Alemtuzumab-Ofatumumab in Previously Untreated Symptomatic Chronic Lymphocytic Leukemia

• Sponsor: Northwestern University (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT01361711
• Collaborator: GlaxoSmithKline (Industry), National Comprehensive Cancer Network (Other)
• Enrollment: 53
• Locations: 2
• Arm: 1
• Duration (Months): 131
• Patients Per Site: 26.5
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This phase II trial studies the side effects and how well giving alemtuzumab and ofatumumab together works in treating patients with previously untreated chronic lymphocytic leukemia (CLL). Monoclonal antibodies, such as alemtuzumab and ofatumumab, can block cancer growth in different ways. Some block the ability of cancer to grow and spread. Others find cancer cells and help kill them or carry cancer killing substances to them. Giving alemtuzumab together with ofatumumab may kill more cancer cells

Condition or Disease	Intervention/Treatment	Phase
Stage I Chronic Lymphocytic Leukemia; Stage II Chronic Lymphocytic Leukemia; Stage III Chronic Lymphocytic Leukemia; Stage IV Chronic Lymphocytic Leukemia	Biological: alemtuzumab; Biological: ofatumumab; Procedure: biopsy	Phase 2

Detailed Description

OBJECTIVES:

1. To determine the efficacy and safety of alemtuzumab-ofatumumab combination treatment in previously untreated CLL.

OUTLINE:

Patients receive alemtuzumab subcutaneously (SC) three times a week in weeks 1-18 and ofatumumab intravenously (IV) over 4-6 hours on day 1 of weeks 3, 5, 7, 9, 11, 13, 15, and 17.

After completion of study treatment, patients are followed up for up to 5 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 53 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Trial of Alemtuzumab-Ofatumumab Combination in Previously Untreated Symptomatic Chronic Lymphocytic Leukemia
• Study Start Date: Jun 1, 2011
• Actual Primary Completion Date: Aug 17, 2015
• Anticipated Study Completion Date: May 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (monoclonal antibody therapy) Patients receive alemtuzumab SC three times a week in weeks 1-18 and ofatumumab IV over 4-6 hours on day 1 of weeks 3, 5, 7, 9, 11, 13, 15, and 17.	Biological: alemtuzumab; Given SC; Other Names: anti-CD52 monoclonal antibody Campath-1H MoAb CD52 Monoclonal Antibody Campath-1H Monoclonal Antibody CD52 ; Biological: ofatumumab; Given IV; Other Names: Arzerra HuMax-CD20 ; Procedure: biopsy; Correlative studies; Other Names: biopsies

Outcome Measures

Primary Outcome Measures

1. Best Response as Defined by the iwCLL2008 (International Workshop on Chronic Lymphocytic Leukemia 2008) [Range of responses between 8 weeks from initiation of treatment to 2 months post-treatment.]

   CR= Absence of clonal lymphocytes in the peripheral blood, significant lymphadenopathy, hepatomegaly or splenomegaly, and constitutional symptoms. Blood counts: Neutrophils ≥ 1,500/μL; Platelets >100,000μL; Hemoglobin > 11.0g/dL. Bone marrow normocellular for age, less than 30% of nucleated cells = lymphocytes. Lymphoid nodules absent. CRi= Fulfills CR but anemia or thrombocytopenia or neutropenia related to drug toxicity. PR= 2 criteria from group A and 1 from Group B. Group A: Decrease in the number of blood lymphocytes of 50% or more. Reduction in lymphadenopathy. No increase in any lymph node, and no new enlarged lymph node. A decrease in liver by at least 50% from baseline. Decrease in the size of the spleen by 50% or more. Reduction in marrow infiltrate or B-lymphoid nodules. Group B: Platelet counts > than 100,000/μL or 50% better. Hemoglobin > than 11.0g/dL or 50% better. Neutrophils>1500/μL or 50% better. Criteria is continued in Analysis Population Description below...

Secondary Outcome Measures

1. Survival Rates [Up to 5 years]

   Survival rates will be calculated for progression-free survival (PFS), therapy-free survival (TFS), and overall survival (OS).

2. Treatment Toxicity as Measured by Adverse Events Experienced While on Treatment [Weeks 1, 3, 5, 7, 9, 11, 13, 15, and 17]

3. Correlation of Disease Characteristics With Disease Outcomes [At baseline and over 18 weeks]

   Clinical outcomes (such as response, PFS and TFS) will be correlated with pre-treatment clinical and biological characteristics(such as Rai staging, presence of bulky lymph nodes, cytogenetics by FISH, CD38, ZAP70 and IgVH mutation status).

4. Compare Efficacy Between This Study and Historical Control Study of Alemtuzumab-rituximab [At baseline and over 18 weeks]

   Response and survival rates will be compared between the two studies.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Patients must be Eastern Cooperative Oncology Group (ECOG) performance status 0-2

• Patients must have a confirmed diagnosis of CLL as defined by the International

Workshop on CLL (iwCLL) 2008 (iwCLL2008) criteria below:

• Presence of at least 5x10^9 B lymphocytes/L (5000/uL) in the peripheral blood

• Morphologically, the lymphocytes must appear of small to moderate size with < 55% prolymphocytes, atypical lymphocytes or lymphoblasts

• The clonality and immunophenotype of the circulating B-lymphocytes must be confirmed by flow cytometry to express CD5, CD23, CD19, CD20, CD52 and either kappa or lambda light chain

• Patients must have symptomatic disease requiring therapy; indications for therapy are defined by the iwCLL2008 criteria as follows (one or more are sufficient):

• Clinical manifestations (if believed by the investigator to be caused by CLL): a) Unintentional weight loss > 10% within the previous 6 months; b) significant fatigue;

1. fevers of greater than 100.5 degrees Fahrenheit (F) (38 degrees Celsius [C]) for 2 weeks without evidence of infection; d) night sweats without evidence of infection

• Evidence of progressive marrow failure as manifested by the development or worsening of anemia (< 11 g/dl), thrombocytopenia (< 100,000/mm^{3) or neutropenia (< 1,500/mm}3)

• Massive (i.e. > 6 cm below left costal margin) or progressive splenomegaly

• Massive nodes/clusters (> 5 cm) or progressive symptomatic adenopathy

• Progressive lymphocytosis with an increase of > 50% over 2 month period, or an anticipated doubling time of less than 6 months

• NOTE: Marked hypogammaglobulinemia or the development of a monoclonal protein in the absence of any of the above criteria for active disease is not sufficient for protocol therapy

• Patients must have evidence of adequate bone marrow reserve as shown by absolute neutrophil count (ANC) of at least 1,000/mm^3; however, if the cytopenias are due to extensive bone marrow involvement by CLL, patients may be included in the study

• And patients must have evidence of adequate bone marrow reserve as shown by platelet count of at least 50,000/mm^3; however, if the cytopenias are due to extensive bone marrow involvement by CLL, patients may be included in the study

• Serum creatinine must be less than 2.0 mg/dl obtained within 2 weeks prior to study enrollment; if serum creatinine is greater than 1.5 mg/dl, the creatinine clearance calculated from a 24 hour urine collection must be greater than 40 ml/min

• Total bilirubin must be less than 2 mg/dl (unless due to CLL involvement of liver or a known history of Gilbert's disease)

• Aspartate aminotransferase (AST), alanine aminotransferase (ALT) must be no more than 2.5 times upper limit of normal unless due to disease involvement of the liver

• Alkaline phosphatase must be no more than 2.5 times upper limit of normal unless due to disease involvement of the liver

• All patients must have given a signed, informed consent prior to enrollment on study

Exclusion Criteria:

• Prior cytotoxic therapies are NOT allowed; the only exception is prior corticosteroid therapy (prednisone up to 1 mg/kg for =< 3 months) which must be stopped at least 1 week prior to study enrollment

• Patients with active autoimmune anemia or autoimmune thrombocytopenia are NOT eligible

• Patients who have current active hepatic or biliary disease (with the exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver involvement by CLL, or stable chronic liver disease per investigator assessment) are NOT eligible

• Patients with active chronic or current infections requiring oral or intravenous antibiotics are NOT eligible for enrollment to the study until resolution of the infection and completion of therapeutic antibiotics

• Patients with a past or current second malignancy are NOT eligible aside from the following exceptions:

• Patients who have been free of malignancy for at least 5 years

• Patients who have a history of completely resected basal or squamous cell skin cancer, successfully treated in situ carcinoma of the breast or cervix, or pre-cancerous lesions of the colon

• Patients with known human immunodeficiency virus (HIV) are NOT eligible for the study

• Patients with history of significant cerebrovascular disease in the past 6 months or ongoing event with active symptoms or sequelae are NOT eligible for the study

• Patients with clinically significant cardiac disease including unstable angina, acute myocardial infarction within six months prior to enrollment, congestive heart failure (New York Heart Association [NYHA ] III-IV), and arrhythmia unless controlled by therapy (with the exception of extra systoles or minor conduction abnormalities), are NOT eligible

• Patients with significant concurrent, uncontrolled medical condition including, but not limited to, cardiovascular, renal, hepatic, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease which in the opinion of the investigator may represent a risk for the patient, are NOT eligible

• Patients with positive serology for Hepatitis B (HB), defined as a positive test for HB surface antigen (HBsAg), are NOT eligible; if negative for HBsAg but HB core antibody (HBcAb) positive a HB deoxyribonucleic acid (DNA) test will be performed; if HB DNA test is positive the patient is NOT eligible; NOTE: patients who are positive for HBcAb but negative for hepatitis B virus (HBV) antigenemia and viremia (HBsAg negative and HB DNA test negative) may be eligible for the study, but must be started on HBV suppression therapy with lamivudine or equivalent anti-HBV agents throughout the treatment and for a year after the completion of the treatments; these patients need to have liver function tests (LFTs) and HBV viral titer monitoring at least monthly during the treatment and for a year after treatment completion

• Patients with positive serology for hepatitis C are NOT eligible

• Women of childbearing potential and sexually active males must commit to the use of adequate contraception from the study start to one year after the last dose of study treatment

• Childbearing potential is defined as any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:

• Has not undergone a hysterectomy or bilateral oophorectomy; or

• Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months)

• Adequate contraception is defined as hormonal birth control, intrauterine device, barrier method or total abstinence; patients who are unable or unwilling to use adequate contraception are NOT eligible

• Women who are pregnant or lactating are NOT eligible

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Northwestern University	Chicago	Illinois	United States	60611
2	Karolinska University Hospital Solna	Stockholm		Sweden

Sponsors and Collaborators

• Northwestern University
• GlaxoSmithKline
• National Comprehensive Cancer Network

Investigators

• Principal Investigator: Shuo Ma, MD, PhD, Northwestern University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Shuo Ma, Principal Investigator, Northwestern University
• ClinicalTrials.gov Identifier: NCT01361711
• Other Study ID Numbers: NU 10H06; NCI-2011-00514; STU00044115
• First Posted: May 27, 2011
• Last Update Posted: Jan 22, 2021
• Last Verified: Dec 1, 2020

• Additional relevant MeSH terms: Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Antineoplastic Agents, Immunological; Alemtuzumab; Ofatumumab; Antibodies; Immunoglobulins; Antibodies, Monoclonal

Study Results

Participant Flow

Recruitment Details

Opened for accrual on June 3, 2011 with goal of 60 patients. First patient started treatment June 13, 2011. Accrual was suspended Sep. 26, 2011 for safety analysis of the first 6 patients. The study opened May 4, 2012 for safety cohort of 6 more patients. Study was suspended July 23, 2012 for safety analysis, and opened again Feb 4, 2013. The study closed Sep 13, 2016 because the total accrual goal for Northwestern University was met.

Arm/Group Title	Alemtuzumab + Ofatumumab
Arm/Group Description	Alemtuzumab: Administered subcutaneously, 3 times per week for up to 18 weeks at a standard dose of 30mg (except for week 1 which will dose escalate from 3mg→10mg→30mg). Ofatumumab: Starting at week 3, administered intravenously on day 1 of every other week prior to alemtuzumab for a total of 8 doses. For week 3 (dose 1) ofatumumab will be given at a dose of 300mg; for weeks 5, 7, 9, 11, 13, 15, and 17 (doses 2-8) ofatumumab will be given at a dose of 2000mg. Toxicity was assessed after completion of the extended safety run-in period of the first 12 patients at an ofatumumab dose of 2000 mg for doses 2-8. Depending on the number of patients who experienced a dose limiting toxicity in the initial 2 safety cohorts, ofatumumab doses 2-8 could have been continued at 2000 mg or reduced to 1000 mg for subsequent patients. Based on the toxicity data of the first 12 patients, ofatumumab doses 2-8 were given at 2000 mg for doses 2-8 for all patients. Based on experience with the initial safety run-in cohort of 6 patients, early stopping is necessary to avoid over-treatment in patients who have achieved a complete remission early. As soon as a patient is determined to have achieved MRD- CR or CRi (per iwCLL2008 criteria), both alemtuzumab and ofatumumab will be stopped.
Period Title: Trial Entry (Registration)
STARTED	53
Received Dose of Study Drug	52
COMPLETED	52
NOT COMPLETED	1
Period Title: Trial Entry (Registration)
STARTED	52
COMPLETED	51
NOT COMPLETED	1
Period Title: Trial Entry (Registration)
STARTED	51
COMPLETED	44
NOT COMPLETED	7
Period Title: Trial Entry (Registration)
STARTED	44
COMPLETED	41
NOT COMPLETED	3
Period Title: Trial Entry (Registration)
STARTED	41
COMPLETED	30
NOT COMPLETED	11
Period Title: Trial Entry (Registration)
STARTED	52
COMPLETED	2
NOT COMPLETED	50

Baseline Characteristics

Arm/Group Title	Alemtuzumab + Ofatumumab
Arm/Group Description	Alemtuzumab: Administered subcutaneously, 3 times per week for up to 18 weeks at a standard dose of 30mg (except for week 1 which will dose escalate from 3mg→10mg→30mg). Ofatumumab: Starting at week 3, administered intravenously on day 1 of every other week prior to alemtuzumab for a total of 8 doses. For week 3 (dose 1) ofatumumab will be given at a dose of 300mg; for weeks 5, 7, 9, 11, 13, 15, and 17 (doses 2-8) ofatumumab will be given at a dose of 2000mg. Toxicity was assessed after completion of the extended safety run-in period of the first 12 patients at an ofatumumab dose of 2000 mg for doses 2-8. Depending on the number of patients who experienced a dose limiting toxicity in the initial 2 safety cohorts, ofatumumab doses 2-8 could have been continued at 2000 mg or reduced to 1000 mg for subsequent patients. Based on the toxicity data of the first 12 patients, ofatumumab doses 2-8 were given at 2000 mg for doses 2-8 for all patients. biopsy: Correlative studies
Overall Participants	52
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	28 53.8%
>=65 years	24 46.2%
Sex: Female, Male (Count of Participants)
Female	23 44.2%
Male	29 55.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 1.9%
Not Hispanic or Latino	51 98.1%
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	2 3.8%
White	50 96.2%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
Sweden	20 38.5%
United States	32 61.5%

Outcome Measures

1. Primary Outcome

Title	Best Response as Defined by the iwCLL2008 (International Workshop on Chronic Lymphocytic Leukemia 2008)
Description	CR= Absence of clonal lymphocytes in the peripheral blood, significant lymphadenopathy, hepatomegaly or splenomegaly, and constitutional symptoms. Blood counts: Neutrophils ≥ 1,500/μL; Platelets >100,000μL; Hemoglobin > 11.0g/dL. Bone marrow normocellular for age, less than 30% of nucleated cells = lymphocytes. Lymphoid nodules absent. CRi= Fulfills CR but anemia or thrombocytopenia or neutropenia related to drug toxicity. PR= 2 criteria from group A and 1 from Group B. Group A: Decrease in the number of blood lymphocytes of 50% or more. Reduction in lymphadenopathy. No increase in any lymph node, and no new enlarged lymph node. A decrease in liver by at least 50% from baseline. Decrease in the size of the spleen by 50% or more. Reduction in marrow infiltrate or B-lymphoid nodules. Group B: Platelet counts > than 100,000/μL or 50% better. Hemoglobin > than 11.0g/dL or 50% better. Neutrophils>1500/μL or 50% better. Criteria is continued in Analysis Population Description below...
Time Frame	Range of responses between 8 weeks from initiation of treatment to 2 months post-treatment.

Outcome Measure Data

Analysis Population Description

Criteria from Outcome Measure Description cont. MRD=Bone marrow with less than one CLL cell per 10,000 leukocytes. To qualify as a PD: at least two of the criteria of in Group A, plus one of the criteria in Group B, must be met. Group A: An increase ≥ 50% of: lymphadenopathy, hepatomegaly, or splenomegaly. An increase ≥ 50% over baseline in blood lymphocytes. Group B: Platelet count decrease of ≥ 50% from baseline secondary to CLL, Hemoglobin decrease of > 2g/dl from baseline secondary to CLL.

Arm/Group Title	Alemtuzumab + Ofatumumab
Arm/Group Description	Alemtuzumab: Administered subcutaneously, 3 times per week for up to 18 weeks at a standard dose of 30mg (except for week 1 which will dose escalate from 3mg→10mg→30mg). Ofatumumab: Starting at week 3, administered intravenously on day 1 of every other week prior to alemtuzumab for a total of 8 doses. For week 3 (dose 1) ofatumumab will be given at a dose of 300mg; for weeks 5, 7, 9, 11, 13, 15, and 17 (doses 2-8) ofatumumab will be given at a dose of 2000mg. Toxicity was assessed after completion of the extended safety run-in period of the first 12 patients at an ofatumumab dose of 2000 mg for doses 2-8. Depending on the number of patients who experienced a dose limiting toxicity in the initial 2 safety cohorts, ofatumumab doses 2-8 could have been continued at 2000 mg or reduced to 1000 mg for subsequent patients. Based on the toxicity data of the first 12 patients, ofatumumab doses 2-8 were given at 2000 mg for doses 2-8 for all patients. biopsy: Correlative studies
Measure Participants	52
Complete Remission (CR), Minimal Residual Disease (MRD) Negative	18 34.6%
Complete Remission (CR), Minimal Residual Disease (MRD) positive	2 3.8%
Complete Remission, MRD status unknown	3 5.8%
Complete Remission with Incomplete Marrow Recovery (CRi)	2 3.8%
Partial Remission (PR)	26 50%
Progressive Disease (PD)	1 1.9%

2. Secondary Outcome

Title	Survival Rates
Description	Survival rates will be calculated for progression-free survival (PFS), therapy-free survival (TFS), and overall survival (OS).
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Secondary Outcome

Title	Treatment Toxicity as Measured by Adverse Events Experienced While on Treatment
Time Frame	Weeks 1, 3, 5, 7, 9, 11, 13, 15, and 17

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Correlation of Disease Characteristics With Disease Outcomes
Description	Clinical outcomes (such as response, PFS and TFS) will be correlated with pre-treatment clinical and biological characteristics(such as Rai staging, presence of bulky lymph nodes, cytogenetics by FISH, CD38, ZAP70 and IgVH mutation status).
Time Frame	At baseline and over 18 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	Compare Efficacy Between This Study and Historical Control Study of Alemtuzumab-rituximab
Description	Response and survival rates will be compared between the two studies.
Time Frame	At baseline and over 18 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	Adverse events were collected over a four year period. Each patient was followed from the time of treatment, and during treatment up to 18 weeks. Adverse events were collected up to 60 days post-therapy. Serious adverse events (SAEs) were collected for one year after treatment discontinuation or until the initiation of second-line therapy.
Arm/Group Title	Alemtuzumab + Ofatumumab
Arm/Group Description	Alemtuzumab: Administered subcutaneously, 3 times per week for up to 18 weeks at a standard dose of 30mg (except for week 1 which will dose escalate from 3mg→10mg→30mg). Ofatumumab: Starting at week 3, administered intravenously on day 1 of every other week prior to alemtuzumab for a total of 8 doses. For week 3 (dose 1) ofatumumab will be given at a dose of 300mg; for weeks 5, 7, 9, 11, 13, 15, and 17 (doses 2-8) ofatumumab will be given at a dose of 2000mg. Toxicity was assessed after completion of the extended safety run-in period of the first 12 patients at an ofatumumab dose of 2000 mg for doses 2-8. Depending on the number of patients who experienced a dose limiting toxicity in the initial 2 safety cohorts, ofatumumab doses 2-8 could have been continued at 2000 mg or reduced to 1000 mg for subsequent patients. Based on the toxicity data of the first 12 patients, ofatumumab doses 2-8 were given at 2000 mg for doses 2-8 for all patients. Based on experience with the initial safety run-in cohort of 6 patients, early stopping is necessary to avoid over-treatment in patients who have achieved a complete remission early. As soon as a patient is determined to have achieved MRD- CR or CRi (per iwCLL2008 criteria), both alemtuzumab and ofatumumab will be stopped.
All Cause Mortality
	Alemtuzumab + Ofatumumab
	Affected / at Risk (%)	# Events
Total	6/52 (11.5%)
Serious Adverse Events
	Alemtuzumab + Ofatumumab
	Affected / at Risk (%)	# Events
Total	20/52 (38.5%)
Blood and lymphatic system disorders
Abnormal Platelets	1/52 (1.9%)
Febrile neutropenia	5/52 (9.6%)
Neutropenic fever	1/52 (1.9%)
Thrombotic thrombocytopenic purpura	1/52 (1.9%)
Cardiac disorders
Sinus tachycardia	1/52 (1.9%)
General disorders
Fever	4/52 (7.7%)
Fever	3/52 (5.8%)
Immune system disorders
Allergic reaction	1/52 (1.9%)
Infections and infestations
Infection	1/52 (1.9%)
CMV infection	1/52 (1.9%)
MRSA Bacteremia	1/52 (1.9%)
Meningitis	1/52 (1.9%)
CMV positive	1/52 (1.9%)
Lung infection	1/52 (1.9%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Prostate Cancer	1/52 (1.9%)
Diffuse Large B-Cell Lymphoma	1/52 (1.9%)
Renal and urinary disorders
Acute kidney injury	1/52 (1.9%)
Respiratory, thoracic and mediastinal disorders
Pneumonitis	1/52 (1.9%)
Skin and subcutaneous tissue disorders
Erythema multiforme	1/52 (1.9%)
Other (Not Including Serious) Adverse Events
	Alemtuzumab + Ofatumumab
	Affected / at Risk (%)	# Events
Total	52/52 (100%)
Blood and lymphatic system disorders
Anemia	5/52 (9.6%)
Decreased IgG	1/52 (1.9%)
Decreased IgA	1/52 (1.9%)
Decreased IgM	1/52 (1.9%)
Diffuse Large B-Cell Lymphoma	1/52 (1.9%)
Easy bruising	1/52 (1.9%)
Elevated neutrophils	1/52 (1.9%)
Febrile neutropenia	9/52 (17.3%)
Hemolysis	1/52 (1.9%)
Leukocytosis	1/52 (1.9%)
Neutropenia	9/52 (17.3%)
Thrombocytopenia	6/52 (11.5%)
Thrombotic thrombocytopenic purpura	1/52 (1.9%)
Cardiac disorders
Atrial fibrillation	1/52 (1.9%)
Chest pain	1/52 (1.9%)
Coronary artery disease	1/52 (1.9%)
Left branch bundle block	1/52 (1.9%)
Nonspecific T Wave Abnormalities	1/52 (1.9%)
Palpitations	2/52 (3.8%)
Sinus tachycardia	1/52 (1.9%)
Ear and labyrinth disorders
Cerumen Impaction	1/52 (1.9%)
Endocrine disorders
Enlarged adrenal glands	1/52 (1.9%)
Hypothyroidism	3/52 (5.8%)
Eye disorders
Blurred vision	2/52 (3.8%)
Brown tint to vision	1/52 (1.9%)
Double vision	1/52 (1.9%)
Keratitis	1/52 (1.9%)
Gastrointestinal disorders
Abdominal cramping	1/52 (1.9%)
Abdominal distension	1/52 (1.9%)
Abdominal pain	4/52 (7.7%)
Constipation	9/52 (17.3%)
Diarrhea	15/52 (28.8%)
Diverticulosis	1/52 (1.9%)
Dry mouth	1/52 (1.9%)
Dyspepsia	3/52 (5.8%)
Gastritis	1/52 (1.9%)
Gastroesophageal reflux disease	3/52 (5.8%)
Gastrointestinal pain	1/52 (1.9%)
Hemorrhoids	1/52 (1.9%)
Mucositis oral	1/52 (1.9%)
Nausea	7/52 (13.5%)
Oral pain	1/52 (1.9%)
Vomiting	3/52 (5.8%)
General disorders
Abdominal discomfort	1/52 (1.9%)
Chest tightness	2/52 (3.8%)
Chills	13/52 (25%)
Edema limbs	4/52 (7.7%)
Fatigue	34/52 (65.4%)
Fever	35/52 (67.3%)
Flu like symptoms	12/52 (23.1%)
Gait disturbance	1/52 (1.9%)
Headache	2/52 (3.8%)
Infusion related reaction	29/52 (55.8%)
Infusion site extravasation	2/52 (3.8%)
Injection site reaction	47/52 (90.4%)
Itchiness in throat	1/52 (1.9%)
Lightheadedness	1/52 (1.9%)
Malaise	2/52 (3.8%)
Night Sweats	11/52 (21.2%)
Pain	6/52 (11.5%)
Hepatobiliary disorders
Hepatitis B positive	1/52 (1.9%)
Immune system disorders
Allergic reaction	4/52 (7.7%)
Autoimmune disorder	1/52 (1.9%)
Cytokine release syndrome	2/52 (3.8%)
Elevated Quantitative IgG	1/52 (1.9%)
Hypogammaglobulinemia	1/52 (1.9%)
Infections and infestations
Abscess	1/52 (1.9%)
Appendicitis	2/52 (3.8%)
CMV reactivation	18/52 (34.6%)
CMV Infection	11/52 (21.2%)
Genital herpes	1/52 (1.9%)
Legionella Pneumonia	1/52 (1.9%)
Lung infection	2/52 (3.8%)
Meningitis	1/52 (1.9%)
MRSA Bacteremia	1/52 (1.9%)
Mucosal infection	1/52 (1.9%)
pneumonia, community acquired	1/52 (1.9%)
Sinusitis	2/52 (3.8%)
Skin infection	2/52 (3.8%)
Upper respiratory infection	4/52 (7.7%)
Urinary tract infection	1/52 (1.9%)
Vaginal infection	1/52 (1.9%)
Investigations
Abnormal C-reactive protein levels	1/52 (1.9%)
Abnormal Hemoglobin count	44/52 (84.6%)
Abnormal neutrophil count	44/52 (84.6%)
Abnormal platelet count	43/52 (82.7%)
Alanine aminotransferase increased	14/52 (26.9%)
Alkaline phosphatase increased	8/52 (15.4%)
Aspartate aminotransferase increased	24/52 (46.2%)
Basal Cell Carcinoma Recurrence	1/52 (1.9%)
Blood bilirubin increased	3/52 (5.8%)
High cholesterol	1/52 (1.9%)
Creatinine increased	16/52 (30.8%)
Decrease absolute CD3+	1/52 (1.9%)
Decrease absolute CD3+CD8+	1/52 (1.9%)
Decrease absolute CD3+CD4+	1/52 (1.9%)
decreased hematocrit	1/52 (1.9%)
Decreased B cell %	1/52 (1.9%)
Elevated LDH	7/52 (13.5%)
Enlarged lymph node in left groin	1/52 (1.9%)
IgM paraprotein	1/52 (1.9%)
Increased C-reactive protein.	1/52 (1.9%)
Iron deficiency	1/52 (1.9%)
Lymphocyte count decreased	24/52 (46.2%)
Lymphocyte count increased	3/52 (5.8%)
Neutrophil count decreased	3/52 (5.8%)
Ringing in ears	1/52 (1.9%)
Rising PSA	1/52 (1.9%)
Weight gain	1/52 (1.9%)
Weight loss	6/52 (11.5%)
White blood cell decreased	35/52 (67.3%)
Metabolism and nutrition disorders
Anorexia	4/52 (7.7%)
Borderline diabetes	1/52 (1.9%)
Diabetes	1/52 (1.9%)
Diabetes Mellitus	1/52 (1.9%)
Diabetic ketoacidosis	1/52 (1.9%)
Hypercalcemia	2/52 (3.8%)
Hyperglycemia	25/52 (48.1%)
Hyperkalemia	4/52 (7.7%)
Hyperlipidemia	1/52 (1.9%)
Hypermagnesemia	1/52 (1.9%)
Hypertriglyceridemia	1/52 (1.9%)
Hyperuricemia	5/52 (9.6%)
Hypoalbuminemia	12/52 (23.1%)
Hypocalcemia	6/52 (11.5%)
Hypoglycemia	4/52 (7.7%)
Hypokalemia	6/52 (11.5%)
Hypomagnesemia	3/52 (5.8%)
Hyponatremia	9/52 (17.3%)
Hypophosphatemia	4/52 (7.7%)
lack of vitamin B12	1/52 (1.9%)
Musculoskeletal and connective tissue disorders
Arthritis	1/52 (1.9%)
Back pain	2/52 (3.8%)
Bone pain	1/52 (1.9%)
Generalized muscle weakness	4/52 (7.7%)
Hip pain	1/52 (1.9%)
Left lumbar spasm	1/52 (1.9%)
Muscle weakness lower limb	1/52 (1.9%)
Muscle weakness trunk	1/52 (1.9%)
Myalgia	2/52 (3.8%)
Neck pain	1/52 (1.9%)
Pain in extremity	2/52 (3.8%)
Pain in shoulder	1/52 (1.9%)
Worsening of gout	1/52 (1.9%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
polyps	1/52 (1.9%)
Prostate cancer	1/52 (1.9%)
surgery to remove two small basiliom	1/52 (1.9%)
Nervous system disorders
Concentration impairment	1/52 (1.9%)
Dizziness	4/52 (7.7%)
Headache	4/52 (7.7%)
Memory impairment	1/52 (1.9%)
Peripheral motor neuropathy	1/52 (1.9%)
Peripheral neuropathy in feet	1/52 (1.9%)
Peripheral sensory neuropathy	8/52 (15.4%)
Restless legs syndrome	1/52 (1.9%)
Sensory numbness	1/52 (1.9%)
Tingling in fingertips to elbows	1/52 (1.9%)
Tingling in lips	2/52 (3.8%)
Psychiatric disorders
Anxiety	3/52 (5.8%)
Depression	2/52 (3.8%)
Insomnia	2/52 (3.8%)
Renal and urinary disorders
Acute kidney injury	2/52 (3.8%)
Decreased urination	1/52 (1.9%)
Pressure with urination	1/52 (1.9%)
Proteinuria	1/52 (1.9%)
Benign prostatic hyperplasia	1/52 (1.9%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	1/52 (1.9%)
Enlargement of prostate gland	1/52 (1.9%)
Erectile dysfunction	1/52 (1.9%)
Testicular pain	1/52 (1.9%)
Vaginal Atrophy	1/52 (1.9%)
Respiratory, thoracic and mediastinal disorders
Cough	6/52 (11.5%)
Dyspnea	2/52 (3.8%)
Epistaxis	1/52 (1.9%)
Hiccups	1/52 (1.9%)
Hoarseness	1/52 (1.9%)
Hyposmia	1/52 (1.9%)
Nasal congestion	1/52 (1.9%)
Pleural effusion	1/52 (1.9%)
Pneumonitis	1/52 (1.9%)
Rhinitis	1/52 (1.9%)
Sore throat	3/52 (5.8%)
Skin and subcutaneous tissue disorders
Actinic keratoses	1/52 (1.9%)
Cherry angiomas	1/52 (1.9%)
Dry skin	1/52 (1.9%)
Erythema multiforme	2/52 (3.8%)
Erythematous Rash	1/52 (1.9%)
guttate psoriasis	1/52 (1.9%)
Lower leg lesions	1/52 (1.9%)
Pain of skin	1/52 (1.9%)
perivascular dermatitis	1/52 (1.9%)
Petechiae on upper abdomen	1/52 (1.9%)
Pruritus	2/52 (3.8%)
Rash	8/52 (15.4%)
Rash maculo-papular	1/52 (1.9%)
redness of the skin with scaling	1/52 (1.9%)
Scalp psoriasis	1/52 (1.9%)
Seborrheic dermatitis	1/52 (1.9%)
Seborrheic keratoses	1/52 (1.9%)
Skin tear on right buttock	1/52 (1.9%)
Spongiotic Dermatitis	1/52 (1.9%)
Subacute Spongiotic Dermatitis	1/52 (1.9%)
Sun damaged skin	1/52 (1.9%)
Sweating	1/52 (1.9%)
Tinea pedis	1/52 (1.9%)
Tingling in the face	1/52 (1.9%)
Surgical and medical procedures
Laparoscopic appendectomy	1/52 (1.9%)
Surgery for testicular varicose	1/52 (1.9%)
Tonsillectomy	2/52 (3.8%)
Vascular disorders
Flushing	1/52 (1.9%)
Hypertension	9/52 (17.3%)
Hypotension	1/52 (1.9%)
Pulmonary emboli	1/52 (1.9%)
Thromboembolic event	5/52 (9.6%)

Limitations/Caveats

The participating site (Karolinska University Hospital Solna) did not meet the total accrual goal. However, the lead site (Northwestern University) did.

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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.