Combination Antibody Therapy for Relapsed Lymphoma and Chronic Lymphocytic Leukemia
| Status: | Terminated |
|---|---|
| Conditions: | Blood Cancer, Lymphoma |
| Therapuetic Areas: | Oncology |
| Healthy: | No |
| Age Range: | 18 - 100 |
| Updated: | 4/6/2019 |
| Start Date: | August 15, 2001 |
| End Date: | March 17, 2017 |
Combination Antibody Therapy With Apolizumab (1D10) and Rituximab (CD20) in Relapsed Lymphoma and CLL
This study will evaluate the safety and effectiveness of a combination of two antibodies,
apolizumab and rituximab (Rituxan ), in treating B-cell lymphomas and chronic lymphocytic
leukemia. Rituximab attaches to a molecule called CD20 on B-cell lymphomas and can cause
significant shrinkage of these tumors in up to half of patients. However, it does not cure
the lymphoma, which usually returns. Also, it is not as effective against leukemia.
Apolizumab attaches to a protein called 1D10 on B-cell cancers and has also been able to
shrink tumors in some patients. There is little experience apolizumab in patients with
leukemia. This study will test whether the two antibodies together are more effective against
these tumors than either one alone.
Patients 18 years and older with B-cell lymphoma or chronic lymphocytic leukemia may be
eligible for this study. Patients' leukemia or lymphoma cells must have both the CD20 and
1D10 antigen receptors and must have had at least one systemic treatment for their disease.
Candidates are screened with a medical history and physical examination, blood and urine
tests, electrocardiogram, x-rays and other imaging studies, and possibly a bone marrow
aspirate (withdrawal of a small marrow sample through a needle inserted into the hip bone)
and lumbar puncture (withdrawal of a small sample of cerebrospinal fluid-fluid that bathes
the brain and spinal cord-through a needle placed between the bones in the lower back).
Participants receive infusions of rituximab and apolizumab once a week for 4 weeks. The first
patients in the study receive lower doses of apolizumab with standard doses of rituximab. If
the apolizumab is well tolerated, subsequent patients are given higher doses. Patients are
also given dexamethasone or another similar steroid, diphenhydramine (Benadryl ), and
acetominophen (Tylenol ) to reduce reactions to the antibodies. After 4 weeks of treatment,
patients are followed frequently to examine the response to treatment and evaluate drug side
effects. Patients whose tumors do not grow during the 4 weeks of therapy may be offered
another course of treatment at a later time. Participants are followed periodically after
treatment ends until their disease worsens or the study ends.
apolizumab and rituximab (Rituxan ), in treating B-cell lymphomas and chronic lymphocytic
leukemia. Rituximab attaches to a molecule called CD20 on B-cell lymphomas and can cause
significant shrinkage of these tumors in up to half of patients. However, it does not cure
the lymphoma, which usually returns. Also, it is not as effective against leukemia.
Apolizumab attaches to a protein called 1D10 on B-cell cancers and has also been able to
shrink tumors in some patients. There is little experience apolizumab in patients with
leukemia. This study will test whether the two antibodies together are more effective against
these tumors than either one alone.
Patients 18 years and older with B-cell lymphoma or chronic lymphocytic leukemia may be
eligible for this study. Patients' leukemia or lymphoma cells must have both the CD20 and
1D10 antigen receptors and must have had at least one systemic treatment for their disease.
Candidates are screened with a medical history and physical examination, blood and urine
tests, electrocardiogram, x-rays and other imaging studies, and possibly a bone marrow
aspirate (withdrawal of a small marrow sample through a needle inserted into the hip bone)
and lumbar puncture (withdrawal of a small sample of cerebrospinal fluid-fluid that bathes
the brain and spinal cord-through a needle placed between the bones in the lower back).
Participants receive infusions of rituximab and apolizumab once a week for 4 weeks. The first
patients in the study receive lower doses of apolizumab with standard doses of rituximab. If
the apolizumab is well tolerated, subsequent patients are given higher doses. Patients are
also given dexamethasone or another similar steroid, diphenhydramine (Benadryl ), and
acetominophen (Tylenol ) to reduce reactions to the antibodies. After 4 weeks of treatment,
patients are followed frequently to examine the response to treatment and evaluate drug side
effects. Patients whose tumors do not grow during the 4 weeks of therapy may be offered
another course of treatment at a later time. Participants are followed periodically after
treatment ends until their disease worsens or the study ends.
While recurrent non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL) are often
responsive to therapy, they are rarely curable and disease control is the primary therapeutic
goal. Rituximab, a chimeric anti-CD20 monoclonal antibody, has shown single agent activity in
these diseases and is currently approved for the therapy of recurrent indolent lymphoma.
However, rituximab induces objective remission in at most 60% of cases with inevitable
relapse. The 1D10 antigen, a subclass of the HLA-DR molecule, is expressed in a majority of
cases of B-cell malignancy. Apolizumab is a humanized monoclonal antibody that targets this
antigen. In a phase I dose escalation trial this antibody has shown clinical activity against
B-cell NHL that express the 1D10 antigen. Acute infusional toxicity has been tolerable, and a
maximum of 5 mg/kg has been given in each of 4 weekly doses. Preclinical in vitro data from
Dr. George Weiner's laboratory suggests at least additive anti-tumor efficacy when cells are
exposed to both antibodies simultaneously. This trial will pilot the use of combination
therapy with rituximab and apolizumab in patients with tumors that express both antigens.
Feasibility and tolerability of the regimen will be determined. Experimental endpoints will
include pharmacokinetics of apolizumab, assessment of apoptosis in circulating CLL cells by
FACS analysis with Annexin 5, assessment of T-and B-cell dynamics, and effects of rituximab
and apolizumab on CLL mRNA as measured by cDNA microarray. Following the first 21 patients on
trial, the administration sequence of rituximab and apolizumab was changed from rituximab
first to apolizumab first to potentially reduce sensitization of apolizumab toxicity by
rituximab.
responsive to therapy, they are rarely curable and disease control is the primary therapeutic
goal. Rituximab, a chimeric anti-CD20 monoclonal antibody, has shown single agent activity in
these diseases and is currently approved for the therapy of recurrent indolent lymphoma.
However, rituximab induces objective remission in at most 60% of cases with inevitable
relapse. The 1D10 antigen, a subclass of the HLA-DR molecule, is expressed in a majority of
cases of B-cell malignancy. Apolizumab is a humanized monoclonal antibody that targets this
antigen. In a phase I dose escalation trial this antibody has shown clinical activity against
B-cell NHL that express the 1D10 antigen. Acute infusional toxicity has been tolerable, and a
maximum of 5 mg/kg has been given in each of 4 weekly doses. Preclinical in vitro data from
Dr. George Weiner's laboratory suggests at least additive anti-tumor efficacy when cells are
exposed to both antibodies simultaneously. This trial will pilot the use of combination
therapy with rituximab and apolizumab in patients with tumors that express both antigens.
Feasibility and tolerability of the regimen will be determined. Experimental endpoints will
include pharmacokinetics of apolizumab, assessment of apoptosis in circulating CLL cells by
FACS analysis with Annexin 5, assessment of T-and B-cell dynamics, and effects of rituximab
and apolizumab on CLL mRNA as measured by cDNA microarray. Following the first 21 patients on
trial, the administration sequence of rituximab and apolizumab was changed from rituximab
first to apolizumab first to potentially reduce sensitization of apolizumab toxicity by
rituximab.
- INCLUSION CRITERIA:
Diagnosis of B-cell lymphoma, Waldenstrom's CLL with surface expression of both CD20 and
1D10 antigen by immunohistochemistry (IHC) or fluorescence of activated cell sorting (FACS)
with anti-CD20 and 1D10 antibody. Positive 1D10 expression in a FACS assay is defined as
more than 2 times the mean fluorescence intensity (MFI) of the control antibody by FACS or
greater than 20% of cells 1D10+ by IHC.
Confirmation of diagnosis in Laboratory of Pathology, NCI or OSU.
Prior therapy with at least one systemic treatment, and not a candidate for potentially
curative (i.e., transplant) treatment at the time of study entry. Prior treatment with
rituximab greater than or equal to 1 month ago is permitted.
Age greater than 18 years.
ECOG performance status less than or equal to 2.
Major organ function: ANC greater than or equal to 500/microliter, Platelet greater than or
equal 25,000/microliter, Creatinine less than or equal to 1.5 mg/dl or creatinine clearance
greater than 60 cc/min; SGPT less than 5 x upper limit of normal; bilirubin less than 2
mg/dl (total) except less than 5 mg/dl in patients with Gilbert's syndrome as defined by
greater than 80% unconjugated; unless impairment due to organ involvement by lymphoma.
Provides informed consent.
EXCLUSION CRITERIA:
Pregnancy or nursing. Both male and female patients must be willing to use adequate
contraception.
Prior apolizumab treatment.
SActive cardiac disease, cerebrovascular disease or peripheral arterial vascular disease.
Active CNS lymphoma.
Systemic cytotoxic chemotherapy within 3 weeks of enrollment or systemic steroids (except
stable doses less than 10 mg/day) within 1 week of enrollment.
We found this trial at
1
site
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
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