Pilot Trial of Sirolimus/MEC in High Risk Acute Myelogenous Leukemia (AML)

• Sponsor: Sidney Kimmel Cancer Center at Thomas Jefferson University (Other)
• Overall Status: Completed
• CT.gov ID: NCT01184898
• Collaborator: University of Pennsylvania (Other)
• Enrollment: 36
• Locations: 2
• Arm: 1
• Duration (Months): 67.1
• Patients Per Site: 18
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the addition of Sirolimus (rapamycin) to standard chemotherapy for the treatment of patients with high risk acute myelogenous leukemia (AML). Cancer cells taken from the patients will be studied in the laboratory to see if rapamycin is affecting the mTOR pathway in the cells and if this effect is correlated with how well patients respond to the therapy.

Condition or Disease	Intervention/Treatment	Phase
AML	Drug: Sirolimus; Drug: Mitoxantrone; Drug: Etoposide; Drug: Cytarabine	N/A

Detailed Description

Recent improvements in our understanding of leukemia biology have led to the introduction of highly effective, molecularly targeted therapies. This is exemplified by the development of BCR-ABL tyrosine kinase inhibitors such as imatinib as monotherapy for chronic myeloid leukemia (CML) and in combination with chemotherapy for BCR-ABL+ acute lymphoblastic leukemia (ALL). Imatinib mesylate blocks the protein made by the BCR-ABL oncogene.

The PI3K (phosphatidylinositol 3-kinases) signaling is critical to leukemia cell survival and can be targeted. Growth and survival stimulating signal transduction pathways are abnormally and universally activated in AML (Acute Myeloid Leukemia). This signal cascade is thought to contribute to survival and growth in tumor cells via downstream effects upon target proteins AKT/Protein kinase B and mammalian target of rapamycin (mTOR) a protein that helps control several cell functions.

In AML, we and others have shown that PI3K signaling is constitutively activated in over 85% of primary samples and that the small molecule PI3K inhibitor LY294002 is cytotoxic in vitro to virtually all samples tested. As LY294002 is poorly suited for drug development, we have concentrated upon other ways to inhibit signal transduction through this pathway. Mammalian target of rapamycin (mTOR) emerged as a reasonable target due to the availability of clinically available, highly specific inhibitors with favorable safety profiles. Mammalian target of rapamycin (mTOR) plays a central but complex role in cancer cells' metabolic regulation and survival. This serine/threonine kinase coordinates several important cellular functions and its activity is modulated in response to amino acid, glucose, oxygen, and ATP availability as well as extracellular growth factor ligation. Mammalian target of rapamycin (mTOR) activity regulates protein translation, nutrient and amino acid uptake, mitochondrial respiration, glycolysis, cell size regulation, cell cycle entry and progression, ribosome biogenesis, and autophagy. Constitutive mammalian target of rapamycin (mTOR) activation is commonly seen in cancer cells and is thought to promote survival in the setting of a wide variety of cellular insults. Importantly, mTOR opening may cause chemotherapy resistance. Although regulation of mTOR signaling in leukemia occurs through by several inputs, mTOR activity in AML is thought to be primarily regulated by PI3K signaling through AKT via the agent tumor suppressor tuberous sclerosis complex (TSC1& 2) and its target rheb GTPase.

Taken together, mammalian target of rapamycin mTOR is a smart target for molecularly targeted therapy in AML due to its importance in the growth and survival of AML cells, its necessity for AML cell survival in certain contexts, and its probable role in chemotherapy resistance and relapse.

Study Design

• Study Type: Interventional
• Actual Enrollment: 36 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Pilot, Pharmacodynamic Correlate, Multi-Institutional Trial of Sirolimus in Combination With Chemotherapy (Mitoxantrone, Etoposide, Cytarabine) for the Treatment of High Risk, Acute Myelogenous Leukemia
• Study Start Date: Jul 1, 2010
• Actual Primary Completion Date: Jan 1, 2012
• Actual Study Completion Date: Feb 1, 2016

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Sirolimus and MEC Sirolimus and MEC (Mitoxantrone, Etoposide, and Cytarabine)

Drug: Sirolimus; Sirolimus, by mouth, will be given as a 12mg loading dose followed by 8 daily doses of 4mg/day.; Other Names: Rapamycin ; Drug: Mitoxantrone; Mitoxantrone 8mg/m2/day IV; Other Names: Mitozantrone Novantrone ; Drug: Etoposide; 100 mg/m2/day IV; Other Names: Etoposide phosphate VP-16 Etopophos ; Drug: Cytarabine; 1000mg/m2/day IV every 24 hours for 5 days; Other Names: Cytosine arabinoside Cytosar-U Depocyt ara-C

Outcome Measures

Primary Outcome Measures

1. Association Between the Magnitude of mTOR Target Inhibition Post-treatment in Leukemic Blasts and Clinical Response in Patients With High Risk AML Treated With Sirolimus MEC [From pre- to post-treatment]

   Percent change compared between response groups (responder vs nonresponder). This outcome measure only includes patients who survived to outcome assessment.

Secondary Outcome Measures

1. Complete Response [Within one week of peripheral count recovery but no later than day 42]

   Complete response is defined as: Peripheral Blood Counts -Neutrophil count >1 x 109/L. Platelet count ≥ 100 x 109/L. Reduced hemoglobin concentration or hematocrit has no bearing on remission status. Leukemic blasts must not be present in the peripheral blood. Cellularity of bone marrow biopsy must be > 20% with maturation of all cell lines with < 5% blasts and no Auer rods. Extramedullary leukemia, such as CNS or soft tissue involvement, must not be present

2. Complete Response in the Absence of Platelet Recovery [Within one week of peripheral count recovery but no later than day 42]

   Complete response in the absence of platelet recovery is defined as: - Bone marrow (<5% blasts) with adequate bone marrow cellularity, no evidence of circulating blasts or extramedullary disease and normalization of peripheral blood counts except for platelets (neutrophil count =1,000/µL)

3. Partial Response [Within one week of peripheral count recovery but no later than day 42]

   Partial response is defined as: Requires that all of the criteria for complete remission be satisfied except that the bone marrow may contain ≥ 5% blasts but < 25% blasts. A marrow with <5% blasts that contain Auer rods will also be considered a PR

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients must have histologic evidence of high risk acute myeloid leukemia defined as one of the following:

1. Primary refractory non-M3 AML (i) Residual leukemia after a minimum of 2 prior courses of chemotherapy (Same or different) (ii) Evidence of leukemia after a nadir bone marrow biopsy demonstrates no evidence of residual leukemia.

2. Relapsed non-M3 AML

3. Any non-M3 AML age >60 with no evidence of favorable karyotype (stratum 2 ONLY), defined by presence of t(8;21)(q22;q22) [AML1-ETO], inv16(p13;q22), or t(16;16)(p13;q22) [CBF;MYH11] by cytogenetics, FISH, or RT-PCR

4. Secondary AML (from antecedent hematologic malignancy or following therapy with radiation or chemotherapy for another disease) with no evidence of favorable karyotype (stratum 2 ONLY), defined by presence of t(8;21)(q22;q22) [AML1-ETO], inv16(p13;q22), or t(16;16)(p13;q22) [CBF;MYH11] by cytogenetics, FISH, or RT-PCR

• Age > or = 18

• ECOG = 0 or 1

Exclusion Criteria:

• Subjects with FAB M3 (t(15;17)(q22;q21)[PML-RAR]) are not eligible

• Subjects taking the following are not eligible:

• Carbamazepine (e.g., Tegretol)

• Rifabutin (e.g., Mycobutin) or

• Rifampin (e.g., Rifadin)

• Rifapentine (e.g., Priftin)

• St. John's wort

• Clarithromycin (e.g., Biaxin)

• Cyclosporine (e.g. Neoral or Sandimmune)

• Diltiazem (e.g., Cardizem)

• Erythromycin (e.g., Akne-Mycin, Ery-Tab)

• Itraconazole (e.g., Sporanox)

• Ketoconazole (e.g., Nizoral)

• Telithromycin (e.g., Ketek)

• Verapamil (e.g., Calan SR, Isoptin, Verelan)

• Voriconazole (e.g., VFEND)

• Tacrolimus (e.g. Prograf)

• Subjects taking fluconazole, voriconazole, itraconazole, posaconazole, and ketoconazole within 72 hours of study entry are not eligible. Reinstitution of fluconazole, voriconazole, itraconazole, posaconazole, ketoconazole and diltiazem is permissible 72 hours after the last dose of sirolimus.

• Subjects must not be receiving any chemotherapy agents (except Hydroxyurea). Intrathecal methotrexate and cytarabine are permissible

• Subjects must not be receiving growth factors, except for erythropoietin

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
2	Thomas Jefferson University	Philadelphia	Pennsylvania	United States	19107

Sponsors and Collaborators

• Sidney Kimmel Cancer Center at Thomas Jefferson University
• University of Pennsylvania

Investigators

• Principal Investigator: Margaret Kasner, MD, Thomas Jefferson University

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Kimmel Cancer Center at Thomas Jefferson University, an NCI-Designated Cancer Center
• Thomas Jefferson University Hospitals

Publications

None provided.

• Responsible Party: Sidney Kimmel Cancer Center at Thomas Jefferson University
• ClinicalTrials.gov Identifier: NCT01184898
• Other Study ID Numbers: 10D.21; 2009-42
• First Posted: Aug 19, 2010
• Last Update Posted: Nov 29, 2016
• Last Verified: Oct 1, 2016

• Keywords provided by Sidney Kimmel Cancer Center at Thomas Jefferson University: AML; mTOR; rapamycin
• Additional relevant MeSH terms: Leukemia, Myeloid; Leukemia, Myeloid, Acute; Cytarabine; Sirolimus; Etoposide; Mitoxantrone; Etoposide phosphate

Study Results

Participant Flow

Arm/Group Title	Sirolimus and MEC
Arm/Group Description	Sirolimus and MEC (Mitoxantrone, Etoposide, and Cytarabine) Sirolimus: Sirolimus, by mouth, will be given as a 12mg loading dose followed by 8 daily doses of 4mg/day. MEC (Mitoxantrone, Etoposide, and Cytarabine): MEC (Mitoxantrone 8mg/m2/day IV, Etoposide 100mg/m2/day IV and Cytarabine 1000mg/ m2/day IV every 24 hours for 5 days) will be administered after sirolimus loading dose and 3 daily doses.
Period Title: Overall Study
STARTED	36
COMPLETED	36
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Sirolimus and MEC
Arm/Group Description	Sirolimus and MEC (Mitoxantrone, Etoposide, and Cytarabine) Sirolimus: Sirolimus, by mouth, will be given as a 12mg loading dose followed by 8 daily doses of 4mg/day. MEC (Mitoxantrone, Etoposide, and Cytarabine): MEC (Mitoxantrone 8mg/m2/day IV, Etoposide 100mg/m2/day IV and Cytarabine 1000mg/ m2/day IV every 24 hours for 5 days) will be administered after sirolimus loading dose and 3 daily doses.
Overall Participants	36
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60.05 (11.84)
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	24 66.7%
>=65 years	12 33.3%
Sex: Female, Male (Count of Participants)
Female	16 44.4%
Male	20 55.6%
Region of Enrollment (participants) [Number]
United States	36 100%

Outcome Measures

1. Primary Outcome

Title	Association Between the Magnitude of mTOR Target Inhibition Post-treatment in Leukemic Blasts and Clinical Response in Patients With High Risk AML Treated With Sirolimus MEC
Description	Percent change compared between response groups (responder vs nonresponder). This outcome measure only includes patients who survived to outcome assessment.
Time Frame	From pre- to post-treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sirolimus and MEC
Arm/Group Description	Sirolimus and MEC (Mitoxantrone, Etoposide, and Cytarabine) Sirolimus: Sirolimus, by mouth, will be given as a 12mg loading dose followed by 8 daily doses of 4mg/day. MEC (Mitoxantrone, Etoposide, and Cytarabine): MEC (Mitoxantrone 8mg/m2/day IV, Etoposide 100mg/m2/day IV and Cytarabine 1000mg/ m2/day IV every 24 hours for 5 days) will be administered after sirolimus loading dose and 3 daily doses.
Measure Participants	27
Responders (17 pts)	69
Nonresponders (10 pts)	-36

2. Secondary Outcome

Title	Complete Response
Description	Complete response is defined as: Peripheral Blood Counts -Neutrophil count >1 x 109/L. Platelet count ≥ 100 x 109/L. Reduced hemoglobin concentration or hematocrit has no bearing on remission status. Leukemic blasts must not be present in the peripheral blood. Cellularity of bone marrow biopsy must be > 20% with maturation of all cell lines with < 5% blasts and no Auer rods. Extramedullary leukemia, such as CNS or soft tissue involvement, must not be present
Time Frame	Within one week of peripheral count recovery but no later than day 42

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sirolimus and MEC
Arm/Group Description	Sirolimus and MEC (Mitoxantrone, Etoposide, and Cytarabine) Sirolimus: Sirolimus, by mouth, will be given as a 12mg loading dose followed by 8 daily doses of 4mg/day. MEC (Mitoxantrone, Etoposide, and Cytarabine): MEC (Mitoxantrone 8mg/m2/day IV, Etoposide 100mg/m2/day IV and Cytarabine 1000mg/ m2/day IV every 24 hours for 5 days) will be administered after sirolimus loading dose and 3 daily doses.
Measure Participants	34
Number [participants]	11 30.6%

3. Secondary Outcome

Title	Complete Response in the Absence of Platelet Recovery
Description	Complete response in the absence of platelet recovery is defined as: - Bone marrow (<5% blasts) with adequate bone marrow cellularity, no evidence of circulating blasts or extramedullary disease and normalization of peripheral blood counts except for platelets (neutrophil count =1,000/µL)
Time Frame	Within one week of peripheral count recovery but no later than day 42

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sirolimus and MEC
Arm/Group Description	Sirolimus and MEC (Mitoxantrone, Etoposide, and Cytarabine) Sirolimus: Sirolimus, by mouth, will be given as a 12mg loading dose followed by 8 daily doses of 4mg/day. MEC (Mitoxantrone, Etoposide, and Cytarabine): MEC (Mitoxantrone 8mg/m2/day IV, Etoposide 100mg/m2/day IV and Cytarabine 1000mg/ m2/day IV every 24 hours for 5 days) will be administered after sirolimus loading dose and 3 daily doses.
Measure Participants	34
Number [participants]	2 5.6%

4. Secondary Outcome

Title	Partial Response
Description	Partial response is defined as: Requires that all of the criteria for complete remission be satisfied except that the bone marrow may contain ≥ 5% blasts but < 25% blasts. A marrow with <5% blasts that contain Auer rods will also be considered a PR
Time Frame	Within one week of peripheral count recovery but no later than day 42

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sirolimus and MEC
Arm/Group Description	Sirolimus and MEC (Mitoxantrone, Etoposide, and Cytarabine) Sirolimus: Sirolimus, by mouth, will be given as a 12mg loading dose followed by 8 daily doses of 4mg/day. MEC (Mitoxantrone, Etoposide, and Cytarabine): MEC (Mitoxantrone 8mg/m2/day IV, Etoposide 100mg/m2/day IV and Cytarabine 1000mg/ m2/day IV every 24 hours for 5 days) will be administered after sirolimus loading dose and 3 daily doses.
Measure Participants	34
Number [participants]	3 8.3%

Adverse Events

Arm/Group Title	Sirolimus and MEC
Arm/Group Description	Sirolimus and MEC (Mitoxantrone, Etoposide, and Cytarabine) Sirolimus: Sirolimus, by mouth, will be given as a 12mg loading dose followed by 8 daily doses of 4mg/day. MEC (Mitoxantrone, Etoposide, and Cytarabine): MEC (Mitoxantrone 8mg/m2/day IV, Etoposide 100mg/m2/day IV and Cytarabine 1000mg/ m2/day IV every 24 hours for 5 days) will be administered after sirolimus loading dose and 3 daily doses.
All Cause Mortality
	Sirolimus and MEC
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Sirolimus and MEC
	Affected / at Risk (%)	# Events
Total	8/36 (22.2%)
Cardiac disorders
Left ventricular systolic dysfunction	1/36 (2.8%)	1
General disorders
Infection	2/36 (5.6%)	2
Bone marrow cellularity	2/36 (5.6%)	2
Abdominal pain	1/36 (2.8%)	1
Prolonged QTc interval	1/36 (2.8%)	1
Sepsis	1/36 (2.8%)	1
Multi-organ failure	1/36 (2.8%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/36 (2.8%)	1
Respiratory syncytial virus	1/36 (2.8%)	1
Other (Not Including Serious) Adverse Events
	Sirolimus and MEC
	Affected / at Risk (%)	# Events
Total	36/36 (100%)
Blood and lymphatic system disorders
Neutropenia	18/36 (50%)	24
Hypotension	12/36 (33.3%)	17
Pancytopenia	8/36 (22.2%)	8
Febrile neutropenia	22/36 (61.1%)	30
Hypertension	9/36 (25%)	15
Thrombocytopenia	10/36 (27.8%)	14
Hypokalemia	16/36 (44.4%)	48
Thrombosis	1/36 (2.8%)	1
Disseminated intravascular coagulation	1/36 (2.8%)	1
Hypomagnesemia	8/36 (22.2%)	31
B-12 deficiency	1/36 (2.8%)	1
Hypocalcemia	11/36 (30.6%)	36
Hypophosphatemia	4/36 (11.1%)	6
Hyperphosphatemia	2/36 (5.6%)	2
Decreased pH	2/36 (5.6%)	2
Hyperglycemia	11/36 (30.6%)	24
Hyperbilirubinemia	3/36 (8.3%)	4
Fluid overload	1/36 (2.8%)	1
Hyponatremia	7/36 (19.4%)	17
Hypernatremia	2/36 (5.6%)	2
Hyperkalemia	2/36 (5.6%)	2
Lymphocytopenia	10/36 (27.8%)	22
Decreased hemoglobin	10/36 (27.8%)	15
Hyopalbuminemia	7/36 (19.4%)	40
Leukopenia	10/36 (27.8%)	16
Hypoglycemia	1/36 (2.8%)	1
Non-occlusive clot	1/36 (2.8%)	1
Hypermagnesemia	2/36 (5.6%)	3
Hypouricemia	1/36 (2.8%)	1
Cardiac disorders
Tachycardia	17/36 (47.2%)	20
Heart irregularity	1/36 (2.8%)	1
Atrial fibrillation	3/36 (8.3%)	3
Heart murmur	1/36 (2.8%)	1
Heart failure	1/36 (2.8%)	1
Elevated cardiac troponin	1/36 (2.8%)	1
Sinus bradycardia	2/36 (5.6%)	2
Restrictive cardiomyopathy	1/36 (2.8%)	2
Heart palpitations	1/36 (2.8%)	1
Sinus tachycardia	1/36 (2.8%)	3
Ear and labyrinth disorders
Cholesteatoma	1/36 (2.8%)	4
JVT (Jahn ventilating tube) to ears	1/36 (2.8%)	1
Eye disorders
Floaters in both eyes	1/36 (2.8%)	1
Eyelid dysfunction	1/36 (2.8%)	1
Dry eyes	2/36 (5.6%)	2
Slightly muddy sclera	1/36 (2.8%)	1
Blurred vision	1/36 (2.8%)	1
Gastrointestinal disorders
Diarrhea	30/36 (83.3%)	49
Constipation	11/36 (30.6%)	14
Mucositis	16/36 (44.4%)	25
Vomiting	13/36 (36.1%)	15
Typhlitis	5/36 (13.9%)	5
Dyspepsia	5/36 (13.9%)	6
Clostridium difficile colitis	1/36 (2.8%)	1
Gas pains	1/36 (2.8%)	1
Bloating	3/36 (8.3%)	3
Pancolitis	1/36 (2.8%)	1
Weight loss	2/36 (5.6%)	2
Gastroesophageal reflux disease	2/36 (5.6%)	2
Colitis	1/36 (2.8%)	1
General disorders
Chest pain	8/36 (22.2%)	12
Sore throat	2/36 (5.6%)	2
Cough	21/36 (58.3%)	39
Back pain	12/36 (33.3%)	15
Nausea	28/36 (77.8%)	47
Pain from bone marrow biopsy	1/36 (2.8%)	1
Fever	6/36 (16.7%)	6
Generalized achiness	2/36 (5.6%)	3
Neck pain	4/36 (11.1%)	7
Lightheadedness	3/36 (8.3%)	3
Fatigue	30/36 (83.3%)	63
Chills	13/36 (36.1%)	17
Headache	14/36 (38.9%)	18
Insomnia	13/36 (36.1%)	22
Unsteady gait	5/36 (13.9%)	5
Night sweats	3/36 (8.3%)	5
Bleeding gums	1/36 (2.8%)	1
Lesions	5/36 (13.9%)	6
Pain at PICC site	3/36 (8.3%)	4
Stomach pain	1/36 (2.8%)	1
Gum pain	4/36 (11.1%)	6
Hoarseness	2/36 (5.6%)	2
Fungal pneumonia	1/36 (2.8%)	1
Blotchy face with itchiness	1/36 (2.8%)	1
Hip pain	5/36 (13.9%)	5
Decreased appetite	7/36 (19.4%)	9
Throat discomfort	1/36 (2.8%)	1
Stool incontinence	2/36 (5.6%)	2
Abdominal pain	15/36 (41.7%)	21
Difficulty swallowing	4/36 (11.1%)	4
Head pain	2/36 (5.6%)	3
Dizziness	8/36 (22.2%)	8
Dry heaves	3/36 (8.3%)	3
Generalized weakness	11/36 (30.6%)	12
Rigors	4/36 (11.1%)	4
Burning sensation	1/36 (2.8%)	1
Shoulder pain	5/36 (13.9%)	5
Sweats	10/36 (27.8%)	10
Eye pain	3/36 (8.3%)	3
Bone pain	1/36 (2.8%)	1
Arm pain	6/36 (16.7%)	7
Trouble sleeping	1/36 (2.8%)	1
Alopecia	5/36 (13.9%)	9
Muscle ache/pain	2/36 (5.6%)	2
Post nasal drip	1/36 (2.8%)	1
Dry oropharynx	1/36 (2.8%)	1
Folliculitis	1/36 (2.8%)	1
Mouth ulcer	2/36 (5.6%)	2
Tooth pain	2/36 (5.6%)	2
Fullness sensation in stomach	3/36 (8.3%)	3
Mouth soreness	3/36 (8.3%)	5
Pain with ambulation	1/36 (2.8%)	1
Esophageal discomfort	1/36 (2.8%)	1
Epistaxis	8/36 (22.2%)	13
Chest pain upon cough	1/36 (2.8%)	1
Sinus congestion	2/36 (5.6%)	2
Anal fissure	1/36 (2.8%)	1
Elevated creatinine level	3/36 (8.3%)	3
Bilateral cracks in lung	2/36 (5.6%)	2
Fullness in abdomen upon cough	1/36 (2.8%)	1
Swollen throat/pharyngeal abscess	1/36 (2.8%)	2
Upper extremity swelling	1/36 (2.8%)	1
Bleeding	2/36 (5.6%)	2
Jaw swelling	1/36 (2.8%)	1
Tongue pain	2/36 (5.6%)	3
Dry mouth	6/36 (16.7%)	8
Periodontal disease	2/36 (5.6%)	5
Leg pain	6/36 (16.7%)	6
Anorexia	21/36 (58.3%)	32
Generalized pain	3/36 (8.3%)	3
Dry mucous membrane	2/36 (5.6%)	3
Throat pain	7/36 (19.4%)	14
Lip pain	1/36 (2.8%)	1
Decreased range of motion	1/36 (2.8%)	1
Abdominal tenderness	3/36 (8.3%)	5
Pelvis pain	1/36 (2.8%)	1
Distension	4/36 (11.1%)	5
Taste alteration	3/36 (8.3%)	3
Thrush	5/36 (13.9%)	7
Ears popping	1/36 (2.8%)	1
Ear pain	2/36 (5.6%)	3
Cracked tooth	1/36 (2.8%)	1
Umbilical hernia	1/36 (2.8%)	1
Hot flashes	1/36 (2.8%)	1
Obesity	2/36 (5.6%)	2
Reducible central hernia	1/36 (2.8%)	1
Tremor	2/36 (5.6%)	2
Cold sore	1/36 (2.8%)	1
Hypoxia	3/36 (8.3%)	6
Decreased electrolytes	1/36 (2.8%)	1
Sinus pain	1/36 (2.8%)	1
Acute infusion reaction	3/36 (8.3%)	3
Hemhorrage	5/36 (13.9%)	13
Increased alkaline phosphatase	2/36 (5.6%)	2
Increased alanine aminotransferase	2/36 (5.6%)	3
Weight gain	1/36 (2.8%)	1
Knee pain	2/36 (5.6%)	2
Rhinitis	3/36 (8.3%)	3
Change in signature	1/36 (2.8%)	1
Jaw pain	1/36 (2.8%)	1
Blister on tongue	1/36 (2.8%)	8
MSSA VRE (infection)	1/36 (2.8%)	1
Increased INR (international normalized ratio)	2/36 (5.6%)	7
Increased PTT (partial thromboblastin time)	3/36 (8.3%)	7
Sinusitis	1/36 (2.8%)	1
Facial pain	2/36 (5.6%)	3
Vaginal bleeding	1/36 (2.8%)	2
General incontinence	2/36 (5.6%)	3
Hemorrhoid pain	2/36 (5.6%)	3
Mouth pain	2/36 (5.6%)	7
Dehydration	6/36 (16.7%)	7
Groin pain	1/36 (2.8%)	6
Increased PT (prothrombin time)	1/36 (2.8%)	9
Hemorrhoids	1/36 (2.8%)	1
Hiccups	1/36 (2.8%)	1
Abdominal cramping	1/36 (2.8%)	1
Esophagitis	1/36 (2.8%)	2
Restlessness in legs	1/36 (2.8%)	1
Gram-negative bacteria	1/36 (2.8%)	2
Hepatobiliary disorders
Increased LFTs	1/36 (2.8%)	1
Increased aspartate aminotransferase	4/36 (11.1%)	7
Decreased fibrinogen	3/36 (8.3%)	4
Low creatinine	2/36 (5.6%)	2
High creatinine	1/36 (2.8%)	1
Immune system disorders
Sepsis	4/36 (11.1%)	4
Infections and infestations
Infection	15/36 (41.7%)	22
Blood infection	1/36 (2.8%)	2
Yeast infection	1/36 (2.8%)	1
Metabolism and nutrition disorders
Diabetes	1/36 (2.8%)	1
Musculoskeletal and connective tissue disorders
Joint pain/stiffness	2/36 (5.6%)	2
Decreased musculature	1/36 (2.8%)	1
Muscle weakness	3/36 (8.3%)	3
Spinal change	1/36 (2.8%)	1
Muscle spasm	1/36 (2.8%)	1
Muscular atrophy	1/36 (2.8%)	2
Nervous system disorders
Neuropathy	4/36 (11.1%)	5
Numbness/tingling	4/36 (11.1%)	4
Saddle anesthesia	1/36 (2.8%)	1
Psychiatric disorders
Anxiety	13/36 (36.1%)	25
Mental status change/confusion	2/36 (5.6%)	2
Depression	4/36 (11.1%)	6
Hallucinations	2/36 (5.6%)	2
Flat affect	1/36 (2.8%)	3
Renal and urinary disorders
Urinary frequency	8/36 (22.2%)	8
Urinary incontinence	3/36 (8.3%)	3
Low urine output	1/36 (2.8%)	1
Hematuria	3/36 (8.3%)	3
Bladder spasm	1/36 (2.8%)	1
Urinary retention	1/36 (2.8%)	1
Dysuria	1/36 (2.8%)	2
Respiratory, thoracic and mediastinal disorders
Dyspnea	19/36 (52.8%)	31
Respiratory distress	1/36 (2.8%)	1
Pleural effusion	4/36 (11.1%)	4
Pneumonia	2/36 (5.6%)	2
Breathing difficulty	1/36 (2.8%)	1
Lobar pneumonia	1/36 (2.8%)	1
Wheezing	3/36 (8.3%)	7
Coarse lung sounds	3/36 (8.3%)	4
Decreased breath sounds	3/36 (8.3%)	3
Pulmonary nodules	1/36 (2.8%)	1
Pericardial effusion	1/36 (2.8%)	1
Skin and subcutaneous tissue disorders
Rash	23/36 (63.9%)	35
Edema	28/36 (77.8%)	55
Cellultitis	1/36 (2.8%)	1
Bruising	8/36 (22.2%)	11
Ecchymosis	2/36 (5.6%)	2
Itching	12/36 (33.3%)	14
Hematoma	1/36 (2.8%)	1
Petechiae	6/36 (16.7%)	10
Erythema	9/36 (25%)	16
Redness at PICC site	2/36 (5.6%)	2
Flushing	2/36 (5.6%)	2
Xanthoma	1/36 (2.8%)	1
Hyperpigmentation	1/36 (2.8%)	1
Hives	2/36 (5.6%)	2
Purpura	1/36 (2.8%)	3
Macular rash	1/36 (2.8%)	1
Dry skin	1/36 (2.8%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.