Back to resultsOfatumumab-based Induction Chemoimmunotherapy in Previously Untreated Patients With CLL/SLL
Primary Purpose
Small Lymphocytic Lymphoma, CLL (Chronic Lymphocytic Leukemia)
Status
Active
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Fludarabine Phosphate
Ofatumumab
Cyclophosphamide
Sponsored by
About this trial
This is an interventional treatment trial for Small Lymphocytic Lymphoma focused on measuring Arzerra, Chemoimmunotherapy, SLL, Monoclonal Antibody Therapy, CLL, Ofatumumab
Eligibility 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.
Sites / Locations
- National Institutes of Health Clinical Center, 9000 Rockville Pike
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
FO Arm (fludarabine and ofatumumab)
FCO Arm (fludarabine, cyclophosphamide, and ofatumumab)
Arm Description
For patients with non-high risk FISH changes
For patients with high risk FISH changes
Outcomes
Primary Outcome Measures
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
Secondary Outcome Measures
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
Participants With Minimal Residual Disease (MRD) Negativity
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
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.
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
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%.
Participants Overall Survival Rate After Initiation of Induction Chemoimmunotherapy
Participants overall survival rate 2 years after initiation of induction chemoimmunotherapy
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.
Full Information
NCT ID
NCT01145209
First Posted
June 15, 2010
Last Updated
October 13, 2022
Sponsor
National Heart, Lung, and Blood Institute (NHLBI)
Collaborators
University of Virginia, GlaxoSmithKline
1. Study Identification
Unique Protocol Identification Number
NCT01145209
Brief Title
Ofatumumab-based Induction Chemoimmunotherapy in Previously Untreated Patients With CLL/SLL
Official Title
A Phase II Study of Ofatumumab-Based Induction Chemoimmunotheraphy Followed by Consolidation Ofatumumab Immunotherapy in Previously Untreated Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Study Type
Interventional
2. Study Status
Record Verification Date
October 2022
Overall Recruitment Status
Active, not recruiting
Study Start Date
July 1, 2010 (undefined)
Primary Completion Date
October 31, 2017 (Actual)
Study Completion Date
September 15, 2023 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Heart, Lung, and Blood Institute (NHLBI)
Collaborators
University of Virginia, GlaxoSmithKline
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Small Lymphocytic Lymphoma, CLL (Chronic Lymphocytic Leukemia)
Keywords
Arzerra, Chemoimmunotherapy, SLL, Monoclonal Antibody Therapy, CLL, Ofatumumab
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
32 (Actual)
8. Arms, Groups, and Interventions
Arm Title
FO Arm (fludarabine and ofatumumab)
Arm Type
Experimental
Arm Description
For patients with non-high risk FISH changes
Arm Title
FCO Arm (fludarabine, cyclophosphamide, and ofatumumab)
Arm Type
Experimental
Arm Description
For patients with high risk FISH changes
Intervention Type
Drug
Intervention Name(s)
Fludarabine Phosphate
Other Intervention Name(s)
Fludara
Intervention Description
Given IV
Intervention Type
Biological
Intervention Name(s)
Ofatumumab
Other Intervention Name(s)
Arzerra
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Other Intervention Name(s)
Cytoxan, Neosar
Intervention Description
Given IV
Primary Outcome Measure Information:
Title
Progression Free Survival Rate 2 Years After Initiation of Induction Therapy
Description
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
Secondary Outcome Measure Information:
Title
Number of Grade 3 and 4 Treatment Related Adverse Events
Description
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
Title
Participants With Minimal Residual Disease (MRD) Negativity
Description
Participants with minimal residual disease (MRD) negativity following the completion of induction chemoimmunotherapy.
Time Frame
2 years
Title
Participants With MRD Negativity at the Completion of Consolidation Immunotherapy Who Failed to Achieve MRD Negativity
Description
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
Title
Participants With Complete Response Rates Following Induction Chemoimmunotherapy.
Description
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
Title
Participants Overall Response Rates Following Induction Chemoimmunotherapy.
Description
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
Title
Participants Overall Survival Rate After Initiation of Induction Chemoimmunotherapy
Description
Participants overall survival rate 2 years after initiation of induction chemoimmunotherapy
Time Frame
Up to 2 years
Title
Median Relationship of CD20 Expression With MRD Negativity Rate
Description
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
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
99 Years
Accepts Healthy Volunteers
No
Eligibility 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Inhye Ahn, M.D.
Organizational Affiliation
National Heart, Lung, and Blood Institute (NHLBI)
Official's Role
Principal Investigator
Facility Information:
Facility Name
National Institutes of Health Clinical Center, 9000 Rockville Pike
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States
12. IPD Sharing Statement
Citations:
Citation
Ahn I, Farooqui M, Lee YS, Marti G, Soto S, Tian X, Stetler-Stevenson M, Yuan CM, Maric I, Wiestner A. Risk-Adapted Induction and Maintenance with Ofatumumab in Previously Untreated Patients with Chronic Lymphocytic Leukemia (CLL) / Small Lymphocytic Lymphoma (SLL). Blood 2015 126(23):1750-1750.
Results Reference
background
PubMed Identifier
33653216
Citation
Desai S, Mo C, Gaglione EM, Yuan CM, Stetler-Stevenson M, Tian X, Maric I, Wake L, Farooqui MZ, Drinkwater DC, Soto S, Valdez J, Hughes TE, Nierman P, Lotter J, Marti GE, Pleyer C, Sun C, Superata J, Nichols C, Herman SEM, Lindorfer MA, Taylor RP, Wiestner A, Ahn IE. Risk-adapted, ofatumumab-based chemoimmunotherapy and consolidation in treatment-naive chronic lymphocytic leukemia: a phase 2 study. Leuk Lymphoma. 2021 Aug;62(8):1816-1827. doi: 10.1080/10428194.2021.1888379. Epub 2021 Mar 2.
Results Reference
background
Links:
URL
https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2010-H-0141.html
Description
NIH Clinical Center Detailed Web Page
Learn more about this trial
Ofatumumab-based Induction Chemoimmunotherapy in Previously Untreated Patients With CLL/SLL
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