital Anomaly/Birth Defect 
• 
Other Serious (Important Medical Events) 
 
Please see the FDA website: http://www.fda.gov/Safety/MedWatch/HowToReport/ucm053087.htm 
for more information regarding the definition of a Serious Adverse Event 
 
7.1.3 Serious Adverse Event Reporting 
Serious Adverse Event (SAE) reporting for this study must follow a two-step reporting process to 
comply with Moffitt AE reporting guidelines (Policy standard CTO.65).  
 
Step 1: All SAEs will be reported to the MCRN Coordinating office in 24 hours of learning of the event 
via 
the 
OnCore 
eCRF. 
In 
addition, 
please 
email 
the 
Sunshine 
Project 
coordinator 
(SunshineProject@moffitt.org) that an SAE has been placed in the system.  
 
The OnCore reporting system will require the following information:  
• 
Event start date 
• 
Event end date 
• 
Reported date 
• 
Date of death (if applicable) 
• 
Event Narrative 
• 
Treating Physician comments 
• 
PI comments 
• 
Attribution 
• 
SAE Classification  
• 
Adverse Event Details (CTCAE v. 4.0 category, grade, expectedness, attributions to all therapies 
administered, and any follow up action or therapy taken as a result of the SAE) 
 
Step 2: Within 24 hours of learning of the event, download a Medwatch form: Form FDA 3500A – 
Mandatory Reporting from the FDA website: 
23TUhttp://www.fda.gov/safety/medwatch/howtoreport/downloadforms/default.htmU23T.  
• 
Fill out required information  
• 
Email Medwatch form to SunshineProject@moffitt.org. 
• 
A follow up Medwatch form will be required to update all information captured on the original 
form.  
 

26 
U 
Serious Adverse Event Reporting at Site LevelU:  
All SAE’s should be reported to the treating institutions IRB or Ethics board per local IRB policy. The 
Moffitt Cancer Center will also report all SAE’s to the Moffitt IRB Supporting documentation for 
serious adverse events will be monitored and the following 
should be available to support reported information:   
o Laboratory reports  
• Emergency room notes  
• Hospital discharge summary  
• Death certificate (if available)  
• Autopsy report (if available)  
 
REMINDER: All Deaths that occur while the subject is receiving a test article or intervention and/or a 
minimum of 30 days post administration of the test article or intervention will be reported as a Serious 
Adverse Event.   
 
7.1.4 Distribution of Adverse Event and Serious Adverse Event Reports 
Routine Adverse Events for each patient will be discussed on the Bi-Weekly calls held by the 
Coordinating center. The calls are a consistent bi-weekly check-in with PIs and site coordinators to 
ensure the continued safety of all patients receiving treatment, and for the distribution of information 
regarding dosing and drug toxicity seen in real time with enrolled patients.  
 
The Sunshine Project Coordinators are responsible for the distribution of Serious Adverse Event reports 
(via Medwatch forms) to the enrolling sites participating on the trial. Sites are responsible for the 
reporting of those Serious Adverse Event reports to the local PI and IRB according to the site’s reporting 
policy.  
 
7.1.5 Expedited Reporting Guidelines- Death  
 
A death on study requires 
UbothU routine and expedited reporting, regardless of causality.  
Attribution to treatment or other cause must be provided. 
 
Death due to progressive disease should be reported as Grade 5 “Neoplasms benign, malignant and 
unspecified (incl cysts and polyps) - Other (Progressive Disease)” under the system organ class 
(SOC) of the same name.  Evidence that the death was a manifestation of underlying disease (e.g., 
radiological changes suggesting tumor growth or progression: clinical deterioration associated with a 
disease process) should be submitted.  
 
7.2       Routine Adverse Event Reporting 
Adverse events (AE) will be monitored throughout the course of the study. The National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) v 4.0 will be utilized for AE 
reporting.   
 
Adverse event data collection and reporting, which are required as part of every clinical trial, are done 
to ensure the safety of patients enrolled in the studies as well as those who will enroll in future studies 
using similar agents.  AEs are reported in a routine manner and must be collected at every assigned or 
unintended study visit and/or contact with the patient (phone call, email, etc.) 
 
An adverse experience is defined as: 
• Any unfavorable and unintended sign, symptom, or disease temporally associated with the use 
of an investigational product, whether or not related to the investigational product.  

27 
• An adverse event can result from use of the drug as stipulated in the protocol or labeling, as 
well as from accidental or intentional overdose, drug abuse, or drug withdrawal.  
• Any worsening of a pre-existing condition or illness is considered an adverse event.  
• Laboratory abnormalities and changes in vital signs are considered adverse events only if they 
result in discontinuation from the study, necessitate therapeutic medical intervention, be 
considered a dose limiting toxicity, and/or if the investigator considers them to be clinically 
significant. 
• The investigator will evaluate all adverse experiences as to their severity and relationship to the 
investigational agent.  
 
For this study, routine reporting will be done through study data submissions via the OnCore system. 
Routine reporting will include: 
• All MedWatch reportable events 
• Any toxicity considered dose-modifying (as per Section 6) 
• Grade 2 or higher neuropathy 
• Any Grade 3 or higher adverse events 
 
A follow-up visit will occur 30 days post day of final treatment. All ongoing toxicities and adverse 
events will be followed until resolution, return to baseline or death for the 30 follow up period. If the 
subject begins another line of therapy or is enrolled on another therapeutic trial, no new adverse events 
that may be attributed to that line of therapy will be collected during the 30 day follow-up period. 
 
Please note: All adverse events must be entered into the OnCore system within 14 days of the study 
visit. All AEs that qualify as SAEs must be reported on the OnCore system Adverse Event CRF log, 
listed as (Serious = Yes).    
 
7.2 
Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a metastasis 
from the initial malignancy).  Second malignancies require ONLY routine AE reporting unless otherwise 
specified. 
 
8. PHARMACEUTICAL INFORMATION 
 
8.0 
Nab-Paclitaxel (Abraxane®) 
 
8.0.1 
UChemistryU: Nab-paclitaxel is a Cremophor EL-free, albumin-bound paclitaxel particle with a mean 
size 
of 
approximately 
130 
nm. 
The 
chemical 
name 
is 
5β,20-Epoxy-
1,2α,4,7β,10β,13αhexahydroxytax-11- en-9-one 4,10-diacetate 2-benzoate 13-ester with (2R,3S)-N-
benzoyl- 3phenylisoserin. 
 
8.0.2 
UMechanism of Action 
U– Nab-paclitaxel is an antimicrotubule agent that promotes the assembly of 
microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization. This 
stability results in the inhibition of the normal dynamic reorganization of the microtubule network 
that is essential for vital interphase and mitotic cellular functions. Paclitaxel induces abnormal 
arrays or “bundles” of microtubules throughout the cell cycle and multiple asters of microtubules 
during mitosis. 
 
8.0.3 
UPharmacokinetics U– Please see package insert for pharmacokinetics. 
 

28 
8.0.4 Known Side Effects and Toxicities 
 
The following side effects have occurred in adult patients taking nab-paclitaxel: 
Common 
(occurring in > 30%  
of patients) 
Less Common 
(occurring in 20-29%  
of patients) 
Uncommon 
(occurring in 10-19%  
of patients) 
Rare 
(occurring in < 10%  
of patients) 
• 
Anemia 
• 
Neutropenia 
• 
Thrombocytopenia 
• 
Alopecia 
• 
Peripheral 
neuropathy 
• 
Fatigue 
• 
Rash 
• 
Nausea, vomiting 
• 
Diarrhea 
• 
Edema of hands 
and feet 
• 
Poor appetite 
• 
Epiphora 
• 
Canalicular and 
nasolacrimal duct 
blockage 
• 
Dehydration 
• 
Myalgias 
• 
Joint pain 
• 
Weakness 
• 
Mouth sores 
• 
Dysgeusia 
• 
Headache 
• 
Hypokalemia 
• 
Cough 
• 
Depression 
• 
Pneumonitis 
• 
Hypersensitivity 
reactions, including 
anaphylaxis 
• 
Hypertension 
 
8.0.5 
UPharmaceutical DataU - Nab-paclitaxel is supplied as a white to yellow, sterile, lyophilized powder for 
reconstitution with 20 mL of 0.9% Sodium Chloride Injection, USP prior to intravenous infusion. 
Each single-use vial contains 100 mg of paclitaxel and approximately 900 mg of human albumin. 
 
8.0.6 
USupplyU – Commercially available. 
 
8.1 
Gemcitabine 
 
8.1.1 
UChemistryU - Gemcitabine (2’-deoxy-2’2’-difluorocyti-dine monohydrochloride) is a purine analog 
structurally similar to cytarabine and an analog to deoxycytidine. Gemcitabine has two fluoride atoms 
in the geminal position of the second carbon of the ribose sugar. 
 
8.1.2 
UMechanism of ActionU - Gemcitabine inhibits DNA synthesis in tumor cells by competing with 
deoxycytidine triphosphate for incorporation into DNA. Gemcitabine metabolites also inhibit 
enzymes in DNA synthesis. Finally, gemcitabine is masked from DNA repair enzymes with the 
addition of one additional nucleotide after gemcitabine is in the DNA chain. 
 
8.1.3 
UPharmacokinetics U - Gemcitabine is metabolized into active metabolites gemcitabine diphosphate and 
gemcitabine triphosphate. It is also metabolized to the inactive compound, gemcitabine difluorouridine. 
Ninety-nine percent of the dose is excreted in the urine and there is negligible protein binding. The 
serum half-life is significantly affected by decreases in creatinine clearance. However, there is no 
schedule for dose reduction in renal dysfunction. 
 
8.1.4 
UKnown Side Effects and Toxicities 
U - The primary dose limiting toxicity of gemcitabine is 
hematological including neutropenia, anemia and thrombocytopenia. Other toxicities include rash, 
constipation, diarrhea, fever, alopecia, pain, dyspnea and stomatitis. A summary of gemcitabine 
toxicities is listed below: 
 
 

29 
 
Possible Side Effects of Gemcitabine: 
 
Common 
Happens to 21-100 
children out of every 100 
     Occasional 
    Happens to 5-20           
children out of every 100 
Rare 
   Happens to <5  
children out of every 100 
Immediate: 
Within 1-2 
days of 
receiving drug 
• 
nausea 
• 
vomiting 
• 
fever 
• 
rash1 
• 
constipation 
• 
pain 
• 
dyspnea 
• 
somnolence1 
• 
diarrhea 
• 
itching 
• 
flu-like symptoms 
(fever, asthenia, 
anorexia, headache, 
cough, chills, myalgia) 
• 
peripheral edema 
• 
anaphylaxis 
• 
bronchospasm 
• 
phlebitis 
• 
hypertension 
Prompt: 
Within 
2-3 
weeks 
before 
next course of 
therapy 
• 
myelosuppression 
• 
elevated 
AST/ALT/alkali
ne phosphatase 
• 
proteinuria 
• 
hematuria 
• 
mucositis/stomatitis 
• 
elevated bilirubin 
• 
elevated BUN/creatinine 
• 
hemorrhage 
• 
infection 
• 
alopecia1 
• 
hemolytic uremic syndrome 
• 
renal failure 
• 
thrombotic microangiopathy1 
• 
cardiovascular 
events1,2 (myocardial 
infarction, 
cerebrovascular 
accident, arrhythmia, 
CHF and 
hypertension) 
• 
severe rashes1 
Delayed: 
Anytime later 
during therapy, 
excluding the 
above 
conditions 
• 
paresthesias 
• 
radiation recall reactions 
• 
interstitial pneumonitis 
• 
pulmonary fibrosis 
• 
pulmonary edema 
• 
ARDS 
• 
sepsis 
• 
liver failure 
Unknown 
Frequency 
and Timing: 
Fetal and teratogenic toxicities: Gemcitabine is embryotoxic causing fetal malformations 
(cleft palate, incomplete ossification) at doses of 1.5 mg/kg/day in mice (about 1/200 the 
recommended human dose on a mg/m2 basis). Gemcitabine is fetotoxic causing fetal 
malformations (fused pulmonary artery, absence of gall bladder) at doses of 0.1 mg/kg/day 
in rabbits (about 1/600 the recommended human dose on mg/m2 basis). Embryotoxicity 
was characterized by decreased fetal viability, reduced live litter sizes, and developmental 
delays. It is not known whether gemcitabine or its metabolites are excreted in human milk. 
1. Toxicity may also occur later 
2. Primarily in patients with pre-existing cardiac disease 
 

30 
8.1.5 Pharmaceutical Data – Gemcitabine is supplied in 200 mg and 1000 mg vials. Two hundred mg 
vials are reconstituted in 5 cc sodium chloride then diluted to a concentration of as low as 
0.1 mg/ml if necessary for infusion. The dose is usually given over 30- 9 0 minutes. One 
thousand mg vials are reconstituted with 25 cc sodium chloride. It is stored at room temperature until 
given. 
8.1.6 Supply – Commercially available. 
 
9. BIOMARKER, CORRELATIVE AND SPECIAL STUDIES 
 
9.0 
Immunohistochemical Expression of SPARC and Cav-1 in Archival Tumor Tissue 
The rationale for analysis of these biomarkers is detailed in Section 2.3.4. This testing will be conducted 
by Dr. Hong Yin at Children’s Healthcare of Atlanta, using previously validated immunohistochemical 
assays [19]. 
 
Testing of tissue for research purposes is optional, and details regarding this testing will be included as a 
separate item in the informed consent document. Instructions for shipping tissue can be located in the lab 
manual. 
 
 
9.1 
Radiomic Analysis of Diagnostic CT Images 
Standardized CT scan parameters are provided in section 10.5, to ensure consistent image data across 
patients and sites. Radiomic analysis will be performed on diagnostic CT scans obtained for RECIST 1.1 
response assessment, and additional scans will not be required.  The rationale for radiomic analysis is 
provided in section 2.3.4. This analysis will be performed by Dr. Natarajan Raghunand and Dr. Olya 
Stringfield in the Image Response Assessment Team (IRAT) Core of the Moffitt Cancer Center, using 
validated software. Images should be anonymized and submitted by subject number. The images should 
be submitted in DICOM format on CD with the image transmittal form to the IRAT Core as listed in the 
lab manual 
 
9.2 
Biomarkers of Minimal Residual Disease 
The rationale for these studies is outlined in 2.6.3.  Briefly, patients with recurrent sarcomas, even those 
who achieve a radiographic complete remission, are rarely cured, strongly suggesting the minimal residual 
disease (MRD) remains at the end of treatment.  Preliminary studies have demonstrated the ability to 
detect circulating tumor cells (CTC) and plasma tumor DNA (ptDNA) in the blood of sarcoma patients 
[reviewed in 40].  There are several platforms for isolation of CTC in sarcoma patients, including the 
CellSieve™ filter, which is applicable to all sarcoma patients. CTC quantification and analysis will be 
performed in the laboratory of Dr. Masanori Hayashi. Plasma can also be processed for extraction of 
circulating nucleic acids, including ptDNA, and subsequent analyses, such as droplet digital PCR (ddPCR) 
and targeted sequencing, for quantification and profiling. For example, ptDNA can be utilized for 
assessment of patient-specific and tumor-specific genomic, epigenomic, and transcriptional variations that 
may be reflective of MRD. Plasma will be isolated, frozen, and banked in the Hayashi Laboratory for 
batched analysis and future studies. When available, remaining archival patient tumor samples collected 
for immunohistochemical expression of putative biomarkers (Dr. Hong Yin) will be sent to the Hayashi 
lab to aid circulating tumor test design.  
 
At the time of enrollment, a package containing sufficient Cell Save Preservative tubes (for CTC analysis) 
and Streck Cell-free DNA BCT® tubes (for cfDNA analysis) will be sent from the Sarcoma research lab 
at the University of Colorado to the enrolling institution by overnight delivery service.  At designated time 
points (Refer to footnote 7) 10 ml of blood will be drawn into a CellSave tube, and another 10 ml drawn into 
a Streck BCT® tube.  Blood will be shipped at ambient temperature by overnight delivery service to the 
address found in the study specific lab manual 
 

31 
Blood for CTC analysis will be processed through CellSieve filters and evaluated per standard protocols.  
Plasma will be isolated by a double centrifugation technique and frozen at -80 Po
PC in 1 ml aliquots in a 
secure freezer with liquid nitrogen backup until needed for analysis.  
 
 

32 
10. STUDY CALENDAR 
Baseline evaluations are to be conducted within 7 days (168 hours) prior to start of protocol therapy.  Scans 
and x-rays must be done U< U28 days prior to the start of therapy.  In the event that the patient’s condition is 
deteriorating, laboratory evaluations should be repeated within 48 hours prior to initiation of the next cycle of 
therapy. 
 
 
 
Cycle 1 
Cycles 2-12 
EOT 
Follow Up 
 
BaselineP
1
P  
 
Day 
1 
Day 
8 
Day 
15 
Days 
16-28 
Day 
1 
Day 
8 
Days 
9-2111 
Day 
15 
Days 
16-28 
End of 
Protocol 
Therapy 
30 Day 
Follow-
up8 
q3 Month 
Follow-
up  
 
 
(+/- 3 days) 
(+/- 3 
days) 
+/- 
7days 
(+/- 1 
month) 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
 
Height, weight, 
BSA 
X 
X 
 
 
 
X 
 
 
 
 
X 
 
 
Performance 
status 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
CBC with 
differentialP2 
X 
X 
X 
X 
 
X 
 
 
X 
 
X12 
 
 
Comprehensive 
Metabolic Panel 
(CMP) 
X 
X 
X 
X 
 
X 
 
 
 
 
X12 
 
 
Pregnancy testP3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
nab-Paclitaxel 
administration10 
 
X 
X 
X 
 
X 
X 
 
X 
 
 
 
 
Gemcitabine 
administration10 
 
X 
X 
X 
 
X 
X 
 
X 
 
 
 
 
Myeloid growth 
factor 
administration4 
 
 
 
 
X 
 
 
X 
 
X 
 
 
 
Archival tumor 
tissueP5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor disease 
evaluationP6 
X 
 
 
 
 
 
 
X 
 
X 
X13 
 
 
23TUMRD 
Biomarkers7 
X 
 
 
 
 
X 
 
X 
 
X 
 
 
 
Disease & 
Survival Status9
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Footnotes: 
1 
If baseline evaluations completed within 1 week prior to the start of protocol therapy, they do not need to be repeated. 
2 
If patients have Grade 4 neutropenia or thrombocytopenia, then CBCs should be checked every 3 to 4 days until recovery 
to Grade 3  
3 
Female patients  of  childbearing  potential  require  a  negative  pregnancy test prior  to  starting  treatment  and  must  use  an 
acceptable method of birth control. Abstinence is an acceptable method of birth control. 
4 
Myeloid growth factor (Neulasta, neupogen or similar agents) to be administered on day 16-18 of each cycle or on days 9-21 for 
patients on 21 day cycles 
5 
Submission of archival tumor tissue is strongly encouraged but NOT required for study enrollment. Samples should only be sent 
from patients who specifically consent for participation in this part of the study. 
6 
To be completed at the end of every other cycle. Tumor response will generally be followed by CT or MRI as detailed in Section 
10.5. PET imaging may be used to complement these modalities, as discussed in Section 11.0.3. 
7 
To be collected at any time prior to the start of study therapy, on day 1 of cycle 2 prior to starting that cycle, and at the end of 
every even-numbered cycle +/- 3 days of when disease evaluation is performed through cycle 10. Sample for MRD will also be 
collected at time of disease progression. 
8 
Patients that come off treatment due to progression of disease will be followed for 30 days after end of treatment or until death, 
whichever occurs first.  
9 
Patients that are removed from treatment due to an adverse event or they have completed all cycles of treatment, will be followed 

33 
every 3 months for survival for 2 years or until death, whichever occurs first.  Patients that remain on gemcitabine and nabpaclitaxel 
therapy but off protocol will have disease status (SD, PR, CR, or PD) and survival data collected at these timepoints. 
10 
Patients on 21 day treatment schedule to receive gemcitabine and nab-Paclitaxel on days 1 and 8 only of each cycle 
11 
Patients with stable or responding disease who experience a dose-modifying hematologic toxicity despite dose reductions and 
pegfilgrastim, may continue treatment on study using an altered schedule of administration 
12 
If CBC and/or CMP completed within 1 week of EOT visit, they do not need to be repeated. 
13 
Required for patients coming off treatment due to disease progression only.  If imaging completed within 2 weeks of EOT visit, it 
does not need to be repeated  
 
 
8 
10.0 
Demographics 
Information regarding the subject’s gender, race, ethnicity and age will be collected at screening. 
 
10.1 
Medical History 
Medical history findings (i.e. previous diagnoses, diseases or surgeries) meeting all criteria listed below 
will be collected at prior to the first dose of study drug: 
 
• 
Previous disease treatments  
• 
Not pertaining to the study indication (general Past Medical and Surgical History) 
• 
Started before signing of the informed consent 
• 
Considered relevant to the study (include planned interventions) 
 
10.2 
Physical Measurements 
The screening examination should include physical measurements (height, weight, performance status). 
Height and weight should be recorded at the start of each cycle. The performance status should be recorded 
prior to starting protocol therapy. 
 
10.3 
Physical Exam 
In addition to physical measurements, signs and symptoms should be assessed at each study visit by the 
appropriate staff. 
 
10.4 
Adverse Events 
Adverse events will be collected starting with the first dose of study agent and until the patient is taken 
off study. Adverse events will be graded according to the NCI-CTCAE version 4.0.  
 
10.5 
Radiologic Evaluations 
CT or MRI are the best currently available and reproducible methods to measure lesions selected for 
response assessment.  
 
Study evaluations will take place in accordance with the table in section 10. All radiographic evaluations 
must be performed within 28 days of start of therapy utilizing CT/MRI. Unusual circumstances related to 
>28 day old scans not involving target lesions may be discussed with the study chair. Tumor response will 
be assessed by the investigator using the RECIST 1.1 (Response Evaluation Criteria in Solid Tumors). 
Use the table below (Table 1) to assist you in identifying landmarks for the various anatomic regions. 
 
Table 1:  Anatomical Coverage Landmarks 
 
Body Region 
Anatomic Landmark 
Superior 
Inferior 
Chest 
Lung Apices 
Adrenal Glands 
Abdomen 
Dome of the Liver 
Iliac Crest 
Pelvis 
Iliac Crest 
Pubic Symphysis 

34 
Brain 
Skull Vertex 
Skull Base 
Whole body 
Base of the Skull 
Mid-Thigh 
 
Subjects will receive standard of care diagnostic-quality CT/MRI scans of the chest, abdomen, pelvis and 
or extremities (Table 2). CT and MRI are the most commonly employed modality for the initial staging 
and the assessment of response in patients with solid tumors. 
 
• Acquire scans according to RECIST 1.1 requirements: 
(a) Patients should be scanned on the same scanner across time points, whenever possible. 
(b) IV and Oral contrast should be administered as appropriate. 
(c) Please note that venous phase imaging is essential for lesion assessments by RECIST criteria; 
arterial phase, delayed phase, and non-contrast phase image acquisition are optional, but not 
required. 
(d) CT scan parameters provided in the following table should be used. 
 
Table 2:  CT Acquisition and Reconstruction Parameters 
 
Parameter 
Guideline 
IV Contrast 
80-150 cc tailored to meet needs/limitations of each subject 
Oral Contrast 
Oral contrast administered according to the institutional 
standard of care procedures 
Superior Extent 
Above Lung Apices 
Inferior Extent 
Pubic Symphysis 
Tube Voltage 
120 kVp 
Tube Current 
Adjust as required (typically 150 – 200 mAs) 
Convolution Kernel 
GE – STANDARD; Siemens – B30f; 
Pitch 
0.969 – 1 (higher is OK for children) 
Field of View (FOV) 
Ideally 40 cm x 40 cm, but adjustable based on patient size 
Reconstructed image matrix 
size 
512 x 512 (Note: in conjunction with the 40 cm FOV, this will 
yield a pixel resolution of 0.781 mm x 0.781 mm) 
Reconstructed Slice Thickness 
3 mm 
Slice Interval 
Contiguous 
Bits Stored / Bits Allocated 
12 / 16 
 
11. MEASUREMENT OF EFFECT 
Although the clinical benefit of this drug combination for sarcoma has not yet been established, the intent of 
offering this treatment is to provide a possible therapeutic benefit, and thus the patient will be carefully 
monitored for tumor response and symptom relief in addition to safety and tolerability.  Patients with 
measurable disease will be assessed by RECIST 1.1 criteria.  For the purposes of this study, patients should 
be re-evaluated after every two cycles.  In addition to a baseline scan, confirmatory scans will also be obtained 
at least 4 weeks following initial documentation of an objective response. 
 
11.0 
Antitumor Effect – Solid Tumors 
Response and progression will be evaluated in this study using the new international criteria  proposed by 
the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) [Eur J Ca 
45:228-247, 2009].  Changes in the largest diameter (unidimensional measurement) of the tumor lesions 
and the shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria. The 
criteria have been modified for this protocol to require a CT slice thickness of 3 mm (see section 10.7). 

35 
 
11.0.1 Definitions 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their first treatment 
with gemcitabine and nab-paclitaxel. 
 
UEvaluable for objective response.U  Only those patients who have measurable disease present at baseline, 
have received at least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for response.  These patients will have their response classified according to the definitions 
stated below.  (Note:  Patients who exhibit objective disease progression prior to the end of cycle 1 will 
also be considered evaluable.) 
 
UEvaluable Non-Target Disease ResponseU.  Patients who have lesions present at baseline that are evaluable 
but do not meet the definitions of measurable disease, have received at least one cycle of therapy, and 
have had their disease re-evaluated will be considered evaluable for non-target disease.  The response 
assessment is based on the presence, absence, or unequivocal progression of the lesions.  
 
11.0.2 Disease Parameters 
Measurable diseaseU.  Measurable lesions are defined as those that can be accurately measured in at least 
one dimension (longest diameter to be recorded) as ≥20 mm (≥2 cm) by chest x-ray or as ≥10 mm (≥1 
cm) with CT scan, MRI, or calipers by clinical exam.  All tumor measurements must be recorded in 
UmillimetersU (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area might considered measurable only 
if there is progression after radiation.   
 
Malignant lymph nodes.U  To be considered pathologically enlarged and measurable, a lymph node must 
be ≥15 mm (≥1.5 cm) in short axis when assessed by CT.  At baseline and in follow-up, only the short 
axis will be measured and followed. 
 
Non-measurable diseaseU.  All other lesions (or sites of disease), including small lesions (longest diameter 
<10 mm [<1 cm] or pathological lymph nodes with ≥10 to <15 mm [≥1 to <1.5 cm] short axis), are 
considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by definition, 
simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, if they 
meet the definition of measurability described above. However, if non-cystic lesions are present in the 
same patient, these are preferred for selection as target lesions. 
 
Target lesions.U  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and measured 
at baseline.  Target lesions should be selected on the basis of their size (lesions with the longest 
diameter), be representative of all involved organs, but in addition should be those that lend themselves 
to reproducible repeated measurements.  It may be the case that, on occasion, the largest lesion does not 
lend itself to reproducible measurement; in this circumstance, the next largest lesion which can be 
measured reproducibly should be selected.  A sum of the diameters (longest for non-nodal lesions, short 
axis for nodal lesions) for all target lesions will be calculated and reported as the baseline sum diameters.  

36 
If lymph nodes are to be included in the sum, then only the short axis is added into the sum.  The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in the 
measurable dimension of the disease. 
 
Non-target lesionsU.  All other lesions (or sites of disease) including any measurable lesions over and 
above the 5 target lesions should be identified as non-target lesions and should also be recorded at 
baseline.  Measurements of these lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow-up.  
 
11.0.3 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All baseline 
evaluations should be performed as closely as possible to the beginning of treatment and never more 
than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each identified 
and reported lesion at baseline and during follow-up. Imaging-based evaluation is preferred to evaluation 
by clinical examination unless the lesion(s) being followed cannot be imaged but are assessable by 
clinical exam. 
 
Clinical lesionsU.. Clinical lesions will only be considered measurable when they are superficial (e.g., skin 
nodules and palpable lymph nodes) and ≥10 mm (≥1 cm) diameter as assessed using calipers (e.g., skin 
nodules).  In the case of skin lesions, documentation by color photography, including a ruler to estimate 
the size of the lesion, is required.  
 
Conventional CT and MRIU. CT acquisition and reconstruction guidelines are provided in section 10.7, 
including the recommended slice thickness of 3 mm   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal resolution; 
however, there are many image acquisition variables involved in MRI, which greatly impact image 
quality, lesion conspicuity, and measurement. As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the evaluation of the type and site 
of disease.  Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence.  It is beyond the scope 
of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, the same type of scanner should be used and the image acquisition protocol 
should be followed as closely as possible to prior scans.  Body scans should be performed with breath-
hold scanning techniques, if possible. 
 
Cytology, Histology. These techniques can be used to differentiate between partial responses (PR) and 
complete responses (CR) in rare cases (e.g., residual lesions in tumor types where known residual benign 
tumors can remain). 
 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens during 
treatment when the measurable tumor has met criteria for response or stable disease is mandatory to 
differentiate between response or stable disease (an effusion may be a side effect of the treatment) and 
progressive disease. 
 
FDG-PET. While FDG-PET response assessments need additional study, it is sometimes reasonable to 
incorporate the use of FDG-PET scanning to complement CT scanning in assessment of progression 
(particularly possible 'new' disease).  New lesions on the basis of FDG-PET imaging can be identified 

37 
according to the following algorithm: 
 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based on a 
new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If the positive FDG-
PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up CT scans 
are needed to determine if there is truly progression occurring at that site (if so, the date of PD will 
be the date of the initial abnormal FDG-PET scan).  If the positive FDG-PET at follow-up 
corresponds to a pre-existing site of disease on CT that is not progressing on the basis of the 
anatomic images, this is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases 
where a residual radiographic abnormality is thought to represent fibrosis or scarring.  The use of 
FDG-PET in this circumstance should be prospectively described in the protocol and supported by 
disease-specific medical literature for the indication.  However, it must be acknowledged that both 
approaches may lead to false positive CR due to limitations of FDG-PET and biopsy 
resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
 
11.0.3.1 
Response Criteria 
While all scans will be sent for central review, the determination of progressive disease and whether 
or not to continue therapy will be made by the enrolling site.  Final determinations of partial and 
complete responses will be determined by central review for statistical endpoints. 
 
11.0.3.2 
Evaluation of Target Lesions 
UComplete Response (CR)U:  Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm (<1 cm). 
 
UPartial Response (PR)U:  At least a 30% decrease in the sum of the diameters of target lesions, taking 
as reference the baseline sum diameters. 
 
UProgressive Disease (PD)U:  At least a 20% increase in the sum of the diameters of target lesions, taking 
as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study).  
In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at 
least 5 mm (0.5 cm).  (Note:  the appearance of one or more new lesions is also considered 
progressions). 
 
UStable Disease (SD)U:  Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD, taking as reference the smallest sum diameters while on study. 
 
11.0.3.3 
Evaluation of Non-Target Lesions 
UComplete Response (CR)U:  Disappearance of all non-target lesions and normalization of tumor marker 
level.  All lymph nodes must be non-pathological in size (<10 mm [<1 cm] short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a patient 
to be considered in complete clinical response. 
 
UNon-CR/Non-PD:U  Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 

38 
 
UProgressive Disease (PD)U:  Appearance of one or more new lesions and/or unequivocal progression 
of existing non-target lesions.  Unequivocal progression should not normally trump target lesion 
status.  It must be representative of overall disease status change, not a single lesion increase. 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the treating 
physician should prevail in such circumstances, and the progression status should be confirmed at a 
later time by the review panel (or Principal Investigator). 
 
11.0.3.4 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started).  The patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
∗ 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**    Only for non-randomized trials with response as primary endpoint. 
*** In exceptional circumstances, unequivocal progression in non-target lesions may be accepted 
as disease progression. 
 
UNoteU: Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 

39 
Any 
Yes 
PD 
∗ 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease   
 
11.0.4 Duration of Response 
Duration of overall responseU:  The duration of overall response is measured from the time measurement 
criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive 
disease is objectively documented (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for CR until 
the first date that progressive disease is objectively documented. 
 
 
Duration of stable diseaseU:  Stable disease is measured from the start of the treatment until the criteria 
for progression are met, taking as reference the smallest measurements recorded since the treatment 
started, including the baseline measurements.  
 
11.0.5 Progression-Free Survival 
Progression-free survival (PFS) is defined as the duration of time from start of treatment to time of 
progression or death, whichever occurs first. 
 
11.0.6 Response Review 
All scans will be independently reviewed per RECIST V1.1 criteria by Rikesh Makanji, M.D., a board 
certified radiologist at Moffitt Cancer Center. 
 
12. DATA REPORTING/REGULATORY REQUIREMENTS 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 (Adverse Events: 
Definition and Reporting Requirements). 
 
12.0 
Data Reporting 
Data collection for this study will be done exclusively through OnCore.  All members of the study team 
are granted access to the trial in OnCore by the MCRN External Research Regulatory Coordinator. See 
instructions in Sunshine Project Handbook for OnCore access.  
 
12.0.1 Method for Data Reporting and Monitoring 
 
Research Monitoring Core 
Data will be captured in OnCore, Moffitt’s Clinical Trials Database.  The Moffitt Research Monitoring 
Core will be responsible for monitoring data at external sites.   The purpose of trial monitoring is to verify 
that the rights, wellbeing, and trial/data integrity of Human Subjects enrolled in Center (or other NCI 
Center) sponsored, Principal Investigator (PI) initiated clinical research trials are protected. Investigator-
initiated clinical research therapeutic and other intervention trials utilizing investigational agents, devices 
or under an MCC held IND/IDE are monitored on-site (or via remote monitoring when appropriate) 
regularly to verify the reported trial data are accurate, complete, and verifiable from source documents; 
and the conduct of the trial is in compliance with the currently approved trial/amendments, data safety-
monitoring plans, Good Clinical Practice (GCP) Guidelines, and applicable regulatory requirements.  
 
Regulatory documents and case report forms will be reviewed routinely for accuracy, completeness and 
source verification of data entry, validation of appropriate informed consent process, adherence to study 
procedures, and reporting of SAEs and protocol deviations according to Moffitt’s Monitoring Policies.  
Monitoring Visits will include a review of data entry to source documentation, regulatory documents, and 
when appropriate, investigational pharmacy or clinical laboratory. 

40 
 
Audit and inspection 
Inspections by regulatory health authority representatives i.e. FDA and IEC(s)/IRB(s) are possible. 
Investigator responsibilities are set out in the ICH guideline for Good Clinical Practice (GCP) and in the 
US code of Federal regulations. 
 
Investigators must enter study data into Moffitt’s electronic database, OnCore. The investigator will 
permit study related audit visit by a sponsor or it’s representatives, IRB/EC review, and regulatory 
inspection(s), providing direct access to the facilities where the study took place, to source documents, to 
CRF’s and to other study documents. 
 
Essential documents shall be archived safely and securely in such a way that ensures that they are readily 
available upon authorities’ request. 
 
Subject (hospital) files will be archived according to local regulations and in accordance with the 
maximum period of time permitted by the hospital, institution or private practice. 
 
Record Retention 
Study documents should be retained for a minimum of 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing applications in an 
ICH region or as required by the State of   Florida   until   10   years   have   elapsed   since   the   
completion   of   the   study, or whichever time period is longer. The informed consent documents (ICF) 
should be kept indefinitely within the electronic medical record. No records will be destroyed without   
the   written   consent   of   the   funding   source(s), if   applicable.   It   is   the responsibility of the 
funding source(s) to inform the investigator when there is no longer a need for these documents to be 
retained. Permission must be acquired from the State of Florida for document destruction after the 10-
year minimum record-retention period described above has elapsed. 
 
Sunshine Project Clinical Trials Oversight Committee (CTOC)  
The CTOC is a group of pediatric oncologists who specialize in phase 1 clinical trials. This group of 
physicians review and evaluate the conduct of each trial the Sunshine Project conducts. Every quarter, the 
CTOC meets to ensure all clinical research conducted or coordinated by PCF is scientifically well 
designed, responsibly managed, appropriately reported, and protects the rights and welfare of human 
participants.  
 
The CTOC provides an independent review of the interim results of each trial and offers objective 
guidance regarding unforeseen events that may occur during the course of a study. The CTOC will help 
to evaluate and ensure events that may have an impact on patient safety are appropriately addressed and 
managed on an on-going basis. At the quarterly meetings, discussions will include adverse events, accrual, 
and protocol deviations. Adverse event and deviation collection begins when a patient is first placed on 
trial. 
 
All events are classified using the NCI Common Toxicity Criteria and are summarized and presented to 
all members at each safety meeting. The CTOC will also help to evaluate and ensure events that may have 
an impact on patient safety are appropriately addressed and managed. The CTOC will make 
recommendations regarding the conduct and safety of the trial and a public report will be made available 
to all participating member sites. The CTOC will be convened in the event of safety concerns brought to 
the attention of investigators or the study chair. 
 
Protocol Monitoring Committee 
The Moffitt Cancer Center reviews investigator initiated trials that take place at Moffitt through the 

41 
Protocol Support Office (PSO) at Protocol Monitoring Committee meeting. The PSO reviews all 
deviations, AEs, and SAEs on all Sunshine trials. Reports for phase I trials are created and reviewed when 
a trial increases a dose level or when a maximized tolerated dose is met.  
 
Sunshine Project Bi-Weekly Teleconference 
Starting with the first patient enrollment, a safety call consisting of principle investigators, a 
biostatistician, and study coordinators will occur biweekly. In addition, all AE’s will be collected and 
shared with drug suppliers for input prior to escalating or de-escalating to the next dose level. 
 
Moffitt Cancer Center Scientific Review Committee and Institutional Review Board  
All Sunshine Project trials undergo an initial review at the center’s Scientific Review Committee and 
Central Institutional Review Board.  
 
12.0.2 Responsibility for Data Submission 
It is the responsibility of the PI(s) at the site to ensure that all study team members at the site understand 
the procedures for data submission, and that protocol specified data is entered accurately and in a timely 
manner into the OnCore system.  
 
All eCRF entries into OnCore will be verified via source documentation during on-site or remote 
monitoring visits. Data must be entered into the OnCore system within 10 business days of a subject 
visit or it will be considered delinquent.  
12.1 
Moffitt Cancer Center Guidelines 
This protocol will adhere to the policies and requirements of the Moffitt Cancer Center Guidelines.   
The Moffitt Cancer Center is responsible for distributing all IND Action Letters or Safety Reports received 
to all participating institutions for submission to their individual IRBs for action as required. 
 
Protocol modifications 
No modifications will be made to the protocol without the agreement of the investigators. Changes that 
significantly affect the safety of the patients, the scope of the investigation, or the scientific quality of the 
study will require Scientific Review Committee and Institutional Review Board approval prior to 
implementation, except where the modification is necessary to eliminate apparent immediate hazard to 
human subjects.  Any departures from the protocol must be fully documented in the case report form and 
the source documentation. 
 
Monitoring of the study and regulatory compliance 
The Principal Investigator and the Clinical Research Coordinator assigned to the case will be primarily 
responsible for maintaining all study related documents including the clinical research forms.  Oncore is 
the database of record for all CRF entries and will be verified with source documentation. The review of 
medical records within the health record will be done in a manner to assure that patient confidentiality is 
maintained. 
 
Suspension/Termination 
 
The PMC and/or the IRB may vote to suspend or terminate approval of a research study not being 
conducted in accordance with the IRB, the Cancer Center and/or regulatory requirements or that has been 
associated with unexpected problems or serious harm to subjects.  The PMC/IRB will notify the PI in 
writing of such suspension or terminations.  It is the responsibility of the PMC/IRB Chairperson to ensure 
prompt written notification of any suspensions or terminations of PMC/IRB approval to the relevant 
Federal Agencies, including OHRP, FDA, the study sponsor/funding source and if applicable, the Affiliate 
Program. 

42 
 
Trial Discontinuation 
For reasonable cause the Investigator and/or sponsor may terminate this study prematurely. Conditions 
that may warrant termination include, but are not limited to: the discovery of an unexpected, significant, 
or unacceptable risk to the patients enrolled in the study or if the accrual goals are met. A written 
notification of termination will be issued. 
 
13. STATISICAL CONSIDERATIONS 
 
13.0 
Study Design/Endpoints 
 
Assessment of Response: Treatment response will be assessed with the most relevant imaging studies 
(e.g., CT or MRI) after every two cycles. Standard RECIST version 1.1 criteria will be used to assess 
responses. 
 
Assessment of Progression-Free Survival (PFS): PFS will be calculated for all patients using KM curve 
analysis and Cox regression, and will be used to determine accrual for osteosarcoma patients as described 
below. PFS will be determined by the progression-free interval (PFI), which will be calculated as the date 
of enrollment until the date of disease progression, date of death, date of removal of all tumor by surgery 
or last patient contact, whichever occurs first. Patients whose end PFI date is disease progression or death 
will be considered to have experienced an event. Patients whose end PFI date is date of removal of all 
tumor by surgery will be considered removed from the analytic set at that time by a competing event. 
Patients whose end PFI date is the date of last patient contact will be considered censored for PFI analysis. 
The probability of remaining progression-free as a function of days since enrollment will be calculated 
according to the method of Gray, accounting for censoring and the competing events. The data from the 
osteosarcoma, Ewing sarcoma, rhabdomyosarcoma and non-rhabdomyosarcoma soft tissue sarcoma strata 
obtained from this study will be compared with a dataset of patients with the appropriate diagnosis from 
the cohort of patients treated on various previously reported studies for similar patients, using the method 
of Gray. 
 
Assessment of Toxicity: Patients will undergo regular physical exams and laboratory monitoring as 
described in the Study Calendar in Section 10.  
 
Correlative studies: For patients who consent to this optional part of the study, archival tumor tissue 
from the most recent available biopsy will be assessed for putative biomarker expression using 
immunohistochemistry as previously established [20]. At least five unstained slides containing tumor will 
be shipped to the laboratory of Dr. Julie Yin at Emory University for this batched analysis, and testing 
will be performed following completion of patient accrual. The extent of protein expression will be scored 
on a standard quantitative scale, and the relationship between protein expression and imaging response 
will be reported in a descriptive fashion. 
 
Statistical Considerations and Patient Accrual: The best response of disease will be examined 
separately in each of the four disease strata. The following Simon’s two stage design will be used for 
each stratum. For osteosarcoma patients, remaining progression-free after 4 cycles will be considered a 
response, as described in Section 2.3.3. For all other patients, RECIST criteria will be used and responding 
patients will be those with complete or partial responses. 
 
The null hypothesis that the true response rate is 10% will be tested against a one-sided alternative 
response rate of 35% or higher. In the first stage, 11 patients will be accrued for each of the four disease 
strata. If there are one or fewer responses in these 11 patients, accrual to that strata will be stopped. If 
two or more responses are seen in the first 11 patients in a disease strata, 7 additional patients will be 

43 
accrued for a total of 18 in that strata. The null hypothesis will be rejected if 5 or more responses are 
observed in 18 patients. This design yields a type I error rate of 0.027 and power of 0.80 when the true 
response rate is 35%. 
 
 
Cumulative Number 
Of Patients with Response (ES, 
RMS, NRSTS) or Progression-
Free at 4 Months (OS) 
 
Decision 
Stage 1: Enter 11 patients 
per strata 
1 or less  
Terminate strata: combination ineffective 
 
2 of those 11 
Proceed to Stage 2 
Stage 2: Enter 7 
additional patients per 
strata 
2  of those 7 
or total of < 4 responses among 18 
cohort 
Terminate strata: combination ineffective 
 
3 of those 7 
(or total of > 5 responses among 
18) 
Recommend combination of interest for further 
study 
ES, Ewing sarcoma; RMS, rhabdomyosarcoma; NRSTS, non-rhabdomyosarcoma soft tissue sarcoma; OS osteosarcoma 
 
Therefore, we will consider the combination not of sufficient interest for further evaluation in a disease 
category if the true response rate is 10% or less, and of sufficient activity if the true response rate is 35% 
or greater. If the combination has a true response rate of 10%, the two-stage design described above will 
identify it to be of insufficient activity for further study with one-sided significance 0.05 (type I error) and 
power 0.80. If the combination has a true response rate of 35%, the probability of identifying it of 
sufficient activity for further study is 0.80 (power against the alternative hypothesis P = .35). 
 
Criteria for assessing which patients are evaluable for response and toxicity, determining which patients 
may be replaced, and how progression-free survival is defined are listed in Sections 5.6 and 5.7. 
  
13.0.1 Safety Analysis 
The population for the safety analysis will be comprised of all patients who received at least one dose of 
study medication. Patients will be monitored for adverse events using the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. All treatment-emergent and 
baseline adverse events and hematological/biochemical toxicities based on laboratory measurements, as well 
as drug related AE’s, will be summarized by NCI CTCAE v. 4.0 worst grade.  
The incidence of deaths and treatment-emergent serious adverse events will be summarized. Also, the 
incidence of adverse events leading to discontinuation of investigational product and/or withdrawal from the 
study will be summarized and listed.  
 
13.0.2 Statistical and Analytical Plans 
General Statistical Approaches: Summary tabulations will be created that display the number of 
observations, mean, standard deviation, median, minimum, and maximum for continuous variables, 
and the number and percent per category for categorical data. 
Demographic and clinical baseline characteristics will be descriptively summarized in an exploratory 
fashion. These include gender, age, race, weight, height, primary diagnosis, performance status, 
number of previous treatment regimens, time to progression (TTP) on most recent treatment regimen, 
size of measurable disease and other parameters, as appropriate. 
 
13.1 
Sample Size/Accrual Rate 
A minimum of 44 eligible and evaluable patients will be enrolled, consisting of 11 in each of the 4 disease 
strata. Providing for possible ineligible and inevaluable patients, the minimum total number of patients 
will be 48. 

44 
 
Expansion will continue based on objective response (ES. RMS, and NRSTS patients) or 4-month PFS 
(OS patients), following the two-stage rule noted above. The maximum number of eligible and evaluable 
patients in a specific cohort is 18, with the maximum number of eligible and evaluable patients in the 
entire study being 72. 
 
13.2 
Analysis of Other Secondary Endpoints 
SPARC, CAV-1, and hENT1 protein expression will be assessed using immunohistochemistry analysis 
of archival tumor tissue from the most recent surgery in which tissue is available, using previously 
validated assays [22]. Expression of these proteins will be scored as 0 = negative; 1+ = weak staining; 2+ = 
moderate staining; and 3+ = strong staining. The proportion of patients falling into each category (relative to the 
total number of patients evaluated) will be calculated. The response status of each patient will be cross-tabulated 
with expression of the proteins of interest. These protein expression data will be examined both with graphical 
tools (e.g., box plot, histogram, scatter plot, etc.) and descriptive statistics such as mean, median, variance, 
skewedness to understand their statistical distributions and characteristics and with univariate statistical 
tests such as chi-square test to find any significant expression differences of these proteins among patients 
with different responses. 
 
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47 
 
APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to 
carry 
on 
all 
pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, 
but 
ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or 
sedentary 
nature 
(e.g., 
light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In 
bed 
<50% 
of 
the 
time.  
Ambulatory and capable of all self-
care, but unable to carry out any 
work activities.  Up and about more 
than 50% of waking hours. 
60 
Requires occasional assistance, but is 
able to care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any self-
care.  Totally confined to bed or 
chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, 
fatal 
processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 

48 
APPENDIX B 
Sample Letter for Insurance Coverage for Gemcitabine and nab-Paclitaxel 
 
Re: 
 
Patient Name Here 
 
DOB: 
 
--/--/-- 
 
To Whom It May Concern: 
 
I am writing in support of the use of gemcitabine and nab-paclitaxel for the treatment of my patient (insert name 
here), who has (name of sarcoma) which has progressed following standard front-line therapy.  Several previous 
studies have demonstrated the activity of combining gemcitabine and docetaxel for patients with 
relapsed/refractory bone and soft tissue sarcoma, and this has become a common salvage regimen for patients in 
this situation. The following evidence suggests that nab-paclitaxel may be a superior taxane to couple with 
gemcitabine: 
 
1) Nab-paclitaxel has single-agent activity against preclinical models of pediatric sarcoma as assessed by 
the National Cancer Institute’s Pediatric Preclinical Testing Program (see attached article by Houghton 
et al.). This data has led to an ongoing pediatric phase I/II trial of nab-paclitaxel which has shown 
encouraging responses in pediatric sarcoma patients (see attached 2016 ASCO abstract). 
 
2) Nab-paclitaxel has superior anti-tumor effects and reduced toxicity when directly compared to docetaxel 
in patients with metastatic breast cancer (J Clin Oncol 2009;27:3611-9). Importantly, there is 
substantially less myelosuppression, which is an issue for our heavily-pretreated patients with recurrent 
sarcoma. Because of decreased toxicity with fewer hospitalizations and less need for myeloid growth 
factor, the use of nab-paclitaxel has shown superior cost-effectiveness when compared to docetaxel for 
the treatment of breast cancer patients (J Oncol Pharm Pract 2009;15:;67-78). 
 
 
3) The combination of gemcitabine and nab-paclitaxel is now approved by the FDA for treatment of 
pancreatic cancer, based on the preclinical synergy, tolerability, and activity of this regimen.  
 
4) A recent report presented at the 2016 American Society of Pediatric Hematology/Oncology has 
demonstrated this combination is well tolerated and demonstrates activity, building on preclinical 
evidence of synergy with this combination against models of pediatric bone sarcoma (see attached 
reports). 
For these reasons, I feel that outpatient treatment with gemcitabine plus nab-paclitaxel using the FDA-approved 
dosing and treatment schedule represents the best available therapy for (insert patient’s name).  Please contact 
me directly at (insert contact information here) if I can provide additional information regarding this patient’s 
past therapy or proposed treatment plans. 
 
Sincerely, 
 
(Insert Investigator/s name here)