Low-dose Oral Clofarabine for the Treatment of IPSS INT-1, INT-2 or HIGH Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia

• Sponsor: University of Utah (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00708721
• Collaborator: Genzyme, a Sanofi Company (Industry)
• Enrollment: 11
• Location: 1
• Arm: 1
• Duration (Months): 80
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Study and Dose Rationale The safety profile of clofarabine appears acceptable within the target populations studied to date in the clinical studies summarized in Section 2.3. clofarabine has demonstrated anti-cancer activity through inhibition of DNA synthesis and repair, induction of apoptosis, and possibly through other mechanisms. The effect of clofarabine on DNA methylation has not been determined. Numerous responses have been observed after treatment with clofarabine in heavily pre-treated relapsed/refractory patients with ALL or AML.

Recently 2 small studies were conducted at the M.D. Anderson Cancer Center looking at the use of clofarabine in the treatment of MDS.31 The first study randomized patients in a Bayesian fashion to 15 vs. 30 mg/m2 given IV daily for 5 days every 4 to 8 weeks. In the 15 mg/m2 arm 3 of 7 patients had a complete remission according to the International Working Group (IWG)32 criteria for response. In the 30 mg/m2 arm, 2 of 6 patients had a complete remission while 1 patient had hematologic improvement according to IWG criteria. In the second study, patients were treated with oral clofarabine at a dose of 40 mg/m2 daily for 5 days every 4 to 8 weeks. Two of 7 patients had hematologic improvement according to IWG criteria. The main toxicities in both trials were prolonged myelosuppression and liver function abnormalities.

Preclinical animal models have shown increased clofarabine activity against multiple different tumors with repetitive daily dosing for prolonged periods of time.33 The use of an oral therapy is advantageous for the treatment of a chronic malignancy such as MDS. Furthermore, based on the pre-clinical data mentioned above daily repetitive dosing over a protracted period may provide increased efficacy. Since most MDS patients are elderly and may not tolerate aggressive therapy, a schedule of administration of low dose oral clofarabine over a protracted period may provide the advantage of increased efficacy without severe toxicity. The safety of a protracted daily dosage of oral clofarabine in humans has not been determined. The dosing scheme for this study will therefore include a dose escalating phase I component followed by a phase II component. The starting dose will be 5 mg (fixed dose) orally daily for 10 days. This dose will be escalated in cohorts of 3 patients as tolerated up to a maximal dose of 15 mg (fixed dose) orally for 10 consecutive days. Note that at the latter dose a patient will receive a total of 150 mg of clofarabine per cycle, which far lower than the MD Anderson study of oral clofarabine in MDS whereby patients received 200 mg/m2 per cycle.

OBJECTIVES:

Study Overview The purpose of this study is to determine the efficacy and toxicity of Clofarabine administered orally at a low daily dose for the treatment of myelodysplastic syndromes.

Condition or Disease	Intervention/Treatment	Phase
Cancer; Chronic Myelomonocytic Leukemia	Drug: Clofarabine	Phase 1/Phase 2

Detailed Description

Primary Objectives

1. Phase I: To determine the MTD within the planned dose range for this patient population and assess the toxicity of oral clofarabine

2. Phase II: To estimate the overall response rate (complete, partial and hematologic improvement by modified IWG criteria) in response to low dose daily oral clofarabine in patients with high risk myelodysplastic syndrome or chronic myelomonocytic leukemia (dysplastic type).

Secondary Objectives

1. To evaluate the toxicity of low dose daily oral clofarabine in this patient population.

2. To determine the time to progression to acute myeloid leukemia (AML) of MDS patients treated with low dose daily oral clofarabine.

3. To determine the duration of response, overall survival (OS) and progression free survival (PFS) of MDS patients treated with low dose daily oral clofarabine.

4. To determine the effect of low dose daily oral clofarabine on global methylation in patients with MDS.

5. To determine the effect of low dose daily oral clofarabine on miRNA and mRNA expression patterns in patients with MDS.

Treatment Patients will take Clofarabine by mouth once daily for 10 days followed by 18 days of no Clofarabine. This 28 day period of time is called one treatment cycle. After they complete three cycles of treatment they will have bone marrow and blood tests done to find out if their MDS or CMML is responding to the treatment. If these tests show the MDS or CMML is responding to treatment they will continue taking the same dose of Clofarabine for 3 more cycles. If the tests show that the MDS or CMML is not responding to treatment the dose of Clofarabine will be increased and they will continue on the same schedule (10 days on, 18 days off) for 3 more cycles.

After 6 cycles patients will again have bone marrow and blood tests done to find out if the MDS or CMML is responding to the treatment. If the tests show that the MDS or CMML is not responding to treatment the dose of Clofarabine will be increased again and they will continue on the same schedule (10 days on, 18 days off) for 6 more cycles.

5-3-11 Update: The phase I portion of the study has now been closed to accrual. The Phase II portion of the trial will enroll up to 20 patients. Patients will be evaluated on a weekly basis for toxicity. At the completion of cycle 3 and within 1 week of starting cycle 4, patients will receive a bone marrow aspirate and biopsy in addition to a complete blood count in order to evaluate for response according to IWG criteria. Patients who have evidence of a response to therapy or stable disease will be continued on the same dose and schedule of oral clofarabine. Bone marrow evaluation for response will be obtained at the completion of 6 and then 12 cycles. If the patient continues treatment after cycle 12 a bone marrow evaluation will be done at the discretion of the investigator. Treatment will continue at the same dose and schedule indefinitely until either disease progression, the development of unacceptable toxicity or the patient decides to go off study.

Follow-up For this protocol, all patients, including those who discontinue protocol therapy early, will be followed for response until progression and for survival for 5 years from the date of registration. All patients must also be followed through completion of all protocol therapy.

Study Design

• Study Type: Interventional
• Actual Enrollment: 11 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I/II Study of Low-dose Oral Clofarabine for the Treatment of IPSS INT-1, INT-2 or HIGH Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia (Dysplastic Type) Patients Who Have Failed Hypomethylating Therapy
• Study Start Date: Mar 1, 2008
• Actual Primary Completion Date: Nov 1, 2014
• Actual Study Completion Date: Nov 1, 2014

Arms and Interventions

Arm

Intervention/Treatment

Experimental: All patients All participants enrolled.

Drug: Clofarabine; Clofarabine is a rationally designed, second generation purine nucleoside analogue. Clofarabine was designed as a hybrid molecule to overcome the limitations and incorporate the best qualities of both fludarabine (F-ara-A) and cladribine (2-CdA, CdA) both of which are currently approved by various regulatory authorities for treatment of hematologic malignancies.; Other Names: Clofarabine (2-chloro-9-[2-deoxy-2-fluoro-D-arabinofuranosyl]adenine; Cl-F-ara A; CAFdA

Outcome Measures

Primary Outcome Measures

1. Number of Participants Who Experienced a Dose-Limiting Toxicity [28 days after the first admistration of oral clofarabine]

   Dose-limiting toxicity was defined as any nonhematologic toxicity grade 3 or greater except for alopecia or nausea (which may be of grade 4 severity), or any grade 4 hematologic toxicity lasting more than 28 days after the last day of therapy.

2. The Overall Response Rate in Response to Low Dose Daily Oral Clofarabine in Patients With High Risk Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia (Dysplastic Type). [4 weeks]

   Response rate was measured as complete, partial and hematologic improvement by modified IWG criteria. For complete remission the following must be present for four weeks in a bone marrow aspirate and biopsy: <5% myeloblasts, normal maturation of all cell lines, persisted dysplasia. Peripheral blood counts need to be hemoglobin >11 g/dL, neutrophils >1000/mm3, platelets>100000/mm3, blasts 0%. Partial remission requires all criteria for complete remission except blasts decreased by >50% over pretreatment. Stable disease is defined as failure to achieve at least partial remission, but no evidence of progression for > 8 weeks. Failure is defined as death during tre3atment or disease progression characterized by worsening of cytopenias, increase in percentage of bone marrow blasts, or progression to a more advanced MDS FAB subtype than pretreatment.

Secondary Outcome Measures

1. Time to Progression to Acute Myeloid Leukemia (AML) [approximately 4 years]

   Longest documented duration of time until progression to AML.

2. Response of MDS Patients Treated With Low Dose Daily Oral Clofarabine. [approximately 4 years]

   Stable disease is defined as failure to achieve at least PR, but no evidence of progression for > 8 weeks.

3. The Effect of Low Dose Daily Oral Clofarabine on Global Methylation in Patients With MDS. [through end of treatment]

   Potential genomic changes following low dose daily oral clofarabine administration will be assessed.

4. The Effect of Low Dose Daily Oral Clofarabine on miRNA and mRNA Expression Patterns in Patients With MDS [through end of treatment]

   Assessment of potential change in miRNA and mRNA genetic expression patterns in patients following administration of low dose daily clofarabine.

5. Number of Participants With Adverse Events [To 30 days after end of treatment or until full resolution.]

   NCI CTCAE version 3.0 will be used to assess adverse events. The number of participants experiencing adverse events and the number of adverse events per patient will be documented through the course of study.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

A bone marrow biopsy confirmed diagnosis of MDS or CMML (dysplastic subtype) according to WHO criteria within 2 weeks of registration.

1. Patients must have an International Prognostic Scoring System (IPSS), see Appendix D, score of INT-1 or higher at study entry.35 Patients with an IPSS score of INT-1 with the 5q- deletion should have failed Lenalidomide therapy and should have more than 5% blasts in the bone marrow or a platelet count < 50,000/mm3 or an absolute neutrophil count < 500/mm3 or be requiring therapy (e.g. being transfusion dependent). Patients with CMML must have a WBC < 12,000/mm3 documented within 4 weeks prior to study entry (two sets of counts that are 2 weeks apart will be taken).

2. Patients with MDS should have failed or relapsed after treatment with one regimen of hypomethylating agents (5-Azacytidine or Decitabine) but no more than 2 prior therapies including only 1 hypomethylating agent... Patients with CMML (dysplastic subtype) may be enrolled even if they have not received any prior therapy.

3. Untreated patients who are ineligible for or unwilling to undergo hypomethylating agent therapy can be enrolled

4. Age ≥ 18 years.

5. Patients must have and ECOG performance status of 0 - 2.

6. Provide signed written informed consent.

7. Have adequate renal and hepatic functions as indicated by the following laboratory values:

• Serum creatinine 1.0 mg/dL; if serum creatinine 1.0 mg/dL, then the estimated glomerular filtration rate (GFR) must be 30 mL/min/1.73 m2 as calculated by the Modification of Diet in Renal Disease equation where Predicted GFR (ml/min/1.73 m2) = 186 x (Serum Creatinine)-1.154 x (age in years)-0.023 x (0.742 if patient is female) x (1.212 if patient is black)

• Serum bilirubin ≤1.5 mg/dL × upper limit of normal (ULN)

• Aspartate transaminase (AST)/alanine transaminase (ALT) 2.5 × ULN

• Alkaline phosphatase 2.5 × ULN

1. Capable of understanding the investigational nature, potential risks and benefits of the study, and able to provide valid informed consent.

2. Female patients of childbearing potential must have a negative serum pregnancy test within 2 weeks prior to enrollment.

3. Male and female patients must use an effective contraceptive method during the study and for a minimum of 6 months after study treatment

Exclusion Criteria:

1. Current concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol.

2. Pre-treatment with more than 2 previous regimens.

3. Use of investigational agents within 30 days or any anticancer therapy within 30 days before study entry with the exception of hydroxyurea. The patient must have recovered from all acute toxicities from any previous therapy.

4. Have any other severe concurrent disease, or have a history of serious organ dysfunction or disease involving the heart, kidney, liver, or other organ system that may place the patient at undue risk to undergo treatment.

5. Patients with a systemic fungal, bacterial, viral, or other infection not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment).

6. Pregnant or lactating patients.

7. Any significant concurrent disease, illness, or psychiatric disorder that would compromise patient safety or compliance, interfere with consent, study participation, follow up, or interpretation of study results.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Huntsman Cancer Institute	Salt Lake City	Utah	United States	84112

Sponsors and Collaborators

• University of Utah
• Genzyme, a Sanofi Company

Investigators

• Principal Investigator: Paul J Shami, MD, Huntsman Cancer Institute

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of Utah
• ClinicalTrials.gov Identifier: NCT00708721
• Other Study ID Numbers: HCI26135
• First Posted: Jul 2, 2008
• Last Update Posted: Jun 1, 2017
• Last Verified: May 1, 2017

• Keywords provided by University of Utah: hypomethylating therapy; CML; myelodysplastic syndromes
• Additional relevant MeSH terms: Leukemia; Preleukemia; Leukemia, Myelomonocytic, Acute; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile; Myelodysplastic Syndromes; Clofarabine

Study Results

Participant Flow

Arm/Group Title	Cohort 1: 5 mg/Day for 10 Days	Cohort 2: 1 mg/Day for 10 Days	Cohort 3: 1 mg/Day for 7 Days	Not Evaluable
Arm/Group Description	5 mg/day for 10 out of 28 days	1 mg/day for 10/28 days and for cycle 1 and then 1 mg/day for 7/28 days for cycle 2 onward	1 mg/day for 7/28 days
Period Title: Overall Study
STARTED	2	4	3	2
COMPLETED	2	4	3	2
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	All Groups
Arm/Group Description
Overall Participants	11
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	4 36.4%
>=65 years	7 63.6%
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	68.3
Sex: Female, Male (Count of Participants)
Female	5 45.5%
Male	6 54.5%
Region of Enrollment (participants) [Number]
United States	11 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants Who Experienced a Dose-Limiting Toxicity
Description	Dose-limiting toxicity was defined as any nonhematologic toxicity grade 3 or greater except for alopecia or nausea (which may be of grade 4 severity), or any grade 4 hematologic toxicity lasting more than 28 days after the last day of therapy.
Time Frame	28 days after the first admistration of oral clofarabine

Outcome Measure Data

Analysis Population Description

9 out of 11 participants were evaluable for this outcome.

Arm/Group Title	Cohort 1: 10 mg/Day for 10 Days	Cohort 2: 1 mg/Day for 10 Days	Cohort 3: 1 mg/Day for 7 Days	Not Evaluable
Arm/Group Description
Measure Participants	2	4	3	2
Number [participants who experienced a DLT]	2 18.2%	4 NaN	0 NaN	0 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort 1: 10 mg/Day for 10 Days, Cohort 2: 1 mg/Day for 10 Days
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Maximum Tolerated Dose
	Estimated Value	1
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on cytopenias observed at day 10 (Phase 1 trial only), and the Phase II dose was determined to be 1 mg per day for 7 consecutive days given on a 28 day cycle.

2. Primary Outcome

Title	The Overall Response Rate in Response to Low Dose Daily Oral Clofarabine in Patients With High Risk Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia (Dysplastic Type).
Description	Response rate was measured as complete, partial and hematologic improvement by modified IWG criteria. For complete remission the following must be present for four weeks in a bone marrow aspirate and biopsy: <5% myeloblasts, normal maturation of all cell lines, persisted dysplasia. Peripheral blood counts need to be hemoglobin >11 g/dL, neutrophils >1000/mm3, platelets>100000/mm3, blasts 0%. Partial remission requires all criteria for complete remission except blasts decreased by >50% over pretreatment. Stable disease is defined as failure to achieve at least partial remission, but no evidence of progression for > 8 weeks. Failure is defined as death during tre3atment or disease progression characterized by worsening of cytopenias, increase in percentage of bone marrow blasts, or progression to a more advanced MDS FAB subtype than pretreatment.
Time Frame	4 weeks

Outcome Measure Data

Analysis Population Description

Two patients were not eligible for analysis.

Arm/Group Title	All Evaluable Patients
Arm/Group Description	All participants enrolled. Clofarabine: Clofarabine is a rationally designed, second generation purine nucleoside analogue. Clofarabine was designed as a hybrid molecule to overcome the limitations and incorporate the best qualities of both fludarabine (F-ara-A) and cladribine (2-CdA, CdA) both of which are currently approved by various regulatory authorities for treatment of hematologic malignancies.
Measure Participants	9
Number [participants who experienced a response]	3 27.3%

3. Secondary Outcome

Title	Time to Progression to Acute Myeloid Leukemia (AML)
Description	Longest documented duration of time until progression to AML.
Time Frame	approximately 4 years

Outcome Measure Data

Analysis Population Description

Cycles are 28 days long. Analysis assessed the longest number of cycles completed on study until progression to AML.

Arm/Group Title	All Evaluable Patients
Arm/Group Description	Only nine of the eleven patients were evaluable for this outcome measure.
Measure Participants	9
Number [cycles]	51

4. Secondary Outcome

Title	Response of MDS Patients Treated With Low Dose Daily Oral Clofarabine.
Description	Stable disease is defined as failure to achieve at least PR, but no evidence of progression for > 8 weeks.
Time Frame	approximately 4 years

Outcome Measure Data

Analysis Population Description

Of 11 patients, 9 were evaluable for response. Two patients had stable disease responses.

Arm/Group Title	All Evaluable Patients
Arm/Group Description	All evaluable patients. Eleven patients were enrolled, but only nine were evaluable.
Measure Participants	9
Count of Participants [Participants]	2 18.2%

5. Secondary Outcome

Title	The Effect of Low Dose Daily Oral Clofarabine on Global Methylation in Patients With MDS.
Description	Potential genomic changes following low dose daily oral clofarabine administration will be assessed.
Time Frame	through end of treatment

Outcome Measure Data

Analysis Population Description

Data were not collected and the outcome measure was not analyzed

Arm/Group Title	All Patients
Arm/Group Description	All participants enrolled.
Measure Participants	0
	0

6. Secondary Outcome

Title	The Effect of Low Dose Daily Oral Clofarabine on miRNA and mRNA Expression Patterns in Patients With MDS
Description	Assessment of potential change in miRNA and mRNA genetic expression patterns in patients following administration of low dose daily clofarabine.
Time Frame	through end of treatment

Outcome Measure Data

Analysis Population Description

Data were not collected and the outcome measure was not analyzed

Arm/Group Title	All Patients
Arm/Group Description	All participants enrolled.
Measure Participants	0
	0

7. Secondary Outcome

Title	Number of Participants With Adverse Events
Description	NCI CTCAE version 3.0 will be used to assess adverse events. The number of participants experiencing adverse events and the number of adverse events per patient will be documented through the course of study.
Time Frame	To 30 days after end of treatment or until full resolution.

Outcome Measure Data

Analysis Population Description

All participants experienced at least 1 adverse event (100% of the patient population; 11/11 participants)

Arm/Group Title	All Patients
Arm/Group Description	All participants enrolled.
Measure Participants	11
Number [participants experiencing adverse events]	11 100%

Adverse Events

Time Frame	Adverse events were collected after the administration of the study drug and followed until resolution.
Arm/Group Title	All Groups
Arm/Group Description	All patients who received study treatment.
All Cause Mortality
	All Groups
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	All Groups
	Affected / at Risk (%)	# Events
Total	8/11 (72.7%)
Blood and lymphatic system disorders
thrombocytopenia	2/11 (18.2%)
cytopenia	1/11 (9.1%)
febrile neutropenia	1/11 (9.1%)
Cardiac disorders
congestive heart failure	2/11 (18.2%)
pulmonary hypertension	1/11 (9.1%)
decreased ejection fraction	1/11 (9.1%)
Gastrointestinal disorders
cholecystitis	1/11 (9.1%)
Infections and infestations
cellulitis right forearm	1/11 (9.1%)
urinary tract infection	1/11 (9.1%)
e. coli positive	1/11 (9.1%)
gram positive cocci	1/11 (9.1%)
Musculoskeletal and connective tissue disorders
femur fracture	1/11 (9.1%)
joint swelling	1/11 (9.1%)
Nervous system disorders
mental status change	1/11 (9.1%)
stroke	1/11 (9.1%)
Renal and urinary disorders
renal failure	1/11 (9.1%)
Reproductive system and breast disorders
Ovarian abscess	1/11 (9.1%)
Respiratory, thoracic and mediastinal disorders
pneumonia	2/11 (18.2%)
hypoxia	1/11 (9.1%)
pleural effusion	1/11 (9.1%)
Vascular disorders
Subdural hematoma	1/11 (9.1%)
Other (Not Including Serious) Adverse Events
	All Groups
	Affected / at Risk (%)	# Events
Total	11/11 (100%)
Blood and lymphatic system disorders
anemia	7/11 (63.6%)
leukopenia	4/11 (36.4%)
lymphopenia	5/11 (45.5%)
neutropenia	6/11 (54.5%)
splenomegaly	1/11 (9.1%)
thrombocytopenia	9/11 (81.8%)
hematomas	1/11 (9.1%)
petechia	4/11 (36.4%)
neutropenic fever	1/11 (9.1%)
Cardiac disorders
Afibrilation with RVR	1/11 (9.1%)
Atrial Flutter with AV Block	1/11 (9.1%)
Ventricular Tachycardia	1/11 (9.1%)
Cardiomegaly	2/11 (18.2%)
Hypertension	1/11 (9.1%)
Inferior Cardiac Infarct	1/11 (9.1%)
pericarditis	1/11 (9.1%)
elevated PTT	1/11 (9.1%)
pericardial thickening	1/11 (9.1%)
Eye disorders
left eye redness	1/11 (9.1%)
eye scratch	1/11 (9.1%)
Gastrointestinal disorders
vomiting	2/11 (18.2%)
abdominal distention	1/11 (9.1%)
abdominal pain	5/11 (45.5%)
blood blisters in mouth	1/11 (9.1%)
constipation	2/11 (18.2%)
diarrhea	3/11 (27.3%)
flatulence	1/11 (9.1%)
heart burn	1/11 (9.1%)
mouth sores	1/11 (9.1%)
nausea	4/11 (36.4%)
oral thrush	2/11 (18.2%)
oral pain	1/11 (9.1%)
throat pain	1/11 (9.1%)
bleeding in mouth	1/11 (9.1%)
General disorders
diaphoretic	1/11 (9.1%)
fatigue	7/11 (63.6%)
fever	3/11 (27.3%)
edema (bilateral lower extremity)	3/11 (27.3%)
pedal edema	1/11 (9.1%)
chest pain	3/11 (27.3%)
pain at port site	1/11 (9.1%)
Infections and infestations
c. differential positive	1/11 (9.1%)
cellulitis	1/11 (9.1%)
eye infection	1/11 (9.1%)
head cold	1/11 (9.1%)
infections with unknown ANC	1/11 (9.1%)
prostatitis	1/11 (9.1%)
sepsis	1/11 (9.1%)
sore throat	1/11 (9.1%)
upper respiratory infection	2/11 (18.2%)
yeast infection	1/11 (9.1%)
urinary tract infection	2/11 (18.2%)
Injury, poisoning and procedural complications
brusing	3/11 (27.3%)
hernia	1/11 (9.1%)
Investigations
elevated alkaline phosphatase	3/11 (27.3%)
elevated ALT	2/11 (18.2%)
elevated amylase	1/11 (9.1%)
elevated AST	4/11 (36.4%)
Hyperbilirubinemia	3/11 (27.3%)
increased creatinine	3/11 (27.3%)
Metabolism and nutrition disorders
anorexia	4/11 (36.4%)
elevated uric acid	1/11 (9.1%)
hypercalcemia	1/11 (9.1%)
hyperglycemia	7/11 (63.6%)
Hypoalbuminemia	6/11 (54.5%)
hypocalcemia	2/11 (18.2%)
hypoglycemia	3/11 (27.3%)
hyponatremia	2/11 (18.2%)
hypokelmia	2/11 (18.2%)
rib pain	1/11 (9.1%)
Musculoskeletal and connective tissue disorders
bilateral leg weakness	1/11 (9.1%)
fracture	2/11 (18.2%)
hand laceration	1/11 (9.1%)
muscle cramps	1/11 (9.1%)
muscle weakness	1/11 (9.1%)
back pain	4/11 (36.4%)
joint pain	1/11 (9.1%)
right knee pain	1/11 (9.1%)
arthritis	1/11 (9.1%)
bone pain	1/11 (9.1%)
Nervous system disorders
confusion	2/11 (18.2%)
dizziness	3/11 (27.3%)
drowsiness	1/11 (9.1%)
hallucination	1/11 (9.1%)
neuropathy: cranial	1/11 (9.1%)
neuropathy: motor	1/11 (9.1%)
anxiety	2/11 (18.2%)
syncope	1/11 (9.1%)
headache	3/11 (27.3%)
Psychiatric disorders
insomnia	2/11 (18.2%)
Renal and urinary disorders
dysuria	1/11 (9.1%)
Respiratory, thoracic and mediastinal disorders
allergic rhinits	1/11 (9.1%)
atelectasis	2/11 (18.2%)
bronchitis	1/11 (9.1%)
chest congestion	1/11 (9.1%)
cough	5/11 (45.5%)
crackles in lungs	1/11 (9.1%)
Dyspenia	3/11 (27.3%)
pleural effusion	3/11 (27.3%)
pneumonia	3/11 (27.3%)
pulmonary edema	1/11 (9.1%)
wheezing	1/11 (9.1%)
Skin and subcutaneous tissue disorders
cracked lips	1/11 (9.1%)
dry skin	2/11 (18.2%)
itching	1/11 (9.1%)
lesions	4/11 (36.4%)
rash: erythemia	3/11 (27.3%)
ulceration	2/11 (18.2%)
night sweats	1/11 (9.1%)
erythematous	2/11 (18.2%)
Vascular disorders
hot flashes	1/11 (9.1%)
lower extremity phlebitis	1/11 (9.1%)
superficial thrombosis	1/11 (9.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT 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.