CLL (Chronic Lymphocytic Leukemia), Small Lymphocytic Lymphoma
Conditions
Keywords
Arzerra, Chemoimmunotherapy, SLL, Monoclonal Antibody Therapy, CLL, Ofatumumab
Brief summary
Background: \- Ofatumumab was approved by the U.S. Food and Drug Administration to treat patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who have not responded to standard chemotherapy. Ofatumumab is a substance that recognizes specific types of white blood cells called B-lymphocytes, which become cancerous in CLL/SLL. Ofatumumab attaches to a molecule called CD20, which is found on the surface of B-cells, and destroys them. Previous studies have shown that ofatumumab can decrease the number of B-cells in patients with CLL/SLL who have been treated with chemotherapy, but more research is needed to determine it if can also be used to treat patients with previously untreated CLL/SLL. Objectives: \- To determine a safe and effective dose of ofatumumab, along with chemotherapy, to treat chronic lymphocytic leukemia or small lymphocytic lymphoma. Eligibility: \- Individuals at least 18 years of age who have been diagnosed with CLL or SLL that has not been treated with chemotherapy. Design: * Eligible participants will be screened with a physical exam, blood samples, lymph node and bone marrow biopsies, and imaging studies. * Participants will be separated into 2 groups: all participants will receive ofatumumab and fludarabine, and some participants will be selected to also receive cyclophosphamide (based on results of certain blood tests). * Participants will receive the study drugs (ofatumumab and fludarabine, and optional cyclophosphamide) by infusion for a maximum of 6 days, followed by 21 days off drug. * Participants will have 6 cycles of treatment according to a schedule set by the study doctors, and may have their dose levels adjusted if side effects develop. * Participants who have disease remaining after 6 cycles will receive additional ofatumumab every 2 months, starting 2 months after the end of the 6th cycle and continuing for a total of 4 doses, before entering the follow-up phase of the trial. Participants who do not have residual disease after 6 cycles will not receive additional therapy, and will immediately enter the follow-up phase of the trial. * Participants will have a follow-up exam every 2 to 4 months for 2 years after the end of treatment, and then as required by the study doctors for as long as the study remains open. These visits will involve a full medical exam, blood samples, lymph node and bone marrow biopsies, and imaging studies.
Detailed description
OUTLINE: Patients with adverse interphase cytogenetics (11q22 or 17p13 deletion) receive FCO induction therapy: * Ofatumumab is given IV on day 1 (300 mg) and day 8 (1000 mg) of course 1 and on day 1 (1000 mg) of all subsequent courses. * Fludarabine phosphate (25mg/m2/d) and cyclophosphamide (250mg/m2/d) are given IV on days 2 through 4 of course 1 and on days 1 through 3 of all subsequent courses. Patients age 70 or older will be given reduced doses of fludarabine (20mg/m2/d) and cyclophosphamide (150mg/m2/d). * Treatment repeats every 28 days for up to 6 courses in the absence of disease progression. Patients without adverse interphase cytogenetics receive FO induction therapy: * Ofatumumab is given IV on day 1 (300mg) and day 8 (1000mg) of course 1 and on day 1 (1000mg) of all subsequent courses. * Fludarabine phosphate (25mg/m2/d) is given IV on days 2 through 6 of course 1 and on days 1 through 5 of all subsequent courses. * Treatment repeats every 28 days for up to 6 courses in the absence of disease progression. All patients are evaluated for minimal residual disease (MRD) by four-color flow cytometric analysis of the peripheral blood after completion of FO or FCO induction therapy, and are subsequently stratified into two groups: * Patients who are MRD-positive and without evidence of disease progression proceed to consolidation therapy beginning approximately 5 months after completion of induction therapy, consisting of ofatumumab (1000mg) given IV on day 1 of all courses. Treatment repeats every 2 months for up to 4 courses in the absence of disease progression. Patients are followed clinically 2 and 6 months after the last dose of ofatumumab is given, and then every 6 months thereafter. * Patients who are MRD-negative and without evidence of disease progression are followed clinically every 4 months for 1 year and every 6 months thereafter.
Interventions
DRUGFludarabine Phosphate
Given IV
BIOLOGICALOfatumumab
Given IV
DRUGCyclophosphamide
Given IV
Sponsors
University of Virginia
GlaxoSmithKline
National Heart, Lung, and Blood Institute (NHLBI)
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
* INCLUSION CRITERIA: Histologically confirmed CLL or SLL as defined by the following: * B-lymphocytosis greater than 5000 cells/micro L (may be less than 5000 cells/micro L if lymphadenopathy is present with histologic confirmation of lymph node involvement by SLL). * Immunophenotypic profile consistent with CLL as demonstrated by flow cytometry * Appropriate immunophonotype (CD5/19/23+) * Clonality of lymphocytosis confirmed by flow cytometry * large lymphocytes less than 55 % of blood lymphocytes Active disease as defined by at least one of the following: * Weight loss greater than or equal to10 percent within the previous 6 months * Extreme fatigue * Fevers of greater than 100.5 degree F for greater than or equal to 2 weeks without evidence of infection * Night sweats for more than one month without evidence of infection * Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia * Massive or progressive splenomegaly * Massive nodes or clusters or progressive lymphadenopathy * Progressive lymphocytosis with an increase of greater than 50% over a 2 month period, or an anticipated doubling time of less than 6 months 0 Measurable disease (defined as two dimensional disease on imaging or quantifiable leukemic disease). Ages 18 and over.
Exclusion criteria
Prior monoclonal antibody therapy with agents having anti-CLL activity Prior cytotoxic chemotherapy with agents having anti-CLL activity (Fludarabine, Cyclophosphamide, Bendamustine, Chlorambucil) Transformed CLL Active autoimmune hemolytic anemia or thrombocytopenia Any medical condition that requires the chronic use of corticosteroids Active or latent Hepatitis B infection HIV infection Severe chronic obstructive pulmonary disease, severe cardiac disease, or other uncontrolled medical condition that would, in the opinion of the principal investigator, place the subject at an unreasonable risk of life-threatening adverse events due to chemoimmunotherapy ECOG performance status 3 or worse Creatinine greater than or equal to 2 mg/dL or creatinine clearance less than or equal to 30 mL/min Bilirubin greater than or equal to 2 mg/dL or active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, or stable chronic liver disease per investigator assessment) Female patients: Current pregnancy or unwilling to take oral contraceptives or refrain from pregnancy if of childbearing potential or currently breastfeeding. Male patients who are unwilling to follow the contraception requirements described in this protocol. Psychiatric illness/social situations that would limit the patient s ability to tolerate and/or comply with study requirements. Unable to understand the investigational nature of the study or give informed consent.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival Rate 2 Years After Initiation of Induction Therapy | 2 years | Death or disease progression defined by the 2008 IWCLL guideline as follows; * Greater than or equal to 50% increase in the SPD of at least 2 lymph nodes (at least one node must be greater than or equal to 2 cm); appearance of any new lymph nodes on physical examination or imaging * Greater than or equal to 50% increase in the size of the liver and/or spleen as determined by measurement below the respective costal margin or CT scan or appearance of palpable hepatomegaly or splenomegaly, which was not previously present * Greater than or equal to 50% increase in the absolute number of circulating lymphocytes to at least 5000/ul * Transformation to a more aggressive histology * Occurrence of any cytopenia attributable to CLL. After treatment: the progression of any cytopenia (unrelated to autoimmune cytopenia), as documented by a decrease of Hb levels by more than 20 g/L (2 g/dL) or to less than 100 g/L (10 g/dL), or by a decrease of platelet counts by more than 50% or to les |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Participants With Minimal Residual Disease (MRD) Negativity | 2 years | Participants with minimal residual disease (MRD) negativity following the completion of induction chemoimmunotherapy. |
| Participants With MRD Negativity at the Completion of Consolidation Immunotherapy Who Failed to Achieve MRD Negativity | 2 years | Participants with MRD negativity at the completion of consolidation immunotherapy who failed to achieve MRD negativity following completion of induction chemoimmunotherapy |
| Participants With Complete Response Rates Following Induction Chemoimmunotherapy. | 2 years | Participants with complete response rates to induction chemoimmunotherapy. Criteria for complete response (CR): CR requires all of the following: * Peripheral blood lymphocytes \< 4000/uL * Absence of significant lymphadenopathy by physical examination and appropriate radiographic techniques (CT or MRI). All lymph nodes must have regressed to \<=1.5cm in greatest diameter * Absence of hepatomegaly or splenomegaly by physical examination, or appropriate radiographic techniques. Spleen, if enlarged before therapy must have regressed in size and must not be palpable by physical exam. * Absence of constitutional symptoms * Normal CBC, defined as: - Polymorphonuclear cells ≥ 1,500/uL - Platelets \> 100,000/uL (untransfused) - Hemoglobin \> 11 g/dL (untransfused) * Bone marrow biopsy demonstrates normal cellularity for age, with less than 30% of nucleated cells being lymphocytes. Lymphoid nodules should be absent |
| Number of Grade 3 and 4 Treatment Related Adverse Events | 2 years | Number of Grade 3 and 4 treatment related adverse events as defined by CTCAE version 3.0 criteria. CTCAE (Common Terminology Criteria for Adverse Events) provides a list of adverse event (AE) terms commonly reported. Each AE term is defined and accompanied by a grading scale that indicates the severity of the AE. The CTCAE v3.0 displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 is a Mild AE; Grade 2 is a Moderate AE; Grade 3 is a Severe AE; Grade 4 is a Life-threatening or disabling AE; and Grade 5 is a Death related to AE |
| Participants Overall Survival Rate After Initiation of Induction Chemoimmunotherapy | Up to 2 years | Participants overall survival rate 2 years after initiation of induction chemoimmunotherapy |
| Median Relationship of CD20 Expression With MRD Negativity Rate | 2 years | Median relationship of biomarker, CD20 expression with MRD negativity clinical response rate. Flow cytometry was use to quantified surface CD20 on peripheral blood. |
| Participants Overall Response Rates Following Induction Chemoimmunotherapy. | 2 years | Participants with complete response rates to induction chemoimmunotherapy. Criteria for complete response (CR) requires all of the following: Peripheral blood lymphocytes \< 4000/uL. No significant lymphadenopathy. Lymph nodes regressed to \<=1.5cm. No hepatomegaly or splenomegaly. Spleen, if enlarged before therapy must have regressed in size and not be palpable. Absence of constitutional symptoms. Bone marrow biopsy demonstrates normal cellularity for age, with less than 30% of nucleated cells being lymphocytes. No lymphoid nodules. Criteria for partial response (PR) requires at least one element of an abnormal CBC and at least one of the following: ≥ 50% decrease in peripheral blood lymphocyte count; ≥ 50% reduction in the sum of the products of lymph nodes up to 6 nodes or nodal masses. No new sites or increase in size of nodes; ≥ 50% reduction in pathologic enlargement of the liver and/or spleen by 50%. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| FO Arm (Fludarabine and Ofatumumab) Fludarabine and ofatumumab for patients with non-high-risk FISH changes | 19 |
| FCO Arm (Fludarabine, Cyclophosphamide, and Ofatumumab) Fludarabine, cyclophosphamide, and ofatumumab for patients with high-risk FISH changes | 13 |
| Total | 32 |
Baseline characteristics
| Characteristic | FO Arm (Fludarabine and Ofatumumab) | FCO Arm (Fludarabine, Cyclophosphamide, and Ofatumumab) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4 Participants | 5 Participants | 9 Participants |
| Age, Categorical Between 18 and 65 years | 15 Participants | 8 Participants | 23 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 0 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants | 13 Participants | 29 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 3 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 17 Participants | 10 Participants | 27 Participants |
| Sex: Female, Male Female | 7 Participants | 5 Participants | 12 Participants |
| Sex: Female, Male Male | 12 Participants | 8 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 0 / 19 |
| other Total, other adverse events | 13 / 13 | 19 / 19 |
| serious Total, serious adverse events | 4 / 13 | 4 / 19 |
Outcome results
Primary
Progression Free Survival Rate 2 Years After Initiation of Induction Therapy
Death or disease progression defined by the 2008 IWCLL guideline as follows; * Greater than or equal to 50% increase in the SPD of at least 2 lymph nodes (at least one node must be greater than or equal to 2 cm); appearance of any new lymph nodes on physical examination or imaging * Greater than or equal to 50% increase in the size of the liver and/or spleen as determined by measurement below the respective costal margin or CT scan or appearance of palpable hepatomegaly or splenomegaly, which was not previously present * Greater than or equal to 50% increase in the absolute number of circulating lymphocytes to at least 5000/ul * Transformation to a more aggressive histology * Occurrence of any cytopenia attributable to CLL. After treatment: the progression of any cytopenia (unrelated to autoimmune cytopenia), as documented by a decrease of Hb levels by more than 20 g/L (2 g/dL) or to less than 100 g/L (10 g/dL), or by a decrease of platelet counts by more than 50% or to les
Time frame: 2 years
Population: The analyses included only those subjects who completed the induction period.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| FO Arm | Progression Free Survival Rate 2 Years After Initiation of Induction Therapy | 14 Participants |
| FCO Arm | Progression Free Survival Rate 2 Years After Initiation of Induction Therapy | 9 Participants |
Secondary
Median Relationship of CD20 Expression With MRD Negativity Rate
Median relationship of biomarker, CD20 expression with MRD negativity clinical response rate. Flow cytometry was use to quantified surface CD20 on peripheral blood.
Time frame: 2 years
Population: The analyses included only those subjects who completed the induction period. It was pre-specified to have arms/groups recombine for this assessment and report irrespective of randomized group.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| FO Arm | Median Relationship of CD20 Expression With MRD Negativity Rate | 10247 sites per cell |
| FCO Arm | Median Relationship of CD20 Expression With MRD Negativity Rate | 15131 sites per cell |
Secondary
Number of Grade 3 and 4 Treatment Related Adverse Events
Number of Grade 3 and 4 treatment related adverse events as defined by CTCAE version 3.0 criteria. CTCAE (Common Terminology Criteria for Adverse Events) provides a list of adverse event (AE) terms commonly reported. Each AE term is defined and accompanied by a grading scale that indicates the severity of the AE. The CTCAE v3.0 displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 is a Mild AE; Grade 2 is a Moderate AE; Grade 3 is a Severe AE; Grade 4 is a Life-threatening or disabling AE; and Grade 5 is a Death related to AE
Time frame: 2 years
Population: All patients included in safety analysis. It was pre-specified to recombine Arms/Groups for this assessment and report irrespective of randomized group.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FO Arm | Number of Grade 3 and 4 Treatment Related Adverse Events | Neutropenia Grade 3 | 4 Number of Grade 3 and Grade 4 AEs |
| FO Arm | Number of Grade 3 and 4 Treatment Related Adverse Events | Thrombocytopenia Grade 3 | 2 Number of Grade 3 and Grade 4 AEs |
| FO Arm | Number of Grade 3 and 4 Treatment Related Adverse Events | Nausea Grade 3 | 1 Number of Grade 3 and Grade 4 AEs |
| FO Arm | Number of Grade 3 and 4 Treatment Related Adverse Events | Infusion reaction Grade 3 | 1 Number of Grade 3 and Grade 4 AEs |
| FO Arm | Number of Grade 3 and 4 Treatment Related Adverse Events | Neutropenia Grade 4 | 17 Number of Grade 3 and Grade 4 AEs |
| FO Arm | Number of Grade 3 and 4 Treatment Related Adverse Events | Lymphopenia Grade 4 | 2 Number of Grade 3 and Grade 4 AEs |
Secondary
Participants Overall Response Rates Following Induction Chemoimmunotherapy.
Participants with complete response rates to induction chemoimmunotherapy. Criteria for complete response (CR) requires all of the following: Peripheral blood lymphocytes \< 4000/uL. No significant lymphadenopathy. Lymph nodes regressed to \<=1.5cm. No hepatomegaly or splenomegaly. Spleen, if enlarged before therapy must have regressed in size and not be palpable. Absence of constitutional symptoms. Bone marrow biopsy demonstrates normal cellularity for age, with less than 30% of nucleated cells being lymphocytes. No lymphoid nodules. Criteria for partial response (PR) requires at least one element of an abnormal CBC and at least one of the following: ≥ 50% decrease in peripheral blood lymphocyte count; ≥ 50% reduction in the sum of the products of lymph nodes up to 6 nodes or nodal masses. No new sites or increase in size of nodes; ≥ 50% reduction in pathologic enlargement of the liver and/or spleen by 50%.
Time frame: 2 years
Population: The analyses included only those subjects who completed the induction period.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| FO Arm | Participants Overall Response Rates Following Induction Chemoimmunotherapy. | Complete Response | 6 Participants |
| FO Arm | Participants Overall Response Rates Following Induction Chemoimmunotherapy. | Partial Response | 4 Participants |
| FCO Arm | Participants Overall Response Rates Following Induction Chemoimmunotherapy. | Complete Response | 2 Participants |
| FCO Arm | Participants Overall Response Rates Following Induction Chemoimmunotherapy. | Partial Response | 16 Participants |
Secondary
Participants Overall Survival Rate After Initiation of Induction Chemoimmunotherapy
Participants overall survival rate 2 years after initiation of induction chemoimmunotherapy
Time frame: Up to 2 years
Population: The analyses included only those subjects who completed the induction period.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| FO Arm | Participants Overall Survival Rate After Initiation of Induction Chemoimmunotherapy | Alive | 18 Participants |
| FO Arm | Participants Overall Survival Rate After Initiation of Induction Chemoimmunotherapy | Deaths | 0 Participants |
| FCO Arm | Participants Overall Survival Rate After Initiation of Induction Chemoimmunotherapy | Alive | 10 Participants |
| FCO Arm | Participants Overall Survival Rate After Initiation of Induction Chemoimmunotherapy | Deaths | 0 Participants |
Secondary
Participants With Complete Response Rates Following Induction Chemoimmunotherapy.
Participants with complete response rates to induction chemoimmunotherapy. Criteria for complete response (CR): CR requires all of the following: * Peripheral blood lymphocytes \< 4000/uL * Absence of significant lymphadenopathy by physical examination and appropriate radiographic techniques (CT or MRI). All lymph nodes must have regressed to \<=1.5cm in greatest diameter * Absence of hepatomegaly or splenomegaly by physical examination, or appropriate radiographic techniques. Spleen, if enlarged before therapy must have regressed in size and must not be palpable by physical exam. * Absence of constitutional symptoms * Normal CBC, defined as: - Polymorphonuclear cells ≥ 1,500/uL - Platelets \> 100,000/uL (untransfused) - Hemoglobin \> 11 g/dL (untransfused) * Bone marrow biopsy demonstrates normal cellularity for age, with less than 30% of nucleated cells being lymphocytes. Lymphoid nodules should be absent
Time frame: 2 years
Population: The analyses included only those subjects who completed the induction period.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| FO Arm | Participants With Complete Response Rates Following Induction Chemoimmunotherapy. | 6 Participants |
| FCO Arm | Participants With Complete Response Rates Following Induction Chemoimmunotherapy. | 2 Participants |
Secondary
Participants With Minimal Residual Disease (MRD) Negativity
Participants with minimal residual disease (MRD) negativity following the completion of induction chemoimmunotherapy.
Time frame: 2 years
Population: The analyses included only those subjects who completed the induction period.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| FO Arm | Participants With Minimal Residual Disease (MRD) Negativity | 4 Participants |
| FCO Arm | Participants With Minimal Residual Disease (MRD) Negativity | 6 Participants |
Secondary
Participants With MRD Negativity at the Completion of Consolidation Immunotherapy Who Failed to Achieve MRD Negativity
Participants with MRD negativity at the completion of consolidation immunotherapy who failed to achieve MRD negativity following completion of induction chemoimmunotherapy
Time frame: 2 years
Population: Participants who achieved MRD negativity at the completion of consolidation immunotherapy
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| FO Arm | Participants With MRD Negativity at the Completion of Consolidation Immunotherapy Who Failed to Achieve MRD Negativity | 14 Participants |
| FCO Arm | Participants With MRD Negativity at the Completion of Consolidation Immunotherapy Who Failed to Achieve MRD Negativity | 4 Participants |