Alternating Thalidomide and Lenalidomide Therapy Plus Rituximab (ThRiL) as Initial Treatment for Patients With CLL

• Sponsor: Weill Medical College of Cornell University (Other)
• Overall Status: Completed
• CT.gov ID: NCT01125176
• Collaborator: Celgene (Industry)
• Enrollment: 15
• Location: 1
• Arm: 1
• Actual Duration (Months): 105
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The investigators' hypothesis is that treatment of CLL with an alternating daily dosing schedule of thalidomide and lenalidomide may result in better tolerability by decreasing each agent's individual toxicities, while preserving efficacy, and therefore lead to a longer duration of therapy and improved responses. Additionally, the combination of the 2 agents may have additive or synergistic effects therapeutically.

In Cycle -1, odd numbered patients will receive oral thalidomide daily days 1-14 followed by no treatment on days 15-28. Even numbered patients will receive oral lenalidomide daily on days 1-14 and then no treatment on days 15-28. Starting with cycle 1, patients will alternate daily thalidomide (every odd day) with daily lenalidomide (every even day) for days 1-28. Rituximab will be given on days 1, 8, 15, and 22 starting with Cycle 1, and then again every 6th cycle thereafter (cycles 7, 13, 19, etc.)

Condition or Disease	Intervention/Treatment	Phase
Chronic Lymphocytic Leukemia	Drug: thalidomide; Drug: lenalidomide; Biological: rituximab	Phase 2

Detailed Description

This is an open label, phase II, single arm, and single institution study investigating daily alternating therapy with IMiD™ compounds, thalidomide and lenalidomide, plus rituximab in untreated CLL patients requiring treatment. In order to obtain correlative samples, patients will receive a two week course of single agent thalidomide or lenalidomide before beginning treatment with the combination regimen. Half of the patients (odd numbered subjects) will start with a two week course of single agent thalidomide and the other half of the patients (even numbered subjects) will start with a two week course of single agent lenalidomide. This will allow the study of correlative samples of monotherapy with either IMiD™ agent. In Cycle -1 half of the patients (odd numbered subjects) will receive thalidomide 50mg PO daily on days 1-14, followed by no treatment days 15-28 and the other half of the patients (even numbered subjects) will receive lenalidomide PO daily on days 1-14, followed by no treatment days 15-28. Starting cycle 1: Patients will receive thalidomide 50 mg every other day (every odd day on days 1-28: Days 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 & 27 of a 28 day cycle) alternating with lenalidomide on alternate every other day, dosed based upon current level with stepwise incremental dosing (every even day on days 1-28: Days 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26 & 28 of a 28 day cycle). The starting dose of lenalidomide will be based on calculated creatinine clearance and the dose of lenalidomide may be escalated as tolerated to maximal dose of 25 mg (see Section 5 for details). Rituximab 375 mg/m2 will be administered on days 1, 8, 15 and 22 starting with Cycle 1 and then again on the same weekly x 4 schedule every 6th cycle thereafter (Cycles 7, 13, 19, etc).

Study Design

• Study Type: Interventional
• Actual Enrollment: 15 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Daily Alternating Thalidomide and Lenalidomide Therapy Plus Rituximab (ThRiL) as Initial Treatment for Patients With CLL
• Actual Study Start Date: Mar 30, 2012
• Actual Primary Completion Date: Dec 20, 2018
• Actual Study Completion Date: Dec 29, 2020

Arms and Interventions

Arm

Intervention/Treatment

Experimental: All subjects In Cycle -1, even numbered patients will receive oral lenalidomide daily on days 1-14 and then no treatment on days 15-28. In Cycle -1, odd numbered patients will receive oral thalidomide daily days 1-14 followed by no treatment on days 15-28. Starting with cycle 1, all patients will alternate daily thalidomide (every odd day) with daily lenalidomide (every even day) for days 1-28. Rituximab will be given on days 1, 8, 15, and 22 starting with Cycle 1, and then again every 6th cycle thereafter (cycles 7, 13, 19, etc.)

Drug: thalidomide; 50 mg oral dosing every other day; Other Names: Thalomid ; Drug: lenalidomide; varying oral doses every other day (max 25 mg/day); Other Names: Revlimid ; Biological: rituximab; 375 mg/m2 intravenously on days 1, 8, 15, and 22 of cycle 1. Then, repeated on days 1, 8, 15, and 22 of every 6th cycle thereafter (Cycle 7, 13, 19, etc.); Other Names: Rituxan

Outcome Measures

Primary Outcome Measures

1. Overall Response Rate as Defined as the Number of Patients Who Experience a Response (Complete or Partial) to Treatment at the Time of Best Response [From date of study drug initiation until date of best response, assessed up to 6 years.]

   Response will be evaluated in this study using the International Workshop on CLL (IWCLL) update of the 1996 NCI-Working Group criteria for CLL, which includes assessment of the following: clonal lymphocytes in the peripheral blood by flow cytometry, blood tests for neutrophil count, hemoglobin, and platelet count, CT examination for lymphadenopathy, hepatomegaly, splenomegaly, constitutional symptoms, bone marrow assessment via biopsy/aspirate, and evaluation for disease transformation.

Secondary Outcome Measures

1. Progression Free Survival [From date of study drug initiation until date of progression or death, whichever occurs first, assessed through study completion up to 100 months.]

   Measured from time of study drug administration to progression or death, measured in months.

2. Duration of Response [From date of end of treatment to progression or death, whichever occurs first, assessed through study completion up to 100 months.]

   Measured from end of treatment to progression or death, measured in months.

3. Time to Response [From date of study drug initiation to date of initial response, assessed up to 12 months.]

   Measured from time of study drug administration to initial response (partial or complete), measured in months.

4. Overall Survival [From date of study drug initiation to date of death, assessed through study completion up to 105 months.]

   Measured from time of study drug administration to death, measured in months.

Eligibility Criteria

Criteria

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

Inclusion criteria:

1. Confirmed diagnosis of CLL or SLL based upon standard criteria as outlined in the IWCLL

Update of the 1996 NCI-Working Group criteria for CLL:

1. Presence of one of the following:

1. more than or equal to 5 x 10^9 B lymphocytes/L in the peripheral blood for a duration of at least 3 months. Patients with a B lymphocytosis will be characterized as CLL, while those without will be characterized as SLL

2. the presence of lymphadenopathy resulting from infiltration with lymphocytes with the phenotype of CLL

3. bone marrow infiltration with lymphocytes with the phenotype of CLL

1. Lymphocytes with the morphologic appearance of small, mature appearing lymphocytes, with less or equal to 55 percent prolymphocytes (blood or bone marrow)

2. Cellular phenotype characterized by the:

1. co-expression of the CD5, CD20, and CD23 surface antigens

2. clonal kappa or lambda light chain expression

3. dim surface immunoglobulin expression

4. No prior therapy for CLL, including treatment for autoimmune conditions that have developed since the initial diagnosis of CLL.

5. Active disease requiring therapy as defined by the IWCLL Update of the 1996 NCIWG guidelines:

6. Evidence of progressive marrow failure as manifested by the development of worsening of anemia and / or thrombocytopenia

7. Massive, progressive, or symptomatic splenomegaly

8. Massive, progressive, or symptomatic lymphadenopathy

9. Progressive lymphocytosis with an increase of more than 50 percent over a 2-month period or a lymphocyte doubling time of less than 6 months.

10. Autoimmune anemia and/or thrombocytopenia poorly responsive to corticosteroids or other standard therapy

11. Presence of disease related symptoms: unintentional weight loss of more than 10 percent within previous six months, significant fatigue, fevers greater than 100.5 F or 38.0 C for 2 or more weeks without evidence of infection, night sweats for more than 1 month without evidence of infection.

12. Understand and voluntarily sign an informed consent form.

13. Age at least 18 years at the time of signing the informed consent form.

14. Able to adhere to the study visit schedule and other protocol requirements.

15. ECOG performance status of at most 2 at study entry.

16. Laboratory test results within these ranges:

• Absolute neutrophil count at least 1000/mm³

• Platelet count at least 50,000/mm³

• Creatinine clearance of at least 30 mL/min by Cockroft-Gault formula. Patients with a baseline creatinine clearance of greater than 30 and less than 60 mL/min will have a starting dose of lenalidomide 5 mg PO every other day per the defined schedule. Patients with a baseline creatinine clearance of ≥ 60 mL/min will have a starting dose of lenalidomide 5 mg PO daily per the defined schedule.

• Total bilirubin at most 1.5 times the ULN, unless abnormality is the result of Gilbert's disease or the result of the CLL.

• AST (SGOT) and ALT (SGPT) at most 3 x ULN (or at most 5 x ULN if due to the CLL)

1. Disease free of prior malignancies for at least 2 years with exception of curatively treated basal cell carcinoma, squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix or breast.

2. All study participants must be registered into the mandatory Revlimid REMS and S.T.E.P.S. ( P-TAP: Protocol Therapy Assistance Program) program(s), and be willing and able to comply with the requirements of Revlimid REMS and S.T.E.P.S.

3. Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10 -14 days prior to and again within 24 hours of starting treatment and again within 24 hours before the first dose of lenalidomide AND thalidomide. FCBP must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide and/or thalidomide. Females of reproductive potential must adhere to the scheduled pregnancy testing as required in the Revlimid REMS program . Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy. All patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure.

4. Able to take aspirin 81 or 325 mg daily as prophylactic anticoagulation, unless already on therapeutic anticoagulation. Patients intolerant to ASA may use coumadin or low molecular weight heparin.

Exclusion criteria:

1. Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from providing informed consent.

2. Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study.

3. Evidence of laboratory TLS by Cairo-Bishop Definition of Tumor Lysis Syndrome. Subjects may be enrolled upon correction of electrolyte abnormalities.

4. Concurrent use of other anti-cancer agents or treatments.

5. Prior treatment with thalidomide or lenalidomide.

6. Active serious infection not controlled with antibiotics.

7. Autoimmune hemolytic anemia or thrombocytopenia requiring treatment.

8. Known positive for HIV

9. Active infection with hepatitis B, defined by being positive for HepBsAg or Hep B DNA by PCR, or hepatitis C

10. Pre-existing peripheral neuropathy greater than grade 2

11. Pregnant or breast feeding females. (Lactating females must agree not to breast feed while taking lenalidomide and/or thalidomide).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Weill Cornell Medical College	New York	New York	United States	10065

Sponsors and Collaborators

• Weill Medical College of Cornell University
• Celgene

Investigators

• Principal Investigator: Richard Furman, MD, Weill Medical College of Cornell University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Aug 28, 2016

More Information

Publications

None provided.

• Responsible Party: Weill Medical College of Cornell University
• ClinicalTrials.gov Identifier: NCT01125176
• Other Study ID Numbers: 1112012062; RV-CLL-PI-0391
• First Posted: May 18, 2010
• Last Update Posted: Jan 21, 2022
• Last Verified: Dec 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Weill Medical College of Cornell University: CLL
• Additional relevant MeSH terms: Leukemia, Lymphocytic, Chronic, B-Cell; Thalidomide; Rituximab; Lenalidomide

Study Results

Participant Flow

Recruitment Details	Participants were accrued to the study at Weill Cornell Medical College between March 2012 and September 2013.
Pre-assignment Detail	One participant was deemed ineligible for the study following the completion of the informed consent process.

Arm/Group Title	All Subjects
Arm/Group Description	In Cycle -1, even numbered patients will receive oral lenalidomide daily on days 1-14 and then no treatment on days 15-28. In Cycle -1, odd numbered patients will receive oral thalidomide daily days 1-14 followed by no treatment on days 15-28. Starting with cycle 1, all patients will alternate daily thalidomide (every odd day) with daily lenalidomide (every even day) for days 1-28. Rituximab will be given on days 1, 8, 15, and 22 starting with Cycle 1, and then again every 6th cycle thereafter (cycles 7, 13, 19, etc.) Thalidomide: 50 mg oral dosing every other day Lenalidomide: varying oral doses every other day (max 25 mg/day) Rituximab: 375 mg/m2 intravenously on days 1, 8, 15, and 22 of cycle 1. Then, repeated on days 1, 8, 15, and 22 of every 6th cycle thereafter (Cycle 7, 13, 19, etc.)
Period Title: Treatment Phase
STARTED	14
COMPLETED	13
NOT COMPLETED	1
Period Title: Treatment Phase
STARTED	13
COMPLETED	2
NOT COMPLETED	11

Baseline Characteristics

Arm/Group Title	All Subjects
Arm/Group Description	In Cycle -1, even numbered patients will receive oral lenalidomide daily on days 1-14 and then no treatment on days 15-28. In Cycle -1, odd numbered patients will receive oral thalidomide daily days 1-14 followed by no treatment on days 15-28. Starting with cycle 1, all patients will alternate daily thalidomide (every odd day) with daily lenalidomide (every even day) for days 1-28. Rituximab will be given on days 1, 8, 15, and 22 starting with Cycle 1, and then again every 6th cycle thereafter (cycles 7, 13, 19, etc.) Thalidomide: 50 mg oral dosing every other day Lenalidomide: varying oral doses every other day (max 25 mg/day) Rituximab: 375 mg/m2 intravenously on days 1, 8, 15, and 22 of cycle 1. Then, repeated on days 1, 8, 15, and 22 of every 6th cycle thereafter (Cycle 7, 13, 19, etc.)
Overall Participants	14
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	11 78.6%
>=65 years	3 21.4%
Sex: Female, Male (Count of Participants)
Female	8 57.1%
Male	6 42.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	14 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	14 100%
More than one race	0 0%
Unknown or Not Reported	0 0%

Outcome Measures

1. Primary Outcome

Title	Overall Response Rate as Defined as the Number of Patients Who Experience a Response (Complete or Partial) to Treatment at the Time of Best Response
Description	Response will be evaluated in this study using the International Workshop on CLL (IWCLL) update of the 1996 NCI-Working Group criteria for CLL, which includes assessment of the following: clonal lymphocytes in the peripheral blood by flow cytometry, blood tests for neutrophil count, hemoglobin, and platelet count, CT examination for lymphadenopathy, hepatomegaly, splenomegaly, constitutional symptoms, bone marrow assessment via biopsy/aspirate, and evaluation for disease transformation.
Time Frame	From date of study drug initiation until date of best response, assessed up to 6 years.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	All Subjects
Arm/Group Description	In Cycle -1, even numbered patients will receive oral lenalidomide daily on days 1-14 and then no treatment on days 15-28. In Cycle -1, odd numbered patients will receive oral thalidomide daily days 1-14 followed by no treatment on days 15-28. Starting with cycle 1, all patients will alternate daily thalidomide (every odd day) with daily lenalidomide (every even day) for days 1-28. Rituximab will be given on days 1, 8, 15, and 22 starting with Cycle 1, and then again every 6th cycle thereafter (cycles 7, 13, 19, etc.) Thalidomide: 50 mg oral dosing every other day Lenalidomide: varying oral doses every other day (max 25 mg/day) Rituximab: 375 mg/m2 intravenously on days 1, 8, 15, and 22 of cycle 1. Then, repeated on days 1, 8, 15, and 22 of every 6th cycle thereafter (Cycle 7, 13, 19, etc.)
Measure Participants	14
Count of Participants [Participants]	12 85.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	All Subjects
	Comments
	Type of Statistical Test	Other
	Comments	Exact Clopper-Pearson 95% confidence interval for overall response rate.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Proportion (percent)
	Estimated Value	85.7
	Confidence Interval	(2-Sided) 95%; 73.5 to 100.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Progression Free Survival
Description	Measured from time of study drug administration to progression or death, measured in months.
Time Frame	From date of study drug initiation until date of progression or death, whichever occurs first, assessed through study completion up to 100 months.

Outcome Measure Data

Analysis Population Description

The one not assessable came off treatment prior to having an assessment.

Arm/Group Title	All Subjects
Arm/Group Description	In Cycle -1, even numbered patients will receive oral lenalidomide daily on days 1-14 and then no treatment on days 15-28. In Cycle -1, odd numbered patients will receive oral thalidomide daily days 1-14 followed by no treatment on days 15-28. Starting with cycle 1, all patients will alternate daily thalidomide (every odd day) with daily lenalidomide (every even day) for days 1-28. Rituximab will be given on days 1, 8, 15, and 22 starting with Cycle 1, and then again every 6th cycle thereafter (cycles 7, 13, 19, etc.) Thalidomide: 50 mg oral dosing every other day Lenalidomide: varying oral doses every other day (max 25 mg/day) Rituximab: 375 mg/m2 intravenously on days 1, 8, 15, and 22 of cycle 1. Then, repeated on days 1, 8, 15, and 22 of every 6th cycle thereafter (Cycle 7, 13, 19, etc.)
Measure Participants	13
Median (Full Range) [months]	48

3. Secondary Outcome

Title	Duration of Response
Description	Measured from end of treatment to progression or death, measured in months.
Time Frame	From date of end of treatment to progression or death, whichever occurs first, assessed through study completion up to 100 months.

Outcome Measure Data

Analysis Population Description

The one not assessable came off treatment prior to having an assessment.

Arm/Group Title	All Subjects
Arm/Group Description	In Cycle -1, even numbered patients will receive oral lenalidomide daily on days 1-14 and then no treatment on days 15-28. In Cycle -1, odd numbered patients will receive oral thalidomide daily days 1-14 followed by no treatment on days 15-28. Starting with cycle 1, all patients will alternate daily thalidomide (every odd day) with daily lenalidomide (every even day) for days 1-28. Rituximab will be given on days 1, 8, 15, and 22 starting with Cycle 1, and then again every 6th cycle thereafter (cycles 7, 13, 19, etc.) Thalidomide: 50 mg oral dosing every other day Lenalidomide: varying oral doses every other day (max 25 mg/day) Rituximab: 375 mg/m2 intravenously on days 1, 8, 15, and 22 of cycle 1. Then, repeated on days 1, 8, 15, and 22 of every 6th cycle thereafter (Cycle 7, 13, 19, etc.)
Measure Participants	13
Median (Full Range) [months]	70

4. Secondary Outcome

Title	Time to Response
Description	Measured from time of study drug administration to initial response (partial or complete), measured in months.
Time Frame	From date of study drug initiation to date of initial response, assessed up to 12 months.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	All Subjects
Arm/Group Description	In Cycle -1, even numbered patients will receive oral lenalidomide daily on days 1-14 and then no treatment on days 15-28. In Cycle -1, odd numbered patients will receive oral thalidomide daily days 1-14 followed by no treatment on days 15-28. Starting with cycle 1, all patients will alternate daily thalidomide (every odd day) with daily lenalidomide (every even day) for days 1-28. Rituximab will be given on days 1, 8, 15, and 22 starting with Cycle 1, and then again every 6th cycle thereafter (cycles 7, 13, 19, etc.) Thalidomide: 50 mg oral dosing every other day Lenalidomide: varying oral doses every other day (max 25 mg/day) Rituximab: 375 mg/m2 intravenously on days 1, 8, 15, and 22 of cycle 1. Then, repeated on days 1, 8, 15, and 22 of every 6th cycle thereafter (Cycle 7, 13, 19, etc.)
Measure Participants	14
Median (Full Range) [months]	10

5. Secondary Outcome

Title	Overall Survival
Description	Measured from time of study drug administration to death, measured in months.
Time Frame	From date of study drug initiation to date of death, assessed through study completion up to 105 months.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	All Subjects
Arm/Group Description	In Cycle -1, even numbered patients will receive oral lenalidomide daily on days 1-14 and then no treatment on days 15-28. In Cycle -1, odd numbered patients will receive oral thalidomide daily days 1-14 followed by no treatment on days 15-28. Starting with cycle 1, all patients will alternate daily thalidomide (every odd day) with daily lenalidomide (every even day) for days 1-28. Rituximab will be given on days 1, 8, 15, and 22 starting with Cycle 1, and then again every 6th cycle thereafter (cycles 7, 13, 19, etc.) Thalidomide: 50 mg oral dosing every other day Lenalidomide: varying oral doses every other day (max 25 mg/day) Rituximab: 375 mg/m2 intravenously on days 1, 8, 15, and 22 of cycle 1. Then, repeated on days 1, 8, 15, and 22 of every 6th cycle thereafter (Cycle 7, 13, 19, etc.)
Measure Participants	14
Median (Full Range) [months]	97

Adverse Events

Time Frame	From date of study drug initiation to 30 days post-date of last dose of study drug, assessed over an average of 3 years, 6 months.
Arm/Group Title	All Subjects
Arm/Group Description	In Cycle -1, even numbered patients will receive oral lenalidomide daily on days 1-14 and then no treatment on days 15-28. In Cycle -1, odd numbered patients will receive oral thalidomide daily days 1-14 followed by no treatment on days 15-28. Starting with cycle 1, all patients will alternate daily thalidomide (every odd day) with daily lenalidomide (every even day) for days 1-28. Rituximab will be given on days 1, 8, 15, and 22 starting with Cycle 1, and then again every 6th cycle thereafter (cycles 7, 13, 19, etc.) Thalidomide: 50 mg oral dosing every other day Lenalidomide: varying oral doses every other day (max 25 mg/day) Rituximab: 375 mg/m2 intravenously on days 1, 8, 15, and 22 of cycle 1. Then, repeated on days 1, 8, 15, and 22 of every 6th cycle thereafter (Cycle 7, 13, 19, etc.)
All Cause Mortality
	All Subjects
	Affected / at Risk (%)	# Events
Total	0/14 (0%)
Serious Adverse Events
	All Subjects
	Affected / at Risk (%)	# Events
Total	4/14 (28.6%)
General disorders
Fever	1/14 (7.1%)	14
Infections and infestations
Pneumonia	1/14 (7.1%)	14
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer	1/14 (7.1%)	14
Renal and urinary disorders
Acute renal insufficiency	1/14 (7.1%)	14
Other (Not Including Serious) Adverse Events
	All Subjects
	Affected / at Risk (%)	# Events
Total	14/14 (100%)
Blood and lymphatic system disorders
Anemia	6/14 (42.9%)
Lymph node pain	5/14 (35.7%)
Cardiac disorders
Paroxysmal atrial fibrillation	2/14 (14.3%)
Aortic valve disease	1/14 (7.1%)
Gastrointestinal disorders
Nausea	3/14 (21.4%)
Constipation	2/14 (14.3%)
Diarrhea	8/14 (57.1%)
Stomach pain	3/14 (21.4%)
General disorders
Fever	4/14 (28.6%)
Malaise	2/14 (14.3%)
Edema Face	1/14 (7.1%)
Localized edema	3/14 (21.4%)
Immune system disorders
Allergic reaction	1/14 (7.1%)
Infections and infestations
Upper Respiratory infection	5/14 (35.7%)
Sinusitis	2/14 (14.3%)
Investigations
Platelet count decreased	7/14 (50%)
Blood bilirubin increased	2/14 (14.3%)
Lymphocyte count increased	3/14 (21.4%)
Lymphocyte count decreased	3/14 (21.4%)
Neutrophil count decreased	7/14 (50%)
Creatinine increased	4/14 (28.6%)
Aspartate aminotransferase increased	3/14 (21.4%)
White blood cell decreased	2/14 (14.3%)
Metabolism and nutrition disorders
Hypocalcemia	2/14 (14.3%)
Hypomagnesemia	2/14 (14.3%)
Hypoalbuminemia	2/14 (14.3%)
Tumor lysis syndrome	1/14 (7.1%)
Musculoskeletal and connective tissue disorders
Arthralgias	2/14 (14.3%)
Back pain	1/14 (7.1%)
Bone pain	1/14 (7.1%)
Nervous system disorders
Headache	4/14 (28.6%)
Dizziness	3/14 (21.4%)
Intermittent hemorhoidal hemorrhage	1/14 (7.1%)
Neuropathy	6/14 (42.9%)
Respiratory, thoracic and mediastinal disorders
Sinus congestion	3/14 (21.4%)
Nasal congestion	2/14 (14.3%)
Dyspnea	2/14 (14.3%)
Skin and subcutaneous tissue disorders
Rash	5/14 (35.7%)

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.