Clinical trial NCT02196857
Conditions: Leukemia
Keywords: Leukemia Acute myeloid leukemia AML High risk myelodysplastic syndrome MDS FLT3-ITD mutation Azacytidine 5-Azacytidine 5-AZA Vidaza 5-AZC AZA-CR Ladakamycin NSC-102816 Sorafenib Nexavar BAY 43-9006
Sponsor: M.D. Anderson Cancer Center
Start date: 2015-02-06; Completion date: 2018-11-27
Enrollment: 16 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The goal of this clinical research study is to learn if 5-azacitidine and sorafenib can help to control the disease in patients with Acute Myeloid Leukemia (AML) and high risk Myelodisplastic Syndrome (MDS) with FLT3-ITD mutation. The safety of this drug combination will also be studied.

Detailed description:
Study Drug Administration:

If you are found to be eligible to take part in this study, you will receive 5-azacitidine either as an injection under the skin or by vein on Days 1-7 of each 28-day cycle. If by vein, the infusion will take about 10-40 minutes.

You will take sorafenib by mouth 2 times a day about 12 hours apart, with at least 1 cup (8 ounces) of water on an empty stomach, every day. If you vomit a dose, do not make it up. You should wait and take your next scheduled dose.

Each study cycle may last a little longer than 28 days, depending on how you are doing.

Study Visits:

Each week, blood (about 1 tablespoon) will be drawn for routine tests.

Each week for the first 6 weeks, and then as often as your doctor thinks it is needed, you will have your blood pressure measured.

Before each cycle, you will have a physical exam.

Before every 2-4 cycles, you will have a bone marrow aspirate to check the status of the disease.

Length of Study:

You may continue taking the study drugs for as long as your doctor thinks it is in your best interest. You will no longer be able to take the study drugs if the disease gets worse or intolerable side effects occur, or if you are unable to follow study directions.

Your participation on the study will be over after the follow-up visits.

End-of-Study Visit:

After you have stopped taking the study drugs, the following tests and procedures will be performed:

* You will have a physical exam.
* You will have a bone marrow aspirate to check the status of disease.
* Blood (about 2 tablespoons) will be drawn for routine tests.

Follow-Up Visits:

After your end-of-study visit, you will return to the clinic every 3 months and have the following tests and procedures:

* You will have a physical exam.
* Blood (about 2 tablespoons) will be drawn for routine tests.

This is an investigational study. Sorafenib is FDA approved and commercially available for the treatment of kidney cancer and liver cancer. 5-azacitidine is FDA approved for the treatment of MDS, but combining it with sorafenib is investigational. The study doctor can tell you how the study drugs are designed to work.

Up to 52 participants will be enrolled in this study. All will take part at MD Anderson.

Arms: arm 1: Azacitidine 75 mg/m2 administered subcutaneously (SQ) or intravenously (IV) daily for 7 days per 28 day cycle. Sorafenib administered orally at a dose of 400 mg twice daily every day continuously.
Interventions: intervention 1: Azacytidine intervention 2: Sorafenib
Intervention descriptions: intervention 1: 75 mg/m2 administered subcutaneously (SQ) or intravenously (IV) on Days 1 - 7 for a 28 day cycle. intervention 2: 400 mg by mouth twice daily about 12 hours apart, every day for a 28 day cycle.

Protocol documents:
Prot_SAP_000.pdf: 
2014-0076
March 9, 2015
Page 1
Protocol Page
Phase II Study of Sorafenib Plus 5-Azacitidine for the Initial Therapy of Patients with 
Acute Myeloid Leukemia and High Risk Myelodysplastic Syndrome with FLT3-ITD 
Mutation
2014-0076
Core Protocol Information
Short Title 
Sorafenib Plus 5-Azacitidine initial therapy of patients with AML and high risk MS with FLT3-ITD 
Mutation
Study Chair: 
Farhad Ravandi-Kashani
Additional Contact:
Andrea L. Booker
Mary Ann Richie
Leukemia Protocol Review Group
Department:
Leukemia
Phone:
713-792-7305
Unit:
428
Full Title: 
Phase II Study of Sorafenib Plus 5-Azacitidine for the Initial Therapy of Patients with Acute 
Myeloid Leukemia and High Risk Myelodysplastic Syndrome with FLT3-ITD Mutation
Protocol Type:
Standard Protocol
Protocol Phase:
Phase II
Version Status:
Terminated 11/27/2018
Version:
12
Submitted by:
Andrea L. Booker--2/23/2017 1:07:00 PM
OPR Action:
Accepted by:  Julie Arevalo -- 3/3/2017 2:39:37 PM
Which Committee will review this protocol?
 The Clinical Research Committee - (CRC)


2014-0076
March 9, 2015
Page 2
Protocol Body
 


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1
 
 
 
 
 
Phase II Study Of Sorafenib Plus 
5-Azacitidine For The Initial Therapy Of Patients With Acute Myeloid 
Leukemia And High Risk Myelodysplastic Syndrome With FLT3-ITD 
Mutation 
 
 
Short Title: Sorafenib Plus 5-Azacitidine initial therapy of patients with AML and high 
risk MS with FLT3-ITD mutation 
 
 
PI: Farhad Ravandi, MD 
Professor of Medicine, 
Department of Leukemia 
University of Texas – MD Anderson Cancer Center 


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Contents 
1.0 
Objectives ......................................................................................................................................... 3 
2.0 
Background ....................................................................................................................................... 3 
3.0 
Patient selection ................................................................................................................................ 9 
4.0 
Treatment Plan ................................................................................................................................ 11 
7.0 
Correlative/Special studies .............................................................................................................. 23 
8.0 
Patient evaluation ............................................................................................................................ 24 
8.2 
Evaluation during treatment: ........................................................................................................... 24 
9.0 
Criteria for response ........................................................................................................................ 25 
10.0 
Criteria for Removal from Study .................................................................................................... 27 
11.0     Background Drug Information ........................................................................................................ 27 
12.0     Adverse Event Reporting ................................................................................................................ 31 
13.0 
 Statistical Considerations ............................................................................................................... 31 
14.0 
Protocol Administration .................................................................................................................. 34 
15.0 
References ....................................................................................................................................... 35 
 
  
 
 
 


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1.0 
Objectives 
1.1 
Primary objectives:  
1. To determine the clinical activity (CR +CRi) of the combination of AZA and 
sorafenib in patients with untreated acute myeloid leukemia and High risk 
MDS with FLT3-ITD mutation. 
1.2 
Secondary objectives:  
1. To determine the toxicity profile of the combination of AZA and sorafenib in 
patients with untreated acute myeloid leukemias and MDS with FLT3-ITD 
mutation. 
 
2. To determine potential mechanisms of synergy with this combination and its 
correlation with response.   
 
2.0 
Background 
Acute myeloid leukemia (AML) is a neoplasm involving immature granulocytes or monocytes. 
AML is characterized by accumulation of leukemic blasts and blockade of normal bone marrow 
hematopoietic cell production resulting in thrombocytopenia, anemia, and neutropenia. In the 
U.S., approximately 12,000 new cases of AML are diagnosed every year, with an estimated 
9,000 deaths attributable to the disease. Almost all newly diagnosed cases, as well as deaths, will 
be in adults. Standard treatment for AML includes systemic combination chemotherapy to 
control bone marrow and systemic disease. Treatment is generally divided into an induction 
phase, to attain remission, and a consolidation phase. Approximately 60% to 70% of adults with 
AML can be expected to attain complete remission status following appropriate induction 
therapy. Remission rates in adult AML are inversely related to age, with an expected remission 
rate of >65% for those younger than 60 years. Increased morbidity and mortality during 
induction appear to be directly related to age (Sheinberg, 2005). 
 
Signaling via receptor tyrosine kinases (RTKs) is frequently deregulated in hematological 
malignancies.1 FLT3 (FMS-like tyrosine kinase III) is a transmembrane tyrosine kinase that 
belongs to the Class III family of RTKs. FLT3 is primarily expressed on immature hematopoietic 
progenitors and also on some mature myeloid and lymphoid cells.2-4 FLT3 is activated following 
binding of FLT3 ligand, which causes receptor dimerization leading to increased kinase activity 
and activation of downstream signaling pathways including Stat5, Ras, and PI3’kinase.5  FLT3 
plays a normal role in the regulation of survival and proliferation of hematopoietic progenitor 
cells, in particular by synergy with other RTKs and cytokine receptors. FLT3 is also expressed in 
AML cells from approximately 90% of patients and stimulates survival and proliferation of 
leukemic blasts.6-8  
 
Additionally, FLT3 is mutated in 30% of AML cases.9 The two leading types of mutations found 
in AML include internal tandem duplications in the juxtamembrane domain (ITD, 17-34%) and 


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mutations in the activation loop (approximately 7%).9  Patients with mutations in FLT3 have a 
worse prognosis when treated with conventional chemotherapy compared to patients with wild-
type FLT3.10 Initial studies using small molecule FLT3 inhibitors have offered encouragement 
that when added to the conventional arsenal of AML treatments, patients with AML expressing 
mutated FLT3 may experience significant clinical benefit.11 
2.1 
Sorafenib 
Sorafenib (Nexavar, Bayer-Onyx) is an oral, small molecule kinase inhibitor that was initially 
developed as a Raf inhibitor. Subsequent laboratory characterization of sorafenib demonstrated 
that it is a multikinase inhibitor of several other targets including vascular endothelial growth 
factor receptor-2 (VEGFR-2), VEGFR-3, and platelet-derived growth factor receptor-beta 
(PDGFR-[beta]). Due to its inhibition of VEGFR, sorafenib has been classified as an 
antiangiogenic drug. Sorafenib garnered initial attention when its antitumor activity in renal cell 
cancer was noted in early clinical trials. More recently, on the basis of a phase III trial, sorafenib 
was approved by the Food and Drug Administration (FDA) for the treatment of metastatic renal 
cancer and hepatocellular cancer. 
Sorafenib was initially identified through a library screen as a small molecule that inhibits C-Raf. 
In addition to C-Raf, sorafenib is a multikinase inhibitor of several other targets including wild 
type and mutant B-Raf, VEGFR-2, VEGFR-3, PDGFR-[beta], Flt-3, c-Kit, and fibroblast growth 
factor receptor-1. In contrast, Erk1, Erk2, insulin-like growth factor, c-met, EGFR, and protein 
kinase C are not inhibited by sorafenib.12 
A series of phase I trials involving a range of sorafenib doses (50–800 mg) and schedules 
(intermittent and continuous) have been conducted. Plasma drug levels of 400 mg twice daily are 
well tolerated and higher than those necessary to inhibit Raf kinase, as well as VEGFR and 
PDFGR. Thus the recommended dose for single agent phase II testing is 400 mg twice daily. 
In the phase I studies, sorafenib was well tolerated; the rate of grade 3 toxicities was low and no 
grade 4 toxicities were reported. The most common drug-related side effects were hand-foot 
syndrome (23%), rash (26%), fatigue (39%), diarrhea (55%), hypertension (35%), stomatitis 
(7%), neuropathy (22%) and alopecia (16%). 
Based on results from preclinical and phase I studies, sorafenib was expected to cause growth 
arrest and clinical disease stabilization rather than tumor shrinkage. Assessment of cytostatic 
drugs and disease stabilization in phase II studies is challenging in that it is often difficult to 
distinguish drug effect versus prolonged natural history of the disease in any single patient. One 
proposed phase II design for cytostatic agents is the randomized discontinuation trial (RDT). 
In the sorafenib RDT phase II trial, all patients initially received sorafenib 400 mg twice daily 
for 12 weeks; patients who experienced >25% tumor reduction in bidimensional measurements 
(modified WHO criteria) at the 12-week evaluation were continued on the drug. Patients with 
>25% tumor growth in bidimensional measurements after the 12-week run-in phase, were taken 
off the study. Patients with <25% reduction and <25% growth within the first 12 weeks were 


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classified as stable disease and were randomized in a placebo-controlled double-blind fashion to 
continue or discontinue sorafenib. The primary endpoint of the study was the fraction of 
randomized patients that maintained stable disease 12 weeks postrandomization.15 In this 
manner, the trial not only determines whether the observed stable disease is a drug effect, but 
also, and perhaps more importantly, selects (or enriches) the trial for patients most likely to 
experience the endpoint of disease stabilization. 
The latter trial design characteristic is especially important as the trial was originally designed to 
evaluate activity of sorafenib in colorectal cancer based on its Raf inhibitory properties and the 
role of the Raf pathway in this disease.  The trial also, however, allowed recruitment of patients 
with other malignancies. During the study, investigators noted tumor regression in renal cell 
cancer (RCC) patients and the protocol was thus amended to expand enrollment of this cohort. A 
total of 202 patients with RCC (502 total with all tumor types) were treated during the run-in 
phase, 73 had tumor shrinkage ≥ 25%; 66 patients with stable disease at 12 weeks were 
randomized to sorafenib or placebo. At 24 weeks, 50% of sorafenib-treated patients were 
progression-free in comparison with 18% of placebo-treated patients (P = 0.007). Additionally, 
median progression-free survival from randomization was significantly longer with sorafenib (24 
weeks) than placebo (6 weeks; P = 0.009). Of note, only a small number of patients 
demonstrated objective tumor regressions that would qualify as partial responses according to 
RECIST criteria; thus the RDT design of this phase II trial allowed investigators to quickly 
identify an active therapy that may have been mistakenly classified as inactive in traditional 
phase II trial designs. 
A large multicenter randomized phase III trial in patients with metastatic clear cell RCC was 
initiated.16 Eligibility was limited to patients with clear cell RCC who progressed on one prior 
systemic therapy within 6 months, Eastern Cooperative Oncology Group (ECOG) performance 
<2, and no brain metastases. The primary end point was overall survival; secondary endpoints 
included progression-free survival toxicity and response rate. The progression-free survival 
analysis was designed to be evaluated after 363 events with a nominal one-sided P-value of 0.01. 
The survival analysis was designed to be evaluated after 540 events with a nominal two-sided P-
value of 0.04 and with interim analyses after 270 events. 905 patients were randomized to 
receive either sorafenib 400 mg twice daily or placebo; no crossover to sorafenib was initially 
allowed on the trial. The preliminary results were presented at the 2005 American Society of 
Clinical Oncology annual meeting. Among the 335 patients who received sorafenib, only 2% 
achieved a partial response according to RECIST criteria, but 78% demonstrated stable disease, 
with a majority of these patients experiencing some tumor shrinkage. Progression-free survival, 
however, was significantly prolonged in the treatment arm, with those receiving sorafenib 
demonstrating a time to progression of 24 weeks versus 12 weeks (P < 0.000001). Due to this 
marked positive clinical benefit, the protocol was amended to allow patients on the placebo arm 
to receive sorafenib. In addition, sorafenib was approved by the FDA in December 2005 for the 
treatment of patients with advanced/metastatic RCC. 
The analysis of this trial was updated recently after 367 survival events occurred: patients on the 
sorafenib arm had a continued improvement in overall survival of 19.3 months versus 15.9 
months for placebo arm (P = 0.015; hazard ratio 0.77), despite the fact that 48% of patients 


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initially randomized to the placebo arm crossed over to receive sorafenib. In the final report, the 
OS of patients receiving sorafenib was comparable with that of patients receiving placebo (17.8 
v 15.2 months, respectively; hazard ratio [HR] = 0.88; P = .146); however, when post-cross-over 
placebo survival data were censored, the difference became significant (17.8 v 14.3 months, 
respectively; HR = 0.78; P = .029).17 
Again, sorafenib was well tolerated with very few grade 3 or 4 toxicities seen. Toxicities 
experienced in the treatment arm included hand–foot syndrome, hypertension, rash, and fatigue. 
In preclinical studies, sorafenib induced dephosphorylation of MEK1/2 and ERK and induced 
apoptosis in AML cells.12 Furthermore, sorafenib was 1000- to 3000-fold more potent in 
inducing apoptosis in Ba/F3 cells with FLT3-ITD or D835G mutations than those with WT 
FLT3.12 In a mouse model of AML with mutant FLT3, sorafenib reduced the leukemic burden 
and prolonged survival.13 It has been approved by the FDA for the treatment of renal cell and 
hepatocellular carcinoma at a standard dose of 400 mg twice daily. In phase I studies and used 
anecdotally in patients with advanced AML, sorafenib was capable of producing significant 
clinical responses.  The objectives of this study were to determine the feasibility, safety and 
efficacy of combining sorafenib with induction chemotherapy. 
2.2 
Azacitidine 
 
Azacitidine (AZA), an analog of the pyrimidine nucleoside cytidine, has effects on cell 
differentiation, gene expression, and deoxyribonucleic acid (DNA) synthesis and metabolism. 
Since the early 1970s, azacitidine has been investigated primarily in the US for the treatment of 
acute leukemia. Clinical studies have focused mainly on patients with disease refractory to 
conventional chemotherapy. Results of these investigations demonstrated activity of azacitidine 
in the treatment of AML. Clinical studies subsequently evaluated the effects of azacitidine in a 
variety of other malignant and hematologic disorders, including solid tumors, 
hemoglobinopathies (eg, thalassemia and sickle cell anemia), and MDS. In 1984, the Cancer and 
Leukemia Group B (CALGB) began a series of clinical studies with azacitidine in patients with 
MDS. These studies, in addition to other supportive data, led to the approval of Vidaza® 
(azacitidine) in May 2004 for the treatment of MDS.  
 
Azacitidine inhibits the methylation of newly synthesized DNA by inhibiting DNA 
methyltransferase (DNMT). Increased methylation of DNA (hypermethylation) may result in the 
silencing of critical genes responsible for cell growth control and differentiation. 
Hypermethylation of CpG islands spanning the promoter regions of tumor suppressor genes is 
commonly associated with cancers. It is now widely recognized that hypermethylation of DNA is 
frequently associated with myelodysplastic syndromes and other cancers, such as renal, 
melanoma, breast, colorectal, non-small cell lung and hematologic malignancies. Azacitidine is 
believed to exert its antineoplastic effects through hypomethylation and cytotoxicity on abnormal 
hematopoietic cells in the bone marrow. Hypomethylation may restore normal function to genes 
that are critical for differentiation and proliferation. The cytotoxic effects of azacitidine cause the 
death of rapidly dividing cells, including cancer cells that are no longer responsive to normal 
growth control mechanisms.  


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The cytotoxicity of azacitidine is proportional to dose and exposure time. Although the 
mechanisms of cytotoxicity are complex and multifaceted, there is general agreement that 
incorporation of azacitidine into DNA and ribonucleic acid (RNA), and inhibition of protein 
synthesis, are critically important. Cytotoxicity is greatest in cells that are proliferating (S phase) 
and metabolically active. Cytotoxic effects may also be mediated through induction of the DNA 
damage response pathways. Non-proliferating cells are relatively insensitive to azacitidine.  
 
Toxicology studies have been conducted in mice, rats, dogs, and Rhesus monkeys. Most of the 
studies were performed during the 1970s and early 1980s according to existing guidelines and 
standards in place during that period. The preclinical studies identified the bone marrow, liver, 
kidneys, and lymphoid tissues (spleen, lymph nodes, and thymus) as the main target organs of 
toxicity for azacitidine.  In single-dose studies, the lethal dose of azacitidine after intravenous 
(IV) administration in mice, rats, and dogs was approximately 250 mg/m2. Repeated daily dosing 
appears to increase the toxicity of azacitidine. The genotoxicity of azacitidine is consistent with 
that of other nucleoside analogs that interact with nucleic acids. Likewise, similar to other agents 
with cytostatic properties, azacitidine was embryotoxic and reduced the reproductive 
performance in mice and rats. 
 
Limited azacitidine pharmacokinetic data are currently available. Based on human plasma 
concentrations of total radioactivity (which represents parent drug plus circulating metabolites), 
azacitidine is rapidly absorbed when given subcutaneously (SC), with maximum plasma 
concentrations found 0.5 to 2 hours after dosing. Azacitidine and/or its by-products are then 
rapidly cleared by the kidneys. The half-lives and percent radioactivity recovered in urine are 
similar following IV and SC routes of administration. The effects of renal or hepatic impairment, 
gender, age, or race on the pharmacokinetics of azacitidine have not been studied. A single dose 
(75 mg/m2) SC versus IV crossover study in 6 MDS subjects revealed an approximate 
bioavailability of 89% for the SC dose (range 52% to 128%) with mean half-lives of 0.69 hour 
and 0.36 hour after SC and IV administration, respectively. These results demonstrated that 
azacitidine is rapidly and nearly completely absorbed after SC administration and that 
elimination is also rapid. The apparent SC clearance (167 L/h or 2791 mL/min) and systemic IV 
clearance (147 L/h) of azacitidine exceeded the glomerular filtration rate (approximately 125 
mL/min) and total renal blood flow (1200 mL/min) in healthy subjects. This indicates that non-
renal elimination (eg, metabolism, hydrolysis, and/or degradation) plays a role in the elimination 
of parent azacitidine. In addition, azacitidine 75 mg/m2 was generally well-tolerated after single 
SC injection or IV infusion over 10 minutes.  
 
A number of studies have looked at different parenteral doses and schedules of azacitidine, 
finding maximum tolerated doses of up to 500 mg/m2 when administered weekly. 
 
During the two decades between the start of the CALGB studies and the approval of azacitidine, 
a new understanding of MDS has developed, such as the World Health Organization (WHO) 
diagnostic criteria, the International Prognostic Scoring System (IPSS), and the International 
Working Group (IWG) response criteria. Silverman et al. reevaluated the combined data 
(N = 309) from 3 of the CALGB studies using the WHO classification system for MDS and 


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AML and the IWG response criteria. Using the IWG response criteria in MDS patients, response 
rates were between 40% and 70% in azacitidine treated patients. Ten to 17% of patients achieved 
a complete remission; partial remission was rare; and 23% to 36% of patients had a hematologic 
improvement. In patients with AML (N = 103), 35% to 48% had hematologic improvement or 
better responses. The median survival time for 27 patients assigned to azacitidine was 19.3 
months compared with 12.9 months for the 25 patients assigned to observation. 
 
A randomized international Phase III trial (Study AZA PH GL 2003 CL 001) for higher-risk 
MDS patients, classified by FAB as RAEB, RAEB-T, or CMML with 0-29% marrow blasts, 
with an IPSS of Intermediate -2 or High by central pathology/cytogenetic review was recently 
reported. Patients were randomized to azacitidine (75 mg/m2/day x 7days in 28 day cycles) or 
conventional care regimens (CCR) , where CCR was pre-selected by the Investigator as best 
supportive care (transfusions, antibiotics, and G-CSF for neutropenic infection), low-dose 
cytarabine (20 mg/m2/day x 14 days in 28 day cycles); or standard chemotherapy (conventional 
induction/consolidation). Patients were stratified by FAB/IPSS and randomized 1:1 to azacitidine 
or CCR. This trial did not allow erythropoietin. Three-hundred fifty eight patients (70% male) 
were randomized at 79 centers to azacitidine (N=179) or CCR (N=179): best supportive care 
only (N=105, 59%), low-dose cytarabine (N=49, 27%), or standard chemotherapy (N=25, 14%). 
Median age was 69 years (range 38-88 years). The azacitidine and CCR groups were comparable 
for baseline patient characteristics. At baseline, 95% of patients were higher risk: RAEB (58%), 
RAEB-T/WHO AML (34%), CMML (3%), and other (5%). By IPSS, 87% were higher risk: 
Intermediate -2 (40%), High (47%), and 13% Indeterminate/other. Azacitidine was administered 
for a median of 9 cycles; low-dose cytarabine for 4 cycles. Median follow-up for the survival 
analysis was 21.1 months. Azacitidine demonstrated statistically superior overall survival 
compared to CCR, with a median overall survival of 24.4 months vs. 15 months for CCR 
(stratified log-rank p=0.0001, hazard ration 0.58). Two-year survival approximately doubled in 
the azacitidine arm compared to CCR: 51% vs. 26% (p<0.0001). Azacitidine was well tolerated 
with safety data consistent with previous reports.  
 
Further details can be found in the azacitidine Investigator’s Brochure, which contains 
comprehensive pharmacology, toxicology, pharmacokinetics, pharmacodynamics, metabolism, 
preclinical, and clinical efficacy and safety data information. 
A potential mechanism of resistance to FLT3 kinase inhibitors is high levels of FLT3 ligand (FL) 
which is commonly seen after treatment with myelosuppressive chemotherapy. We hypothesized 
that combining sorafenib with a less myelosuppressive agent, such as 5-azacytidine (AZA), may 
lead to higher and more durable responses. We have previously conducted a clinical trial 
combining azacytidine and sorafenib for the treatments of patients with relapsed AML. Patients 
received 5-azacytidine (AZA) 75 mg/m(2) intravenously daily for 7 days and sorafenib 400 mg 
orally twice daily continuously; cycles were repeated at ~1-month intervals. This trial was 
registered at clinicaltrials.gov as #NCT01254890. Overall, 57 patients with AML with a median 
age of 65 years (range, 21-87) were enrolled. They included 27 (47%) patients with normal 
cytogenetics, 12 (21%) with chromosome 5/7 or complex cytogenetic abnormalities, 15 (26%) 
with other miscellaneous abnormalities; 3 (5%) had insufficient metaphases. Prior to the 
initiation of treatment, FLT3-ITD was detected in 53/57 (93%) patients with a median allelic 


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ratio of 0.348 (range, 0.009 – 0.934). They had received a median of 2 prior treatments (range, 0 
-7) including 13 previously untreated patients. Twenty (35%) patients had received ≥3 prior 
regimens and 12 had failed prior therapy with FLT3 kinase inhibitors (6 with AC220, 2 with 
PKC412, and 9 with sorafenib, either as monotherapy or with chemotherapy or plerixafor); 4 
patients had failed 2 prior FLT3 inhibitors. The overall CR/CRi/PR rate among the 57 patients is 
44%, including 16 (28%) with CRi and 8 (14%) with CR and 1 (2%) with PR. The response rate 
among the previously untreated patients was 62% and among relapsed patients 39%. Patients 
have received a median of 3 (range, 1 - 27) treatment cycles with the median number of cycles to 
response among the responders being 2 (range, 1 – 4) and the median time to achieving response, 
2.1 months (range, 0.8 – 4.6 months). The median duration of CR/CRi Is 2.4 months (range, 0.8 
– 24.8 months). Seven patients have proceeded to allogeneic stem cell transplant. The most 
common study drug-related adverse events were rash and fatigue with no deaths attributable to 
study medications. One patient developed grade 3 cardiomyopathy. With a median follow-up of 
8.6 months (range, 6.1 – 26.9), 13 patients remain alive, 5 still in remission. The median overall 
survival of the 57 patients was 6.3 months, and 12.4 months in the 25 responding patients. Mean 
FL levels at cycle 2, day 0 and cycle 2, day 10 were 27 pg/mL and 54 pg/mL, respectively, 
which is significantly lower than those seen previously in studies of FLT3 kinase inhibitor plus 
chemotherapy.18  
3.0 
Patient selection 
3.1 
Inclusion criteria: 
1. 
Patients with untreated AML (≥ 20% blasts in bone marrow and/or 
peripheral blood) or high risk MDS (≥ 10% blasts in bone marrow) 
Patients with AML and history of MDS who have received prior therapy 
with a hypomethylating agent (including azacytidine) and/or with 
lenalidomide for prior MDS are eligible if the treating physician feels that 
participation in the study is in the patients’ best interest.  Patients should 
have molecular evidence of the presence of FLT3-ITD mutation with a 
molecular burden of at least 10%. 
2. 
Age 60 years; patients younger than 60 who are unsuitable for or  
unwilling to receive standard cytotoxic chemotherapy are also eligible to 
be enrolled. 
3. 
ECOG Performance Status  2 
4. 
Adequate liver (bilirubin  1.5x ULN, ALT or AST ≤ 2.5 x ULN and 
Alkaline phosphatase < 4 x ULN if not related to leukemic disease) and 
renal (creatinine  1.5x ULN) function.  
5. 
Patients must provide written informed consent. 
6. 
Patients must have been off therapy for MDS for 2 weeks prior to entering 
this study, and must have recovered from the toxic effects of that therapy 
to at least grade 1, unless there is evidence of rapidly progressive disease. 
Use of hydroxyurea (any dose) or ara-C (up to 1 g/m2 x 2 doses) for 
patients with rapidly proliferative disease is allowed before the start of 


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study therapy; these should be stopped for 24 hours prior to the initiation 
of azacitidine and sorafenib. 
7. 
Women of childbearing potential should be advised to avoid becoming 
pregnant with an adequate method of contraception (barrier or hormonal 
methods) and men should be advised to not father a child while receiving 
treatment with azacitidine.  All men and women of childbearing potential 
must use acceptable methods of birth control throughout the study as 
described below: Women of childbearing potential must have a negative 
serum pregnancy test performed within 7 days prior to the start of 
treatment. Men should use adequate birth control for at least 30 days after 
the last administration of sorafenib. Post-menopausal women (defined as 
no menses for at least one year) and surgically sterilized women are not 
required to undergo a pregnancy test 
 
Females of childbearing potential: Recommendation is for 2 effective 
contraceptive methods during the study. Adequate forms of contraception 
are double-barrier methods (condoms with spermicidal jelly or foam and 
diaphragm with spermicidal jelly or foam), oral, depo provera, or 
injectable contraceptives, intrauterine devices, and tubal ligation. 
Male patients with female partners who are of childbearing potential: 
Recommendation is for male and partner to use at least 2 effective 
contraceptive methods, as described above, during the study. 
8. 
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. 
9. 
INR < 1.5.  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 weekly, or as defined by the local standard of care, until INR is 
stable.  
 
3.2 
 Exclusion criteria: 
 
Nursing and pregnant females.  
 
Patients with acute promyelocytic leukemia are excluded  
 
Patients with known allergy to sorafenib or azacitidine, mannitol or any of their 
components. 
 
Patients with known severe impairment of gastrointestinal (GI) function or GI 
disease that may significantly alter the absorption of sorafenib. 
 
Patients with any other known disease (except carcinoma in-situ) or concurrent 
severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, 
cardiovascular disease including congestive heart failure, myocardial infarction 


Sorafenib plus 5-Azacitidine Initial Therapy – 2014-0076 
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11 
 
 
11
within 6 months and uncontrolled hypertension, chronic renal disease (creatinine 
clearance < 20 ml/min using the Cockroft and Gault formula), or active 
uncontrolled infection) which could compromise participation in the study. 
 
Patients with a known confirmed diagnosis of HIV infection or active viral 
hepatitis (B or C). 
 
Patients who have had any major surgical procedure within 28 days prior to Day 
1. 
 
Patients unwilling or unable to comply with the protocol. 
 
Cardiac disease: Congestive heart failure > class II NYHA.  Patients must not 
have unstable angina (anginal symptoms at rest) or new onset angina (began 
within the last 3 months) or myocardial infarction within the past 6 months. 
 
Uncontrolled hypertension defined as systolic blood pressure > 150? mmHg or 
diastolic pressure > 90 mmHg, despite optimal medical management. 
 
Active clinically serious infection > CTCAE v4. Grade 2 not controlled with 
antibiotics. 
 
Thrombolic or embolic events such as a cerebrovascular accident including 
transient ischemic attacks within the past 6 months. 
 
Pulmonary hemorrhage/bleeding event > CTCAE v4. Grade 2 within 4 weeks of 
first dose of study drug. 
 
Any other hemorrhage/bleeding event > CTCAE v4. Grade 3 within 4 weeks of 
first dose of study drug. 
 
Serious non-healing wound, ulcer, or bone fracture. 
 
Evidence of bleeding diathesis or coagulopathy within the past 6 months 
 
Known or suspected allergy to sorafenib or any agent given in the course of this 
trial. 
 
Substance abuse, medical, psychological or social conditions that may interfere 
with the patient’s participation in the study or evaluation of the study results 
including known non-compliance issues on study trials. 
 
Use of strong CYP3A4 inducer 
 
4.0 
Treatment Plan 
4.1 
General 
 
All patients will be registered through CORe. The objective will be to administer azacitidine and 
sorafenib at full dose.  
4.2 
Schedule 
 
PROTOCOL SUMMARY/SCHEMA 
 
 
SCHEDULE OF EVALUATIONS / STUDY CALENDAR 


Sorafenib plus 5-Azacitidine Initial Therapy – 2014-0076 
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12 
 
 
12
 
Parameter 
 
Pre-
study 
 
Weekly
***** 
Before 
Each  
Cycle  
Before  
Every 
2 - 4 
Cycles  
Study 
Termination 
Follow
- 
Up 
History 
x 
 
 
 
x 
x 
Physical examination 
x 
 
x 
x 
x 
x 
BP** 
x 
x 
x 
x 
x 
x 
Weight 
x 
 
x 
x 
x 
x 
Measurement of 
extramedullary 
tumor****** 
x 
 
x 
x 
x 
x 
Performance status  
x 
 
x 
x 
x 
x 
CBC, differential, 
platelet count 
x 
x 
x 
x 
x 
x 
Serum Chemistries (must 
include, Bilirubin, Alk 
Phos, ALT orAST) 
x 
x 
x 
x 
x 
x 
Glucose and Electrolytes 
(Na, K, C1, CO2) 
x 
x 
x 
x 
x 
x 
PT/PTT/INR*** 
x 
 
x 
x 
x 
x 
Bone marrow exam with 
cytogenetics and 
molecular studies for 
FLT3 and NPM1**** 
x 
 
 
x 
x 
 
Beta HCG 
x 
 
 
 
 
 
Chest x-ray  
x 
 
 
 
 
 
Brain CT or MRI scan * 
x 
 
 
 
 
 
 
 As appropriate 
*Brain imaging (CT/MRI) should be performed only in patients with neurological signs and 
symptoms concerning for intracranial metastatic masses. 
**Blood pressure should be monitored weekly during the first 4 weeks of sorafenib therapy and 
thereafter monitored and treated, if required, in accordance with standard medical practice.  In 
cases of severe or persistent hypertension, despite institution of antihypertensive therapy, 
temporary or permanent discontinuation of sorafenib should be considered.   
***Infrequent bleeding events or elevations in the International Normalized Ratio (INR) have 
been reported in some patients taking warfarin while on sorafenib therapy.  Patients taking 
concomitant warfarin should be monitored weekly for changes in prothrombin time, INR or 
clinical bleeding episodes. 
****Bone marrow exam should be performed at Screening the end of Cycle 1, every 2-3 cycles 
for the first year, then at the discretion of the treating physician. Any change to this schedule that 
the treating physician feels is in the best interest of the patient must be approved by the PI. 


Sorafenib plus 5-Azacitidine Initial Therapy – 2014-0076 
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13 
 
 
13
Molecular studies (FLT3 and NPM1) performed at baseline only and on patients with unknown 
status. 
 
***** Labs will be collected once weekly for the first 2 cycles, then monthly thereafter 
(differential can be omitted if WBC is ≤0.5 x109/L) 
******Any tumor masses will be measured before and after the treatment to assess their 
response to treatment. 
 
4.2.1 Patients will be treated according to the following schedule: 
 
 Azacitidine 75 mg/m2 will be administered subcutaneously (SQ) or intravenously 
(IV) daily for 7 days per cycle. Cycles should be repeated every 4-8 weeks at the 
discretion of the treating physician. The next azacitidine course may be started 
before 4 weeks or after 8 weeks if felt to be in the best interest of the patient and 
only after discussion with the PI. 
 Sorafenib will be administered orally at a dose of 400 mg twice daily every day 
continuously. Sorafenib will only be held for sorafenib-related toxicity. 
 
Both agents will start on the same day of the first cycle. Sorafenib will be given continuously 
thereafter unless there is a Sorafenib-related toxicity.  It will be re-started as soon as that toxicity 
has resolved to a Grade 1 or baseline status. The first dose of each course of Azacitidine will 
constitute the beginning of the next cycle of treatment.  
 
Dose reductions for both agents are allowed but should be discussed with the PI and 
documentation of the justification recorded in the chart. 
 
One cycle of therapy is defined 7 days of azacitidine and continuous dosing of 
sorafenib. Patients will receive one cycle of therapy every 4 weeks (with a desired 
dose schedule of 4 week cycles) and can be delayed up to 56 days.  If the treating 
physician feels that one or both of the drugs must be held for a longer period of 
time, then it must have PI approval.   
 
Subsequent courses of azacitidine will be given if the ANC is equal or greater than 
1.0 x109/L (or lower if the treating physician feels in the best interest of the patient 
and after discussion with PI) and the platelets are equal to or greater than 30 x109/L 
(unless transfusion dependent), in the absence of residual leukemia in the bone 
marrow (for the first 3 cycles of therapy, it is intended that the azacitidine cycles 
are administered every 4 weeks despite cytopenias and even if full recovery to the 
above levels has not occurred). If prolonged myelosuppression (more than 60 days) 
with evidence of a hypocellular marrow (marrow cellularity less than 5% without 
evidence of leukemia) is observed subsequent courses of azacitidine may be given 
at a lower dose after discussion with the PI. If the peripheral counts do not recover 
(ANC <1 x109/L (or to baseline value) and/or platelets <30 x109/L (unless 
transfusion dependent) but there is evidence of residual leukemia in the bone 
marrow, subsequent cycles can be administered earlier than 4 weeks at the 


Sorafenib plus 5-Azacitidine Initial Therapy – 2014-0076 
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14 
 
 
14
discretion of the treating physician, but not earlier than 3 weeks after the previous 
cycle.  
 
Sorafenib is supplied as an immediate-release film-coated, round, and salmon color 
tablet containing 200 mg of the free base, Sorafenib, and the excipient croscarmellose 
sodium, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium lauryl 
sulfate, and magnesium stearate. The film-coat consists of hydroxypropyl 
methylcellulose, polyethylene glycol, titanium dioxide and red iron oxide. The film 
coating has no effect on the rate of release of the active sorafenib.   
 
Sorafenib will be administered 400 mg twice daily for 28 days/or until next cycle 
of Azacitidine is administered in each cycle. Drug doses must be separated by 
intervals of approximately 12 hours (+/-3 hours).  
 
If a dose is missed, the next dose should not be increased to account for missing a 
dose. The subject should take the next regular dose at the regularly scheduled time. 
If a dose is vomited, do not take another dose of medication.  Wait until the next 
dose is due.  Take the next regular dose and do not increase it to account for 
missing a dose. 
 
Modifications to the schedule and/or dose of both/either drugs that are thought to 
be in the best interest of the patient are allowed after discussion with and approval 
by the PI. 
 
It is recommended that patients receive at least 3 cycles of therapy (as long as they 
are not clearly progressing and are tolerating it without significant toxicity) before 
deciding on termination of treatment. Patients will be eligible for efficacy 
assessment if they have received at least one full cycle of therapy (7 days of 
azacytidine and 28 days of sorafenib. 
4.3 
Duration of Therapy:  
In the absence of treatment delays due to adverse events, treatment may continue 
until one of the following criteria applies: 
 
1. Progressive disease 
2. Intercurrent illness that prevents further administration of treatment, 
3. Patient request or 
4. General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
 
It is planned that up to a total of 24 cycles of therapy will be administered for patients deriving 
benefit from this regimen. Continuation of therapy for patients completing 24 cycles of therapy 
may be considered on a case by case basis after discussion with the PI.  
 


Sorafenib plus 5-Azacitidine Initial Therapy – 2014-0076 
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15 
 
 
15
A minimum of 1 full course (defined as the administration of azacitidine for 7 days and 
sorafenib for up to 28 days) will be required for a patient to be considered as having received an 
adequate trial to evaluate efficacy.  All patients receiving at least one dose of any of the two 
drugs will be considered evaluable for toxicity.   
 
4.4 
Concomitant medications 
In general, the use of any concomitant medication/therapies deemed necessary for patient 
supportive care and safety are permitted. Other anticancer agents including systemic 
chemotherapy, radiation therapy, or biologic response modifiers are not permitted during the 
study.  No other investigational drug is allowed during the study. Patients must be off growth 
factors for five days in order to declare a neutrophil response. Prophylaxis may be used for the 
prevention of nausea and vomiting. Patients may be given ondansetron up to 3 times a day or 
granisetron up to 2 times a day.  Ondansetron and granisetron are federally approved drugs and 
will not be supplied by Bayer/Onyx or Celgene. Patients who suffer from Grade 3 or 4 nausea 
and/or vomiting, should be withheld from treatment and only restart if recovery occurs  when 
symptoms are controlled to a Grade 1 status Other antibiotics may be used at the discretion of 
the investigator include, but are not limited to, metoclopramide, promethazine, cyclizine, and 
prochlorperazine. 
 
In the event of severe anemia, thrombocytopenia or neutropenia, patients may receive 
appropriate supportive care (e.g., transfusions, prophylactic antibiotics, antifungals and/or 
antivirals, hematopoietic growth factors). In the event of high white blood cell (WBC) counts, 
patients may receive hydroxyurea or up to 2 doses of ara-C prior to start of study medication in 
order to keep their WBC at an acceptable level.  During the trial they may undergo 
Leukapheresis or receive further doses of hydroxyurea for the same purpose (if necessary).  
 
Concomitant administration of any other therapy specific for MDS, CMML or AML, including 
any use of systemic retinoids, is prohibited. Concomitant administration of any other anticancer 
therapy is prohibited. Intrathecal chemotherapy is allowed, when indicated. 
 
Subjects may receive anti-infective prophylaxis including azoles according to institutional 
practices. Use of recombinant myeloid colony stimulating factors (CSF) is allowed, if patients 
have febrile neutropenia or documented infections. The use of strong CYP3A4 inducers are not 
allow. 
5.0 
Dosing Delays/Dose Modifications 
 
Patients experiencing unacceptable toxicity directly attributable to the study drugs should 
temporarily stop treatment according to the guidelines in the dose adjustment schema. 
 
Toxicity grading will be according to the NCI CTCAE, v4. To prevent unnecessary morbidity, 
the following guidelines for dose adjustment for drug-related toxicities are recommended.  


Sorafenib plus 5-Azacitidine Initial Therapy – 2014-0076 
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16 
 
 
16
Dose Reductions for non-hematologic toxicity possibly related to study drugs should be performed 
according to the following table: 
 
Toxicity 
Grade 
Actions 
Non-hematological 
(excludes myalgia/ 
arthralgia responding to 
treatment, inadequately 
treated vomiting and 
diarrhea, or electrolyte 
abnormalities unless 
not responding to 
optimal 
supplementation) 
3 or 4 
Hold therapy until recovery to 
Grade  1, then re-start and reduce 
one dose level unless approved by 
PI on case to case basis. If toxicity 
recurs again, hold therapy until 
recovery to grade 1, then re-start 
and reduce one dose level.  Dose 
reductions below dose level -2 will 
be considered on an individual 
basis after discussion with the PI. 
For grade 4, the recommendation 
is to discontinue Sorafenib 
Non-hematological 
(excludes myalgia/ 
arthralgia responding to 
treatment, inadequately 
treated vomiting and 
diarrhea, or electrolyte 
abnormalities unless 
not responding to 
optimal 
supplementation)  
Persistent 2- 
considered 
clinically 
significant or upon 
patient’s request  
Hold therapy until recovery to 
Grade  1, then re-start and reduce 
one dose level unless approved by 
PI on case to case basis. If toxicity 
recurs again, hold therapy until 
recovery to grade 1, then re-start 
and reduce one dose level.  Dose 
reductions below dose level -2 will 
be considered on an individual 
basis after discussion with the PI. 
 
Patients in whom the toxicity occurs or persists beyond the planned completion of drug 
administration for the cycle will have the dose reductions implemented in subsequent cycles 
provided the toxicity has resolved as specified in the table above.  
5.1 
Myelosuppression:  
Patients with leukemias and MDS usually present with abnormal peripheral blood counts at the 
time therapy is started and myelosuppression is an expected event during the course of therapy 
for acute leukemias and myelodysplastic syndromes. Thus, no dose adjustments or treatment 
interruptions for myelosuppression will be planned for the first 4 weeks of therapy. After this 
time, treatment interruptions and dose adjustments may be considered according to the following 
guidelines: 
 
Patients with neutropenia or thrombocytopenia as a consequence of the disease, do not require 
treatment interruptions for myelosuppression. Dose-reductions in these patients should be 
considered in an individual case after discussion with the PI. The following guidelines can be 
used for these patients: 
 


Sorafenib plus 5-Azacitidine Initial Therapy – 2014-0076 
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17 
 
 
17
Patients with a response and pre-cycle counts of neutrophils > 1 x109/L and platelets >30 x109/L 
who have sustained low counts of neutrophils <0.5 x109/L or a platelet count <20 x x109/L for 
more than 2 consecutive weeks in the current cycle, may receive a subsequent course.  A 
reduction of up to 2 dose levels may be considered if the myelosuppression was deemed severe 
and life threatening by the treating physician, and if it is in the patient's best interest after 
discussion with the PI. 
 
If there are persistent peripheral blood blasts, or the bone marrow shows >5% blasts, continue 
treatment regardless of neutrophil and platelet count and give supportive care as needed. After 3 
cycles, there should be clear evidence of benefit (reduction in bone marrow blasts, improving 
counts with reduction in transfusion requirement or other clinical improvement in the opinion of 
the treating physician) in order to continue treatment regardless of the counts. 
 
If no marrow evidence of leukemia, may hold therapy with azacytidine until recovery of 
granulocytes to ≥1 x109/L and platelets ≥ 30 x109/L, then resume at same or 1 lower dose level 
according to guidelines mentioned above. In general, in the absence of other toxicity, it is 
recommended that therapy with sorafenib is not interrupted in a responding patient even in the 
presence of cytopenias (unless discussed with PI). 
5.2 
Dose escalation:   
Dose escalation of sorafenib to 600 mg twice daily will be permitted provided: 
 
 Patient has not experienced any grade 3 or higher non-hematologic toxicity, and 
 Patient has not experienced hematologic grade 4 toxicity believed to be treatment related, 
and 
 This has been discussed and approved by the PI and recorded in the patient’s clinical 
records 
Dose reductions/modifications/delays:   
Dose reductions for sorafenib-specific non hematologic toxicity during subsequent cycles should 
be performed according to the table in section 5.3 above.  Dose modification suggestions for 
specific toxicities can be found below. 
 
Dose reduction to 200 mg twice daily, 200 mg once daily, and then 200 mg every other day will 
be allowed depending on the type and severity of toxicity encountered, provided that criteria for 
patient withdrawal from study treatment have not been met. The following tables describe the 
recommended dose modifications for sorafenib-associated toxicities:   
 
Variation in the dosing schedules discussed may be allowed if thought to be in the best interest 
of the patient and after discussing with the study PI. 
 
 
Suggested dose levels for each drug (adjustments to the dose of each drug can be done 
independently of the other): 
 


Sorafenib plus 5-Azacitidine Initial Therapy – 2014-0076 
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18 
 
 
18
Dose level 
Sorafenib 
Dose level 
Azacytidine 
-2 
200 mg po daily 
-2 
50 mg/m2 SC/IV daily x 3 
-1 
200 mg po bid 
-1 
50 mg/m2 SC/IV daily x 5 
0 
400 mg po bid 
0 
75 mg/m2 SC/IV daily x 7 
+1 
600 mg po bid 
+1 
None 
 
 
Proposed Dose modification for Sorafenib Associated toxicity 
 
Table 1:  Suggested Dose Modifications for Sorafenib for Hand-Foot Skin Reaction   
Skin Toxicity Grade 
Occurrence 
Suggested Dose 
Modification 
Grade 1 
Numbness, dysesthesia, 
paresthesia, tingling, 
painless swelling, erythema 
or discomfort of the hands 
or feet which does not 
disrupt the patient’s normal 
activities 
Any Occurrence 
Continue treatment with 
Sorafenib and consider 
topical treatment for 
symptomatic relief.   
Grade 2 
Painful erythema and 
swelling of the hands or feet 
and/or discomfort affecting 
the patient’s normal 
activities  
 
1st Occurrence 
Continue treatment with 
Sorafenib and consider 
topical treatment for 
symptomatic relief. 
If no improvement within 
7 days see below 
No improvement within 7 
days or 2nd or 3rd 
occurrence 
Interrupt Sorafenib until 
toxicity resolves to Grade 
0-1.  When resuming 
treatment, decrease by 1 
dose level 
4th occurrence 
Discontinue Sorafenib 
treatment 
Grade 3 
Moist desquamation, 
ulceration, blistering or 
severe pain of the hands or 
feet, or severe discomfort 
that causes the patient to be 
unable to work or perform 
activities of daily living 
1st or 2nd occurrence 
Interrupt Sorafenib 
treatment until toxicity 
resolves to Grade 0-1.  
When resuming treatment 
decrease Sorafenib by 1 
dose level  
3rd Occurrence 
Discontinue Sorafenib 
treatment 
 


Sorafenib plus 5-Azacitidine Initial Therapy – 2014-0076 
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19 
 
 
19
At first occurrence of HFSR, independent of grade, prompt institution of supportive measures 
such as topical emollients, low potency steroids, or urea-containing creams should be 
administered. 
 
Table 2:  Dose Modifications for Sorafenib-Associated Toxicity1 
Toxicity 
Grade 1 
Grade 2 
Grade 3* 
Grade 4* 
Non-
hematologic 
Continue at the 
same dose 
level. 
Reduce and 
Continue at the 
same dose 
level. 
Withholdb dose until 
toxicity is grade <1, 
then resume 
treatment. decreasing 
by 1 dose level.  If 
patient experiences a 
second grade 3 
toxicity, withholdb 
dose until toxicity is 
grade <1, then 
reduce dose by an 
additional dose level  
. 
 
Discontinue 
protocol therapy 
a.Also excludes nausea/vomiting that has not been pre-medicated, and diarrhea 
b: If no recovery after 60 day interruption, treatment should be discontinued unless subject is 
deriving clinical benefit 
c: If more than 2 dose reductions are required, treatment should be discontinued. 
Toxicity 
Grade 1 
Grade 2 
Grade 3* 
Grade 4* 
Hematologic 
Continue at the 
same dose 
level. 
Continue at the 
same dose 
level. 
Withhold dose until 
toxicity is grade <2, 
then resume 
treatment decreasing 
by 1 dose levelb. If 
patient experiences a 
second grade 3 
toxicity, withhold 
dose until toxicity is 
grade <2, then 
reduce dose by an 
additional dose level 
Withholda dose 
until toxicity is 
grade <2, then 
reduce dose by 2 
dose levelsb and  
resume treatment, 
or discontinue at 
the discretion of  
the principal 
investigator after 
discussion with 
study supporter. 
 
a.If no recovery after 28 day delay, treatment should be discontinued  
b. If more than 2 dose reductions are required, treatment should be discontinued.  
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 
cycle 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 have a Blood Pressure Diary on 
which to record the measurements, which will be kept with research chart. If the patient’s blood 


Sorafenib plus 5-Azacitidine Initial Therapy – 2014-0076 
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20 
 
 
20
pressure is sustained at an elevated level at any time (>150/100), they should contact their 
treating physician. 
Blood pressure measurements considered out of the normal range are diastolic pressure > 90 mm 
Hg and/or systolic pressure > 150 mm Hg, or a 20 mm Hg increase in diastolic pressure if the 
previous measurement was within normal limits.  
The dose-modification schedule to be followed in the event of treatment-induced hypertension is 
outlined in Table 3.  The choice of anti-hypertensive medication to be used in cases 
of  treatment-induced hypertension will be at the investigator's discretion and based on 
site-specific treatment guidelines as applicable.  All anti-hypertensive medications used for the 
management of treatment-emergent hypertension should be recorded in the subject’s eCRF. 
Table 3 Dose Modifications of Sorafenib for Hypertension 
Grade 
(CTCAE v4.0) 
Antihypertensive 
       Therapy 
Blood Pressure  
Monitoring 
Sorafenib Dose 
Grade 1 
Pre-hypertension 
(systolic BP 120-139 
mm Hg or diastolic 
BP 80-89 mm Hg 
None 
Consider 
increased BP 
monitoring 
No change 
Grade 2 
(asymptomatic)  
systolic BP 140-159 
mm Hg or diastolic 
BP 90-99 mm Hg 
Begin anti-hypertensive 
therapy as prescribed by 
the investigator based on 
site-specific treatment 
guidelines as applicable. 
Increase 
frequency and 
monitor (by 
health  
professional) 
every 2 days 
until stabilized 
No change 
Grade 2  recurrent or 
persistent (> 24 hrs); 
sympotomatic 
increase by 20 mm 
Hg(diastolic)/  
OR 
Diastolic BP > 90 mm 
Hg and systolic  > 140 
mm Hg if previously 
WNL 
OR 
Grade 3 
Add agent(s): as 
prescribed by the 
investigator based on site-
specific treatment 
guidelines as applicable 
 
Increase 
frequency and 
monitor (by 
health  
professional) 
every 2 days 
until stabilized;  
continue qod 
monitoring  
to stabilization 
after dosing 
restarted. 
HoldaSorafenib until 
symptoms resolve and 
diastolic BP < 90 
mm/Hg. 
 
Resume treatment at 1 
dose level lowerb.  If 
diastolic not 
controlled  (< 90) on 
therapy, reduce 
another dose levelc 
 
Grade 4 
Life Threatening 
 
 
Off protocol therapy 


Sorafenib plus 5-Azacitidine Initial Therapy – 2014-0076 
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21 
 
 
21
a Subjects requiring a delay of > 28 days should go off protocol therapy. 
b May be able to resume full dose later once blood pressure is adequately controlled. 
c Subjects requiring > 2 dose reductions 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 HTN (systolic 140-159 mm Hg or diastolic BP 90-99Hg, medical intervention 
indicated; recurrent or persistent (>24 hrs) or symptomatic increase by >20 mmHg (diastolic) 
or to > 140/90if previously WNL; monotherapy indicated. 
Grade 3:Stage 2 HTN (systolic BP > =  160 mm Hg or diastolic BP > = 100 mm Hg): medical 
intervention indicated; requiring more than one drug or more intensive therapy than previously 
Grade 4: life threatening (e.g.,malignant hypertension, transient or permanent neuorologic 
deficit,  hypertensive crisis) 
 
Patients who develop GI perforation should discontinue therapy and be taken off   
 
     
study. 
 
6.0 
Agent Formulation and Procurement 
 
Dose Preparation and Storage of azacitidine (VIDAZA): Azacitidine is commercially 
available and will not be provided for the study by Celgene. Standard procedures should 
be used for preparation and administration of azacitidine. The following guidelines are 
suggested: 
 
VIDAZA is a cytotoxic drug and, as with other potentially toxic compounds, caution 
should be exercised when handling and preparing VIDAZA suspensions. (See Handling 
and Disposal.) 
 
If reconstituted VIDAZA comes into contact with the skin, immediately and thoroughly 
wash with soap and water.  If it comes into contact with mucous membranes, flush 
thoroughly with water. 
 
The VIDAZA vial is single-use and does not contain any preservatives. Unused portions 
of each vial should be discarded properly.  See Handling and Disposal. Do not save any 
unused portions for later administration.  
 
Preparation for Subcutaneous Administration: VIDAZA should be reconstituted 
aseptically with 4 mL sterile water for injection.  The diluent should be injected slowly 
into the vial.  Vigorously shake or roll the vial until a uniform suspension is achieved.  
The suspension will be cloudy. The resulting suspension will contain azacitidine 25 
mg/mL.  
 


Sorafenib plus 5-Azacitidine Initial Therapy – 2014-0076 
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22 
 
 
22
Preparation for Immediate Subcutaneous Administration:  Doses greater than 4 mL 
should be divided equally into at least 2 syringes. The product may be held at room 
temperature for up to 1 hour, but must be administered within 1 hour after reconstitution.  
 
Preparation for Delayed Subcutaneous Administration:  The reconstituted product 
may be kept in the vial or drawn into a syringe. Doses greater than 4 mL should be 
divided equally into at least 2 syringes. The product must be refrigerated immediately, 
and may be held under refrigerated conditions (2ºC–8ºC, 36ºF–46ºF) for up to 8 hours. 
After removal from refrigerated conditions, the suspension may be allowed to equilibrate 
to room temperature for up to 30 minutes prior to administration.  
 
Subcutaneous Administration: To provide a homogeneous suspension, the contents of 
the syringe must be re-suspended by inverting the syringe 2–3 times and vigorously 
rolling the syringe between the palms for approximately 30 seconds immediately prior to 
administration. VIDAZA suspension is administered subcutaneously. Doses greater than 
4 mL should be divided equally into 2 syringes and injected into 2 separate sites. Rotate 
sites for each injection (thigh, abdomen, or upper arm). New injections should be given at 
least 1 inch from an old site and never into areas where the site is tender, bruised, red, or 
hard.  
Suspension Stability: Azacitidine reconstituted for subcutaneous administration may be 
stored for up to 1 hour at 25°C (77°F) or for up to 8 hours between 2°C and 8°C (36°F 
and 46°F).   
 
Preparation for Intravenous Administration: Reconstitute the appropriate number of 
VIDAZA vials to achieve the desired dose. Reconstitute each vial with 10 mL sterile 
water for injection.  Vigorously shake or roll the vial until all solids are dissolved.  The 
resulting solution will contain azacitidine 10mg/mL. The solution should be clear. 
Parenteral drug product should be inspected visually for particulate matter and 
discoloration prior to administration, whenever solution and container permit. 
Withdraw the required amount of VIDAZA solution to deliver the desired dose and inject 
into a 50-100 mL infusion bag of either 0.9% Sodium Chloride Injection or Lactated 
Ringer’s Injection. 
 
Intravenous Solution Incompatibility: VIDAZA is incompatible with 5% Dextrose 
solutions, Hespan, or solutions that contain bicarbonate. These solutions have the 
potential to increase the rate of degradation of VIDAZA and should therefore be avoided. 
 
Intravenous Administration: VIDAZA solution is administered intravenously.  
Administer the total dose over a period of 10-40 minutes. The administration must be 
completed within 1 hour of reconstitution of the VIDAZA vial. 
 
Solution Stability: VIDAZA reconstituted for intravenous administration may be stored 
at 25°C (77°F), but administration must be completed within 1 hour of reconstitution. 
 


Sorafenib plus 5-Azacitidine Initial Therapy – 2014-0076 
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23
Storage: Store un-reconstituted vials at 25º C (77º F); excursions permitted to 15º-30º C 
(59º-86º F) (See USP Controlled Room Temperature).  There is no need to protect 
azacitidine from exposure to light. 
 
Handling and Disposal: Procedures for proper handling and disposal of anticancer drugs 
should be applied.  
 
Sorafenib is supplied as an immediate-release film-coated, round, and salmon color tablet 
containing 200 mg of the free base, Sorafenib, and the excipient croscarmellose sodium, 
microcrystalline cellulose, hydroxypropyl methylcellulose, sodium lauryl sulfate, and magnesium 
stearate. The film-coat consists of hydroxypropyl methylcellulose, polyethylene glycol, titanium 
dioxide and red iron oxide. The film coating has no effect on the rate of release of the active 
sorafenib.  
 
 
Sorafenib 200 mg tablets are supplied in bottles of 120 tablets.  Sorafenib is 
                    Commercially available. 
 
 
 
Taken twice daily without food (at least 1 hour before or 2 hours after a meal) 
 
 
 
Storage 
 
 
Store at 25°C (77°F): excursions permitted to 15° - 30°C (59° - 86°F) (see USP 
controlled room temperature).  Store in a dry place. 
7.0 
Correlative/Special studies 
 
These studies are not mandatory for every patient and will be done when possible. 
 
Molecular testing for cytogenetics, FLT3 and NPM1 will be performed on all bone marrow 
samples obtained during the study (unless normal at baseline or thought to not be needed by the 
treating physician). 
 
Whenever feasible and through the MDACC Moonshot bone marrow procurement protocol, we 
will attempt to submit all patients’ initial, pre-treatment bone marrow specimens as well as any 
follow-up specimens to the Cancer Genomics Laboratory (directed by Dr. Futreal)  for 
comprehensive genomic evaluation to discern patterns of genomic evolution in responders versus 
non-responders. 
 
Peripheral blood for correlative studies days (+/- 3 days) on days 0, 2, 7, 21 and 28 of the first 
cycle (done at MD Anderson, for Dr. Garcia-Manero’s laboratory) will be optional. On 
subsequent courses samples will be obtained on day 0 (pretreatment), and day 7. All these 
samples can be obtained +/- 3 days. Peripheral blood samples for correlative studies (Plasma 
inhibitory assay and FLT3 ligand levels done at Johns Hopkins) will also be performed on days 
0, 7 and 28 of the first course as well as days 0 and 7 of subsequent courses.  Every effort will be 
made to collect these optional specimens – but any missed time point will not be considered a 


Sorafenib plus 5-Azacitidine Initial Therapy – 2014-0076 
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24 
 
 
24
deviation. Samples will be sent to:  Mark Levis MD PhD, Professor of Oncology, Johns Hopkins Medical 
Institutes, Cancer Research Building I, 1650 Orleans Street Room 230, Baltimore, MD 21287. 
8.0 
Patient evaluation 
8.1 
Pre-treatment evaluation:  
 All pretreatment studies should be obtained within 14 days of entry into the trial (except 
bone marrow that should be done within 28 days or 14 days if patient has received 
medication for their disease within that period of time.  
 A complete history and physical, documentation of all measurable disease, and 
performance status should be performed within 48 hours before initiation of study. 
o CBC, platelet count, differential (differential can be omitted if WBC is ≤0.5 
x109/L) 
o Creatinine, total bilirubin, ALT or AST, electrolytes and chemistry, PT, PTT,INR, 
Pregnancy test (urine or serum) in females, should be performed 48 hours before 
initiation of study unless 12 months menopausal or surgically sterilized. 
o Bone marrow aspirate during the last 28 days preceding study initiation unless 
patient has received medication for their disease within that period of time. 
Cytogenetics and Molecular studies (FLT3 and NPM1) will be obtained prior to 
therapy (results from prior analysis can be used for this purpose). . Molecular 
studies (FLT3 and NPM1) performed at baseline only and on patients with 
unknown status. 
o Pretreatment optional correlative studies (see 8.2.5 below) 
 
8.2 
Evaluation during treatment: 
 
 Physical exam at the start of each cycle (± 4 days) for the first 24 cycles, then every 2-3 
cycles. 
 CBC, platelet count, differential once weekly for the first  2 cycles, then  monthly 
(differential can be omitted if WBC is ≤0.5 x109/L) 
 Creatinine, total bilirubin, ALT or AST, electrolytes and chemistry, weekly for the first 2  
cycles, then  monthly. PT, PTT, INR if greater than 1.5 at baseline if clinically indicated 
 Bone marrow aspiration on Cycle 1 Day 28 (+/- 4 days), every  2-3 cycles for the first 
two years, and then at the discretion of the treating physician. 
 Peripheral blood for correlative studies days (+/- 3 days) on days 0, 2, 7, 21 and 28 of the 
first course (done at MD Anderson) will be optional. On subsequent courses samples will 


Sorafenib plus 5-Azacitidine Initial Therapy – 2014-0076 
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25
be obtained on day 0 (pretreatment), and day 7. All these samples can be obtained +/- 3 
days. 
9.0 
Criteria for response 
 
Criteria for response will be as per the international working group for MDS and AML. 
 
9.1 
Response criteria for MDS: Response criteria will be according to the International 
Working Group (Blood 2006; 108: 419-425). Responders are patients who obtain a CR, CRi, or 
PR, with or without cytogenetic response, hematologic improvements, and morphologic 
leukemia-free state. Briefly, criteria are as follows: 
 
9.1.1 Morphologic Complete Response (CR) 
 
 
 Peripheral blood counts: 
No circulating blasts 
Neutrophil count >1.0 x109/L 
 
Platelet count >100 x109/L 
 
 Bone marrow aspirate and biopsy: 
< 5% blasts 
No extramedullary leukemia 
 
9.1.2 Partial Response (PR) 
 
 All CR criteria if abnormal before treatment  except: 
 50 % reduction in bone marrow blast but still >5% 
 
9.1.3 Marrow CR 
 Bone marrow: 5% myeloblasts and decrease by 50% over 
pretreatment 
 Peripheral blood: if HI responses, they will be noted in addition to 
marrow CR 
 
9.1.4 Hematologic Improvement (HI): Hematologic response must be described by the 
number of positively affected cell lines. 
 
 Erythroid response (E) (pretreatment Hgb <11 g/dL) 
 
Hgb increase by 1.5 g/dL 
 Platelet response (P) (pretreatment platelets <100 x109/L) 
 Absolute increase of 30 x 109/L for patients starting with > 
20 x 109/L platelets 
Increase from < 20 x 109/L to > 20 x 109/L and by at least 
100% 


Sorafenib plus 5-Azacitidine Initial Therapy – 2014-0076 
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26
 Neutrophil response (N) (pretreatment ANC <1.0 x109/L) 
At least 100% increase and an absolute increase > 0.5 x 
109/L 
 
9.2 
Response criteria for AML: Response criteria will be mdified from the 
International Working Group for AML (JCO 2003; 21: 4642-9). Responders are patients 
who obtain a CR, CRi, or PR, with or without cytogenetic response, hematologic 
improvements, and morphologic leukemia-free state. Briefly, criteria are as follows: 
 
9.2.1 Complete remission (CR):  
 
 Peripheral blood counts: 
No circulating blasts 
Neutrophil count ≥1.0 x109/L 
 
Platelet count ≥100 x109/L 
 
 Bone marrow aspirate and biopsy: 
< 5% blasts 
No Auer rods 
No extramedullary leukemia 
 
9.2.2 Complete remission with incomplete blood count recovery (CRi): 
 
 Peripheral blood counts: 
No circulating blasts 
Neutrophil count <1.0 x109/L, or 
Platelet count <100 x109/L 
 
 Bone marrow aspirate and biopsy: 
< 5% blasts 
No Auer rods 
No extramedullary leukemia 
 
9.2.3 Partial remission:  
All CR criteria if abnormal before treatment except: 
50 % reduction in bone marrow blast but still >5% 
 
 Morphologic leukemia-free state:  
 
Bone marrow: 5% myeloblasts   
 
9.2.4 Hematologic Improvement (HI): Hematologic response must be described by the 
number of positively affected cell lines. 
 
 Erythroid response (E) (pretreatment Hgb <11 g/dL) 
Hgb increase by 1.5 g/dL 


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27
 
 Platelet response (P) (pretreatment platelets <100 x109/L) 
Absolute increase of 30 x 109/L for patients starting with > 20 x 
109/L platelets 
Increase from < 20 x 109/L to > 20 x 109/L and by at least 100% 
 
 Neutrophil response (N) (pretreatment ANC <1.0 x109/L) 
At least 100% increase and an absolute increase > 0.5 x 109/L 
 
 
10.0 Criteria for Removal from Study 
 
 Progressive disease 
 Intercurrent illness that prevents further administration of treatment, 
 Patient request,  
 Pregnancy or 
 General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator. 
11.0     Background Drug Information 
 
      11.1   Sorafenib  
 
 
 
 Chemical Name:  
4–{4-[3-(4-chloro-3-trifluoromethyl-phenyl) ureido]-phenoxy}-pyridine-2 carboxylic 
acid methylamide-4-methylbenzensulfonate. 
 
 
 
Other Names:   
 
 
BAY 54-9085 is the tosylate salt of SORAFENIB 
 
 
 
Classification:   
 
 
Kinase inhibitor (Raf, VEGF-R, and PDGF-R) 
 
 
 
Mechanism of Action:  
 
The ras/raf signaling pathway is an important mediator of responses to growth signals 
and angiogenic factors. This pathway is often aberrantly activated in human tumors due 
to presence of activated ras, mutant b-raf, or over expression of growth factor receptors.  
 
 
 
 
 
 
SORAFENIB is a potent inhibitor of c-raf, and wild-type and mutant b-raf in vitro. 
Additionally, further characterization of SORAFENIB revealed that this agent inhibits 
several receptor tyrosine kinases (RTKs) that are involved in tumor progression (VEGF-
R, PDGF-R, Flt3, and c-KIT) and p38α, a member of the MAPK family. 
 
 
Molecular Formula: 
 
 
 
C12H16CIF3N4O3 X C7H8O3S 
 


Sorafenib plus 5-Azacitidine Initial Therapy – 2014-0076 
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28
 
 
 
M.W.: 
 
 
 
 
SORAFENIB: 637 Daltons; SORAFENIB (free base): 465 Daltons  
 
 
 
Approximate Solubility:  
 
 
 
0.19 mg/100 mL in 0.1 N HCl, 453 mg/100 mL in Ethanol, and 2971 mg/100 mL in PEG 
400.  
 
 
 
How Supplied:   
 
SORAFENIB  is supplied as an immediate-release film-coated, round, and salmon color 
tablet 
containing 
200 
mg 
of 
the 
free 
base, 
SORAFENIB, 
and 
the 
excipientcroscarmellosesodium,microcrystallinecellulose,hydroxypropylmethylcellulos
e, sodium lauryl sulfate, and magnesium stearate. The film-coat consists of 
hydroxypropylmethyl cellulose, polyethylene glycol, tiranium dioxide and red iron 
oxide. The film coating has no effect on the rate of release of the active SORAFENIB .  
 
 
 
SORAFENIB 200 mg tablets are supplied in bottles of 120 tablets. 
 
 
 
Storage:   
 
 
 
Store at controlled room temperature (15ºC – 25ºC). Storage conditions should not 
exceed 25ºC. 
 
 
 
Stability:  
 
 
Stability studies with the 200 mg dosage form are ongoing. The current shelf life is 24 
months when stored at controlled room temperature.  
 
 
 
Route(s) of Administration:  
 
 
 
Orally   
 
 
 
Reported Adverse Events and Potential Risks:   
 
Body as a whole:  
 
 
fatigue, flu-like syndromes, fever, arthralgia 
 
 
Gastrointestinal:  
 
 
diarrhea, pancreatitis, elevated amylase/lipase, abdominal pain/cramping, nausea, 
 
flatulence, dyspepsia 
 
 
Hepatic: 
 
increased bilirubin, ALT,AST, GGT, LDH, and alkaline phosphatase 
 
 
Metabolic and Nutritional:  
 
 
anorexia 
 
 
Skin: 


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29
hand-foot syndrome, characterized by palmar and plantar erythema; rash/desquamation, 
hypersensitivity reactions, dry skin, alopecia, nail changes, vitiligo 
 
The following adverse events have been reported on trials but with the relationship 
to SORAFENIB still undetermined:   
arthritis, brain stem stroke, dyspnea, hypertension, increase PT and PTT, and weight loss. 
 
 
 
Method of Administration:  
 
Patients will be instructed to take SORAFENIB on an empty stomach (1 hour before or 
2 hours after eating). 
 
 
 
Potential Drug Interactions: 
 
SORAFENIB is metabolized by the P450 CYP3A enzyme and has been shown in 
 
preclinical studies to inhibit multiple CYP isoforms. Therefore, it is possible that 
SORAFENIB may interact with drugs that are metabolized by the P450 CYP isoenzymes 
or with drugs that inhibit CYP 3A. Close monitoring is recommended for patients taking 
agents with narrow therapeutic indices and metabolized by the liver, such as warfarin, 
phenytoin, quinidine, carbamazepine, phenobarbital, cyclosporine, and digoxin. 
Additionally, SORAFENIB is 97% to 99% protein bound; however, no drug interactions 
have been reported in studies, thus far. 
 
 
 
Availability 
SORAFENIB is commercially available. 
 
Consult the package insert on www.nexavar.com for additional information 
 
 
 
11.2   Azacitidine  
 
 
 
 Chemical Name:  
4-amino-1-beta-D-ribofuranosyl-1,3,5-triazin-2(1H)-one 
 
 
 
Other Names:   
 
 
5-azacytidine, azacytidine, 5-AC, 5-AZC 
 
 
 
Classification:   
 
 
DNA methylation inhibitor 
 
 
 
Mechanism of Action:  
 
Azacitidine is a pyrimidine nucleoside analog of cytidine.  Azacitidine is believed to 
exert its antineoplastic effects by causing hypomethylation of DNA and direct 
cytotoxicity on abnormal hematopoietic cells in the bone marrow.  Hypomethylation may 
restore normal function to genes that are critical for differentiation and proliferation. 
 
 
Molecular Formula: 
 
 
 
C8H12N4O5  


Sorafenib plus 5-Azacitidine Initial Therapy – 2014-0076 
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30 
 
 
30
 
 
 
M.W.: 
 
 
 
 
Azacitidine : 244 Daltons  
 
 
 
How Supplied:   
 
Azacitidine  is supplied in a sterile form for reconstitution as a suspension for 
subcutaneous infection or reconstitution as a solution for further dilution for intravenous 
infusion.  Vials of azacitidine contain 100 mg of azacitidine and 100 mg of mannitol as 
a sterile lyophilized powder. 
 
 
 
Storage:   
 
Store un-reconstituted vials at 25º C (77º F); excursions permitted to 15º-30º C (59º-
86º F) (See USP Controlled Room Temperature).  There is no need to protect 
azacitidine from exposure to light. 
 
 
 
Stability:  
 
 
Azacitidine reconstituted for subcutaneous administration may be stored for up to 1 
hour at 25°C (77°F) or for up to 8 hours between 2°C and 8°C (36°F and 46°F).    
Azacitidine reconstituted for intravenous administration may be stored at 25°C (77°F), 
but administration must be completed within 1 hour of reconstitution. 
 
 
 
Route(s) of Administration:  
 
 
 
Subcutaneous or intravenous 
 
 
 
Reported Adverse Events and Potential Risks:   
 
Body as a whole:  
 
 
weakness, rigors, fever, arthralgia, myalgia,  
 
 
Gastrointestinal:  
 
 
diarrhea, constipation, abdominal pain/cramping, nausea, vomiting 
 
 
Hematologic:  
 
 
Anemia, thrombocytopenia, neutropenia 
 
 
Metabolism and Nutrition: 
 
hypokalemia, anorexia 
 
 
Renal: 
Elevated serum creatinine, renal failure, renal tubular acidosis  
 
Skin: 
injection site erythema, petechiae, ecchymosis 
 
Other: 
hepatic coma, dizziness, headache, shortness of breath 


Sorafenib plus 5-Azacitidine Initial Therapy – 2014-0076 
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31 
 
 
31
 
 
 
Method of Administration:  
 
See section 6.1 for complete details. 
 
 
 
Potential Drug Interactions: 
 
No formal assessments of drug-drug interactions between azacitidine and other agents 
have been conducted.   
 
 
 
Availability 
Azacitidine is commercially available. 
 
Consult the package insert on www.vidaza.com for additional information 
12.0     Adverse Event Reporting 
 
Refer to Appendix C for Leukemia-Specific Adverse Event Recording and Reporting 
Guidelines.  Only unexpected AEs will be recorded in the Case Report Form (CRF).  
 
12.1 
Pregnancies:  
 
If a female subject or partner of a male subject becomes pregnant during the study dosing period 
or within 3 months from the discontinuation of dosing, the investigator should report the 
information to the MDACC IRB as if it is an SAE. The expected date of delivery or expected 
date of the end of the pregnancy, last menstruation, estimated fertility date, pregnancy result and 
neonatal data etc., should be included in this information. The investigator will follow the 
medical status of the mother, as well as the fetus, as if the pregnancy is an SAE.  
When the outcome of the pregnancy falls under the criteria for SAEs [spontaneous abortion, 
induced abortion, stillbirth, death of newborn, congenital anomaly (including anomaly in a 
miscarried fetus)], the investigator should respond in accordance with the report procedure for 
SAEs.  
- "Spontaneous abortion" includes abortion and missed abortion.  
- Death of an infant within 1 month after birth should be reported as an SAE regardless of its 
relationship with the study drug.  
- If an infant dies more than 1 month after the birth, it should be reported if a relationship 
between the death and intrauterine exposure to the study drug is judged as "possible" by the 
investigator.  
- In the case of a delivery of a living newborn, the "normality" of the infant is evaluated at the 
birth.  
- "Normality" of the miscarried fetus is evaluated by visual examination unless test results which 
indicate a congenital anomaly are obtained prior to miscarriage.  
   
13.0  Statistical Considerations 
 


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32 
 
 
32
This is a single arm study using the dosage level recommended from a previously conducted and 
published phase I/II study in patients with relapsed AML. The sample size is 52. The trial will be 
continuously monitored for efficacy and toxicity (non-hematological ≥grade 3). The method of 
Thall, Simon, and Estey will be used to perform interim efficacy and safety monitoring.14  
13.1 
Efficacy  
The primary endpoint is the overall response (CR+CRi) after three cycles of treatment. The 
historical data suggested the overall response rate is 45%. With the assumption that the improved 
overall response rate to be 65%, it is estimated that a total of 52 evaluable patients will yield 
83% power at a significance level of 5% based on chi-square test. The trial will be continuously 
monitored. The study will be stopped early if the data suggest that: 
                                      Pr (> 0.45|data) < 0.05 
 
Here  is the overall response (OR) rate. That is, if at any time during the study we determine that 
there is a less than 5% chance that the average OR rate is greater than 45%, we will terminate the 
study.  The OR rate is assumed to follow a non-informative prior of Beta (0.9, 1.1).  
13.2 
Monitoring Of non-hematological ≥grade 3 toxicities 
With the concern of treatment related toxicity, the non-hematological toxicity (≥grade 3) will 
also be closely monitored during the study.   
 
Denote the probability of toxicity by PE. We assume PE ~ beta (0.6,1.4).  Our stopping rule is given 
by the following probability statement:  
                                       Pr(PE > 0.3 | data)  > 0.95 .  
 
That is, we will stop the trial if, at any time during the study, we determine that there is more than 
95% chance that the toxicity is more than 30%.  
 
Patients will be monitored by a cohort size of 4 according to the following stopping boundaries for 
overall response and toxicity. The design software Multc Lean Desktop (version 2.1) developed 
by the Department of Biostatistics at M. D. Anderson Cancer Center (MDACC) was used to 
generate the futility/toxicity stopping boundaries and the OC table. 
 
Table 13.1. Stopping boundaries for overall response and toxicity 
 
Number of patients evaluated 
Stop the trial if there are this 
many responses 
Stop the trial if there are 
this many toxicities 
4 
0 
4 
8 
0-1 
5-8 
12 
0-2 
7-12 
16 
0-3 
9-16 
20 
0-5 
10-20 


Sorafenib plus 5-Azacitidine Initial Therapy – 2014-0076 
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33 
 
 
33
24 
0-6 
12-24 
28 
0-8 
13-28 
32 
0-9 
15-32 
36 
0-11 
16-36 
40 
0-12 
18-40 
44 
0-14 
19-44 
48 
0-15 
20-48 
 
 
Table 13.2. Operating characteristics of futility and safety monitoring  
True Toxicity 
Rate 
True overall 
response Rate 
Prob (stop the trial early) 
Average sample size 
0.2 
0.25 
0.94 
17.2 
0.35 
0.59 
31.9 
0.45 
0.21 
43.8 
0.55 
0.07 
48.8 
0.65 
0.03 
50.6 
0.3 
0.25 
0.95 
16.4 
0.35 
0.64 
29.7 
0.45 
0.32 
40.4 
 
0.55 
0.2 
44.9 
0.65 
0.16 
46.5 
0.4 
0.25 
0.97 
14.0 
 
0.35 
0.82 
23.1 
0.45 
0.66 
30.1 
0.55 
0.61 
33.2 
0.65 
0.59 
34.3 
0.5 
0.25 
1.0 
10.9 
 
0.35 
0.97 
15.1 
 
0.45 
0.95 
18.1 
 
0.55 
0.94 
19.5 
 
0.65 
0.93 
20 
13.3 
Analysis method 
 


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34 
 
 
34
Data analysis will be performed using SAS or S-plus, as appropriate. All patients who received at 
least 1 dose of the combined agents will be included in the intent-to-treat analysis for efficacy.  
Demographic and disease characteristics of the patients at registration will be summarized using 
descriptive statistics such as mean, standard deviation (SD), median and range. Overall response 
rates will be presented with 95% confidence intervals. The association between response and 
patient and disease characteristics will be examined by two-sample t-test or Chi-square test.  
 
The data from all patients who received the combined therapy during the study will be included 
for safety analysis. Subjects who entered the study and did not take any of the study drugs and had 
this confirmed will not be evaluated for safety. The severity of the toxicities will be graded 
according to the NCI CTCAE v4.0 whenever possible. We will follow standard reporting 
guidelines for adverse events. Safety data will be summarized by category, severity and frequency. 
The proportion of patients with AEs will be estimated, along with the Bayesian 95% credible 
interval. These descriptive summaries will be provided for all patients for each safety parameter 
by cycle, grade, and relationship to treatment.   
This study will be conducted as described in this protocol, except for an emergency situation in 
which the protection, safety, and wellbeing of the patient requires immediate intervention, based 
on the judgment of the investigator or his/her designee. In the event of a significant deviation 
from the protocol, the investigator will notify the MDACC surveillance committee following the 
institutional guidelines. 
14.0 Protocol Administration 
14.1 
Protocol amendments 
Changes to the protocol will be made only when protocol amendments have been signed by the 
principal investigator, and by the ethical committee of the study center. 
14.2 
Archival of data 
 
All patient data (including source data) generated in connection with this study will be kept in 
the archives of the MDACC for at least 15 years after the study has been completed. All data will 
be available for inspection by company representatives of the Medical Department and by 
regulatory authorities. 


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35
15.0 References 
 
1. 
Ravandi F, Talpaz M, Estrov Z: Modulation of cellular signaling pathways: 
prospects for targeted therapy in hematological malignancies. Clin Cancer Res 9:535-50, 2003 
 
2. 
Rosnet O, Marchetto S, deLapeyriere O, et al: Murine Flt3, a gene encoding a 
novel tyrosine kinase receptor of the PDGFR/CSF1R family. Oncogene 6:1641-50, 1991 
 
3. 
Rosnet O, Buhring HJ, Marchetto S, et al: Human FLT3/FLK2 receptor tyrosine 
kinase is expressed at the surface of normal and malignant hematopoietic cells. Leukemia 
10:238-48, 1996 
 
4. 
Maroc N, Rottapel R, Rosnet O, et al: Biochemical characterization and analysis 
of the transforming potential of the FLT3/FLK2 receptor tyrosine kinase. Oncogene 8:909-18, 
1993 
 
5. 
Mizuki M, Fenski R, Halfter H, et al: Flt3 mutations from patients with acute 
myeloid leukemia induce transformation of 32D cells mediated by the Ras and STAT5 pathways. 
Blood 96:3907-14, 2000 
 
6. 
Carow CE, Levenstein M, Kaufmann SH, et al: Expression of the hematopoietic 
growth factor receptor FLT3 (STK-1/Flk2) in human leukemias. Blood 87:1089-96, 1996 
 
7. 
Drexler HG: Expression of FLT3 receptor and response to FLT3 ligand by 
leukemic cells. Leukemia 10:588-99, 1996 
 
8. 
Stacchini A, Fubini L, Severino A, et al: Expression of type III receptor tyrosine 
kinases FLT3 and KIT and responses to their ligands by acute myeloid leukemia blasts. 
Leukemia 10:1584-91, 1996 
 
9. 
Gilliland DG, Griffin JD: The roles of FLT3 in hematopoiesis and leukemia. 
Blood 100:1532-42, 2002 
 
10. 
Kottaridis PD, Gale RE, Frew ME, et al: The presence of a FLT3 internal tandem 
duplication in patients with acute myeloid leukemia (AML) adds important prognostic 
information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 
854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood 
98:1752-9, 2001 
 
11. 
Levis M, Pham R, Smith BD, et al: In vitro studies of a FLT3 inhibitor combined 
with chemotherapy: sequence of administration is important to achieve synergistic cytotoxic 
effects. Blood 104:1145-50, 2004 
 
12. 
Zhang W, Konopleva M, Ruvolo VR, et al: Sorafenib induces apoptosis of AML 
cells via Bim-mediated activation of the intrinsic apoptotic pathway. Leukemia 22:808-18, 2008 
 
13. 
Zhang W, Konopleva M, Shi YX, et al: Mutant FLT3: a direct target of sorafenib 
in acute myelogenous leukemia. J Natl Cancer Inst 100:184-98, 2008 
 
14.  
Thall PF, Simon RM and Estey EH. Bayesian sequential monitoring designs for 
single-arm clinical trials with multiple outcomes. Statistics in Medicine 14, 357-379, 1995 
 
15. 
Ratain MJ, Eisen T, Stadler WM, et al. Phase II placebo-controlled randomized 
discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol; 
24:2505–2512, 2006 
 
16. 
Escudier B, Eisen T, Stadler W M, Szczylik C, Oudard S, Siebels M, et al. 
Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med; 356: 125–134, 2007 
17.  
Escudier  B, Eisen T, Stadler WM, et al. Sorafenib for treatment of renal cell 
carcinoma: Final efficacy and safety results of the phase III treatment approaches in renal cancer 
global evaluation trial. J Clin Oncol 27(20):3312-8. 2009 


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18.  
Ravandi F, Alattar ML, Grunwald MR, et al. Phase 2 study of azacytidine plus 
sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication 
mutation. Blood. 121(23):4655-62. 2013