Ofatumumab-based Induction Chemoimmunotherapy in Previously Untreated Patients With CLL/SLL
- Conditions
- Small Lymphocytic LymphomaCLL (Chronic Lymphocytic Leukemia)
- Interventions
- Registration Number
- NCT01145209
- Lead Sponsor
- National Heart, Lung, and Blood Institute (NHLBI)
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 32
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description FCO Arm (fludarabine, cyclophosphamide, and ofatumumab) Ofatumumab For patients with high risk FISH changes FO Arm (fludarabine and ofatumumab) Ofatumumab For patients with non-high risk FISH changes FO Arm (fludarabine and ofatumumab) Fludarabine Phosphate For patients with non-high risk FISH changes FCO Arm (fludarabine, cyclophosphamide, and ofatumumab) Fludarabine Phosphate For patients with high risk FISH changes FCO Arm (fludarabine, cyclophosphamide, and ofatumumab) Cyclophosphamide For patients with high risk FISH changes
- Primary Outcome Measures
Name Time Method 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 Outcome Measures
Name Time Method 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 AEParticipants 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 absentParticipants 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%.Participants With Minimal Residual Disease (MRD) Negativity 2 years Participants with minimal residual disease (MRD) negativity following the completion of induction chemoimmunotherapy.
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 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
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center, 9000 Rockville Pike
🇺🇸Bethesda, Maryland, United States