Conditions: Malignant Neoplasms of Mesothelial and Soft Tissue Gastrointestinal Stromal Tumor With Neurogenic Differentiation
Keywords: Malignant Neoplasms of Mesothelial and Soft Tissue Gastrointestinal Stromal Tumor GIST Iron-deficiency anemia Ferric Carboxymaltose Injectafer Iron supplement Health Questionnaire Survey
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 3
Healthy volunteers: no

Brief summary:
The goal of this clinical research study is to compare Injectafer® (ferric carboxymaltose) with an iron supplement to learn which may be more effective in improving red blood cell counts in patients who have iron-deficiency anemia (a low red blood cell count) because of a gastrointestinal stromal tumor (GIST) and/or systemic therapy.

The safety of ferric carboxymaltose will also be studied.

This is an investigational study. Ferric carboxymaltose is FDA approved and commercially available to treat iron deficiency anemia; however, it is considered investigational to use in patients who have cancer-related or systemic therapy-related anemia.

Up to 50 participants will take part in this study. All will be enrolled at MD Anderson.

Detailed description:
Study Groups and Study Drug Administration:

If you are found to be eligible to take part in this study, you will be randomly assigned (as in the flip of a coin) to 1 of 2 study groups. This is done because no one knows if one group is better, the same, or worse than the other.

* If you are in Group A, you will receive ferric carboxymaltose injection by vein over about 15 minutes. You will receive 2 injections about 7 days apart (for example, on Days 0 \[the day you are assigned to a study group\] and 7).
* If you are in Group B, you will take iron supplements by mouth every day. This is considered standard of care for iron deficiency anemia and the study staff will discuss with you which iron supplements you will take and their risks.

You and the study staff will know to which group you are assigned.

Length of Study:

You may receive up to 2 injections of ferric carboxymaltose (if you are in Group A) or up to 3 months of oral iron supplements (if you are in Group B). You will no longer be able to take the study drug if intolerable side effects occur or if you are unable to follow study directions.

Your participation on the study will be over after you have completed the Week 24 visit.

Study Visits:

Baseline (within 1 week after you have been assigned to a study group):

* You will have a physical exam.
* You will complete a questionnaire about your health. It should take about 5 minutes to complete.
* Blood (about 1 tablespoon) will be drawn for routine tests and to test the level of iron in your blood.

One (1) time every week during Months 1-3, blood (about 1 tablespoon) will be drawn for routine tests.

At about Weeks 4, 8, 12, and 24 (the end-of-study visit):

* You will have a physical exam (Weeks 12 and 24 only).
* You will complete the same questionnaire you did at baseline.
* Blood (about 1 tablespoon) will be drawn for routine tests and to test the level of iron in your blood.

During Weeks 16 and 20, blood (less than 1 tablespoon) will be drawn to test the level of iron in your blood.

If you leave the study before Week 24, you will have the Week 24 study visits as soon as possible after you leave the study.

Arms:
arm 1: Participants receive a Ferric Carboxymaltose injection by vein. Dose repeated 1 week later.

Health questionnaire completed at Baseline and at Weeks 4, 8, 12, and 24. arm 2: Participants take iron supplements by mouth every day for up to 3 months.

Health questionnaire completed at Baseline and at Weeks 4, 8, 12, and 24.

Interventions: intervention 1: Ferric Carboxymaltose intervention 2: Iron Supplements intervention 3: Questionnaire
Intervention descriptions: intervention 1: 15 mg/kg by vein (up to 750 mg) over 15 min infusion. Dose repeated 1 week later. intervention 2: Participants take iron supplements by mouth every day for up to 3 months. intervention 3: Health questionnaire completed at Baseline and at Weeks 4, 8, 12, and 24.

Protocol document:
Prot_SAP_000.pdf: 
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Efficacy of Ferric Carboxymaltose in Patients with Gastrointestinal Stromal 
Tumor Receiving Systemic Therapy 
1.0 Objectives  
 
Primary Objective: 
To evaluate the efficacy of Ferric Carboxymaltose (Injectafer) in anemia in 
gastrointestinal stromal tumor (GIST) patients planned to receive or receiving systemic 
therapy and presenting with anemia. 
 
Secondary Objectives: 
(1) To evaluate the toxicity of Ferric Carboxymaltose in GIST patients planned to 
receive or receiving systemic therapy and presenting with anemia. 
(2) To evaluate effect of Ferric Carboxymaltose on patient reported outcomes (fatigue) 
by Functional Assessment of Cancer Therapy-Fatigue Scale (FACT-F).  
  
2.0  Background 
 
2.1 Cancer and Chemotherapy-related Anemia 
Anemia is a common complication in patients who have cancer and those who receive 
Chemotherapy [1]. Depending on the type of cancer, 30% to 90% of patients have 
anemia, defined as a hemoglobin <11.0 g/dL [2, 3]. Results from a survey, including 
more than 15,000 cancer patients, demonstrated that the incidence of anemia was 
53.7%; however, only 38.9% of the patients with anemia were treated.  In relation to the 
patient, anemia is a 
symptoms such as fatigue and weakness [4, 5]. Anemia in cancer patients is often 
multifactorial and can be caused by hemolysis, iron deficiency due to blood loss, 
inadequate nutrition, impaired RBC production due to direct effects of the cancer or 
myelosuppressive chemotherapy or radiation therapy [5]. The severity of anemia 
depends on the type and extent of the cancer, the schedule and intensity of therapy, 
and whether the patient has received prior chemotherapy and/or radiation. 
 
Iron deficiency anemia (IDA), is the top-ranked type of anemia worldwide [6]. The 
reported prevalence of IDA in cancer is around 32-60%. Iron deficiency (ID) plays a 
pivotal role in the development of anemia in cancer. ID in cancer may be separated into 
two components, absolute iron deficiency and functional iron deficiency. Absolute ID is 
defined as depleted iron stores. Most iron-deficient patients with cancer present with 
functional ID [7]. Functional ID is characterized by iron sequestration, and thus, the lack 
of available iron with normal or elevated ferritin levels. Functional ID is often caused by 
a chronic inflammatory state which many cancer patients may have [8]. Two studies 
have examined the administration of IV iron without ESAs, and both studies 
demonstrated that IV iron alone can reduce transfusion rates [9, 10]. 
 
2.2 Anemia in GIST Patients Receiving Systemic Therapy 
A gastrointestinal stromal tumor (GIST) is a type of tumor that occurs in the 
gastrointestinal tract, most commonly in the stomach or small intestine [11]. Chronic 


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blood loss is more common for GIST patients [12]. Many GIST patients are diagnosed 
with anemia due to chronic blood loss [13]. GIST patients presenting anemia can be 
due to iron deficiency anemia either from inadequate iron intake or from blood loss (as 
from a GIST bleeding into the GI tract), surgery, or drug-induced anemia; Gleevec and 
other Tyrosine Kinase Inhibitors (TKIs) may decrease production of new red blood cells 
[14]. 
 
2.3 Prevention/Treatment for IDA  
Iron replacement therapy is essential for replenishing iron stores and raising 
hemoglobin levels in patients with IDA, regardless of the etiology, and can be 
administered orally, intramuscularly, or intravenously [6,15]. Patients with IDA should 
receive iron supplementation and the prescribed use of oral iron is a convenient, 
inexpensive, and effective treatment regimen in stable patients.  However, use of oral 
iron is limited by side effects, including nausea, vomiting, constipation, and metallic 
taste, resulting in non-adherence and limited treatment response [6, 15].  
 
There is considerable efficacy and safety experience with the various oral iron 
preparations available. Intravenous iron replacement therapy is also a treatment 
alternative. However, prior to the approval of non-dextran formulations, the risk of 
systemic adverse reactions restricted their use [6, 15].  
 
More recently approved, non-dextran intravenous irons, like iron sucrose and iron 
gluconate, do not contain the dextran moiety, but they have significant dosage and 
administration rate limitations [16, 17]
store, and transport) iron is overwhelmed, a reaction to excess free iron referred to as a 
bioactive iron reaction may occur. These IV iron compounds carry a significant risk of 
bioactive iron reactions at higher doses. These reactions are characterized by 
hypotension (without allergic signs) accompanied by pain in the chest, abdomen, flank 
and/or nausea, vomiting, diarrhea [6, 15]. 
 
2.4 Injectafer, a Newly Approved Iron Preparation 
Injectafer (Ferric Carboxymaltose Injection) is a stable Type I polynuclear iron (III)-
hydroxide carbohydrate complex developed as an intravenous iron replacement therapy 
for the treatment of IDA. After intravenous administration, Injectafer is mainly found in 
the liver, spleen, and bone marrow. The iron slowly dissociates from the complex and 
can be efficiently used in the bone marrow for hemoglobin synthesis. The carbohydrate 
moiety of Injectafer is metabolized by the glycolytic pathway [18-21]. 
 
Due to its structure, Injectafer is more stable than iron gluconate and iron sucrose, 
producing a slow delivery of the complexed iron to endogenous iron binding sites and 
has an acute toxicity in animals approximately 1/5 that of iron sucrose. These 
characteristics of Injectafer make it possible to administer much higher single doses 
over shorter periods of time than iron gluconate or iron sucrose, resulting in the need for 
fewer administrations to replenish iron stores, consequently making it better suited for 
outpatient use (Table below).  
 


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Comparison of the Administration of Intravenous Iron with Currently US 
Available Iron Preparations 
Iron 
Preparation 
Test Dose 
Required 
Maximum 
Infusion Dose 
Infusion Time 
Number of 
Infusions 
Iron dextran 
Yes 
100 mg* 
2 minutes 
15 + test dose 
Iron gluconate 
No 
125 mg 
10 minutes 
12 
Iron sucrose 
No 
200 mg 
5 minutes 
8 
Iron sucrose 
No 
400 mg 
2.5 hours 
4 
Ferumoxytol 
No 
510 mg 
< 1 minute 
3 
Injectafer 
No 
750 to 1000 
mg** 
8 to 15 minutes
2 
* Higher doses are administered off label and are approved outside the US 
**1000 mg maximum dose is approved in the European Union; 750 mg maximum is the 
U.S. FDA approved dose that will be evaluated in this trial 
 
Compared to other available intravenous iron preparations, the larger Injectafer doses 
result in less frequent administration of intravenous iron and represents an improvement 
in convenience for patients and physicians, especially for those individuals with 
conditions amenable to complete replacement dosing in a single setting such as heavy 
uterine bleeding, inflammatory bowel disease, bariatric surgery, hereditary hemorrhagic 
telangiectasia or any condition where blood loss exceeds maximum absorption [18-21]. 
 
2.4.1 Pharmacodynamics 
A clinical pharmacokinetic study (VIT-IV-CL-001) using positron emission tomography 
(PET) demonstrated a fast initial elimination of radioactively labeled iron (Fe) 52Fe/59Fe 
Injectafer from the blood, with rapid transfer to the bone marrow and rapid deposition in 
the liver and spleen. Eight hours after administration, 5 to 20% of the injected amount 
was still in the blood, compared with 2 to 13% for iron sucrose. The projected terminal 
half-life (t½) was calculated to be approximately 16 hours, compared to 3 to 4 days for 
iron dextran and 6 hours for iron sucrose. An ascending dose pharmacokinetic study 
(VIT-IV-CL-002), demonstrated that following the 500 and 1,000 mg Injectafer dose, the 
majority of the Injectafer iron complex was utilized or excreted by 72 hours [18-21]. 
 
Using PET it was demonstrated that red cell uptake of 59Fe and 52Fe from Injectafer 
ranged from 61% to 99%. In patients with iron deficiency, red cell uptake of radio-
labeled iron ranged from 91% to 99% at 24 days after Injectafer dose. In patients with 
renal anemia, red cell uptake of radio-labeled iron ranged from 61% to 84% after 24 
days Injectafer dose. 
After administration of a single dose of Injectafer of 100 to 1000 mg of iron in iron 
deficient patients, maximum iron levels of 37 µg/mL to 333 µg/mL were obtained 
respectively after 15 minutes to 1.2 hours post dose. The volume of distribution was 
estimated to be 3 L. The iron injected or infused was rapidly cleared from the plasma, 
the terminal half-life ranged from 7 to 12 hours. Renal elimination of iron was negligible 
[18-21]. 


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2.4.2 Clinical Experience 
The efficacy of lnjectafer® for the treatment of IDA was demonstrated in 2 randomized, 
open-label, controlled clinical studies (1VIT09030 and 1 VIT09031).  In these 2 studies, 
Injectafer® was administered at a dose of 15 mg/kg body weight up to a maximum 
single dose of 750 mg of iron on 2 occasions separated by at least 7 days up to a 
cumulative dose of 1500 mg of iron [21-23].   
 
Study 1 VIT09031 enrolled subjects with iron-deficiency anemia who had an 
unsatisfactory response to oral iron or who were intolerant to or inappropriate for oral 
iron therapy during the 14-day, oral iron run-in period.  Study 1VIT09030 enrolled 
subjects with iron-deficiency anemia and impaired renal function [21-23].   
 
The overall incidence of treatment-emergent serious adverse events in the 2 studies 
was 12.8% in the Injectafer® group and 12.5% in the pooled comparators group.  No 
notable differences (1.0% and at least a 2-fold difference in incidence) were observed 
between the Injectafer® group and the pooled comparators groups for specific events. 
 
The overall incidence of treatment-emergent adverse events resulting in premature 
discontinuation of study drug was 2.9% in the Injectafer® group and 2.1% in the pooled 
comparators group.  The most common treatment-emergent adverse events resulting in 
premature discontinuation of study drug in the Injectafer® group were flushing and 
hypertension (0.5% and 0.6%, respectively) [21-23]. 
 
The percentage of subjects with treatment-emergent low phosphorus, defined as a 
baseline value that was Grade 0, 1, or 2 and decreased to a value defined as Grade 3 
(<2.0 to 1.0 mg/dL) or Grade 4 (<1.0 mg/dL) per Common Terminology Criteria for 
Adverse Event version 3.0, was the only notable difference between the Injectafer® 
(29.6%) and the pooled comparators (0.7) groups.  Mean decreases from baseline in 
phosphorus in the Injectafer® group were highest at Day 14 and were returning toward 
baseline at Day 28/35 in Studies 1VIT09030 and 1VIT09031.  The trend toward 
baseline continued through Day 56 in Study 1VIT09030 [21-23]. 
 
Safety results for 5799 Injectafer®-treated subjects treated in 20 short-term Phase 2/3 
studies of iron-deficiency anemia or congestive heart failure (CHF) were similar to 
studies 1VIT09030 and 1VIT09031 [21-23]. 
 
In summary, Injectafer® is a safe and effective treatment of IDA in adult patients who 
are [20]: 
 Intolerance to oral iron or have had unsatisfactory response to oral iron; 
 Non-dialysis-dependent chronic kidney disease. 
 
2.5 Rationale for the Study 
The incidence of anemia in patients with gastrointestinal stromal tumor (GIST) receiving 
TKIs therapy is high [13]. Anemia in GIST patients can be multifactorial such as: anemia 
of chronic disease, primary therapy, surgery, blood loss and Iron/vitamin deficiency [6]. 


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In our experience, GIST patients with anemia and IDA do response to oral iron if they 
can tolerate it.  In our observations in patients with GIST on iron therapy, approximately  
29% of patients tolerated and had response to oral iron vs 75% had response to IV iron 
such as iron sucrose. This experience is similar to response rate (73%-77%) reported 
with iv iron in clinical trials in cancer patients receiving chemotherapy [27]. However, the 
GIST patients seem to have lower tolerance to oral iron due to the underlying disease 
and treatment with TKIs. This can explain lower success rate (~29%) in our experience 
as compared to ~45% reported in clinical trials to oral drugs in cancer patients receiving 
chemotherapy. Also, multiple infusions of iron sucrose are needed to deliver the total 
dose of iron. Patients with GIST often present with IDA and anemia often worsens 
during therapy with TKIs like Gleevac [14]. These patients often have nausea from their 
systemic therapy and not all patients tolerate oral iron well. Also there is a time lag for 
response to oral iron. Injectafer is a newly approved, non-dextran IV iron that can be 
administered in a large dose of 2 infusions 1 week apart (15 mg/kg for a maximum 
single dose of 750 mg, a total of up to 1500 mg). The safety profile is excellent and has 
been found effective in correcting IDA. Based on these observations, we are proposing 
a clinical trial of IV injectafer vs oral iron (to avoid patient selection bias) in GIST 
patients with IDA planning to start or have recently started systemic therapy to evaluate 
efficacy and safety with IV injectafer.  
 
3.0  Background Drug Information 
 
3.1 Ferric Carboxymaltose (Injectafer) 
Injectafer® (ferric carboxymaltose injection) is a colloidal iron (III) hydroxide in complex 
with carboxymaltose, a carbohydrate polymer that releases iron [20]. 
A. Physical Description of Study Drug 
Injectafer® is a dark brown, non-transparent amorphous powder that is readily soluble 
in water.  The active pharmaceutical ingredient of Injectafer® contains about 28% 
weight to weight (w/w) of iron, equivalent to about 53% w/w iron (III) hydroxide, about 
37% w/w of ligand, < S6% w/w of sodium chloride and < S10% w/w of water [20]. 
 
B. Formulation Packaging, Labeling and Storage 
Ferric carboxymaltose, an iron replacement product, is an iron carbohydrate complex 
with the chemical name of polynuclear iron (III) hydroxide 4(R)-(poly-
-O- -D-
glucopyranosyl)-oxy-2(R),3(S),5(R),6-tetrahydroxy-hexanoate. It has a relative 
molecular weight of approximately 150,000 Da corresponding to the following empirical 
formula: [FeOx(OH)y(H2O)z]n [{(C6H10O5)m (C6H12O7)}I]k
3 
[20].  
Injectafer will be supplied as 15 mL vials, containing 750 mg of iron as 5% w/v iron 
solution in water for injection. 
 
The dosage of Injectafer® is expressed in mg of elemental iron. Each mL of Injectafer® 
contains 50 mg of elemental iron.  Injectafer® is intended for intravenous (IV) 
administration, either as a slow IV push or by IV infusion.  When administered as a slow 
IV push, lnjectafer® can be injected without dilution at a rate of 100 mg/minute. When 


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administered as an infusion, up to 750 mg of lnjectafer® is diluted in no more than 250 
mg of sterile 0.9% weight to volume (w/v) sodium chloride, such that the concentration 
of the infusion is not less than 2 mg of iron/mL and administered over 15 minutes.  No 
other IV dilution solutions should be used and no other therapeutic agent should be 
added, as there is a potential for interaction. 
 
All IV study drugs will be supplied by Luitpold Pharmaceuticals, Inc. They should be 
kept in a secure place at the investigational site, and stored at room temperature (see: 
USP). The study medication should not be frozen. Vials may not be used for more 
than 1 dose or for more than 1 subject. 
 
C. Drug Accountability 
Ferric Carboxymaltose (Injectafer®) will be provided by Luitpold Pharmaceuticals, Inc. 
from the commercial drug supply according to Good Manufacturing Practices (GMP). 
 
It is the responsibility of the clinical investigator or trained designee to ensure that all 
study drug received at the site is inventoried and accounted for throughout the study by 
the designated personnel and is recorded in the inventory log kept with the pharmacy 
study documentation. The drug accountability will be verified by a trained designee 
upon completion of the study. Study drug will be stored in a secured area with restricted 
access to the dosing preparers only.  
The clinical investigator or trained designee must store all study drugs pending 
reconciliation. The investigator agrees that study drug(s) will be dispensed by the 
investigator or sub-investigator(s) named on the Investigator Agreement or their 
qualified designees.  The investigator, sub-investigators, or qualified designees also 
agree that the study drug(s) will be dispensed only to study subjects who have provided 
written informed consent and have met all entry criteria and in accordance with the 
instructions provided in the pharmacy manual.  
After study drug reconciliation, the clinical site may destroy used/unused study drug 
product locally in accordance with all applicable institutional standard operating 
procedures, local and federal laws. Documentation of such destruction must be 
recorded and provided Luitpold Pharmaceuticals, Inc.  
 
D. Contraindications 
Hypersensitivity to Injectafer® or any of its inactive components. 
 
3.2 Oral Iron Supplement 
Oral iron supplement like Ferrous sulphate, Ferrosequels will be used from the 
commercial source.  
 
3.3 Other Drugs 
TKIs like Imatinib/Gleevec, sunitinib are all commercially available drugs. 
 


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4.0  Patient Eligibility 
 
Inclusion Criteria 
 
1) 
GIST patients with IDA planned to start or receiving systemic therapy with TKIs 
 
2) 
Evidence of iron deficiency anemia including, Hgb < 11 g/dL, but > 8 g/dL; and 
transferrin saturation (TSAT) < 20%. 
 
3) 
No H/O allergic reaction to iron therapy. 
 
4) 
No clinical signs active of bleeding. 
 
5) 
Adequate hematologic (ANC > 1500/mm3, platelet count > 100,000/mm3), renal 
(serum creatinine < 1.5mg/dL), hepatic (serum bilirubin count < 1.5 x normal and SGOT 
or SGPT < 3 x normal) functions. 
 
6)     Patients must have Eastern Cooperative Oncology Group (ECOG) performance 
status of 0  2. 
 
7) 
Signed informed consent to the study. 
 
8) 
Male and Females of child bearing potential must use acceptable methods of birth 
control which include oral contraceptives, spermicide with either a condom, diaphragm 
or cervical cap, use of an intrauterine device (IUD) or abstinence. 
 
9) 
Patients are required to read and understand English to comply with protocol 
requirements. 
 
10)  Age >18 years old. 
 
11)  Life expectancy of at least 6 months. 
 
Exclusion Criteria 
 
1) 
Pregnant or lactating women. 
 
2) 
Patients with any co-morbid condition which renders patients at high risk of 
treatment complication. 
 
3) 
Patient has uncontrolled angina, congestive heart failure (New York Heart 
Association > class II or known ejection fraction < 40%), uncontrolled cardiac arrhythmia 
or hypertension, or acute myocardial infarction within 3 months. 
 


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4) 
Patient has an active seizure disorder. (Patients with a previous history of seizure 
disorders will be eligible for the study, if they have had no evidence of seizure activity, 
and they have been free of antiseizure medication for the previous 5 years). 
 
5) 
Psychological, social, familial, or geographical reasons that would prevent 
scheduled visits and follow-up. 
 
6)     Prior surgery or radiotherapy (RT) within 2 weeks of study entry. 
7)     Known hypersensitivity reaction to any component of ferric carboxymaltose. 
 
8)     Any anemia treatment within 4 weeks before inclusion (oral iron, IV iron, 
or erythropoiesis-stimulating agents), or transfusion of PRBCs in 2 weeks. 
9)     Hemochromatosis or other iron storage disorders. 
10)   Known positive hepatitis with evidence of active disease. 
11)   Patients with overt bleeding. 
12)   Ferritin > 800 ng/mL. 
 
5.0  Treatment Plan 
 
5.1 Study Drug Treatment 
 
This is an open label, randomized, phase II trial. Approximately 50 evaluable subjects 
will be randomly assigned to arm A and arm B (1:1).  
Prior to randomization, all patients will be stratified into < 10g/dL vs. >10g/dL. 
 
Treatment Plan: 
Fifty patients with GIST will be randomized 1:1 into two treatment arms; total 25 patients 
in each of the two arms:  
 
Arm A/ investigational arm: all subjects (n=25) will receive 2 doses of  Injectafer® at15 
mg/kg for a maximum single dose of 750 mg, given 7 days apart for a total of up to 1500 
mg. The first IV infusion will be given prior to starting systemic therapy. The dose will be 
repeated 1 week later. It will be diluted in no more than 250 mL of normal saline and 
infused over 15 minutes. 
 
Arm B/control arm: all patients (n=25) will receive oral iron (dose equivalent of 150-200 
mg of elemental iron/day) supplement daily (such as Ferrosequels, BID, or ferrous 
sulphate, TID) for 3 months. Different iron preparation can be used based on 
tolerance/preference. 
 
  


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5.2 Chemotherapy  
Standard treatment for GIST with TKI-based therapy.  
 
5.3 Duration of Therapy:  
Patients can receive 2 doses of Injectafer® IV, given 7 days apart for a total of up to 
1500 mg, or oral iron supplement e.g. Ferrosequels, BID, or ferrous sulphate, TID for 3 
months, whichever arm they were assigned originally. If the patient on arm B does not 
tolerate oral preparations (even one dose of oral iron per day), then the patient can 
come off the protocol and receive IV iron as per standard of care.  
 
 
6.0  Pretreatment Evaluation 
 
 Standard History and Physical examination including weight and height and 
performance status (appendix D)  
 Laboratory studies will include a CBC with differential, and platelet count,       
electrolytes and serum chemistries. 
 Serum beta hCG or urinary pregnancy test (when indicated).   
 All screening labs/pretreatment evaluations can be done within 1 week before 
registration. 
 
7.0  Evaluation During Study 
 
 Interim History and Physical examination including weight will be done before 
and after 3 months of the initiation of treatment. 
 CBC differential and platelet counts will be monitored at least once a week for 
3 months.  
 Serum electrolytes and chemistries will be performed prior to and as 
frequently as needed during the treatment. 
 Serum iron, serum ferritin, and total iron binding capacity (TIBC),and 
percentage serum transferrin saturation (TSAT) will be done at baseline, and 
every month for 3 months and then at 6 months. 
 Patients will report the FACT-Fatigue and energy score at baseline and every 
month for 3 months and then at 6 months. In addition, patients will continue to 
report on daily symptom record diary the adverse events for 3 months [24]. 
 Management of hypersensitivity to the study drug: Patients with allergic 
reactions can be symptomatically managed. All patients with grade 4 
hypersensitivity reactions (anaphylaxis) will be removed from the study.  
 
8.0  End of Study/Early Withdrawal 
 
Standard History and Physical examination including weight will be documented. 
Laboratory studies will include a CBC with differential, and platelet count. 
 
9.0  Criteria for Response 


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9.1 Response 
All patients who receive one dose of study drugs under this protocol will be evaluable 
for toxicity.All patients randomized will be considered evaluable for response in the 
intent-to-treat analysis. 
 
Efficacy assessments will include: 
 
atient reported outcomes questionnaires (FACT-Fatigue) 
  
transfusions, ESA, or both) 
 
9.2 Response will be defined as proportion of achieving an increase in hemoglobin at 
any time from baseline to end of 3 months, as described below: 
 
Complete response (CR): increase in HGB 2.0 g/dL above baseline, and/ or     
                                            transfusion free. 
Partial response (PR): increase in HGB (>1g/dL-2g/dL) above baseline 
Minor response (MR): increase in HGB (> 0.5 g/dL-1g/dL) above baseline 
 
 
9.3 Toxicity: Toxicities will be graded using the Common Terminology Criteria   for   
Adverse Events v4.03  CTCAE (see Appendix C).  Uncomplicated, severe, or life 
threatening neutropenia and thrombocytopenia are expected toxicities of the systemic 
therapy and as such will not be collected as adverse events in this study since the data 
is already captured through the CORe. 
 
10.0 Criteria for Discontinuation from Treatment 
 
Patients may be discontinued from study treatment at any time.  Specific reasons for 
discontinuing treatment include the following: 
 Serious or life-threatening adverse event 
 Risk to patients as judged by the Investigator and/or Sponsor 
 Severe noncompliance with protocol as defined by not receiving at least 70% of the 
planned treatment (judged by the Investigator and/or Sponsor). 
 Request of the patient  
 Patient becomes pregnant 
 Progressive disease 
 Investigator becomes aware of conditions or events that suggest a possible hazard to 
patients if the clinical study continues 


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10.1 Discontinuation from Study 
Patients who discontinue from treatment will continue to receive follow-up assessments 
as part of the study unless they are discontinued from study by one of the following 
events: 
 Withdrawal of consent 
 Loss to follow-up 
 Death from any cause 
 Termination of the study 
 
11.0 Statistical Consideration and Sample Size 
 
Statistical Considerations and Analysis  
 
This study will assess the efficacy of IV Injectafer in improving HGB level in GIST 
patients planned to receive or receiving systemic therapy and presenting with anemia.   
 
Design and Sample Size/Power 
This is a randomized, open label, 2-arm trial of 2-dose IV Injectafer in patients with 
GIST planned to receive or receiving systemic therapy and presenting with anemia. Arm 
A patients will receive 2 doses of  IV Injectafer over 15 min infusion (prior to start 
systemic therapy and another same dose 1 week later).  Arm B patients will receive oral 
iron supplement (such as Ferrosequels BID, or ferrous sulphate TID) for 3 months. The 
primary objective is to evaluate the efficacy of IV Injectafer in patients with GIST 
planned to receive or receiving systemic therapy and presenting with anemia as 
compared to the effect of oral iron supplement.  
 
A patient will be considered as to have a complete response (CR) if his/her HGB level 
increase > 2 g/dL from baseline to any time during 3 months following initiation of the 
study drug, and/or transfusion free. The primary endpoint is CR rate in 3 months. A total 
of 50 patients, 25 in each arm, will provide the study 93% power to detect the differences 
of response between the two arms using a Chi-square test with a 0.05 two-sided 
significance level when the respective CR rates are 75% (6/8) and 28.6% (8/28) in Arm 
A, and B (according to our clinical experience ).  All patients who are randomized will be 
evaluable for response in the intent-to-treat analysis. nQuery 7.0 was used for the sample 
size or power calculation. 
 
Analysis Plans 
descriptive statistics such as mean, standard deviation, median, interquartile range (IQR), 
frequency where appropriate. We will apply Student t-test/Wilcoxon test and Kruskal-
Wallis test/ANOVA to compare continuous variables between different patient group, and 
the chi-
en two 
categorical variables [25].  
 


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For the analysis of the primary endpoint, Chi-square test will be used to test the difference 
of CR rates between the two arms. CR rates along with their 95% confidence intervals 
(CIs) will be estimated by study arm. We will use logistic regression model [26] to assess 
the effect of patient specific covariates, such as treatment group, gender, etc.  on the 
complete response.  
 
Toxicity data will be summarized by frequency tables for all patients and by treatment 
arm.  For the efficacy endpoint, intent-to-treat analysis will be applied to all randomized  
patients. For the toxicity endpoint, per-treated analysis will be used to include any patient 
who received one dose of the treatment regardless of the eligibility nor the duration or 
dose of the treatment received. 
 
We will analyze patient reported outcomes using standard statistical methods for 
analyzing continuous data, discrete data, and survival data whenever appropriate. 
Additional analyses in furtherance of the stated objectives may be conducted as 
warranted. 
 
 
Randomization 
Stratified randomization will be carried out via CORe. The stratification factor is baseline 
 
 
12.0 Data and Protocol Management 
 
Data will be collected and entered in CORe by the research staff assigned to the study. 
 
12.1 Good Clinical Practice  
The conduct of the study will conform to the recommendations for clinical studies in 
ICH guidelines]. 
 
13.0 Serious Adverse Events  and Reporting Requirement 
 
13.1 Adverse Events  
 
An adverse event (AE) is any new, undesirable medical occurrence or change 
(worsening) of an existing condition in a subject that occurs during or after treatment, 
whether or not considered to be product related. Therefore, adverse events are 
treatment-emergent signs or symptoms.   
 
For the purposes of this study, non-serious anemia (Hgb or Hct below the normal range 
or worsened from baseline) or iron deficiency (iron indices below the normal range or 
worsened from baseline) will not be considered adverse events. Anemia or iron 
deficiency will be considered end points if an intervention is required. 
 


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In this study, the following adverse effects are expected and will not be reported. They 
will be summarized in the updated and final analysis.  Myelosuppression and its 
associated complications are part of the treatment of sarcoma.  Therefore, low blood 
counts and related complications such as infections, bleeding and hospitalizations due 
to myelosuppression will not be reported as severe adverse drug reactions related to 
Injectafer. 
 
AEs will be collected from the time of informed consent to 30 days after last study drug 
administration.  AEs that occur before the first study drug administration, concomitant 
illnesses, which existed before study entry, but did not worsen during the treatment 
period and any pre-
-
(e.g., physical examination, laboratory assessment, electrocardiograms [ECG], reported 
by patient), must be documented. 
 
Each AE will be assessed by the Investigator with regard to the intensity.  
Intensity should be assessed in accordance with the Common Terminology Criteria for 
Adverse Events (CTCAE v.4.03, Appendix C). Attribution of AE to study treatment will 
be recorded as follows: 
Relationship (Causality): The Investigator will be asked to document his/her opinion of 
the relationship of the event to the study drug* as follows: 
 NONE           There is no evidence of any causal relationship. 
 UNLIKELY    There is little evidence to suggest there is a causal relationship.  
                     There is another reasonable explanation for the event (e.g., the                   
                      
inical condition, other concomitant treatments). 
 POSSIBLE   There is some evidence to suggest a causal relationship (i.e. there    
                      is a reasonable possibility that the adverse experience may have 
been caused by the agent). However, the influence of other factors 
may have contributed to the event (e.g., the subj
condition, other concomitant events). 
 PROBABLE There is evidence to suggest a causal relationship, and the   
                     influence of other factors is unlikely. 
 
Timing: Non-serious AEs will be reported from the initial treatment with study drug* 
through the completion of the study. All ongoing adverse events related to study drug 
(i.e., Injectafer, ferrous sulfate) should be followed until they are no longer related, have 
taken a confounding medication or return to baseline grade. 
 
* 
Injectafer, oral iron 
supplement. 
 
 
Follow-up of Adverse Events 
All AEs experienced by a patient, irrespective of the suspected causality, will be 
monitored until the AE has resolved, any abnormal laboratory values have returned to 


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baseline or stabilized at a level acceptable to the Investigator, until there is a 
satisfactory explanation for the changes observed, until the patient is lost to follow-up, 
or until the patient has expired. 
 
For the purposes of this study, non-serious anemia (Hgb or Hct below the normal range 
or worsened from baseline) or iron deficiency (iron indices below the normal range or 
worsened from baseline) will not be considered adverse events. Anemia or iron 
deficiency will be considered end points if an intervention is required. 
 
13.2 Serious Adverse Events  
 
Definition: An adverse event is classified as SERIOUS if it meets any one of the 
following criteria: 
 Death 
 Life-Threatening: The subject was at substantial risk of dying at the time of the 
adverse event or it is suspected that the use / continued use of the product would 
result in the subject's death. 
 Hospitalization (initial or prolonged): Required admission to the hospital or 
           prolongation of a hospital stay. 
 Disability: Resulted in a significant, persistent, or permanent change, 
impairment, damage or disruption in the subject's body function/structure, 
physical activities or quality of life. 
 Congenital Anomaly/Birth Defect 
 Important medical events: Other medically important events that, in the opinion 
of the investigator, may jeopardize the subject or may require intervention to 
prevent one of the other outcomes listed above. 
 
A distinction should be drawn between SAE and severe AE. A severe AE is a major 
experience of its type. A severe AE is not necessarily serious: e.g. nausea, which 
persists for several hours, may be considered severe nausea, but it is not an SAE. On 
the other hand, a stroke, which results in only a limited degree of disability may be 
considered a mild stroke, but would be a SAE. 
 
Timing: SAEs as well as AEs will be elicited during study visits and contact with 
subject. These AEs/SAEs as well as SAEs discovered through passive reporting from 
the time of initial treatment with study drug up to the completion of the study will be 
reported. Hospitalizations resulting from historical conditions (present prior to initial 
treatment with study drug or prescheduled prior to treatment with study drug) that have 
not increased in severity or led to prolongation of hospital stay should not be considered 
SAEs. All reported serious adverse events should be followed until they are no longer 
serious, or return to baseline grade. 
 
Reporting: Any SAE, starting with the first dose of study drug, that is to be reported (as 
outlined in Timing section above) must be reported immediately (by the end of the next 
business day) to Luitpold Pharmaceuticals, Inc. by telephone, email and/or fax of the 
written SAE report form to the contacts listed below: 


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                                                                                                                                                 May 16, 2016                  
 
Safety Monitor 
Luitpold Pharmaceuticals, Inc. 
pv@luitpold.com 
Tel: (610) 650-4200 Fax: (610) 650-0170 
 
All serious adverse events will be reported to the University of Texas M.D. Anderson 
Cancer Center IRB within 24 hours of knowledge of the event. 
 
13.3 Other Reportable Information  
 
As part of the continuous assessment of the risk-benefit profile for the life cycle of 
pharmaceutical products regulatory agencies require monitoring of occurrences that 
while not 
this protocol, other reportable information refers to: drug exposure during pregnancy 
and / or lactation exposure (irrespective of any reported fetal abnormalities or any 
adverse effect in mother and/or child). Pregnancy exposure and lactation exposure 
 Pharmacovigilance Department by email and/or fax 
using the pregnancy tracking form to the contact listed below: 
Safety Monitor 
Luitpold Pharmaceuticals, Inc. 
pv@luitpold.com 
Tel: (610) 650-4200 Fax: (610) 650-0170 
 
14.0 Monitoring Plan 
 
All protocol participants will be registered in CORe.  The principal investigator will 
and entered into CORe. 
 
 
 
 
 
 


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15. References 
 
1.  Ludwig H, Van Belle S, Barrett-Lee P, et al. The European Cancer Anaemia Survey 
(ECAS): a large, multinational, prospective survey defining the prevalence, 
incidence, and treatment of anaemia in cancer patients. Eur J Cancer. 
2004;40:2293-306. 
2.  Dicato M, Plawny L, Diederich M. Anemia in cancer. Ann Oncol. 2010; Oct;21 Suppl 
7:vii167-72.  
3.  Knight K, Wade S, Balducci L. Prevalence and outcomes of anaemia in cancer: a 
systematic review of the literature. Am J Med. 2004; 116 Suppl 7A: 11S 26S. 
4.  Cella D. Factors influencing quality of life in cancer patients: anemia and fatigue. 
Semin Oncol. 1998;25:43-6. 
5.  Gilreath JA, Stenehjem DD, and Rodgers GM. Diagnosis and treatment of cancer-
related anemia. Am J Heamtol. 2014;89:203-12. 
6.  Camaschella, C. Iron-Deficiency Anemia. N Engl J Med 2015; 372:1832-1843 
7.  Ludwig H, Muldur E, Endler G, et al. Prevalence of iron deficiency across different 
     tumors and its association with poor performance status, disease status, and 
anemia. Ann Oncol. 2013;24:1886-92. 
8.  Aapro M, Osterborg A, Gascon P, et al. Prevalence and management of cancer-
related anaemia, iron deficiency, and the specific role of i.v. iron. Ann Oncol. 2012; 
23:1954-62. 
9.  Kim Y, Kim S, Yoon B, et al. Effect of intravenously administered iron sucrose on the 
prevention of anemia in the cervical cancer patients treated with concurrent 
chemoradiotherapy. Gyn Oncol. 2007;105:199-204. 
10. Dangsuwan P, Manchana T. Blood transfusion reduction with intravenous iron in 
gynecologic cancer patients receiving chemotherapy. Gyn Oncol. 2010;116:522-5. 
11.Søreide K, Sandvik OM, Søreide JA, et al. Global epidemiology of gastrointestinal 
stromal tumours (GIST): A systematic review of population-based cohort studies. 
Cancer Epidemiol. 2016; 40:39-46.  
12. Rammohan A1, Sathyanesan J, Rajendran K, et al.  A gist of gastrointestinal 
stromal tumors: A review. World J Gastrointest Oncol. 2013; 5(6):102-12.  
13. https://liferaftgroup.org/2012/12/anemia-has-multiple-causes-and-treatments/ 
14. Duffaud F1, Even C, Ray-Coquard I, et al. Recombinant erythropoietin for 
the anaemia of patients with advanced Gastrointestinal Stromal Tumours (GIST) 
receiving imatinib: an active agent only in non progressive patients. Clin Sarcoma 
Res. 2012; 2(1):11.  
15. Lopez A, Cacoub P, Macdougall IC, et al. Iron deficiency anaemia. Lancet. 2015; pii: 
S0140-6736(15)60865-0.  
16.Vadhan-Raj S, Strauss W, Ford D, et al. Efficacy and safety of IV ferumoxytol for 
adults with iron deficiency anemia previously unresponsive to or unable to tolerate 
oral iron. Am J Hematol. 2014; 89(1):7-12.  
17.Vadhan-Raj S, Ford DC, Dahl NV, et al. Safety and efficacy of ferumoxytol for the 
episodic treatment of iron deficiency anemia in patients with a history of 
unsatisfactory oral iron therapy: Results of a phase III, open-label, 6-month 
extension study. Am J Hematol. 2016; 91(2):E3-5.  


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18.http://www.centerwatch.com/drug-information/fda-approved 
drugs/drug/1280/injectafer-ferric-carboxymaltose-injection 
19.Lyseng-Williamson KA, Keating GM.  Ferric Carboxymaltose: A Review of its Use in 
Iron-Deficiency Anaemia. Drugs. 2009;  69 (6): 739-756 
20. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/203565s000lbl.pdf 
21. http://www.fda.gov/ohrms/dockets/ac/08/briefing/2008-4337b1-01-fda.pdf 
22. Onken JE, Bregman DB, Harrington RA, et al. Ferric carboxymaltose in patients with 
iron-deficiency anemia and impaired renal function: the REPAIR-IDA trial. Nephrol 
Dial Transplant. 2014;54:306-15. 
23. Onken JE, Bregman DB, Harrington RA, et al. A multicenter, randomized, active 
     controlled study to investigate the efficacy and safety of intravenous ferric 
     carboxymaltose in patients with iron deficiency anemia.Transfusion. 2014;29:833-42. 
24. Jean-Pierre P, Figueroa-Moseley CD, Kohli S, Fiscella K, et al. Assessment 
of cancer-related fatigue: implications for clinical diagnosis and treatment. 
Oncologist. 2007;12 Suppl 1:11-21.  
25. Woolson, RF and Calrke, WR. Statistical Methods for the Analysis of Biomedical 
Data. 2nd Edition, John Wiley & Sons, New York, 2000. 
26. Hosmer DW, Lemeshow S. Applied logistic regression. 2nd Edition, Wiley, New 
York, 2000. 
27. Henry D, Dahl NV, Auerbach M, Tchekmedyian, Laufman LR. Intravenous Ferric 
Gluconate significantly improves response to Epoietin Alfa versus oral iron or no iron 
in anemic patients with cancer receiving chemotherapy. The Oncologist 207; 12:231-
242.