Treatment of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): DNA Microarray Gene Expression Analysis

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00001586
• Collaborator: (none)
• Enrollment: 105
• Location: 1
• Arms: 2
• Duration (Months): 170
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

Background:

• Combined therapy with rituximab and fludarabine is the treatment of choice for advanced stage chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

• A new technology called deoxyribonucleic acid (DNA) microarray can be used to gain knowledge about the genetic basis of CLL/SLL.

• Genetic studies of CLL/SLL may improve our understanding of what happens in the disease, help determine which patients are most likely to respond to treatment with fludarabine and rituximab, and identify new treatments.

Objectives:

-To gain further knowledge about CLL/SLL and the role of rituximab and fludarabine in treating the disease.

Eligibility:

-Patients 18 years of age and older with low, intermediate or high-risk CLL/SLL.

Design:

• Patients with low-risk CLL/SLL do not receive treatment, but are followed every 3 to 6 months and donate cells (through apheresis) or lymph nodes, or both, for research purposes.

• Patients with intermediate or high-risk CLL/SLL receive standard treatment with rituximab and fludarabine for six 28-day treatment cycles. Rituximab is given on day 1 and fludarabine is given on days 1-5. (For the first cycle only, fludarabine treatment starts on day 2. This delay permits blood sampling on day 1 for the effect of rituximab on white blood cells.)

• Laboratory tests and imaging studies are done periodically to monitor drug side effects and the response to treatment. Tests include bone marrow biopsy and aspiration, blood tests and x-rays, including positron emission tomography (PET) and computed tomography (CT) scans.

Condition or Disease	Intervention/Treatment	Phase
Chronic Lymphocytic Leukemia	Biological: Rituximab; Drug: Fludarabine phosphate; Other: Leukemic or stroma cells	Phase 2

Detailed Description

Background:

• Due to their synergistic action and non-overlapping toxicity profiles, the combination of Rituximab and Fludarabine is the treatment of choice for advanced stage chronic lymphocytic lymphoma (CLL)/small lymphocytic lymphoma (SLL).

• As such, we have designed this protocol to better understand the genetic basis of CLL/SLL, to identify predictors of treatment response and to study the molecular effects of Rituximab Fludarabine on the leukemic cells.

• A new technology utilizing complementary deoxyribonucleic acid (cDNA) microarrays now permits the simultaneous quantitation of the expression of thousands of genes; this methodology can evaluate defined cellular pathways, and also discover novel genes influencing cell biology.

• In addition to improving our understanding of the pathogenesis of CLL/SLL, these molecular studies may identify new therapeutic targets in CLL/SLL, and may help to identify those CLL/SLL patients most likely to respond to the combination of Fludarabine and Rituximab.

Objectives:

• Evaluate CLL/SLL patients during and following Rituximab Fludarabine chemotherapy for changes in lymphocyte gene expression using DNA microarray analysis.

• Evaluate gene expression by DNA microarray analysis of leukemic cells in blood, bone marrow and lymph nodes.

Eligibility:

• Low, Intermediate or High-Risk Category of CLL/SLL, using the Modified Three- Stage Rai Staging System

• Age greater than or equal to 18 years.

• Patients must have received no previous cytotoxic or monoclonal antibody therapy.

• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.

• Patients must not be pregnant or breast-feeding.

• Patients with active autoimmune hemolytic anemia (AIHA)) grade III or higher (transfusion or steroids indicated) or immune thrombocytopenia (ITP) grade III or higher (platelets less than 50,000/microL) shall not be enrolled.

• Any patient with a medical condition that requires chronic use of corticosteroids shall not be enrolled.

Design:

• Patients who do not require treatment will be followed every 3-6 months and will donate cellular products, bone marrow biopsies, bone marrow aspirates and/or lymph nodes for research purposes.

• Patients who do require treatment will received the standard dose of the Rituximab monoclonal antibody and the standard dose of Fludarabine for a total of six cycles. In the first cycle, Rituximab will be given on day 1 with Fludarabine being given on days 2-6. This will allow for appropriate samplings of the effects of Rituximab on lymphocytes before during and at the end of the first 24 hours. In subsequent cycles 2-6, the Rituximab and day 1 Fludarabine can both be given on day 1.

Study Design

• Study Type: Interventional
• Actual Enrollment: 105 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Treatment of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): DNA Microarray Gene Expression Analysis
• Study Start Date: Sep 1, 1997
• Actual Primary Completion Date: Nov 1, 2011
• Actual Study Completion Date: Nov 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Low-Intermediate Risk B-Cell Pts Previously untreated low or intermediate risk B-cell chronic lymphocytic lymphoma (CLL)/small lymphocytic lymphoma (SLL) patients (pts) not requiring chemotherapy. No rituximab fludarabine administered. Eligible to donate cells.	Other: Leukemic or stroma cells; Patients are eligible to donate cells for the purpose of analyzing leukemic cells. Cells can be donated by apheresis (e.g. 60-90 minute intravenous technique), lymph node biopsy (e.g. 3 biopsy/excision of lymph nodes)bone marrow biopsy (e.g. 2-4 separate bone marrow biopsies), and bone marrow aspiration (e.g. 3 to 5cc of marrow per aspirate).
Experimental: Intermediate-high Risk B-Cell Pts Previously untreated intermediate or high risk B-cell chronic lymphocytic lymphoma (CLL)/small lymphocytic lymphoma (SLL) patients requiring chemotherapy. Rituximab 375 mg/m^2 by infusion on day 1, cycle 1 followed by fludarabine on day 2-6, 25 mg/m^2 day x 5 days administered as an intravenous push or intravenous piggyback over 10-30 minutes, repeated every 28 days.	Biological: Rituximab; Rituxan; Other Names: Rituximab 375 mg/m^2 by infusion on day 1, cycle 1. Repeated every 28 days. ; Drug: Fludarabine phosphate; Fludara; Other Names: Fludarabine on day 2-6, 25 mg/m^2 day x 5 days administered as an intravenous push or intravenous piggyback over 10-30 minutes, repeated every 28 days.

Outcome Measures

Primary Outcome Measures

1. Change in Gene Expression Post Chemo [6 hours post treatment, and 24 hours post treatment]

   Changes in lymphocyte gene expression was measured by deoxyribonucleic acid (DNA) microarray analysis of circulating leukemic cells after completion of study treatment. A change in expression is defined as a >50% increase in circulating leukemic cells or a 30% decrease in circulating leukemic cells.

Secondary Outcome Measures

1. Number of Participants With Adverse Events [13 years, 10.5 months]

   Here is the number of participants with adverse events. For the detailed list of adverse events see the adverse event module.

Eligibility Criteria

Criteria

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

• INCLUSION CRITERIA:

Diagnosis of chronic lymphocytic lymphoma (CLL)/small lymphocytic lymphoma (SLL) will be made according to the World Health Organization (WHO) diagnostic classification. A lymphocyte count in excess of 5000/mcl is typically found in the leukemic variant but is not a pre-requisite for a diagnosis of SLL. Low, Intermediate or High-Risk Category of

CLL/SLL, using the Modified Three-Stage Rai Staging System as follows:

Risk Category: Low Risk

Rai Stage: 0

Clinical Features: Elevated blood and marrow lymphocyte numbers only (L). (lymphocytes greater than 5000/microl in blood, and lymphocytes greater than 30 percent in marrow).

Risk Category: Intermediate Risk

Rai Stage: I

Clinical Features: L + enlarged lymph nodes (LN)

Risk Category: Intermediate Risk

Rai Stage: II

Clinical Features: L + enlarged spleen or liver

Risk Category: High Risk

Rai Stage: III

Clinical Features: L + anemia (Hemoglobin less than 11 gm/dl)

Risk Category: High Risk

Rai Stage: IV

Clinical Features: L + thrombocytopenia (platelets less than 100,000/microl)

Patients in the modified Rai high risk group and select patients in the intermediate risk group will undergo treatment with Rituximab Fludarabine. To meet treatment criteria patients in the intermediate risk group should have evidence of active disease as demonstrated by at least one of the following criteria:

1. massive or progressive splenomegaly or lymphadenopathy;

2. presence of weight loss greater than 10% over the preceding 6 months;

3. constitutional symptoms of extreme fatigue, night sweats or recurrent fever of greater than 100 degrees F (documented fevers must be occurring without evidence of specific infection), and bone pain;

4. progressive lymphocytosis with an increase of greater than 50% over a 2 month period, or an anticipated doubling time of less than 6 months;

5. chronic infections either increased number or prolonged infections;

6. other high risk prognostic indicators such as excess elevation of beta-2-microglobulin, cluster differentiation 38 (CD38) expression and adverse cytogenetics may be used to better appraise the risk in each individual patient.

Patients with a diagnosis of CLL/SLL who do not meet the eligibility criteria for receiving Rituximab and Fludarabine (are not intermediate- or high-risk CLL/SLL), can enroll on the protocol for the purpose of donating cellular products. Such patients will not receive rituximab and fludarabine chemotherapy. At a later date, if it is documented that the patient does meet the criteria, then the patient may receive Rituximab and Fludarabine (after discussion with the Principal Investigator).

In a limited number of cases, patients with low-risk CLL/SLL may be initiated on Rituximab and Fludarabine treatment. For example, individuals who are candidates for bone marrow transplantation may be started on Rituximab Fludarabine as an induction regimen prior to transplantation. Additionally, some low-risk patients may be started on Rituximab and Fludarabine for psychological reasons (patient insistence on starting chemotherapy prior to disease progression). However, it must be stressed that low-risk CLL/SLL patients will be discouraged from initiating therapy except in these specific cases.

Age greater than or equal to 18 years of age.

Patients must have received no prior cytotoxic or monoclonal antibody therapy.

Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.

Required initial laboratory tests: Blood urea nitrogen (BUN) and Creatinine values must be less than or equal to 1.5 times the normal values; alternatively, patients with creatinine clearance of greater than 50 ml per minute will also be eligible. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) values must be less than or equal to 2.0 times normal values; patients with laboratory values greater than these levels may be enrolled on the protocol (after a specific approval from the Principal Investigator) if the values are due to a known, pre-existing liver disease. Bilirubin must be less than or equal to 2.0 mg/dl unless due to Gilbert's disease.

The patient must be competent to sign an informed consent, and sign the protocol consent form.

EXCLUSION CRITERIA:

Patients must not be pregnant or breastfeeding.

Patients with active autoimmune hemolytic anemia (AIHA)) grade III or higher (transfusion or steroids indicated) or immune thrombocytopenia (ITP) grade III or higher (platelets less than 50,000/microL) shall not be enrolled. Patients with a history of prior therapy to control either AIHA or ITP will be eligible, provided they do not require maintenance corticosteroids, and have not received monoclonal antibody therapy in the past 6 months. Patients developing AIHA or ITP on protocol may be managed as medically indicated on protocol but will generally not undergo fludarabine/rituximab treatment until resolution of hemolysis or thrombocytopenia to less than grade III.

Any patient with a medical condition that requires chronic use of corticosteroids shall not be enrolled.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Institutes of Health Clinical Center, 9000 Rockville Pike	Bethesda	Maryland	United States	20892

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Wyndham H Wilson, M.D., National Cancer Institute, National Institutes of Health

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• NIH Clinical Center Detailed Web Page

Publications

• Keating MJ. Fludarabine phosphate in the treatment of chronic lymphocytic leukemia. Semin Oncol. 1990 Oct;17(5 Suppl 8):49-62. Review.
• Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS. Clinical staging of chronic lymphocytic leukemia. Blood. 1975 Aug;46(2):219-34.
• Raife TJ, Demetroulis EM, Lentz SR. Regulation of thrombomodulin expression by all-trans retinoic acid and tumor necrosis factor-alpha: differential responses in keratinocytes and endothelial cells. Blood. 1996 Sep 15;88(6):2043-9.

• Responsible Party: Wyndham Wilson, M.D., Principal investigator, National Institutes of Health Clinical Center (CC)
• ClinicalTrials.gov Identifier: NCT00001586
• Other Study ID Numbers: 970178; 97-C-0178; NCT00019370
• First Posted: Nov 4, 1999
• Last Update Posted: May 15, 2013
• Last Verified: Mar 1, 2013

• Keywords provided by Wyndham Wilson, M.D., Principal investigator, National Institutes of Health Clinical Center (CC): Genetics; Bone Marrow Transplantation; Immunosuppression; T Lymphocytes; Marrow Purging
• Additional relevant MeSH terms: Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Vidarabine; Rituximab; Fludarabine; Fludarabine phosphate

Study Results

Participant Flow

Arm/Group Title	Intermediate-high Risk B-Cell Pts	Low-Intermediate Risk B-Cell Pts
Arm/Group Description	Previously untreated intermediate or high risk B-cell chronic lymphocytic lymphoma (CLL)/small lymphocytic lymphoma (SLL) patients requiring chemotherapy. Rituximab 375 mg/m^2 by infusion on day 1, cycle 1 followed by fludarabine on day 2-6, 25 mg/m^2 day x 5 days administered as an intravenous push or intravenous piggyback over 10-30 minutes, repeated every 28 days.	Previously untreated low or intermediate risk B-cell chronic lymphocytic lymphoma (CLL)/small lymphocytic lymphoma (SLL) patients (pts) not requiring chemotherapy. No rituximab fludarabine administered. Eligible to donate cells.
Period Title: Overall Study
STARTED	49	56
COMPLETED	49	56
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Intermediate-high Risk B-Cell Pts	Low-Intermediate Risk B-Cell Pts	Total
Arm/Group Description	Previously untreated intermediate or high risk B-cell chronic lymphocytic lymphoma (CLL)/small lymphocytic lymphoma (SLL) patients requiring chemotherapy. Rituximab 375 mg/m^2 by infusion on day 1, cycle 1 followed by fludarabine on day 2-6, 25 mg/m^2 day x 5 days administered as an intravenous push or intravenous piggyback over 10-30 minutes, repeated every 28 days.	Previously untreated low or intermediate risk B-cell chronic lymphocytic lymphoma (CLL)/small lymphocytic lymphoma (SLL) patients (pts) not requiring chemotherapy. No rituximab fludarabine administered.	Total of all reporting groups
Overall Participants	49	56	105
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	39 79.6%	39 69.6%	78 74.3%
>=65 years	10 20.4%	17 30.4%	27 25.7%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	56.2 (9.34)	58.42 (11.32)	57.98 (11.11)
Sex: Female, Male (Count of Participants)
Female	19 38.8%	21 37.5%	40 38.1%
Male	30 61.2%	35 62.5%	65 61.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	1 1.8%	1 1%
Not Hispanic or Latino	49 100%	55 98.2%	104 99%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	1 2%	1 1.8%	2 1.9%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	6 12.2%	2 3.6%	8 7.6%
White	42 85.7%	52 92.9%	94 89.5%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	1 1.8%	1 1%
Region of Enrollment (participants) [Number]
United States	49 100%	56 100%	105 100%

Outcome Measures

1. Primary Outcome

Title	Change in Gene Expression Post Chemo
Description	Changes in lymphocyte gene expression was measured by deoxyribonucleic acid (DNA) microarray analysis of circulating leukemic cells after completion of study treatment. A change in expression is defined as a >50% increase in circulating leukemic cells or a 30% decrease in circulating leukemic cells.
Time Frame	6 hours post treatment, and 24 hours post treatment

Outcome Measure Data

Analysis Population Description

There were only 12 patients analyzed for various reasons such as timing of treatment, ability to collect samples, and viability of samples.

Arm/Group Title	Intermediate-high Risk B-Cell Pts	Low-Intermediate Risk B-Cell Pts
Arm/Group Description	Previously untreated intermediate or high risk B-cell chronic lymphocytic lymphoma (CLL)/small lymphocytic lymphoma (SLL) patients requiring chemotherapy. Rituximab 375 mg/m^2 by infusion on day 1, cycle 1 followed by fludarabine on day 2-6, 25 mg/m^2 day x 5 days administered as an intravenous push or intravenous piggyback over 10-30 minutes, repeated every 28 days.	Previously untreated low or intermediate risk B-cell chronic lymphocytic lymphoma (CLL)/small lymphocytic lymphoma (SLL) patients (pts) not requiring chemotherapy. No rituximab fludarabine administered.
Measure Participants	12	0
6 hours post treatment (e.g. ># cells)	30
24 hours post treatment (e.g. > # cells)	50

2. Secondary Outcome

Title	Number of Participants With Adverse Events
Description	Here is the number of participants with adverse events. For the detailed list of adverse events see the adverse event module.
Time Frame	13 years, 10.5 months

Outcome Measure Data

Analysis Population Description

The low-intermediate risk patients received no treatment so their tissue/blood was not analyzed for change.

Arm/Group Title	Intermediate-high Risk B-Cell Pts	Low-Intermediate Risk B-Cell Pts
Arm/Group Description	Previously untreated intermediate or high risk B-cell chronic lymphocytic lymphoma (CLL)/small lymphocytic lymphoma (SLL) patients requiring chemotherapy. Rituximab 375 mg/m^2 by infusion on day 1, cycle 1 followed by fludarabine on day 2-6, 25 mg/m^2 day x 5 days administered as an intravenous push or intravenous piggyback over 10-30 minutes, repeated every 28 days.	Previously untreated low or intermediate risk B-cell chronic lymphocytic lymphoma (CLL)/small lymphocytic lymphoma (SLL) patients (pts) not requiring chemotherapy. No rituximab fludarabine administered.
Measure Participants	49	0
Number [Participants]	18 36.7%

Adverse Events

Adverse Event Reporting Description	The low-intermediate risk B cell patients did not receive any treatment. No adverse events were collected for these patients. This group does not have adverse events.
Arm/Group Title	Intermediate-high Risk B-Cell Pts		Low-Intermediate Risk B-Cell Pts
Arm/Group Description	Previously untreated intermediate or high risk B-cell chronic lymphocytic lymphoma (CLL)/small lymphocytic lymphoma (SLL) patients requiring chemotherapy. Rituximab 375 mg/m^2 by infusion on day 1, cycle 1 followed by fludarabine on day 2-6, 25 mg/m^2 day x 5 days administered as an intravenous push or intravenous piggyback over 10-30 minutes, repeated every 28 days.		Previously untreated low or intermediate risk B-cell chronic lymphocytic lymphoma (CLL)/small lymphocytic lymphoma (SLL) patients (pts) not requiring chemotherapy. No rituximab fludarabine administered.
All Cause Mortality
	Intermediate-high Risk B-Cell Pts		Low-Intermediate Risk B-Cell Pts
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Intermediate-high Risk B-Cell Pts		Low-Intermediate Risk B-Cell Pts
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	19/49 (38.8%)		0/0 (NaN)
Blood and lymphatic system disorders
Hemoglobin	8/49 (16.3%)	11	0/0 (NaN)	0
Leukocytes (total WBC)	19/49 (38.8%)	31	0/0 (NaN)	0
Lymphopenia	18/49 (36.7%)	36	0/0 (NaN)	0
Platelets	2/49 (4.1%)	2	0/0 (NaN)	0
Gastrointestinal disorders
Hemorrhage, GI::Oral cavity	1/49 (2%)	1	0/0 (NaN)	0
General disorders
Fever (in the absence of neutropenia, where neutropenia is defined as ANC <1.0 x 10e9/L)	1/49 (2%)	1	0/0 (NaN)	0
Immune system disorders
Allergic reaction/hypersensitivity (including drug fever)	2/49 (4.1%)	3	0/0 (NaN)	0
Autoimmune reaction	4/49 (8.2%)	4	0/0 (NaN)	0
Infections and infestations
Infection	2/49 (4.1%)	2	0/0 (NaN)	0
Infection with normal ANC or Grade 1 or 2 neutrophils::Blood	1/49 (2%)	1	0/0 (NaN)	0
Infection with normal ANC or Grade 1 or 2 neutrophils::External ear (otitis externa)	1/49 (2%)	1	0/0 (NaN)	0
Infection with normal ANC or Grade 1 or 2 neutrophils::Lung (pneumonia)	1/49 (2%)	1	0/0 (NaN)	0
Infection with normal ANC or Grade 1 or 2 neutrophils::Skin (cellulitis)	1/49 (2%)	1	0/0 (NaN)	0
Infection with normal ANC or Grade 1 or 2 neutrophils::Upper airway NOS	1/49 (2%)	1	0/0 (NaN)	0
Nervous system disorders
Pain::Neuralgia/peripheral nerve	1/49 (2%)	1	0/0 (NaN)	0
Respiratory, thoracic and mediastinal disorders
Hemorrhage, pulmonary/upper respiratory::Nose	1/49 (2%)	1	0/0 (NaN)	0
Pleural effusion (non-malignant)	1/49 (2%)	1	0/0 (NaN)	0
Skin and subcutaneous tissue disorders
Rash/desquamation	3/49 (6.1%)	3	0/0 (NaN)	0
Vascular disorders
Thrombosis/embolism (vascular access-related)	1/49 (2%)	1	0/0 (NaN)	0
Other (Not Including Serious) Adverse Events
	Intermediate-high Risk B-Cell Pts		Low-Intermediate Risk B-Cell Pts
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	18/49 (36.7%)		0/0 (NaN)
Blood and lymphatic system disorders
Hemorrhage, GI::Oral cavity	1/49 (2%)	1	0/0 (NaN)	0
Hemorrhage, pulmonary/upper respiratory: Nose	1/49 (2%)	1	0/0 (NaN)	0
Transfusion	3/49 (6.1%)	3	0/0 (NaN)	0
Hemoptysis	2/49 (4.1%)	2	0/0 (NaN)	0
Leukocytes (total WBC)	16/49 (32.7%)	55	0/0 (NaN)	0
Lymphopenia	13/49 (26.5%)	29	0/0 (NaN)	0
Neutrophils/granulocytes (ANC/AGC)	18/49 (36.7%)	55	0/0 (NaN)	0
PTT (Partial Thromboplastin Time)	2/49 (4.1%)	2	0/0 (NaN)	0
Platelets	18/49 (36.7%)	45	0/0 (NaN)	0
Thrombotic microangiopathy	1/49 (2%)	1	0/0 (NaN)	0
Cardiac disorders
Cardiac arrhythmia - Other, Specify, unknown	1/49 (2%)	1	0/0 (NaN)	0
Pain::Chest wall	1/49 (2%)	1	0/0 (NaN)	0
Gastrointestinal disorders
Anorexia	6/49 (12.2%)	6	0/0 (NaN)	0
Diarrhea	5/49 (10.2%)	6	0/0 (NaN)	0
Heartburn/dyspepsia	1/49 (2%)	1	0/0 (NaN)	0
Mucositis/stomatitis (clinical exam)::Oral cavity	2/49 (4.1%)	2	0/0 (NaN)	0
Nausea	9/49 (18.4%)	16	0/0 (NaN)	0
General disorders
Edema: limb	1/49 (2%)	1	0/0 (NaN)	0
Fatigue (asthenia, lethargy, malaise)	5/49 (10.2%)	5	0/0 (NaN)	0
Fever (in the absence of neutropenia, where neutropenia is defined as ANC <1.0 x 10e9/L)	8/49 (16.3%)	9	0/0 (NaN)	0
Bone pain	4/49 (8.2%)	6	0/0 (NaN)	0
Hepatobiliary disorders
AST, SGOT(serum glutamic oxaloacetic transaminase)	10/49 (20.4%)	11	0/0 (NaN)	0
Alkaline phosphatase	3/49 (6.1%)	3	0/0 (NaN)	0
Bilirubin (hyperbilirubinemia)	4/49 (8.2%)	6	0/0 (NaN)	0
Immune system disorders
Rhinorrhea	15/49 (30.6%)	25	0/0 (NaN)	0
Allergic reaction/hypersensitivity (including drug fever)	3/49 (6.1%)	4	0/0 (NaN)	0
Allergic rhinitis (including sneezing, nasal stuffiness, postnasal drip)	5/49 (10.2%)	6	0/0 (NaN)	0
Autoimmune reaction	3/49 (6.1%)	3	0/0 (NaN)	0
Infections and infestations
Febrile neutropenia	3/49 (6.1%)	3	0/0 (NaN)	0
Infection w/neutropenia	1/49 (2%)	1	0/0 (NaN)	0
Infection with normal ANC or Grade 1 or 2 neutrophils::Skin (cellulitis)	1/49 (2%)	1	0/0 (NaN)	0
Infection with normal ANC or Grade 1 or 2 neutrophils::Upper aerodigestive NOS	2/49 (4.1%)	2	0/0 (NaN)	0
Infection with normal ANC or Grade 1 or 2 neutrophils::Upper airway NOS	2/49 (4.1%)	2	0/0 (NaN)	0
Infection with unknown ANC::Skin (cellulites)	1/49 (2%)	1	0/0 (NaN)	0
Metabolism and nutrition disorders
Calcium, serum-low (hypocalcemia)	2/49 (4.1%)	2	0/0 (NaN)	0
Glucose, serum-low (hyperglycemia)	12/49 (24.5%)	17	0/0 (NaN)	0
Glucose, serum-low (hypoglycemia)	4/49 (8.2%)	4	0/0 (NaN)	0
Magnesium, serum-high (hypermagnesemia)	5/49 (10.2%)	5	0/0 (NaN)	0
Magnesium, serum-low (hypomagnesemia)	3/49 (6.1%)	4	0/0 (NaN)	0
Musculoskeletal and connective tissue disorders
Pain::Bone	3/49 (6.1%)	5	0/0 (NaN)	0
Nervous system disorders
Dizziness	4/49 (8.2%)	5	0/0 (NaN)	0
Syncope	1/49 (2%)	1	0/0 (NaN)	0
Insomnia	2/49 (4.1%)	2	0/0 (NaN)	0
Mood alteration::Anxiety	1/49 (2%)	1	0/0 (NaN)	0
Neuropathy: sensory	1/49 (2%)	1	0/0 (NaN)	0
Psychiatric disorders
Confusion	1/49 (2%)	1	0/0 (NaN)	0
Renal and urinary disorders
Creatinine	1/49 (2%)	4	0/0 (NaN)	0
Reproductive system and breast disorders
Pain::Abdomen NOS	2/49 (4.1%)	2	0/0 (NaN)	0
Respiratory, thoracic and mediastinal disorders
Cough	4/49 (8.2%)	5	0/0 (NaN)	0
Dyspnea (shortness of breath)	3/49 (6.1%)	3	0/0 (NaN)	0

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.