Stage I Chronic Lymphocytic Leukemia, Stage II Chronic Lymphocytic Leukemia, Stage III Chronic Lymphocytic Leukemia, Stage IV Chronic Lymphocytic Leukemia
Conditions
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
Detailed description
OBJECTIVES: I. 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.
Interventions
BIOLOGICALalemtuzumab
Given SC
BIOLOGICALofatumumab
Given IV
PROCEDUREbiopsy
Correlative studies
Sponsors
GlaxoSmithKline
National Comprehensive Cancer Network
Northwestern University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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; c) 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| Survival Rates | Up to 5 years | Survival rates will be calculated for progression-free survival (PFS), therapy-free survival (TFS), and overall survival (OS). |
| Treatment Toxicity as Measured by Adverse Events Experienced While on Treatment | Weeks 1, 3, 5, 7, 9, 11, 13, 15, and 17 | — |
| 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). |
| 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. |
Countries
Sweden, United States
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.
Participants by arm
| Arm | Count |
|---|---|
| Alemtuzumab + Ofatumumab 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 | 52 |
| Total | 52 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| 10 Year Follow-up | Death | 7 |
| 10 Year Follow-up | Developed new cancer | 1 |
| 10 Year Follow-up | Lost to Follow-up | 2 |
| 10 Year Follow-up | New treatment started | 6 |
| 10 Year Follow-up | Progressive Disease | 1 |
| 10 Year Follow-up | Progressive Disease and New treatment started | 11 |
| 10 Year Follow-up | Still in follow-up | 22 |
| Completed Week 18 of Treatment | Complete Remission | 2 |
| Completed Week 18 of Treatment | Other | 9 |
| Continued Treatment After 12 Weeks | Complete Remission in Week 12 | 2 |
| Continued Treatment After 12 Weeks | Progressive Disease at Week 11 | 1 |
| Continued Treatment After 9 Weeks | Complete Remission in Week 9 | 7 |
| Trial Entry (Registration) | Patient did not meet Protocol criteria for trial entry | 1 |
| Week 9 Bone Marrow Response Assessment | Complete Remission in Week 8 | 1 |
Baseline characteristics
| Characteristic | Alemtuzumab + Ofatumumab |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 24 Participants |
| Age, Categorical Between 18 and 65 years | 28 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 51 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 50 Participants |
| Region of Enrollment Sweden | 20 participants |
| Region of Enrollment United States | 32 participants |
| Sex: Female, Male Female | 23 Participants |
| Sex: Female, Male Male | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 6 / 52 |
| other Total, other adverse events | 52 / 52 |
| serious Total, serious adverse events | 20 / 52 |
Outcome results
Primary
Best Response as Defined by the iwCLL2008 (International Workshop on Chronic Lymphocytic Leukemia 2008)
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.
Population: 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 | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Alemtuzumab + Ofatumumab | Best Response as Defined by the iwCLL2008 (International Workshop on Chronic Lymphocytic Leukemia 2008) | Complete Remission (CR), Minimal Residual Disease (MRD) Negative | 18 Participants |
| Alemtuzumab + Ofatumumab | Best Response as Defined by the iwCLL2008 (International Workshop on Chronic Lymphocytic Leukemia 2008) | Complete Remission (CR), Minimal Residual Disease (MRD) positive | 2 Participants |
| Alemtuzumab + Ofatumumab | Best Response as Defined by the iwCLL2008 (International Workshop on Chronic Lymphocytic Leukemia 2008) | Complete Remission, MRD status unknown | 3 Participants |
| Alemtuzumab + Ofatumumab | Best Response as Defined by the iwCLL2008 (International Workshop on Chronic Lymphocytic Leukemia 2008) | Complete Remission with Incomplete Marrow Recovery (CRi) | 2 Participants |
| Alemtuzumab + Ofatumumab | Best Response as Defined by the iwCLL2008 (International Workshop on Chronic Lymphocytic Leukemia 2008) | Partial Remission (PR) | 26 Participants |
| Alemtuzumab + Ofatumumab | Best Response as Defined by the iwCLL2008 (International Workshop on Chronic Lymphocytic Leukemia 2008) | Progressive Disease (PD) | 1 Participants |
Secondary
Compare Efficacy Between This Study and Historical Control Study of Alemtuzumab-rituximab
Response and survival rates will be compared between the two studies.
Time frame: At baseline and over 18 weeks
Secondary
Correlation of Disease Characteristics With Disease Outcomes
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
Secondary
Survival Rates
Survival rates will be calculated for progression-free survival (PFS), therapy-free survival (TFS), and overall survival (OS).
Time frame: Up to 5 years
Secondary
Treatment Toxicity as Measured by Adverse Events Experienced While on Treatment
Time frame: Weeks 1, 3, 5, 7, 9, 11, 13, 15, and 17