Clinical trial NCT02050919
Conditions: Pleomorphic Rhabdomyosarcoma Stage IIB Adult Soft Tissue Sarcoma AJCC v7 Stage III Adult Soft Tissue Sarcoma AJCC v7 Stage IV Adult Soft Tissue Sarcoma AJCC v7
Sponsor: OHSU Knight Cancer Institute
Start date: 2013-12-03; Completion date: 2020-12-31
Enrollment: 20 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well sorafenib tosylate, combination chemotherapy, radiation therapy, and surgery work in treating patients with high-risk stage IIB-IV soft tissue sarcoma. Sorafenib tosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as epirubicin hydrochloride and ifosfamide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x rays to kill tumor cells. Giving sorafenib tosylate, combination chemotherapy, radiation therapy, and surgery may be an effective treatment for soft tissue sarcoma.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the pathologic response rate (\>= 95% necrosis) after preoperative treatment with sorafenib (sorafenib tosylate), epirubicin (epirubicin hydrochloride), ifosfamide, and hypofractionated radiation for high risk soft tissue sarcomas of the extremities or body wall.

SECONDARY OBJECTIVES:

I. To further characterize the safety of sorafenib plus chemoradiotherapy, including wound complication rate.

II. To estimate time-to-event rates, including overall survival, overall disease-free survival, distant disease-free survival, and local disease-free survival in patients with high risk soft tissue sarcomas of the extremities or body wall treated with preoperative sorafenib plus chemoradiotherapy and postoperative sorafenib plus chemotherapy.

OUTLINE:

Patients receive sorafenib tosylate orally (PO) once daily (QD) on days 1-71 and 85-155, epirubicin hydrochloride intravenously (IV) over 3-5 minutes, and ifosfamide IV over 90 minutes on days 15-17, 36-38 (ifosfamide only), 57-59, 99-101, 120-122, and 141-143. Patients undergo external beam radiation therapy (EBRT) on days 36-45 and surgical resection on day 78. Patients with positive margins, undergo EBRT boost on days 91-98.

After completion of study treatment, patients are followed up every 4 months for 2 years, every 6 months for 1 year, and then yearly for 2 years.

Arms: arm 1: Patients receive sorafenib tosylate PO QD on days 1-71 and 85-155, epirubicin hydrochloride IV over 3-5 minutes, and ifosfamide IV over 90 minutes on days 15-17, 36-38 (ifosfamide only), 57-59, 99-101, 120-122, and 141-143. Patients undergo EBRT on days 36-45 and surgical resection on day 78. Patients with positive margins, undergo EBRT boost on days 91-98.
Interventions: intervention 1: Epirubicin Hydrochloride intervention 2: External Beam Radiation Therapy intervention 3: Ifosfamide intervention 4: Laboratory Biomarker Analysis intervention 5: Sorafenib Tosylate intervention 6: Therapeutic Conventional Surgery
Intervention descriptions: intervention 1: Given IV intervention 2: Undergo EBRT intervention 3: Given IV intervention 4: Correlative studies intervention 5: Given PO intervention 6: Undergo surgical resection

Protocol documents:
Prot_SAP_000.pdf: 
Oregon Health & Science University 
OHSU Knight Cancer Institute 
IRB Protocol #: 9464 
 
 
A Phase II Study of Sorafenib with Chemotherapy, Radiation, and Surgery for High-
Risk Soft Tissue Sarcomas 
 
 
 
Principal Investigator: 
Christopher W. Ryan, M.D. 
 
 
 
 
Hematology/Oncology 
Oregon Health & Science University 
3303 SW Bond Ave., CH14R 
Portland, OR 97239 
(503) 494-8487 
 
Co-Investigators: 
 
James B. Hayden, M.D., Ph.D. 
Orthopedic Oncology, OHSU 
 
Yee-Cheen Doung, M.D. 
Orthopedic Oncology, OHSU 
 
Arthur Y. Hung, M.D. 
Radiation Oncology, OHSU 
 
John T. Vetto, M.D. 
Kevin G. Billingsley, M.D. 
Rodney F. Pommier, M.D. 
Surgical Oncology, OHSU 
 
Suman Malempati, M.D. 
Pediatric Oncology, OHSU 
 
Atiya Mansoor, M.D. 
Pathology, OHSU 
 
Yiyi Chen, Ph.D 
Biostatistics, OHSU 
 
Original Protocol Date: 
08 March 2013 
Revision Date:                              29 December 2015 
 
 
15 September 2016 


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SCHEMA 
 
 
 
 
 
• Epirubicin:  30 mg/m2/day I.V., days 1-3 of each cycle.  Epirubicin  to be omitted 
during cycle 2 (concomitant chemoradiation) 
• Ifosfamide:  2500 mg/m2/day I.V., days 1-3 of each cycle.  Administered with 
hydration and Mesna.   
• Peg-filgrastim or filgrastim:  S.C. administered after each chemotherapy cycle.  
• Sorafenib:  400 mg p.o. once daily beginning 2 weeks before first chemotherapy 
cycle, held 1 week before and after surgery. 
• Radiation:  28 Gy (350cGy x 8 fractions in 10 days) beginning at the start of cycle 2.  
*Boost: postoperative boost of 12 Gy (200 cGy x 6 fractions) for patients with 
positive surgical margins only. 
 
 
 


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TABLE OF CONTENTS 
 
Page 
SCHEMA .................................................................................................................... 2 
1. __ OBJECTIVES ................................................................................................................ 5 
2. __ BACKGROUND ............................................................................................................ 5 
2.1 
Soft-Tissue Sarcomas_____________________________________________ 5 
2.2 
Adjuvant Radiotherapy ___________________________________________ 5 
2.3 
Adjuvant Chemotherapy __________________________________________ 6 
2.4 
Neoadjuvant Chemoradiotherapy ___________________________________ 7 
2.5 
Antiangiogenic Therapies for Sarcoma _______________________________ 7 
2.6 
Sorafenib ______________________________________________________ 9 
2.7 
Antiangiogenics plus Chemoradiotherapy ____________________________ 10 
2.8 
Sorafenib with Chemoradiotherapy _________________________________ 10 
2.9 
Study Rationale ________________________________________________ 11 
3. __ PATIENT SELECTION ............................................................................................. 12 
3.1 
Eligibility Criteria ______________________________________________ 12 
3.2 
Exclusion Criteria ______________________________________________ 13 
3.3 
Removal of Subjects from Study ___________________________________ 14 
4. __ TREATMENT PLAN .................................................................................................. 15 
4.1 
Study Drug ____________________________________________________ 16 
4.2 
Chemotherapy Dose and Suggested Administration Guidelines (may be 
modified per institutional standards) ______________________________________ 16 
4.3 
Radiation _____________________________________________________ 17 
4.4 
Surgery _______________________________________________________ 17 
4.5 
Supportive Care Guidelines _______________________________________ 18 
4.6 
Other Concomitant Medications ___________________________________ 18 
4.7 
Duration of Therapy _____________________________________________ 19 
5. __ DOSE MODIFICATIONS .......................................................................................... 19 
5.1 
Sorafenib Dose Modifications _____________________________________ 19 
5.2 
Chemotherapy Dose Modifications _________________________________ 23 
6. __ AGENT FORMULATION AND PROCUREMENT ............................................... 24 
6.1 
Sorafenib (Nexavar) _____________________________________________ 24 
6.2 
Epirubicin (Ellence) _____________________________________________ 26 
6.3 
Ifosfamide (Ifex) ________________________________________________ 27 
6.4 
Mesna (Mesnex) ________________________________________________ 28 
6.5 
Pegfilgrastim (Neulasta) _________________________________________ 29 
7. __ CORRELATIVE / SPECIAL STUDIES ................................................................... 30 
7.1 
Angiogenic Biomarkers __________________________________________ 30 


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8. __ STUDY PROCEDURES AND SCHEDULE OF EVENTS ..................................... 31 
8.1 
Subject Registration _____________________________________________ 31 
8.2 
Baseline Screening ______________________________________________ 31 
8.3 
Study Visits ___________________________________________________ 31 
8.4 
Pathology Sample Submission _____________________________________ 31 
8.5 
Assessment of Wound Complications _______________________________ 32 
8.6 
Follow-up _____________________________________________________ 32 
8.7 
Schedule of Events ______________________________________________ 33 
9. __ MEASUREMENT OF EFFECT ................................................................................ 34 
9.1 
Pathologic Response ____________________________________________ 34 
9.2 
Radiographic and Clinical Response ________________________________ 34 
9.3 
Response Criteria _______________________________________________ 34 
9.4 
Confirmatory Measurement/Duration of Response _____________________ 35 
9.5 
Time-to-Event Measures _________________________________________ 35 
10. _ ETHICAL AND REGULATORY REQUIREMENTS ............................................ 36 
10.1 
Protocol Review ________________________________________________ 36 
10.2 
Informed Consent_______________________________________________ 36 
10.3 
Changes to Protocol _____________________________________________ 36 
10.4 
Maintenance of Records _________________________________________ 37 
10.5 
OHSU IRB Reporting of Unanticipated Problems and Adverse Events _____ 37 
10.6 
Adverse Event Definitions ________________________________________ 37 
10.7 
Reporting of Serious Adverse Events to the Sponsor ___________________ 40 
10.8 
OHSU Knight Cancer Institute Data and Safety Monitoring Plan _________ 41 
10.9 
Inclusion of Women, Minorities and Children ________________________ 41 
11. _ STATISTICAL CONSIDERATIONS ....................................................................... 43 
11.1 
Study endpoints ________________________________________________ 43 
11.2 
Statistical analysis plan __________________________________________ 43 
11.3    Sample size consideration _________________________________________ 43 
11.4 
Duration of Accrual _____________________________________________ 43 
 ___ REFERENCES ............................................................................................................. 43 
 
 


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1. OBJECTIVES 
• Primary objective 
o 
To determine the pathologic response rate (≥95% necrosis) after preoperative 
treatment with sorafenib, epirubicin, ifosfamide, and hypofractionated radiation 
for high risk soft tissue sarcomas of the extremities or body wall. 
• Secondary objectives 
O 
To further characterize the safety of sorafenib plus chemoradiotherapy, including 
wound complication rate 
o 
To estimate time-to-event rates, including overall survival, overall disease-free 
survival, distant disease-free survival, and local disease-free survival in patients 
with high risk soft tissue sarcomas of the extremities or body wall treated with 
preoperative sorafenib plus chemoradiotherapy and postoperative sorafenib plus 
chemotherapy. 
2. BACKGROUND 
2.1 Soft-Tissue Sarcomas 
Soft-tissue sarcomas are a group of heterogeneous, rare tumors that are diagnosed in 
approximately 8,000 patients per year in the United States.  While limb-salvage 
procedures combining wide excision with radiation therapy achieve local control in 
up to 90% of patients with extremity soft-tissue sarcomas, approximately half of 
patients with high-grade, >5 cm, deep tumors will die from metastatic disease.1-4  The 
outcome of these patients is unacceptable.  Improving the survival of patients 
diagnosed with such high-risk tumors is a priority. 
2.2 Adjuvant Radiotherapy 
The ability to perform limb-salvage surgery was facilitated by the introduction of 
adjunctive radiotherapy.  Adjuvant radiotherapy for soft-tissue sarcoma was initially 
described by Suit and Lindberg, who demonstrated improved local control rates of 
extremity sarcomas in over 80% of patients.1,2,5  Preservation of function of the limb 
was achieved in greater than 90% of cases.  Randomized trials have validated the 
efficacy of the limb-sparing approach in achieving excellent local control rates that 
have eliminated the need for amputation for the majority of patients. A prospective, 
randomized clinical trial of limb-sparing surgery plus radiation versus amputation 
found equivalent recurrence-free survival rates.6   A randomized study of limb-
sparing surgery plus or minus adjuvant radiation showed a significant decrease in 
local recurrence in those patients receiving radiation.3 Radiotherapy has clearly 
demonstrated its utility in improving local control rates and reducing the amputation 
rate. 
Administration of radiation can be performed either pre- or postoperatively.  A 
randomized study showed an increased acute wound complication rate with 
preoperative radiation compared to postoperative radiation.7 However, longer follow-
up has suggested that postoperative radiation is associated with a greater incidence of 
long-term complications, such as subcutaneous fibrosis, that tend to be permanent 
problems and are probably due to the larger field size and higher radiation dose that 


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are used with postoperative treatment.8  In terms of efficacy, local control rates are 
the same whether the radiation is administered pre- or postoperatively.7 The use of 
pre- vs. postoperative radiation varies between institutions and is a matter of 
preference of the surgeon and radiation oncologist.  Preoperative administration has 
been the preference at our institution.  Theoretical advantages of preoperative 
radiation include delivery to undisturbed, well-oxygenated tissue.  The field size does 
not need to be increased as it does in post-operative radiotherapy, allowing for lower 
radiation doses.9 Importantly, pathologic examination of the tumor specimen after 
surgery for necrosis allows assessment of the efficacy of the pre-operative treatment 
that may correlate with overall survival.10 
2.3 Adjuvant Chemotherapy 
The utility of chemotherapy in treatment of localized sarcomas remains controversial.  
Theoretically, treatment with drugs active against advanced sarcoma, such as 
anthracyclines or ifosfamide, may eradicate micro-metastases and thus increase the 
cure rate over surgery plus radiation alone.  The first generation of adjuvant studies 
included doxorubicin as the key active agent.  These small studies reported 
conflicting results. A meta-analysis using updated data on 1568 patients treated on 
trials using doxorubicin-based adjuvant therapy was published in 1997,11 and was 
subsequently updated with data from additional studies for a total population of 1953 
patients.12  A statistically significant benefit favoring chemotherapy was 
demonstrated for local, distant, and overall recurrence.  The absolute risk reduction 
for overall recurrence was 10%.12 A trend towards absolute overall survival benefit of 
4% at 10 years was not statistically significant, but did reach statistical significance 
upon subgroup analysis of extremity sarcomas (P=.029).11  The studies on which 
these meta-analyses were based had a number of faults, including heterogeneity of 
stage and grade, incorporation of non-active chemotherapy drugs into the treatment 
regimens, and possible under-dosing of doxorubicin. 
Randomized, controlled, adjuvant studies containing ifosfamide and using intensified 
chemotherapy doses with hematopoietic growth factor support were begun in the 
1990's.  The first to be published was an Italian study that randomized patients with 
high-risk sarcomas to observation or to post-operative chemotherapy with ifosfamide 
and epirubicin.13  This study included only high-risk patients with high-grade, large 
(≥5 cm) or recurrent sarcomas of the extremities or girdle.  One-hundred-four patients 
were randomized to chemotherapy or to observation, and accrual was halted in 1996 
after an interim analysis suggested significant benefit from chemotherapy. Subjects in 
the treatment group received 5 cycles of epirubicin 60 mg/m2 days 1 and 2 and 
ifosfamide 1.8 g/m2 days 1 through 5, with hydration, mesna, and granulocyte colony-
stimulating factor support.  The median disease-free survival was 48 months in the 
treatment group and 16 months in the control group (P =.04) and the median overall 
survival was 75 months for treated and 46 months for untreated patients (P =.03).    
The study has been criticized for its small size and early stopping based on 
recurrence-free survival; indeed, with longer follow-up the overall survival advantage 
lost statistical significance.14 


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2.4 Neoadjuvant Chemoradiotherapy 
There are advantages, both practical and theoretical, to treating high-risk extremity 
soft tissue sarcomas with pre-operative chemotherapy and radiation.  Chemotherapy 
may act both in the early systemic treatment of micrometastatic disease and as a 
radiosensitizer for improved local control.  In combination with pre-operative 
radiotherapy, neoadjuvant chemotherapy may improve tumor downsizing and 
potential resectability.  Preoperative radiation has the advantage of delivery to 
undisturbed, well-oxygenated tissue.  The field size does not need to be increased as it 
does in post-operative radiotherapy, allowing for lower radiation doses.9  
Additionally, preoperative therapy allows evaluation of treatment effect from the 
surgical specimen: the degree of pathologic necrosis in the surgical specimen after 
chemoradiation has been associated with improved local control and overall survival 
in patients with soft-tissue sarcoma. In a study published by Eilber,10 treatment-
induced pathologic necrosis after neoadjuvant treatment with chemotherapy and 
radiation was found to be an independent predictor of both local recurrence and 
overall survival for patients with high-grade sarcomas. The 10-year overall survival 
rate for patients who had achieved ≥ 95% necrosis was 71%, compared with 55% in 
patients with < 95% necrosis. While combined chemotherapy and radiation prior to 
surgery has been reported by a number of different groups, there exists no standard 
regimen. 15-20 
We previously published a 25 patient, phase II study investigating a dose-intense, pre-
operative chemoradiotherapy regimen for patients with large, intermediate- and high-
grade sarcomas of the extremity or body wall.20 Intense doses of epirubicin and 
ifosfamide were given pre- and post-surgery, and 28 Gy of radiation in 8 fractions 
was given preoperatively, partly in conjunction with ifosfamide.  This 
“hypofractionated” or “rapid fractionation” scheme was based on that previously 
reported by the UCLA group, a short-course treatment plan that provides for 
convenient and effective administration of radiation.15 The rate of ≥95% pathologic 
necrosis in the resected tumors was 40% (95% C.I. 21%, 59%) and estimates of 2-
year overall and disease-free survival were 84% (95% CI, 66% to 100%) and 62% 
(95% CI, 37% to 86%), respectively.  Postoperative wound complications requiring 
an operative procedure occurred in 20%, within the expected and acceptable range for 
pre-operative radiotherapy.7  Due to expected chemotherapy side effects and related 
patient drop-out, only 64% of patients completed all chemotherapy cycles and the 
average delivered dose intensity relative to intended therapy was 69%.  Notable 
toxicities included neutropenic fever (40%), ifosfamide encephalopathy (24%), and 
grade 3-4 anemia (64%).  While the toxicity was manageable and expected from the 
agents utilized, it did impact our ability to deliver the intended dose intensity. The 
rate of ≥95% pathologic necrosis found in a subsequent analysis of 37 patients treated 
both on- and off- study was 32%.21 The high rate of pathologic necrosis with this 
regimen has been encouraging, and has prompted us to consider alternate methods of 
augmenting neoadjuvant chemoradiotherapy in soft tissue sarcoma. 
2.5 Antiangiogenic Therapies for Sarcoma 
Development of new blood vessel formation is critical in the progression of tumors.  
Folkman’s hypothesis22 of targeting this process as an antineoplastic strategy has 


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become practical reality three decades later with the advent of antiangiogenic agents 
now in widespread use based on clinical trials that have shown benefit in combination 
with chemotherapy23,24 or as monotherapy in select diseases.25-27 Common among 
these treatments is inhibition of the vascular endothelial growth factor (VEGF) 
activity, a key pathway in tumor angiogenesis. 
Soft tissue sarcomas frequently overexpress VEGF28,29 and elevated circulating levels 
of the pro-angiogenic factors VEGF and basic fibroblast growth factor (bFGF) are 
found in patients with soft tissue sarcoma.30-33 Tumor VEGF concentration has been 
found to correlate with grade, stage, and prognosis of soft-tissue sarcomas.29,34  
VEGF-directed therapies have now demonstrated to have activity in a variety of 
advanced soft tissue sarcomas. Pazopanib, an inhibitor of VEGF-R and multikinase 
inhibitor was approved by the FDA in 2012 for treatment of advanced soft tissue 
sarcoma after previous chemotherapy.  This approval was based on the results of a 
phase III study that showed improvement in progression-free survival over placebo 
control.35 Several studies have looked at sorafenib, a multi-kinase inhibitor of VEGF 
receptors, PDGF receptor, Raf/MEK/ERK, and others, as a single-agent in patients 
with metastatic soft tissue sarcoma.  The first of these studies to be reported observed 
a small number of radiographic responses in subjects with angiosarcoma and 
leiomyosarcoma, as well as stable disease in these and other sarcoma subtypes.36 At 
least 2 other studies of sorafenib in advanced sarcoma have been conducted, 
including a phase II study by the Southwest Oncology Group in which OHSU led 
accrual and developed a sizeable pilot experience using the agent for this disease (19 
subjects).37  While no objective radiographic responses were observed in this study, 
patients with vascular-type sarcomas were noted to have prolonged stable disease. 
 
While the activity of these antiangiogenic agents against soft-tissue sarcomas may 
appear low when evaluated with the traditional metric of radiographic response rates, 
this measure is far from optimal in assessing the activity of antiangiogenic agents 
which typically may not cause rapid involution of tumors.  Radiographic disease 
stabilization as a clinically meaningful effect has been demonstrated in studies with 
sorafenib in renal carcinoma, in which traditional response rates are low but 
progression-free survival is improved.25 Additionally, the use of these agents as 
monotherapy in the high-disease burden setting of metastatic disease may not reveal 
their full activity, and studying their use in combination with chemotherapy in the 
locally advanced, micrometastatic setting may yield greater impact.  In a VEGF-
overexpressing preclinical sarcoma model, VEGF receptor blockade enhanced 
chemotherapy responsiveness and decreased development of pulmonary metastases, 
suggesting that combining anti-VEGF therapy with chemotherapy might be most 
useful in high VEGF-secreting sarcoma patients at high risk of eventual metastatic 
spread.38 
 
 
 


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2.6 Sorafenib 
Sorafenib (BAY 43-9006) is an oral multi-kinase inhibitor with effects on tumor 
proliferation and tumor angiogenesis.39  It was initially selected based on inhibitory 
activity against the serine/threonine kinases Raf-1 and wild-type B-Raf, which are 
pivotal components of the Ras/Raf/MEK/ERK signaling pathway.  Inhibitory activity 
was subsequently demonstrated against the tyrosine kinases for vascular endothelial 
growth factor (VEGF) receptor and platelet-derived growth factor (PDGF) receptor as 
well as Flt-3 and c-Kit.39  
The Raf/MEK/ERK pathway is an important mediator of responses to growth factors, 
and a strong inducer of genes involved in tumorigenesis, angiogenesis, apoptosis, and 
tumorigenesis.40  In preclinical studies, sorafenib demonstrated broad-spectrum anti-
tumor activity by inducing complete tumor stasis and inhibition of tumor 
angiogenesis in a variety of tumor types.39   
The safety and clinical activity of sorafenib, alone 41-44 or in combination45,46 with 
chemotherapy, has been examined in a series of phase I studies conducted in patients 
with solid tumors. Results of a multi-center, randomized, placebo-controlled, double-
blind phase III trial of sorafenib in advanced renal cell carcinoma (RCC) were first 
reported in 2005.47,48 The co-primary endpoints of the trial were overall survival (OS) 
and progression-free survival (PFS).  Patients with advanced clear cell renal 
carcinoma with good performance status following one prior systemic therapy were 
randomized to either sorafenib or blinded placebo with best supportive care.  At the 
time of a per-protocol interim analysis of PFS, 769 of 884 planned patients had been 
randomized, and 342 PFS events had been reported. Median PFS was 24 weeks for 
sorafenib versus 12 weeks for placebo (hazard ratio 0.44; p<0.00001) and the 12 
week progression-free rate was 79% for sorafenib versus 50% for placebo.  Based on 
these results, the study in May 2005 was unblinded and patients in the placebo group 
were allowed to cross over and receive sorafenib.  At the time of cross over, an 
interim analysis of overall survival was conducted based on 220 events. Median 
overall survival in the placebo group was 14.7 months and had not been reached in 
the sorafenib group.  The Hazard Ratio (sorafenib over placebo) was 0.72 with a p-
value of p = 0.018. The threshold for statistical significance for this interim analysis 
was not reached (p < 0.0005).  Final analysis of OS was reported at ASCO 2007.49  
Overall survival in the sorafenib group was 17.8 months and 15.2 months in the 
placebo group (HR 0.88, p=0.146).  For this study, however, OS was likely 
confounded by the fact that approximately half of the placebo patients crossed over at 
the time of unblinding to receive sorafenib.  To illustrate that point, overall survival 
analysis with placebo patients censored at the time of cross over indicated that 
sorafenib treated patients had a statistically significant 22% reduction in mortality 
risk compared to placebo patients (OS 17.8 mo vs. 14.3 mo, HR 0.78, p=0.0287).   
A multi-center, randomized, placebo-controlled, double-blind phase III trial of 
sorafenib in advanced hepatocellular carcinoma (HCC) was also reported at ASCO in 
2007.26  In this study 602 patients with advanced HCC, Child Pugh class A, having 
received no prior systemic therapy were randomized to receive either sorafenib 
(n=299) at 400 mg bid or placebo (n=303).  In February 2007, based on a planned 
interim analysis of overall survival, the DMSB recommended unblinding and closure 


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of the study.  OS in the sorafenib group was 46.3 wks versus 34.4 wks in the placebo-
treated group. This represented a 44% increase in relative OS (HR 0.69, p=0.00058).  
PFS was also significantly increased in the sorafenib group (24 wks) vs. the placebo 
group (12.3 wks); HR 0.58, p=0.000007.     
As mentioned previously, several studies with sorafenib monotherapy have been 
conducted in soft tissue sarcoma, and activity has been seen in several histologic 
subtypes including angiosarcoma and leiomyosarcoma.36 
2.7 Antiangiogenics plus Chemoradiotherapy 
Antiangiogenics have been shown to increase the effects of chemotherapy and 
radiation in pre-clinical and clinical studies. Bevacizumab has been demonstrated to 
increase overall survival when added to chemotherapy for advanced colorectal cancer 
and non-small cell lung cancer.23,24   This may seem counterintuitive, as anti-vascular 
therapies would be expected to reduce blood flow, thus potentially decreasing 
delivery of drug and oxygen to the tumor needed for the therapeutic effects of 
chemotherapy and radiation, respectively.  However, tumor vasculature is thought to 
be abnormal due to an imbalance of pro- and antiangiogenic factors leading to a 
number of effects that can be a barrier to drug and oxygen delivery including 
impedance of blood flow and interstitial hypertension.50 The concept of 
“normalizing” tumor vasculature with antiangiogenic therapy has been proposed as a 
method whereby drug delivery and oxygenation are improved and thus can amplify 
the effect of chemotherapy and radiation.50  Blockade of VEGF signaling can “prune” 
immature vessels, helping to normalize the vasculature and tumor microenvironment, 
thus improving tumor oxygenation and delivery of drugs.51,52 Early evidence suggests 
that combined VEGF-blockade and chemoradiotherapy is safe and promising in 
locally advanced rectal cancer.52,53  Many phase I-II studies investigating combined 
antiangiogenic and chemoradiotherapy are ongoing, but to our knowledge none are 
currently investigating this approach in soft tissue sarcomas.54 
2.8 Sorafenib with Chemoradiotherapy 
Given the early clinical activity observed with antiangiogenic agents in advanced soft 
tissue sarcomas and given that the greatest effect of antiangiogenics may not be as 
monotherapy but in their ability to potentiate the effects of chemotherapy and 
radiotherapy, we have found it compelling to study the effect of combined 
antiangiogenic therapy with chemoradiotherapy in patients with localized, high-risk, 
extremity soft tissue sarcomas.   We thus conducted a 16 subject phase I study with 
escalating doses of sorafenib to determine the maximum tolerated dose of sorafenib in 
combination with a dose-modified version of our previously published regimen of 
preoperative chemoradiation and postoperative chemotherapy with epirubicin and 
ifosfamide.55  At a sorafenib dose of 400 mg twice daily, dose-limiting toxicities 
included grade 4 neutropenic sepsis in 1 patient and grade 3 hand-foot syndrome in 
all 3 patients treated. We determined a maximum-tolerated-dose for sorafenib to be 
400 mg daily when combined with a regimen of 28 Gy of preoperative 
hypofractionated radiation and pre- and post-operative chemotherapy (epirubicin 30 
mg/m2/day days 1-3 and ifosfamide 2.5 g/m2/day days 1-3). At this dose level, 
toxicity was similar to that seen with chemoradiotherapy alone. Grade 3-4 
hematologic toxicity was common including a 50% rate of neutropenic fever and 


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neutropenic infections. The most common grade 3-4 nonhematologic toxicity was 
hypophosphatemia, a known side effect of both sorafenib and ifosfamide, which was 
easily managed with phosphorus replacement and did not lead to any significant 
sequelae.  The rate of wound complications was 38%, which is similar to the 35% 
that has been reported with preoperative radiation alone.  
 
We observed a promising rate of pathologic response (≥95% necrosis) across all dose 
levels of 44%.  Eleven of the subjects were enrolled in a companion study evaluating 
DCE-MRI to assess preoperative therapy effect, and results indicate that treatment 
effect of sorafenib could be detected in some patients after only 2 weeks of sorafenib, 
and that the change in a novel DCE-MRI biomarker, ∆Ktrans, at this time point 
correlated with pathologic necrosis found at the time of eventual surgery (Figure 1). 
 
Figure 1: Myxoid round cell liposarcoma of thigh demonstrating change in 3 different DCE-MRI 
biomarkers (SM Ktrans, SSM Ktrans, and ΔKtrans) from baseline (TP0) to 2 weeks after sorafenib treatment 
(TP1) 
 
 
2.9 Study Rationale 
The optimal chemoradiotherapy regimen for soft-tissue sarcomas remains undefined.  
We have extended our neoadjuvant chemoradiotherapy experience by confirming the 
safety and feasibility of combined treatment with sorafenib in a dose-finding phase I 
study.55  We now propose to further study the efficacy and safety of sorafenib 400 
mg/daily when combined with chemoradiotherapy (epirubicin, ifosfamide, and 
hypofractionated radiation) as an adjunct to surgery for extremity soft tissue sarcomas 
in the setting of a phase II trial. 
 
T
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T
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We hypothesize that this regimen will improve clinical outcome in patients with high-
risk disease by potentiating the effects of chemoradiotherapy on the local tumor and 
enhancing the effects of chemotherapy on micrometastatic disease.  Treatment effect 
will be assessed by the pathologic response rate (≥95% necrosis), and subjects will be 
followed for local recurrence, distant relapse, and overall survival. 
 
3. PATIENT SELECTION 
3.1 Eligibility Criteria 
3.1.1 Histologically confirmed, soft-tissue sarcoma: excluding 
rhabdomyosarcoma (pleomorphic rhabdomyosarcoma patients are eligible), 
Ewing’s, PNET, osteosarcoma, or gastrointestinal stromal tumor 
3.1.2 AJCC (7th Edition) Stage IIb, III, or  IV patients planned for resection 
of the primary tumor  
• 
>5 cm in greatest dimension 
• 
Intermediate or High-Grade (see 3.1.4) 
• 
Superficial or Deep 
3.1.3 Sarcoma located on upper (includes shoulder) or lower (includes hip) 
extremities or on body wall 
3.1.4 Intermediate or High-Grade: Grades 2 or 3 on scale of 1-3  
3.1.5 LVEF ≥ 50% 
3.1.6 Required initial laboratory values: 
ANC  
≥ 1500 /µL 
Hgb 
 
≥ 9.0 g/dL 
Platelets 
≥ 100,000 /µL 
Creatinine 
≤ 1.5 x ULN 
Bilirubin 
≤ 1.5 mg/dL 
AST/ALT 
≤ 1.5 x ULN 
3.1.7 INR < 1.5 or a PT/PTT within normal limits.  Patients receiving anti-
coagulation treatment with an agent such as warfarin or heparin may be 
allowed to participate.  For patients on warfarin, the INR should be 
measured prior to initiation of sorafenib and monitored at least weekly, or as 
defined by the local standard of care, until INR is stable.  
3.1.8 No prior chemotherapy, radiation, or biotherapy 
3.1.9 No major surgery within 4 weeks prior to study entry 
3.1.10 No contraindications to limb-sparing surgery.  Patient should be 
evaluated by a surgeon who specializes in sarcoma resections prior to study 
enrollment to ensure pt is a candidate for limb-sparing surgery. 
3.1.11 No severe peripheral vascular disease 
3.1.12 Adequate contraception must be used and patients must not be 
pregnant or breastfeeding. Women of childbearing potential and men must 


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agree to use adequate contraception (barrier method of birth control) prior to 
study entry and for the duration of study participation.  Men and women 
should use adequate birth control for at least thirty days after the last 
administration of sorafenib. 
3.1.13 Women of childbearing potential must have negative serum pregnancy 
test performed within 7-days prior to registration.   
3.1.14 Age≥18 
3.1.15 ECOG PS 0-1 
3.1.16 Patient must sign a study-specific consent form prior to registration 
3.1.17 Ability to understand and the willingness to sign a written informed 
consent. A signed informed consent must be obtained prior to any study 
specific procedures. 
3.2 Exclusion Criteria 
3.2.1 Patients with known brain metastases.  Patients with neurological 
symptoms must undergo a CT scan/MRI of the brain to exclude brain 
metastases.  
3.2.2 Uncontrolled intercurrent illness including, but not limited to, ongoing 
or active serious infection >CTCAE Grade 2, symptomatic congestive 
heart failure, unstable angina pectoris, cardiac ventricular arrhythmia 
requiring anti-arrhythmic therapy, or psychiatric illness/social 
situations that would limit compliance with study requirements.  
Patients must not have unstable angina (angina symptoms at rest) or 
new onset angina (began within the last 3 months) or myocardial 
infarction within the past 6 months. 
3.2.3 Uncontrolled hypertension defined as systolic blood pressure > 150 
mmHg or diastolic pressure > 90 mmHg, despite optimal medical 
management. 
3.2.4 Known human immunodeficiency virus (HIV) infection or chronic 
Hepatitis B or C. 
3.2.5 Thrombolic or embolic events such as a cerebrovascular accident 
including transient ischemic attacks within the past 6 months. 
3.2.6 Pulmonary hemorrhage/bleeding event > CTCAE Grade 2 within 4 
weeks of first dose of study drug. 
3.2.7 Any other hemorrhage/bleeding event  > CTCAE Grade 3 within 4 
weeks of first dose of study drug. 
3.2.8 Serious non-healing wound, ulcer, or bone fracture. 
3.2.9 Evidence or history of bleeding diathesis or coagulopathy. 
3.2.10 Major surgery or significant traumatic injury within 4 weeks of first 
study drug. 
3.2.11 Use of strong CYP3A4 inducers (See Section 4.6).  


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3.2.12 Known or suspected allergy to sorafenib or any agent given in the 
course of this trial. 
3.2.13 Any condition that impairs patient‘s ability to swallow whole pills. 
3.2.14 Any malabsorption problem. 
3.2.15 Pregnant or lactating women are excluded from this study because of 
possible risk to the fetus or infant. 
3.2.16 Patients with a "currently active" second malignancy other than non-
melanoma skin cancers are not to be registered. Patients are not 
considered to have a "currently active" malignancy if they have 
completed therapy and considered by their physician to be at less than 
30% risk of relapse. 
3.2.17 Any uncontrolled thyroid disease. 
3.2.18   Requirement for hemodialysis or peritoneal dialysis 
 
3.3 Removal of Subjects from Study 
3.3.1 Criteria for stopping therapy: 
• Substantial non-compliance with the requirements of the study. 
• Any adverse event which, in the Investigator’s opinion, requires termination of 
the study medication. 
• Disease progression, unless at the discretion of the investigator (in 
collaboration with Bayer/Onyx) continued treatment with study drug is 
appropriate. 
• The patient would benefit from additional radiation therapy beyond that 
specified in the protocol. 
• Request by the patient or a legal representative/relative to stop the treatment. 
• The patient presents with a beta-HCG test consistent with pregnancy.  
Pregnancy will be reported along the same timelines as a serious adverse event 
• The patient uses illicit drugs or other substances that may, in the opinion of the 
Investigator, have a reasonable chance of contributing to toxicity or otherwise 
interfering with results. 
• The development of a second malignancy that requires treatment, which would 
interfere with this study. 
• The patient is lost to follow-up. 
• Interruption in study drug’s administration for greater than 3-week delay.  
Following surgery, interruption in study drug’s administration is allowed for up 
to 10-weeks from initial surgery. 
• Development of an intercurrent illness or situation which would, in the 
judgment of the investigator, affect assessments of clinical status and study 
endpoints to a significant degree. 
3.3.2 Criteria for study withdrawal: 
• Disease progression, unless at the discretion of the investigator (in 
collaboration with Bayer/Onyx) continued treatment with study drug is 


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appropriate. 
• Study closure, 
• Unacceptable adverse event(s), 
• Patient decision to withdraw from the study, or 
• In the judgment of the investigator, further treatment would not be in the best 
interest of the patient. 
 
The Investigator will make every reasonable effort to keep each patient in the study 
unless it is in the patient’s best interest to discontinue participation.  If a patient is 
removed from the study or declines further participation, all End of Treatment 
evaluations should be performed if the patient is willing and able to be assessed.  A 
description of the reason(s) for withdrawal from the study will be recorded on the 
case report form (CRF).  The Investigator should also ensure that all patients are 
followed up for survival and recurrence after the Final Visit. 
Relevant visit data should be entered on the CRF and any unused study medication 
will be accounted for and returned for all patients participating in the study, even 
for a brief period of time.  Patients who discontinue following entry will have 
relevant information completed and recorded on the CRF.  All patients who 
discontinue because of adverse events or clinically significant laboratory 
abnormalities should be followed up until they recover or stabilize, and the 
subsequent outcome will be recorded.  If any patient should die during the trial or 
within 30 days of stopping study treatment, the Investigator will inform the OHSU 
IRB and the Bayer representative.  The cause of death should be recorded in detail, 
within 24 hours, on a serious adverse event (SAE) form and reported to the sponsor 
Drug Safety Unit (refer to Section 10)). 
4. TREATMENT PLAN 
 
TX 
SORAFENIB 
RUN-IN 
CYCLE 1 
DAYS 
CYCLE 2 
DAYS 
CYCLE 3 
DAYS 
SURGERY 
CYCLE 4 
DAYS 
CYCLE 5 
DAYS 
CYCLE 6 
DAYS 
EPI 
 
15-17 
OMIT 
57-59 
 
99-101 
120-122 
141-143 
IFOS 
 
15-17 
36-38* 
57-59 
 
99-101 
120-122 
141-143 
MESNA 
 
15-17 
36-38* 
57-59 
 
99-101 
120-122 
141-143 
SORAFENIB 
1-14 
15-35 
36-56 
57-71** 
85-98** 
99-119 
120-140 
141-155 
PEG-
FILGRASTIM♦ 
 
18 
39 
60 
 
102 
123 
144 
RT 
 
 
36-45* 
 
 
BOOST*** 
 
 
SURGERY 
 
 
 
 
78** 
 
 
 
 


Version 1: 04 March 2013 
 
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1 cycle = 21 days in length 
♦ PEG-Filgrastim should be administered 24-48 hours after completing chemotherapy.  10 
days of filgrastim may be substituted. 
* Radiation administration will consist of 8 fractions over 10 days, as it is common practice 
in many centers not to administer radiation therapy on weekends. Whenever possible, both 
radiation and chemotherapy should be administered together on days 36-38. Initiating 
chemoradiation on a Monday, Tuesday, or Wednesday for cycle 2 will help ensure 
concomitant administration during these 3 days prior to the weekend break. 
** Sorafenib should be discontinued 1 week before surgery and resumed 1 week after 
surgery.  Note that the timing of surgery and resumption of post-operative chemotherapy 
presented here are estimations.  While adherence to this schedule is a goal, treatment-
related complications and other logistical factors may alter scheduled events.  In general, 
surgery should be planned for 2-4 weeks after the initiation of chemotherapy for cycle 3.  
Deviation from this schedule will be reported in the final analysis.  In case of delays, the 
dates specified above should be appropriately recalculated.  If a major wound 
complication requires additional surgery, reinstitution of chemotherapy (cycle 4) should 
be initiated only after adequate wound healing has been achieved (a minimum of 2 weeks 
following the second surgery).   Patients who require a delay of greater than 10 weeks 
since initial surgery due to inadequate wound healing will be removed from further 
protocol therapy. 
*** For patients with positive surgical margins, 12 Gy (200 cGy x 6 fractions) will be given 
by external beam prior to restarting chemotherapy.  Begin radiation 2 weeks after 
surgery (approximately day 91) assuming wound is healing well. 
4.1 Study Drug 
Sorafenib will be administered orally 400 mg once daily. Sorafenib will begin 2 
weeks before first chemotherapy cycle with epirubicin and ifosfamide.  Sorafenib will 
be held 1 week before and after surgery 
4.2 Chemotherapy Dose and Suggested Administration Guidelines (may 
be modified per institutional standards) 
Chemotherapy can be administered on either an inpatient or outpatient basis.  No 
investigational or commercial agents or therapies other than those described in the 
protocol may be administered with the intent to treat the patient's malignancy. 
Patients will receive 3 cycles of pre-operative chemotherapy and 3 cycles of post-
operative chemotherapy. 
Recommended hydration is 0.45 NS + 50 mEq NaHCO3 1L over 2 hours prior to 
ifosfamide daily. 
 
• Epirubicin: 30 mg/m2/day I.V., days 1-3 of each cycle.  Epirubicin is to be 
omitted during cycle 2 (concomitant chemoradiation) 
• Ifosfamide: 2.5 g/m2 over 90 minutes I.V., days 1-3 of each cycle.  Begin 
after  1 L hydration 


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• Mesna:  Suggested dosing: 850 mg/m2 mixed in same bag as ifosfamide, 
then 850 mg/m2 I.V. over 15 minutes given 4 hours and 8 hours after start of 
ifosfamide, days 1-3 of each cycle 
• PEG-filgrastim 6 mg administered as a subcutaneous injection starting 24-
48 hours after completion of chemotherapy (may substitute filgrastim  5 
mcg/kg/day (rounded to nearest vial size) administered as a subcutaneous 
injection starting 24-48 hours after completion of chemotherapy for 10 days, 
or until white blood count has recovered after nadir (ANC > 10,000) 
4.3 Radiation 
Treatment is to consist of one course of external beam radiation therapy (EBRT) 
coinciding with the start of cycle 2 of chemotherapy.  Treatment will consist of a 
total dose of 28 Gy (350cGy x 8 fractions in 10 days).  If treatment falls on a 
weekend or holiday, treatment can resume the next business day. 
The target volume of radiation therapy will include the site of the primary lesion 
and those tissues suspected of involvement by microscopic disease to a clinically 
important probability.  Physical exam in conjunction with MRI or CT scans 
obtained during evaluation will be used in defining the target volume.  The margins 
beyond clinically or radiologically-evident sarcoma will be 7 cm.  Optimal field 
arrangement, beam parameters, and shaped blocks will be used to achieve the 
closest approximation of treatment volume to target volume to minimize irradiation 
of uninvolved normal tissue.  Immobilization devices should be used daily to ensure 
reproducibility of treatment. 
Post-operative EBRT boost will be given for patients with positive margins.  The 
radiation treatment is to be completed by administering 12 Gy in 6 fractions (once a 
day) to the bed of the residual tumor (including a margin of 1 cm).  Boost will not 
be given for patients with 100% necrosis.  EBRT will begin approximately 2 weeks 
following resection, assuming there is satisfactory healing of the surgical wound.   
The target volume for the post-operative radiation therapy will be the tumor bed as 
defined by the operative and pathological findings.  Chemotherapy can resume 
thereafter. 
4.4 Surgery 
Surgical treatment necessary to resect the tumor with negative margins should be 
used.  All lesions of the trunk and extremities will be treated with conservative 
resection (minimal wide excision) after pre-operative therapy.  Surgical resection 
should remove as wide a margin of tissue around the tumor as possible without 
compromising function.  Dissection should always be done through grossly normal 
tissue planes and should be done beyond fascial plane adjacent to the tumor.  If the 
tumor is close to or displaces major vessels or nerves, these need not be removed if 
the adventitia or perineurium is removed and the margin is not involved 
pathologically.  Frozen section at the time of surgery should be done from the 
closest margin and should be confirmed as being free of tumor.  If postoperative 
pathology evaluation reveals positive soft-tissue margins other than bone, nerve, or 
large blood vessels, this margin should be resected if possible.  If bone, major blood 
vessel or nerve is microscopically positive additional radiation should be given as 


Version 1: 04 March 2013 
 
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noted in the protocol.  In general, lymph node dissection is not recommended, but a 
sampling can be performed if the primary tumor is over a major node station.  
Primary tumors overlying major lymph node stations may best be treated with 
surgical resection including node dissection.   Marker clips (titanium) may be 
placed to help guide the radiation oncologist.  Closed wound suction drainage 
should be used in all anatomic regions (Davol, Hemavac, etc.)  The drains should 
exit the skin close to the edge of the surgical incision.  External compression for 
extremity resections with ace wraps or compression dressings is advised. 
State clearly in the operative note what type of surgical procedure was performed, 
and from where the frozen section of the margins was taken. 
Because all patients will have had radiation, special care must be given to skin 
flaps.  Use of muscle flaps, pedicled myocutaneous flaps, and even free flaps is 
encouraged to fill dead space and used if there is any concern about the viability of 
the wound flaps. 
In general, the following principles should be followed in post-operative 
management of these patients: 
• Maintain staples or skin sutures per surgeon preference but because of potential 
delay in wound healing, 3-4 weeks is recommended 
• Leave drains until the drainage meets the criteria for surgeon preference for 
discontinuation 
• Begin rehabilitation slowly 
Resectability will depend upon the judgment of the operating surgeon.  For the 
extremities, resection must be limb salvage procedure.  For other anatomic areas, it 
must be the judgment of the operating surgeon that he/she may reasonably expect to 
obtain negative margins. Extremity patients who are not resectable without 
amputation may be amputated, and should complete chemotherapy per protocol.  
Unresectable tumors elsewhere may be palliated with additional chemotherapy, per 
protocol.  Patients who would benefit from additional radiation therapy will be 
withdrawn from protocol therapy. 
Note that documentation of wound complications is an integral part of this 
clinical trial.  Wound complications are defined in section 8.5 and must be 
accurately recorded and reported to the coordinating center. 
4.5 Supportive Care Guidelines 
Appropriate anti-emetics per institutional standard and at the investigator’s 
discretion should be used with this highly-emetogenic regimen. 
Use of erythroid growth factors to support hemoglobin levels are permitted, at the 
discretion of the investigator. 
Prophylactic antibiotics for prevention of neutropenic fever may be used at the 
discretion of the investigator.  Use of prophylactic antibiotics must be recorded in 
the case report forms. 
4.6 Other Concomitant Medications 
Sorafenib is metabolized primarily by liver enzymes, in particular CYP3A4. Caution 
is recommended when administering sorafenib with inducers of the CYP3A4 family. 


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Concurrent administration of strong CYP3A4 inducers (such as, phenyoin, rifabutin, 
and rifampin) is not permited.  In a clinical interaction study, concurrent 
administration of sorafenib with rifampin resulted in a 37% decrease in mean 
sorafenib AUC. Other agents known to moderately induce CYP3A4 should be 
avoided if possible.  
4.7 Duration of Therapy 
Treatment should continue until the end of protocol therapy or until one of the 
following criteria applies: 
Disease progression, 
The patient would benefit from additional radiation therapy beyond that 
specified in the protocol, 
Intercurrent illness that prevents further administration of treatment, 
Unacceptable adverse events(s), 
Greater than 3-week delay in therapy due to adverse event 
The patient presents with a beta-HCG test consistent with pregnancy.  
Patient or legal representative/relative requests to withdraw from the study, or 
General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
5. DOSE MODIFICATIONS 
5.1 Sorafenib Dose Modifications 
General Considerations.  Sorafenib dosing will be modified for adverse events that 
are at least in-part attributable to sorafenib according to the following dose levels:   
 
 
 
 
 
 
 
All patients will start treatment at dose level 0.  
 
Patients will be removed from protocol treatment if dose reduction below -2 is 
indicated. 
 
Dose Level 
Sorafenib 
0 
400 mg once daily 
-1 
200 mg once daily 
-2* 
200 mg every other day 


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5.1.1 Dose Modifications for Sorafenib for Hand-Foot Skin Reaction 
Grade 
Occurrence 
Suggested Dose Modification 
Grade 1 
Minimal skin changes 
or dermatitis (e.g., 
erythema, edema, or 
hyperkeratosis) 
without pain 
Any  
Promptly institute supportive measures  such as topical therapy for 
symptomatic relief and continue sorafenib treatment  
Grade 2 
Skin changes (e.g., 
peeling, blisters, 
bleeding, edema, or 
hyperkeratosis) with 
pain;  
limiting instrumental 
ADL 
 
First  
Promptly institute supportive measures such as topical therapy for 
symptomatic relief and consider a decrease of sorafenib by one 
dose level for a minimum of 7 days and up to 28 days 
• 
If toxicity resolves to grade 0–1 after dose reduction, increase 
sorafenib  back to previous dose level 
• 
If toxicity does not resolve to grade 0-1 despite dose reduction, 
interrupt sorafenib treatment for a minimum of 7 days and 
until toxicity has resolved to grade 0–1.   
 
When resuming treatment after dose interruption, 
resume sorafenib at a one dose level reduction  
 
If toxicity is maintained at grade 0–1 at reduced dose 
for a minimum of 7 days and up to 28 days, increase 
back sorafenib to previous dose level 
Second or Third 
occurrence 
As for first occurrence. Upon resuming sorafenib, decrease dose by 
one dose level. 
Decision whether to dose re-escalate should be based on clinical 
judgment and patient preference. 
Fourth 
occurrence 
Decision whether to discontinue sorafenib should be made based 
on clinical judgment and patient preference 
Grade 3 
Severe skin changes 
(e.g., peeling, blisters, 
bleeding, edema, or 
hyperkeratosis) with 
pain; limiting self 
care ADL 
 
First occurrence 
Institute supportive measures such as topical therapy for 
symptomatic relief and interrupt sorafenib treatment for a minimum 
of 7 days and until toxicity has resolved to grade 0–1 
• 
When resuming treatment after dose interruption, 
decrease sorafenib by one dose level   
• 
If toxicity is maintained at grade 0–1 at reduced 
dose for a minimum of 7 days and up to 28 days, 
increase by one dose level 
Second 
occurrence 
As for first occurrence. Upon resuming sorafenib treatment, 
decrease dose by one dose level. 
Decision whether to dose re-escalate should be made based on 
clinical judgment and patient preference.  
Third occurrence 
Decision whether to discontinue sorafenib treatment should be 
made based on clinical judgement and patient preference. 


 
21 
5.1.2 Dose Modifications for Sorafenib-Associated Hypertension 
Hypertension is a known and potentially serious adverse event associated with sorafenib 
treatment. Patients will have their blood pressure monitored and recorded weekly during 
the first 6 weeks of therapy, either at the doctor’s office or by using any calibrated 
electronic device (such as those found at a local drug store or pharmacy). Patients will 
record their weekly blood pressure during the first 6 weeks on their drug diary, a copy of 
which will remain in the research chart. If the patient’s blood pressure is elevated at any 
time (>150/100), even outside clinic visits, they should contact their treating physician. 
 
Grade 
(CTCAE v4.0) 
Antihypertensive 
       Therapy 
Blood Pressure  
Monitoring 
Sorafenib Dose 
Grade 1 
None 
Routine 
No change 
Grade 2 
 
Initiate monotherapy 
(suggest 
dihydropyridine 
calcium-channel 
blocker) 
Increase frequency and 
monitor (by health  
professional) every 2 
days 
until stabilized 
No change 
 
Grade 3 
Add agent(s):  
Ca++ channel blocker  
(if not already used),  
K+ channel opener 
(angiotensin blockers), 
beta-blocker,  
thiazide diuretic 
 
Increase frequency and 
monitor (by health  
professional) every 2 
days until stabilized;  
continue qod 
monitoring  
to stabilization after 
dosing restarted. 
Hold* sorafenib until 
symptoms resolve and 
diastolic BP < 100 
mm/Hg. 
 
Resume treatment at 1 
dose level lower 
 
Grade 4 
 
 
Off protocol therapy 
* Patients requiring a delay of > 21 days should go off protocol therapy  
CTCAE v4.0 definitions 
Grade 1: Prehypertension (systolic BP 120 - 139 mm Hg or diastolic BP 80 - 89 mm Hg) 
Grade 2: Stage 1 hypertension (systolic BP 140 - 159 mm Hg or diastolic BP 90 - 99 mm Hg); 
medical intervention indicated; recurrent or persistent (>=24 hrs); symptomatic increase by >20 
mm Hg (diastolic) or to >140/90 mm Hg if previously WNL; monotherapy indicated. Pediatric: 
recurrent or persistent (>=24 hrs) BP >ULN; monotherapy indicated 
Grade 3: Stage 2 hypertension (systolic BP >=160 mm Hg or diastolic BP >=100 mm Hg); 
medical intervention indicated; more than one drug or more intensive therapy than previously 
used indicated. Pediatric: Same as adult 
Grade 4: Life-threatening consequences (e.g., malignant hypertension, transient or permanent 
neurologic deficit, hypertensive crisis); urgent intervention indicated. Pediatric: Same as adult 
 
 


 
22 
5.1.3 Dose Modifications for  Other Sorafenib-Associated Toxicity 
 
Toxicity 
Grade 1 
Grade 2 
Grade 3* 
Grade 4* 
Non-
hematologic 
Continue at the 
same dose level. 
Continue at the 
same dose level. 
Withhold dose until 
toxicity is grade <1, 
then resume 
treatment at the same 
dose level.  If patient 
experiences a second 
grade 3 toxicity, 
withhold dose until 
toxicity is grade <1, 
then reduce one dose 
level and resume 
treatment.  
Withhold dose until 
toxicity is grade <1, 
then reduce one dose 
level and resume 
treatment, or 
discontinue at the 
discretion of the 
principal 
investigator. 
Hematologic 
Continue at the 
same dose level. 
Continue at the 
same dose level. 
Withhold dose until 
toxicity is grade <2, 
then resume 
treatment at the same 
dose level.  If patient 
experiences a second 
grade 3 toxicity, 
withhold dose until 
toxicity is grade <2, 
then reduce one dose 
level and resume 
treatment. 
Withhold dose until 
toxicity is grade <2, 
then reduce one dose 
level and resume 
treatment, or 
discontinue at the 
discretion of  the 
principal 
investigator after 
discussion with 
study supporter. 
*Patients who develop grade 3 fever/chills, grade 3 hyperlipasemia or hyperamylasemia without clinical or other 
evidence of pancreatitis, grade 3 leukopenia, or grade 3/grade 4 lymphopenia may continue study treatment without 
interruption at the discretion of the investigator. 
 
Because certain grade 3-4 adverse events are common with epirubicin, ifosfamide 
and radiotherapy, the above table should be modified for these adverse events as 
defined below (unless the adverse events are definitely attributable only to 
sorafenib, in which case refer to above table).  Attribution to sorafenib at least in-
part should be present in order to justify sorafenib dose-reduction: 
• Neutropenia – Grade 3 or Grade 4 lasting ≤7 days: no action.  Grade 4 lasting 
>7 days: refer to table above 
• Neutropenic Fever – Grade 3 lasting ≤5 days: no action.  Grade 3 lasting >5 
days or Grade 4: refer to table above 
• Leukopenia –  No dose reduction 
• Thrombocytopenia -- Grade 3: no action.  Grade 4 lasting ≤ 5 days: no action, 
Grade 4 lasting > 5 days: refer to table above.  Grade 3-4 thrombocytopenia 
with clinically significant bleeding: refer to table above.  
• Anemia – Grade 3: no action. Grade 4: refer to table above 


 
23 
• Nausea/Vomiting – Per above table, only if persistent Grade 3-4 despite 
maximal anti-emetic adjustment 
• Fatigue – Grade 3: no action.  Grade 4: refer to table above. 
• Diarrhea – Diarrhea should be initially managed with anti-diarrhea agents 
including loperamide or Lomotil.  If persistent Grade 3- 4 toxicity, refer to 
table above. 
• Hypophosphatemia/Hypokalemia – Grade 3: replacement therapy.  Grade 4: 
refer to above table only if refractory to replacement therapy 
• Transaminitis – Grade 3 with ALT and AST:  Monitor liver function tests 
until resolution. Consider dose reduction at investigator’s discretion. 
5.2 Chemotherapy Dose Modifications 
Dose modifications for epirubicin and ifosfamide-related toxicity will be based on the 
following dose level schema.  All patients will start treatment at dose level 0.  Patients 
who require a reduction of dose below Dose Level –3 will be removed from the study. 
 
Dose 
Level 
Dose 
Epirubicin 
(mg/m2 D1-3) 
Dose 
Ifosfamide 
(mg/m2 D1-3) 
0 
30 
2500 
-1 
22.5 
2500 
-2 
22.5 
2000 
-3 
20 
1750 
 
5.2.1 Hematologic Toxicity 
5.2.1.1 A treatment cycle may not begin unless the patient's absolute 
neutrophil count (ANC) is ≥1500/µL and platelet count is ≥75,000/µL 
(without transfusion). 
5.2.1.2 Grade 4 neutropenic fever,  grade 3 neutropenic fever lasting >5 
days, or grade 4 neutropenia for >7days:  reduce by one dose level 
for next and all subsequent cycles  
5.2.1.3 Grade 3-4 thrombocytopenia with clinically significant bleeding or 
grade 4 thrombocytopenia lasting >5 days: reduce by one dose level 
for next and all subsequent cycles  
5.2.1.4 Anemia: Institution of erythropoietin or darbopoietin at physician's 
discretion 
5.2.2 Non-hematologic Toxicity 
Patients who experience Grade 3 or 4 toxicity that is attributable to 
chemotherapy and not to the underlying disease should have chemotherapy held 
until the toxicity resolves to ≤ Grade 1.  Treatment should then be resumed at a 


 
24 
reduction of one dose level for the next and all subsequent cycles (see 
exceptions below).  Patients who are delayed greater than 3 weeks due to non-
resolution of such toxicity will be taken off study.  
5.2.2.1 Nausea and Vomiting: Grade 3 or 4 nausea or vomiting should be 
managed with anti-emetic adjustments (at treating physicians 
discretion) before a dose-reduction is performed 
5.2.2.2 Cardiac Toxicity:  Patients who experience a Grade 3 or greater 
impairment in left ventricular function (decline of ≥ 20% of baseline 
LVEF or symptomatic congestive heart failure) or Grade 3 or greater 
left ventricular systolic dysfunction should immediately be removed 
from protocol therapy. 
5.2.2.3 Renal Toxicity:  Patients who experience grade 2 or greater Acute 
Kidney Injury or Hematuria should have therapy held until the toxicity 
resolves to ≤ Grade 1.  Treatment should then be resumed at the next 
lower dose level that includes a lower dose of ifosfamide (i.e. reduce 
from dose level 0 or -1 to dose level -2, reduce from dose level -2 to 
dose level -3) for the next and all subsequent cycles, at the discretion 
of the treating physician. 
5.2.2.4 Electrolyte Wasting:  Electrolyte wasting, especially potassium and 
phosphorous, is a common effect of ifosfamide therapy due to renal 
tubular effects.  Grade 3 or greater hypokalemia and/or 
hypophosphatemia should be managed with appropriate electrolyte 
replacement.  If electrolyte wasting is refractory to replacement 
therapy, a dose reduction should be undertaken to the next lower dose 
level that includes a lower dose of ifosfamide 
5.2.2.5 CNS Toxicity:  Patients who experience grade 3 or greater 
Encephalopathy should have therapy held until the toxicity resolves to 
≤ Grade 1.  Treatment should then be resumed at the next lower dose 
level that includes a lower dose of ifosfamide (i.e. reduce from dose 
level 0 or -1 to dose level -2, reduce from dose level -2 to dose level -
3) for the next and all subsequent cycles.  If a patient is to be removed 
from study due to reaching the maximum allowable number of dose 
level reductions, and if these reductions were due to ifosfamide-related 
CNS toxicity, then the patient will be allowed to continue on treatment 
with omission of ifosfamide and continuation of epirubicin and 
sorafenib. 
6. AGENT FORMULATION AND PROCUREMENT 
6.1 Sorafenib (Nexavar) 
Availability:   Sorafenib will be supplied for this study 
Product description:  Sorafenib 200 mg is supplied as round, biconvex, red-film-
coated tablets, debossed with the 'Bayer cross' on one side and '200' on the other 
side.  The tablets contain sorafenib tosylate equivalent to 200 mg of the free base 
sorafenib, and the excipients croscarmellose sodium, microcrystalline cellulose, 
hypromellose, sodium lauryl sulfate, and magnesium stearate. The film-coat consists of 


 
25 
hypromellose, polyethylene glycol, titanium dioxide and red iron oxide. The film 
coating has no effect on the rate of release of the active sorafenib tosylate. Study Drug 
can be supplied as sorafenib 200 mg commercial tablets in bottles of 140 tablets with a 
product identification label affixed or as commercial Nexavar in bottles of 120 tablets. 
Storage requirements:  Do not store above 25°C (77°F). Store in the original package. 
Stability:  The current shelf life is 36 months. 
Route of administration:  Orally. Sorafenib should be given on an empty stomach 1 hour 
before 2 hours after a meal. 
Pregnancy: Women should avoid becoming pregnant while on therapy.  Women of 
childbearing potential must be apprised of the potential hazard to the fetus, which 
includes sever malformation (teratogenicity), failure to thrive and fetal death 
(embryotoxicity).  Sorafenib should not be used during pregnancy.  Breastfeeding 
should be discontinued during sorafenib therapy. 
Expected adverse events:  The following additional drug-related adverse events and 
laboratory abnormalities were reported from clinical trials of sorafenib in 1286 cancer 
patients who received sorafenib as monotherapy (very common 10% or greater, 
common 1 to less than10%, uncommon 0.1% to less than 1%): 
Cardiovascular: Uncommon: hypertensive crisis, myocardial ischemia and/or 
infarction 
Dermatologic: Very common: erythema Common: exfoliative dermatitis, acne, 
flushing Uncommon: folliculitis, eczema, erythema multiforme 
Digestive: Very common: increased lipase, increased amylase Common: mucositis, 
stomatitis (including dry mouth and glossodynia), dyspepsia, dysphagia Uncommon: 
pancreatitis, gastrointestinal reflux, gastritis. Note that elevations in lipase are very 
common; a diagnosis of pancreatitis should not be made solely on the basis of 
abnormal laboratory values 
General Disorders: Very common: asthenia, pain (including mouth pain, bone pain, 
and muscle pain) Common: decreased appetite, influenza-like illness, pyrexia 
Uncommon: infection 
Hematologic: Very common: leukopenia, lymphopenia Common: anemia, 
neutropenia, thrombocytopenia Uncommon: INR abnormal 
Hypersensitivity: Uncommon: hypersensitivity reactions (including skin reactions 
and urticaria) 
Metabolic and Nutritional: Very common: hypophosphatemia Common: transient 
increases in transaminases Uncommon: dehydration, hyponatremia, transient 
increases in alkaline phosphatase, increased bilirubin (including jaundice), 
hypothyroidism 
Musculoskeletal: Common: arthralgia, myalgia 
Nervous System and Psychiatric: Common: depression Uncommon: tinnitus 
Reproductive: Common: erectile dysfunction Uncommon: gynecomastia 
Respiratory: Common: hoarseness Uncommon: rhinorrhea  
In addition, the following medically significant adverse events were reported 


 
26 
infrequently during clinical trials of sorafenib: cerebral hemorrhage, transient 
ischemic attack, cardiac failure, arrhythmia, thromboembolism, acute renal failure. 
For these events, the causal relationship to sorafenib has not been established. 
Effects on fertility: Results from animal studies indicate that sorafenib can impair 
male and female fertility. 
6.2 Epirubicin (Ellence) 
Availability:   Epirubicin is commercially available.  
Product description:  Epirubicin is available in polypropylene single-use vials 
containing 2 mg epirubicin hydrochloride per mL as a sterile, preservative-free ready-
to-use solution in 50 mg and 200 mg vials. 
Solution preparation: Epirubicin is available as a preservative-free, ready-to-use 
solution. 
Storage requirements:  Store refrigerated between 2ºC and 8ºC (36ºF and 46ºF).  Do 
not freeze.  Protect from light. 
Stability: Epirubicin should be used within 24 hours of first penetration of the rubber 
stopper. 
Route of administration:  Intravenous administration of epirubicin should be 
performed with caution.  It is recommended that epirubicin be administered into the 
tubing of a freely flowing intravenous infusion (0.9% sodium chloride or 5% glucose 
solution) over a period of 3 to 5 minutes.  This technique is intended to minimize the 
risk of thrombosis or perivenous extravasation, which could lead to severe cellulites, 
vesication, or tissue necrosis.  A direct push injection is not recommended due to the 
risk of extravasation, which may occur even in the presence of adequate blood return 
upon needle aspiration.  Venous sclerosis may result from injection into small vessels 
or repeated injections into the same vein. 
Pregnancy: Women should avoid becoming pregnant while on therapy.  Breastfeeding 
should be discontinued during therapy. 
Expected adverse events:  
Hematologic: A dose-dependent, reversible leukopenia and/or neutropenia is the 
predominant manifestation of hematologic toxicity.  Severe thrombocytopenia and 
anemia may also occur. 
Gastrointestinal: Nausea and vomiting, diarrhea, stomatitis 
Dermatologic: Alopecia, flushes, skin and nail hyperpigmentation, photosensitivity, 
hypersensitivity to irradiated skin. 
Extravasation: Infiltration can cause severe inflammation, tissue necrosis, and 
ulceration.   If the drug is infiltrated, consult institutional policy, apply ice to area, 
and elevate the limb.  May require debridement. 
Cardiac: Anthracycline-induced cardiac toxicity may be manifested by early or late 
events.  Early cardiac toxicity consists mainly of sinus tachycardia and/or ECG 
abnormalities such as non-specific ST-T wave changes, but tachyarrhythmias , 
bradycardia, as well as atrioventricular and bundle-branch block have also been 
reported.  Delayed cardiotoxicity results from a characteristic cardiomyopathy that is 
manifested by reduced LVEF and/or signs and symptoms of congestive heart failure.  


 
27 
The probability of developing CHF increases with increasing cumulative doses of 
epirubicin.  The risk of developing CHF in the absence of other cardiac risk factors 
increases steeply after an epirubicin cumulative dose of 900 mg/m2. 
Secondary Leukemia:  The occurrence of secondary acute myelogenous leukemia 
has been reported in patients treated with anthracyclines.  
Miscellaneous: Allergic reaction, anaphylaxis. 
6.3 Ifosfamide (Ifex) 
Availability:   Ifosfamide is commercially available.  
Product description:  Ifosfamide is available as a powder for reconstitution in 1 and 3 
g vials. 
Solution preparation: Dilute powder with SWI or NS to a concentration of 50 mg/mL 
as follows. DO NOT USE BACTERIOSTATIC SWI OR NS - incompatible; 
solution is stable for 7 days at room temperature and 6 weeks under refrigeration  
  
1 g vial = 20 mL  
  
3 g vial = 60 mL  
Storage and Stability: Further dilution in NS, D5W or LR is stable for 7 days at room 
temperature and 6 weeks under refrigeration. Compatible with mesna in NS for up to 9 
days at room temperature.  Store intact vials at room temperature or under refrigeration. 
Route of administration:  Administer ifosfamide IVPB over 90 minutes. Adequate 
hydration (at least 2 L/day) of the patient during therapy is recommended to minimize 
the risk of hemorrhagic cystitis.  Mesna should be administered concomitantly, 4 hours 
after and 8 hours after ifosfamide administration. 
Pregnancy: Women should avoid becoming pregnant while on therapy.  Breastfeeding 
should be discontinued during therapy. 
Expected adverse events:  
Central nervous system: Somnolence, confusion, hallucinations in 12% and coma 
(rare) have occurred and are usually reversible; usually occur with higher doses or in 
patients with reduced renal function; depressive psychoses, polyneuropathy. Note: 
CNS depression can be reversed with methylene blue (50 mg intravenously) and 
methylene blue is recommended for prophylaxis for subsequent doses if the patient 
has CNS manifestations with the first dose.  
Dermatologic: Alopecia occurs in 50% to 83% of patients 2-4 weeks after initiation 
of therapy; may be as high as 100% in combination therapy. Phlebitis, dermatitis, 
nail ridging, skin hyperpigmentation, impaired wound healing. 
Gastrointestinal: Nausea and vomiting in 58% of patients is dose and schedule 
related (more common with higher doses and after bolus regimens); nausea and 
vomiting can persist up to 3 days after therapy; also anorexia, diarrhea, constipation, 
transient increase in LFTs and stomatitis noted.  
Genitourinary: Hemorrhagic cystitis has been frequently associated with the use of 
ifosfamide; a urinalysis prior to each dose should be obtained; ifosfamide should 
never be administered without a uroprotective agent (MESNA); hematuria has 
been reported in 6% to 92% of patients; renal toxicity occurs in 6% of patients and is 


 
28 
manifested as an increase in BUN or serum creatinine and is most likely related to 
tubular damage; renal toxicity, including ARF, may occur more frequently with 
high-dose ifosfamide; metabolic acidosis may occur in up to 31% of patients. 
Endocrine & metabolic: SIADH  
Hematologic: Myelosuppression: Leukopenia is mild to moderate, thrombocytopenia 
and anemia are rare. However, myelosuppression can be severe when used with 
other chemotherapeutic agents or with high-dose therapy; be cautious with patients 
with compromised bone marrow reserve  
Respiratory: Nasal stuffiness, pulmonary fibrosis 
Cardiovascular: Cardiotoxicity  
Miscellaneous: Immunosuppression, sterility, possible secondary malignancy, 
allergic reactions 
6.4 Mesna (Mesnex) 
Availability:  Mesna is commercially available. 
Product description:  Mesna is available as a sterile, preservative-free aqueous 100 
mg/mL solution in 200 mg ampules or 1 g multidose vials.  Mesna tablets are available 
as a white, oblong, scored, film coated 400 mg tablet. 
Mechanism of action:  Mesna is a uroprotecant whose oxidized form dimesna binds to 
and inactivates acrolein, a urotoxic metabolite of cyclophosphamide and ifosfamide.  
Solution preparation: Mesna can be diluted in D5W or NS to a final concentration of 
1-20 mg/mL. 
Storage and Stability: Diluted solutions are chemically and physically stable for 24 
hours at room temperature; polypropylene syringes are stable for 9 days at refrigeration 
or room temperature; injection diluted for oral administration is stable 24 hours at 
refrigeration 
Route of administration:  Mesna may be mixed in same bag as ifosfamide or 
administered separately IVPB over 15 minutes. 
Mesna injection may also be administered orally.  For oral administration, injection 
may be diluted in 1:1, 1:2, 1:10, 1:100 concentrations in carbonated beverages (cola, 
ginger ale, Pepsi®, Sprite®, Dr Pepper®, etc), juices (apple or orange), or whole milk 
(chocolate or white), and is stable 24 hours at refrigeration.  Mesna tablets should be 
given orally and absorption is not affected by food.  Mesna tablets are approximately 
50% bioavailable and are generally dosed at 2 & 6 hours after the first mesna dose, 
which is usually given intravenously, to account for the delayed absorption with an oral 
vs. the intravenous product 
Pregnancy: Women should avoid becoming pregnant while on therapy.  Breastfeeding 
should be discontinued during therapy. 
Expected adverse events:  
Cardiovascular: Hypotension  
Central nervous system: Malaise, headache  
Gastrointestinal: Diarrhea, nausea, vomiting, bad taste in mouth, soft stools 
Neuromuscular & skeletal: Limb pain  


 
29 
Dermatologic: Skin rash, itching 
6.5 Pegfilgrastim (Neulasta) 
Availability: Pegfilgrastim is commercially available. 
Product Description: Neulasta™ is supplied as a preservative-free solution containing 
6 mg (0.6 mL) of pegfilgrastim (10 mg/mL) in a single-dose syringe with a 27 gauge, 
1/2 inch needle with an UltraSafe® Needle Guard.  Neulasta™ is provided in a 
dispensing pack containing one syringe (NDC 55513-190-01). 
Storage and Stability: Neulasta™ should be stored refrigerated at 2° to 8°C (36° to 
46°F); syringes should be kept in their carton to protect from light until time of use. 
Shaking should be avoided. Before injection, Neulasta™ may be allowed to reach room 
temperature for a maximum of 48 hours but should be protected from light. Neulasta™ 
left at room temperature for more than 48 hours should be discarded. Freezing should 
be avoided; however, if accidentally frozen, Neulasta™ should be allowed to thaw in 
the refrigerator before administration. If frozen a second time, Neulasta™ should be 
discarded. 
Route of Administration:  The recommended dosage of Neulasta™ is a single 
subcutaneous (SC) injection of 6 mg administered once per chemotherapy cycle. 
Neulasta™ should not be administered in the period between 14 days before and 24 
hours after administration of cytotoxic chemotherapy. The 6 mg fixed-dose formulation 
should not be used in infants, children, and smaller adolescents weighing less than 45 
kg.  Neulasta™ should be visually inspected for discoloration and particulate matter 
before administration. Neulasta™ should not be administered if discoloration or 
particulates are observed. 
Neulasta™ is supplied in prefilled syringes with UltraSafe® Needle Guards. Following 
administration of Neulasta™ from the prefilled syringe, the UltraSafe® Needle Guard 
should be activated to prevent accidental needle sticks. To activate the UltraSafe® 
Needle Guard, place your hands behind the needle, grasp the guard with one hand, and 
slide the guard forward until the needle is completely covered and the guard clicks into 
place. NOTE: If an audible click is not heard, the needle guard may not be completely 
activated. The prefilled syringe should be disposed of by placing the entire prefilled 
syringe with guard activated into an approved puncture-proof container. 
Pregnancy: Women should avoid becoming pregnant while on therapy.  Breastfeeding 
should be discontinued during therapy. 
Expected Adverse Events: 
Bone pain was the most frequent adverse event attributable to pegfilgrastim in clinical 
trials.  Hypoxia was observed in one patient. Toxicities associated with the parent 
compound, filgrastim include: 
Central nervous system: Neutropenic fever, fever. 
Dermatologic: Alopecia. 
Gastrointestinal: Nausea, vomiting, diarrhea, mucositis, splenomegaly (this occurs 
more commonly in patients with cyclic neutropenia/congenital agranulocytosis who 
received S.C. injections for a prolonged (>14 days) period of time; ~33% of these 


 
30 
patients experience subclinical splenomegaly; ~3% of these patients experience 
clinical splenomegaly). 
 Neuromuscular & skeletal: Medullary bone pain (24% incidence--this occurs most 
commonly in lower back pain, posterior iliac crest, and sternum and is controlled 
with non-narcotic analgesics), weakness. 
Cardiovascular: Chest pain, fluid retention, transient supraventricular arrhythmia, 
pericarditis. 
Central nervous system: Headache. 
Dermatologic: Skin rash. 
Gastrointestinal: Anorexia, stomatitis, constipation. 
Hematologic: Leukocytosis. 
Local: Pain at injection site, thrombophlebitis. 
Respiratory: Dyspnea, cough, sore throat. 
Miscellaneous: Anaphylactic reaction. 
7. CORRELATIVE / SPECIAL STUDIES 
7.1 Angiogenic Biomarkers 
Plasma will be collected for measurement of tumorigenic and angiogenic markers 
including p-ERK, VEGF, sVEGFR2, and bFGF at baseline, week 2 (after sorafenib 
run-in), and then every 3 weeks through completion of treatment.  Blood samples (10 
mL) will be drawn using venipuncture into a Vacutainer containing potassium EDTA 
and inverted gently several times to mix with anticoagulant. Within 10-15 minutes after 
collecting, blood samples will be centrifuged in a refrigerated (4°C) centrifuge for 10 
minutes to separate the plasma. If a refrigerated centrifuge is not available, the tubes 
should be chilled in an ice bath for 5-15 minutes and then placed in a standard 
centrifuge for 10 minutes to separate the plasma. The plasma will be transferred to 
polypropylene tubes and frozen at -70°C or lower. The tubes will be labeled with the 
investigator’s name, study number, and subject’s study number, and time and date of 
the sample acquisition. 
Fresh tumor tissue will be collected when possible at baseline and at time of resection.  
Tissue will be immediately frozen with liquid nitrogen and stored at –70°C or lower. 
Tumor tissue will be mechanically homogenated for 5 minutes on ice in 1 ml of 
extraction buffer per 100 mg tissue wet weight, and extract obtained after centrifugation 
for 20 minutes at 4°C will be transferred to polypropylene tubes and frozen at -70°C or 
lower. The tubes will be labeled with the investigator’s name, study number, and 
subject’s study number, and time and date of the sample acquisition. 
Quantitative enzyme-linked immunosorbent assays (ELISA) for p-ERK, VEGF, 
sVEGFR2, and bFGF will be performed on plasma and tumor extracts using 
commercial kits.  Manufacturers' protocols will be followed and samples are to be 
measured in duplicate.  
Paraffin block of the primary tumor biopsy and resected tumor will be obtained. 
Representative areas from each whole-mount paraffin block chosen as the best 
composite representation of tumor based on H&E morphology will be placed in 


 
31 
standard-sized tissue cassettes. These will be re-embedded, sectioned at 4 µm, and 
mounted on poly-L-lysine–coated slides for immunohistochemistry.  Sections of 
paraffin embedded tissue will be deparaffinized and rehydrated.  After appropriate 
antigen retrieval methods, staining with commercial antibodies for p-ERK, VEGF-R2, 
phospho-VEGF-R2, PDGFR, and phospho-PDGFR will be performed using an 
automated Dako immunostainer.  Staining will be visualized by incubating the slides 
with 3,3'-diaminobenzidine solution, after which they will be rinsed, counterstained 
with hematoxylin, dehydrated in a Leica Autostainer XL, coverslipped, and reviewed 
by a single experienced pathologist who will score the percentage of positively staining 
cells  
8. STUDY PROCEDURES AND SCHEDULE OF EVENTS 
8.1 Subject Registration 
Written informed consent must be obtained before any study specific medical 
procedures are performed. 
All patients must be registered with the Oregon Health & Science University Cancer 
Center. 
8.2 Baseline Screening 
To be completed within 6 weeks of registration: 
  
CT of Chest 
  
CT or MRI of primary disease site 
To be completed within 4 week of registration: 
  
History & Physical, including vitals, PS 
  
EKG 
  
MUGA or ECHO 
To be completed within 1 week of registration: 
  
Labs, pregnancy test, urinalysis 
(Pregnancy test must be repeated prior to dispensing Sorafenib to the patient if 
completed >7 days before treatment start) 
8.3 Study Visits 
See table 8.7  
Toxicities and adverse experiences will be assessed at each visit using the NCI 
Common Toxicity Criteria for Adverse Events v4.0 (http://ctep.cancer.gov).  
Assessment of study drug attribution will be made by an Investigator. Acute and long-
term radiation toxicity will be assessed for the following CTCAE categories: 1)  
Injury, poisoning and procedural complications: Dermatitis radiation  2) 
Musculoskeletal and connective tissue disorders: Fibrosis (superficial and/or deep) 
3) other appropriate Musculoskeletal and connective tissue disorders AEs 
appropriate to limb function. 
8.4 Pathology Sample Submission 
All pathology slides from the initial diagnostic biopsy and the post-chemoradiation 


 
32 
excision must be submitted for central review at OHSU by a pathologist experienced in 
sarcoma.  For the post therapy excision, the specimen should be sectioned parallel to 
the long axis of the tumor; a full face of the plane of greatest cross sectional area should 
be fixed and blocked in, up to 20 sections. If there are central cystic necrotic areas, they 
can be noted in a specimen diagram and not sampled.  
8.5 Assessment of Wound Complications 
An accurate assessment of post-operative wound complications is vital for the accurate 
reporting of toxicity associated with this regimen.  Major wound complications will be 
defined as described by O’Sullivan et. al. in the prospective, randomized study of 
preoperative vs. postoperative radiation.7 
A major wound complication is defined as a secondary operation under general or 
regional anesthesia for wound repair (debridement, operative drainage, and 
secondary wound closure including rotationplasty, free flaps, or skin grafts), or 
wound management without secondary operation.  Wound management includes 
an invasive procedure without general or regional anesthesia (such as aspiration of 
seroma), readmission for wound care such as intravenous antibiotics, or persistent 
deep packing for 120 days or longer. 
8.6 Follow-up 
Follow-up for all patients registered on this study, including those who do not receive 
any protocol therapy, will be required until the patient’s death.  Follow-up after 
completion of protocol therapy will be limited to monitoring for 1) development of 
local tumor recurrence, 2) development of distant metastatic disease, 3) survival, and 4) 
late toxicity, including limb function impairment and secondary malignancy.  Follow-
up reports are due every 4 months. 
 
 


 
33 
8.7 Schedule of Events 
 
 
Prior to 
Registration 
Prior to  
Day 1 of 
each  cycle* 
Time of 
Pre-Surgical 
Restaging** 
Post 
Treatment 
Follow-up 
Tests & Observations 
 
 
 
 
History and Progress Notes 
X 
X 
X 
X 
Physical Examination 
X 
X 
X 
X 
Pulse, Blood Pressure### 
X 
X 
X 
X 
Height/Weight*** 
X 
X 
 
 
Performance Status 
X 
X 
X 
X 
Treatment Toxicity 
Assessment 
 
F 
F 
F 
Pathology Review 
A 
 
A 
 
Laboratory Studies 
 
 
 
 
CBC, Differential, Platelets 
X 
B,C 
X 
PRN 
Serum Chemistries# 
X 
B,C 
X 
PRN 
Urinalysis 
X 
C 
 
 
Pregnancy Test## 
X 
X 
 
 
INR 
X 
H 
 
 
EKG 
X 
 
  
PRN 
MUGA or ECHO 
X 
 
X 
D 
 
 
 
 
 
Blood for correlative studies 
(Section 7.1) 
X 
X 
X 
 
Staging 
 
 
 
 
Chest CT 
X 
 
X 
E 
MRI or CT of primary site 
G 
 
G 
E 
* 
To be performed within 1 week of each chemotherapy cycle 
** 
After completion of cycle 3 of chemoradiotherapy and within 4 weeks of surgery 
*** 
Height only needs to be checked prior to cycle #1 if the patient’s height is stable (i.e. not currently in puberty). 
# 
Electrolytes (including Phos, Mg), BUN, creatinine, bilirubin, AST, ALT, alkaline phosphatase 
## 
For women of childbearing potential.  Screening pregnancy test does not need to be repeated if within 7 days of 
start of Sorafenib run-in.  Will be repeated prior to each cycle of chemotherapy. 
### 
Blood pressure to be monitored weekly during the first 6 weeks of protocol treatment 
A 
Initial diagnostic pathology specimen as well as post-operative specimen must be submitted for central review.  
Both specimens may be submitted together after surgery  
B   
To be checked once weekly during each cycle or as clinically indicated 
C 
Must be checked within 24 hours prior to each chemotherapy cycle 
D 
As clinically indicated  
E 
Post-treatment imaging studies for disease recurrence is at investigator's discretion.  It is suggested that a chest CT 
or chest X-ray be performed every 4 months for the first 2 years, every 6 months for the 3rd year, and yearly for the 
4th and 5th year.  It is suggested that MRI or CT of the primary site be obtained yearly for the first 3 years. 
F 
Toxicity assessments per CTCAE v 4.0 (See section 8.3).  Long term follow-up for radiation toxicity and limb 
function required per section 8.3 
G 
An MRI or CT of the primary tumor should be performed within 6 weeks prior to registration and again prior to 
surgery per standard care decision of the subject’s surgeon 


 
34 
H 
INR should be closely monitored for patients receiving warfarin.  INR does not need to be monitored during study 
for patients not receiving warfarin. 
 
9. MEASUREMENT OF EFFECT 
9.1 Pathologic Response 
All specimens of primary tumor will be examined for pathologic response at the time of 
surgery.  The study pathologist will estimate the amount of viable tumor, and report the 
percentage of necrosis.  For purpose of analysis, tumors will be classified as either 
≥95% necrosis or <95% necrosis. 
9.2 Radiographic and Clinical Response 
The radiographic and/or clinical response of the primary tumor to preoperative therapy 
will be evaluated.  For subjects with stage IIb or III disease, the primary lesion will 
serve as the sole target lesion and will be recorded and measured at baseline.  For 
patients with stage IV disease, target lesions will be chosen according to RECIST 
procedure. The longest diameter (LD) of the target lesions will be measured and 
reported as the baseline LD. The baseline LD will be used as reference to further 
characterize the objective tumor response of the measurable dimension of the disease. 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) 
Committee.56  Changes in only the largest diameter (unidimensional measurement) of 
the tumor lesions are used in the RECIST criteria. 
9.3 Response Criteria 
9.3.1 Evaluation of target lesions 
Complete Response (CR):  
Disappearance of all target lesions 
Partial Response (PR): 
 
At least a 30% decrease in the sum of the 
longest diameter (LD) of target lesions, taking 
as reference the baseline sum LD 
Progressive Disease (PD):  
At least a 20% increase in the sum of the LD of 
target lesions, taking as reference the smallest 
sum LD recorded since the treatment started or 
the appearance of one or more new lesions 
Stable Disease (SD): 
 
 
Neither sufficient shrinkage to qualify for PR 
nor sufficient increase to qualify for PD, taking 
as reference the smallest sum LD since the 
treatment started 
 
 


 
35 
 
9.3.2 Evaluation of best overall response 
The best overall response is the best response achieved prior to surgical 
resection of the target lesion. 
  
Target Lesions 
 
New Lesions 
 
Overall Response 
 
CR 
 
No 
 
CR 
 
PR 
 
No 
 
PR 
 
SD 
 
No 
 
SD 
 
PD 
 
Yes or No 
 
PD 
 
Any 
 
Yes 
 
PD 
 
Note: 
In some circumstances, it may be difficult to distinguish residual disease from 
normal tissue.  When the evaluation of complete response depends upon this 
determination, this will be determined at the time of surgical resection. 
 
9.4 Confirmatory Measurement/Duration of Response 
9.4.1 Confirmation 
Given that the target lesion will be surgically removed after the first evaluation 
for response, no confirmatory scans will be able to be performed. 
9.4.2 Duration of overall response 
The duration of overall response is measured from the time measurement 
criteria are met for CR or PR (whichever is first recorded) until the first date 
that recurrent or progressive disease is objectively documented (taking as 
reference for progressive disease the smallest measurements recorded since the 
treatment started). 
The duration of overall CR is measured from the time measurement criteria are 
first met for CR until the first date that recurrent disease is objectively 
documented. 
9.4.3 Duration of Stable Disease 
Stable disease is measured from the start of the treatment until the criteria for 
progression are met, taking as reference the smallest measurements recorded 
since the treatment started.  
9.5 Time-to-Event Measures 
9.5.1 Time to Local Recurrence 
Defined as the duration of time from surgical resection of the primary tumor 
until local recurrence (amputated patients excluded). 


 
36 
9.5.2 Local Disease-Free Survival 
Defined as the duration of time from surgical resection of the primary tumor 
until local recurrence or death, whichever occurs first. 
9.5.3 Distant Disease-Free Survival 
  
 Defined as the duration of time from registration until development of distant 
metastatic disease or death, whichever occurs first.  Subjects with stage IV 
disease will be censored from this analysis. 
9.5.4 Disease-Free Survival 
Defined as the duration of time from surgical resection to local recurrence, 
distant metastatic disease, or death, whichever occurs first.  Subjects with stage 
IV disease will be censored from this analysis. 
9.5.5 Progression-Free Survival 
Defined as the duration of time from registration to progressive disease (per 
RECIST), local recurrence, distant metastatic disease (exclusive of stage IV 
subjects), or death, whichever occurs first. 
9.5.6 Overall Survival 
  
 Defined as the interval of time from registration until death from any cause. 
10. ETHICAL AND REGULATORY REQUIREMENTS 
10.1 Protocol Review 
The protocol and informed consent form for this study must be reviewed and approved 
in writing by the OHSU Knight Cancer Institute (CI) Clinical Research Review 
Committee (CRRC) and appropriate Institutional Review Board (IRB) prior to any 
patient being registered on this study. 
10.2 Informed Consent 
Written informed consent will be obtained from all patients, or the legally authorized 
representative of the patient, participating in this trial, as stated in the Informed Consent 
section of the case of Federal Regulations, Title 21, Part 50.  If a patient’s signature 
cannot be obtained, and for all patients under the age of 18, the investigator must ensure 
that the informed consent is signed by the patient’s legally authorized representative.  
Documentation of the consent process and a copy of the signed consent shall be 
maintained in the patient’s medical record.  
10.3 Changes to Protocol  
Any modification of this protocol must be documented in the form of a protocol 
revision or amendment signed by the principal investigator and approved by the CRRC 
and IRB, before the revision or amendment may be implemented.  The only 
circumstance in which the amendment may be initiated without regulatory approval is 
for a change necessary to eliminate an apparent and immediate hazard to the patient.  In 
that event, the investigator must notify the CRRC and IRB in writing within 10 working 
days after the implementation. Investigators holding the IND must notify FDA of 
substantive changes to the protocol. 


 
37 
10.4 Maintenance of Records 
If the investigator relocates or for any reason withdraws from the study, the study 
records must be transferred to an agreed upon designee, such as another institution, 
another investigator, or to OHSU Knight Cancer Institute Clinical Research 
Management.  Records must be maintained according to sponsor or FDA requirements. 
10.5 OHSU IRB Reporting of Unanticipated Problems and Adverse Events 
Unanticipated Problems (UP) and Adverse Events (AE) will be reported to IRB 
according to the policies, procedures and guidelines posted on the OHSU IRB web site 
http://www.ohsu.edu/research/rda/irb/policies.shtml. 
Fatal and life-threatening UP will be reported to OHSU IRB within 7 days of 
notification of the event.  All other UP reports will be submitted to OHSU IRB no later 
than 15 days of occurrence or notification of the event. Copies of the report documents 
will be kept in the study regulatory binder.  If any of these require a change (as 
determined by the PI or the IRB) to the protocol or consent form, the PI will make 
those changes promptly and  
submit the revised documents to the OHSU IRB. 
UP and AE reports are submitted through OHSU e-IRB and will be reviewed by OHSU 
Knight Cancer Institute and IRB.  Monthly accumulative reports will be reviewed by a 
DSMC Oncologist and forwarded to the CRRC.   
10.6 Adverse Event Definitions 
10.6.1 Adverse Event 
An adverse event is any untoward medical occurrence in a subject or clinical 
investigation subject administered with a pharmaceutical product. The adverse 
event does not necessarily have to have a causal relationship with this treatment.  
An adverse event can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an investigational product, whether or not considered 
related to the medicinal product. 
Adverse events associated with the use of a drug in humans, whether or not 
considered drug related, include the following:  
• An adverse event occurring in the course of the use of a drug product in 
professional practice. 
• An adverse event occurring from an overdose whether accidental or 
intentional. 
• An adverse event occurring from drug abuse. 
• An adverse event occurring from drug withdrawal.  
• An adverse event where there is a reasonable possibility that the event 
occurred purely as a result of the subject’s participation in the study (e.g. 
adverse event or serious adverse event due to discontinuation of anti-
hypertensive drugs during wash-out phase) must also be reported as an 
adverse event even if it is not related to the investigational product. 
The clinical manifestation of any failure of expected pharmacological action is 
not recorded as an adverse event as it is already reflected as a data point 


 
38 
captured in the CRF.  If, however, the event fulfills any of the criteria for a 
“serious” adverse event, it must be recorded and reported as such. 
10.6.2 Serious Adverse Event 
A serious adverse event is any untoward medical occurrence that at any dose:  
• Results in death. 
• Is life-threatening. 
• Requires in-patient hospitalization or prolongation of existing 
hospitalization. 
• Results in persistent or significant disability or incapacity. 
• Is a congenital anomaly or birth defect. 
• Is an important medical event. 
Life-threatening: The term “life-threatening” in the definition of “serious” refers 
to an adverse event in which the subject was at risk of death at the time of the 
event. It does not refer to an adverse event which hypothetically might have 
caused death if it were more severe. 
Hospitalization: Any adverse event leading to hospitalization or prolongation of 
hospitalization will be considered as Serious, UNLESS at least one of the 
following exceptions is met:  
• The admission results in a hospital stay of less than 12 hours. 
OR 
• The admission is pre-planned (i.e., elective or scheduled surgery arranged 
prior to the start of the study).  
OR 
• The admission is not associated with an adverse event (e.g., social 
hospitalization for purposes of respite care). 
However it should be noted that invasive treatment during any hospitalization 
may fulfil the criteria of ‘medically important’ and as such may be reportable as 
a serious adverse event dependant on clinical judgement.  In addition where 
local regulatory authorities specifically require a more stringent definition, the 
local regulation takes precedent. 
   Disability means a substantial disruption of a person’s ability to conduct normal            
   life’s functions. 
Important medical event: Any adverse event may be considered serious because 
it may jeopardize the subject and may require intervention to prevent another 
serious condition. As guidance for determination of important medical events 
refer to the “WHO Adverse Reaction Terminology – Critical Terms List. These 
terms either refer to or might be indicative of a serious disease state.  Such 
reported events warrant special attention because of their possible association 
with a serious disease state and may lead to more decisive action than reports on 
other terms.  
10.6.3 Unexpected Adverse Event 


 
39 
An unexpected adverse event is any adverse drug event, the specificity or 
severity of which is not consistent with the current Package Inserts for Nexavar 
(sorafenib).  Also, reports which add significant information on specificity or 
severity of a known, already documented adverse event constitute unexpected 
adverse events.  An event more specific or more severe than described in the 
package insert would be considered “unexpected”.  
10.6.4 Relationship of Adverse Event to Investigational Product 
The assessment of the relationship of an adverse event to the administration of 
study drug is a clinical decision based on all available information at the time of 
the completion of the case report form. 
An assessment of ‘No’ would include: 
• The existence of a clear alternative explanation, e.g. mechanical bleeding at 
surgical site. 
OR 
• Non-Plausibility, e.g. the subject is struck by an automobile when there is no 
indication that the drug caused disorientation that may have caused the 
event; cancer developing a few days after the first drug administration.  
An assessment of ‘Yes’ indicates that there is a reasonable suspicion that the 
adverse event is associated with the use of the investigational drug. 
Factors to be considered in assessing the relationship of the adverse event to 
study drug include: 
• The temporal sequence from drug administration: The event should occur 
after the drug is given.  The length of time from drug exposure to event 
should be evaluated in the clinical context of the event. 
• Recovery on discontinuation (de-challenge), recurrence on reintroduction 
(re-challenge): Subject’s response after drug discontinuation (de-challenge) 
or subjects response after drug re-introduction (re-challenge) should be 
considered in the view of the usual clinical course of the event in question. 
• Underlying, concomitant, intercurrent diseases: Each report should be 
evaluated in the context of the natural history and course of the disease 
being treated and any other disease the subject may have. 
• Concomitant medication or treatment: The other drugs the subject is taking 
or the treatment the subject receives should be examined to determine 
whether any of them may be suspected to cause the event in question. 
• The pharmacology and pharmacokinetics of the test drug: The 
pharmacokinetic properties (absorption, distribution, metabolism and 
excretion) of the test drug(s), coupled with the individual subject’s 
pharmacodynamics should be considered. 
10.6.5 Intensity (Severity) of the Adverse Event 
The intensity or severity of adverse events should be graded according to NCI-
CTC version 4.0 criteria.  
10.6.6 Adverse Event Documentation 


 
40 
All adverse events occurring after the subject has signed the informed consent 
must be fully recorded in the subject’s case record form. 
Documentation must be supported by an entry in the subject’s file.  A laboratory 
test abnormality considered clinically relevant, e.g., causing the subject to 
withdraw from the study, requiring treatment or causing apparent clinical 
manifestations, or judged relevant by the investigator, should be reported as an 
adverse event.  Each event should be described in detail along with start and 
stop dates, severity, relationship to investigational product, action taken and 
outcome. 
10.7 Reporting of Serious Adverse Events to the Sponsor 
Each serious adverse event must be followed up until resolution or stabilization, by 
submission of updated reports to the designated person. An isolated laboratory 
abnormality that is assigned grade 4, according to CTC definition, is not reportable as 
an SAE, unless the investigator assesses that the event meets standard ICH criteria for 
an SAE.  CTC grade 4 baseline laboratory abnormalities that are part of the disease 
profile should not be reported as an SAE, specifically when they are allowed or not 
excluded by the protocol inclusion/exclusion criteria.   
When required, and according to local law and regulations, serious adverse events must 
be reported to the Ethics Committee and Regulatory Authorities.  
All serious adverse events should be reported to Bayer/Onyx within 24 hours.  In the 
event of such an event, the investigator should refer to the Pharmacovigilance section 
of the contract for reporting procedures.  In brief: 
The Investigator/Sponsor may report serious adverse drug reactions (SADRs) 
using either: 
An ADEERS form (Adverse Event Expedited Reporting System) available at 
http://ctep.cancer.gov/reporting/adeers.html   
OR 
A MedWatch form available at http://www.fda.gov/medwatch/  
 
All reports shall be sent electronically to: 
Electronic Mailbox: 
DrugSafety.GPV.US@bayer.com  
Facsimile: 
(973) 709-2185  
Address: 
Global Pharmacovigilance - USA  
Mail only 
Bayer HealthCare Pharmaceuticals Inc. 
 
P.O. Box 1000 
 
Montville, NJ 07045-1000  
Address: 
340 Changebridge Road  
FDX or UPS only 
Pine Brook, NJ  07058  
Reports for all Bayer products can also be phoned in via our Clinical 
Communications Dept:  
Phone: 
1-888-842-2937 


 
41 
 
10.8 OHSU Knight Cancer Institute Data and Safety Monitoring Plan 
In addition to complete study and pharmacy files, complete records must be maintained 
on each patient treated on this protocol.  OHSU Knight Cancer Institute (CI), through 
the auditing function of the Knight Clinical Trials Office, is responsible for ensuring that all 
member investigators and affiliate investigators conduct clinical research studies in 
compliance with local IRB standards, FDA regulations and NIH policies.  The Data and 
Safety Monitoring Committee (DSMC) is responsible for conducting Quality 
Assurance audits on CI approved protocols according to the Data and Safety 
Monitoring Plan policies and procedures 
http://ozone.ohsu.edu/cancer/sharedres/kctoresdocs.cfm  
 
Locally initiated studies will be audited by an OHSU Knight CI Auditor. Newly 
approved studies may be audited any time after enrollment has been initiated.  Each 
OHSU Knight approved treatment protocol will be audited on an annual basis in 
accordance with the Knight Data and Safety Monitoring Plan.  .   
10.9   Inclusion of Women, Minorities and Children 
10.9.1    Inclusion of Women and Minorities 
No OHSU Knight Cancer Institute study will focus on any particular gender, 
racial or ethnic subset. No subject will be excluded from the study on the basis 
of gender, racial or ethnic origin. Male, female and minority volunteers will 
be recruited for this study from the general population and approximately 50% 
men and 50% women will be studied. 
 
 
 
 
 
 
 
Table 1: Population Demographics - Oregon (%) 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
11.7 
Not Hispanic or Latino 
88.3 
Ethnic Category: Total of all subjects* 
100* 
Racial Category 
American Indian or Alaskan Native 
1.4 
Asian 
3.7 
Black or African American 
1.8 
Native Hawaiian or other Pacific Islander 
0.3 
White 
83.6 


 
42 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
More than one race 
3.8 
Unknown/Other 
5.3 
Racial Category: Total of all subjects* 
100* 
TOTALS 
50.4 
49.6 
100* 
Source:   Adapted from U.S. Census Bureau, 2000    *Totals may not equal 100 due to rounding 
 
Table 2: Projected Accrual for the Present Study (enter actual estimates, not percentages). 
Ethnic Category 
Sex/Gender 
Females 
Males 
Unknown 
Total 
Hispanic or Latino 
1-2 
1-2 
0 
2-3 
Not Hispanic or Latino 
8-9 
8-9 
0 
17-18 
Unknown 
0 
0 
0 
0 
Ethnic Category: Total of all subjects 
10 
10 
0 
20 
Racial Category 
American Indian or Alaskan Native 
0-1 
0-1 
0 
0-1 
Asian 
0-1 
0-1 
0 
0-1 
Black or African American 
0-1 
0-1 
0 
0-1 
Native Hawaiian or other Pacific Islander 
0-1 
0-1 
0 
0-1 
White 
8-9 
8-9 
0 
16-17 
More than one race 
0-1 
0-1 
0 
0-1 
Unknown 
0-1 
0-1 
0 
0-1 
Racial Category: Total of all subjects 
10 
10 
0 
20 
Source:   Adapted from U.S. Census Bureau, 2010. 
 
 
 
10.9.2    Inclusion of Children 
In accordance with NIH guidelines on the inclusion of children as participants 
in research involving human subjects, children under the age of 18 years must 
be included in all human subjects’ research, conducted or supported by the 
NIH, unless there are clear and compelling reasons not to include them. 
Therefore, proposals for research involving human subjects must include a 
description of plans for the inclusion of children. 
 
This protocol does not include children <18 years of age for the following 
reason:  no dosing or adverse event data are currently available on the use of 
sorafenib in combination with ifosfamide and epirubicin in children, therefore, 


 
43 
children <18 years of age are excluded from this study but will be eligible for 
future pediatric phase 2 combination trials. 
11. STATISTICAL CONSIDERATIONS 
This is a single-stage, single-arm phase II clinical trial to determine the pathologic response 
rate (≥ 95% necrosis) in the operative specimen. 
11.1 
Study endpoints 
11.1.1 Primary endpoint 
The primary endpoint is the pathologic response rate.  
11.1.2 Secondary endpoint 
Secondary endpoints include level of toxicity, would complication rate, overall 
survival, overall disease-free survival, distant disease-free survival and local 
disease-free survival.  
11.2 
Statistical analysis plan 
Descriptive statistical analysis will be conducted for the primary and secondary 
endpoints. The proportion with 95% confidence interval will be summarized for 
the categorical variables. Method of Kaplan-Meier will be used to estimate the 
survival functions.  
We will also conduct exploratory analysis to investigate levels of tumor 
proliferation and angiogenic markers including p-ERK, VEGF, sVEGFR-2, bFGF 
in the plasma and tumor tissue at baseline, during, and after treatment with 
sorafenib plus chemoradiotherapy and to evaluate expression of tumorigenic and 
angiogenic factors including p-ERK, VEGF-R2 and PDGFR in tumor tissue by 
immunohistochemical staining. These analyses will be conducted in an 
exploratory manner with the aim of generating clinically and biologically 
interesting hypotheses.   
11.3    Sample size consideration   
This is a single-stage single-arm phase II clinical study. We expect to enroll a total 
of 20 patient for achieving 80% power at a significance level of 5% using one-
sided binomial test. The null hypothesis to be tested is that the pathologic response 
rate is 25%, and we assume the pathologic response rate after preoperative 
treatment with sorafenib, epirubicin, ifosfamide and hypofractionated radiation for 
high risk soft tissue sarcomas is at least 52%.  
11.4 Duration of Accrual 
This study will be conducted in a single stage.  Based on an estimated accrual rate 
of 1 patient per month, we expect to complete the enrollment within 20 months.  
 
 
 
 
 
 
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