- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00589316
Iodine I 131 Monoclonal Antibody BC8, Fludarabine Phosphate, Cyclophosphamide, Total-Body Irradiation and Donor Bone Marrow Transplant in Treating Patients With Advanced Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, or High-Risk Myelodysplastic Syndrome
Hematopoietic Bone Marrow Transplantation for Patients With High-risk Acute Myeloid Leukemia (AML), Acute Lymphoblastic Leukemia (ALL), or Myelodysplastic Syndrome (MDS) Using Related HLA-Mismatched Donors: A Trial Using Radiolabeled Anti-CD45 Antibody Combined With Immunosuppression Before and After Transplantation
Study Overview
Status
Conditions
- Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome
- Chronic Myelomonocytic Leukemia
- Previously Treated Myelodysplastic Syndrome
- Adult Acute Myeloid Leukemia in Remission
- Adult Acute Lymphoblastic Leukemia in Remission
- Refractory Anemia With Excess Blasts
- Refractory Anemia With Ring Sideroblasts
- Refractory Cytopenia With Multilineage Dysplasia
- Refractory Cytopenia With Multilineage Dysplasia and Ring Sideroblasts
- CD45-Positive Neoplastic Cells Present
Detailed Description
PRIMARY OBJECTIVES:
I. To estimate the maximum tolerated dose of radiation delivered via 131 I-BC8 antibody (iodine I 131 monoclonal antibody BC8) when combined with pre- and post-transplant cyclophosphamide (CY), fludarabine phosphate (FLU), 2 Gy total-body irradiation (TBI), tacrolimus, mycophenolate mofetil (MMF), and a haploidentical allogeneic hematopoietic marrow transplant in patients who have advanced acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or high risk myelodysplastic syndromes (MDS).
II. To estimate rates of immune reconstitution, engraftment, and donor chimerism resulting from this combined preparative regimen.
III. To determine rates of disease relapse, acute graft-versus-host disease (GVHD), and day 100 disease-free survival in patients receiving 131 I-BC8 antibody (Ab) combined with CY, FLU, 2 Gy TBI, tacrolimus, MMF, and human leukocyte antigen (HLA)-haploidentical allogeneic hematopoietic cell transplant (HCT).
OUTLINE: This is a dose-escalation study of iodine I 131 monoclonal antibody BC8.
RADIOIMMUNOTHERAPY: Patients receive therapeutic iodine I 131 monoclonal antibody BC8 via central line on day -14.
NONMYELOABLATIVE CONDITIONING: Patients receive FLU intravenously (IV) over 30 minutes on days -6 to -2 and CY IV over 1 hour on days -6 and -5. Patients undergo TBI on day -1.
TRANSPLANTATION: Patients undergo allogeneic bone marrow transplantation on day 0.
POST-TRANSPLATATION IMMUNOSUPPRESSION: Patients receive CY IV over 1-2 hours on day 3, MMF IV or orally (PO) thrice daily (TID) on days 4 to 35, and tacrolimus IV over 1-2 hours or PO on days 4 to 180 with taper on day 84.
Treatment continues in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 6, 9, 12, 18, and 24 months, and then annually thereafter.
Study Type
Enrollment (Actual)
Phase
- Phase 1
Contacts and Locations
Study Locations
-
-
Washington
-
Seattle, Washington, United States, 98109
- Fred Hutch/University of Washington Cancer Consortium
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-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Patients with advanced AML or ALL defined as beyond first remission, primary refractory disease, or evolved from myelodysplastic or myeloproliferative syndromes; or patients with MDS expressed as refractory anemia with excess blasts (RAEB), refractory cytopenia with multilineage dysplasia (RCMD), RCMD with ringed sideroblasts (RCMD-RS), or chronic myelomonocytic leukemia (CMML)
- Patients not in remission must have cluster of differentiation (CD)45-expressing leukemic blasts; patients in remission do not require phenotyping and may have leukemia previously documented to be CD45 negative (because in remission patients, virtually all antibody binding is to non-malignant cells which make up >= 95% of nucleated cells in the marrow)
- Patients should have a circulating blast count of less than 10,000/mm^3 (control with hydroxyurea or similar agent is allowed)
Patients must have a creatinine clearance greater than 50/ml per minute by the following formula (test must be performed within 28 days prior to registration):
- Creatinine clearance (CrCl) = (140-age) (Wt in Kg) x 0.85 (female) OR 1.0 (male)/72 x serum Cr
- Bilirubin < 2 times the upper limit of normal
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2 times the upper limit of normal
- Karnofsky score >= 70 or Eastern Cooperative Oncology Group (ECOG) =< 2
- Patients must have an expected survival of > 60 days and must be free of active infection
- Patients must have a related donor who is identical for one human leukocyte antigen (HLA) haplotype and mismatched at the HLA-A, -B or class II, DR beta 1 (DRB1) loci of the unshared haplotype with the exception of single HLA-A, -B or DRB1 mismatches
- DONOR: Related donor who is identical for one HLA haplotype and mismatched at the HLA-A, -B, or DRB1 loci of the unshared haplotype with the exception of single HLA-A, -B, or DRB1 mismatches
Exclusion Criteria:
- Circulating antibody against mouse immunoglobulin (HAMA)
- Prior radiation to maximally tolerated levels to any critical normal organ
- Cross-match positive with donor
- Patients may not have symptomatic coronary artery disease and may not be on cardiac medications for anti-arrhythmic or inotropic effects
- Left ventricular ejection fraction < 35%
- Corrected diffusion capacity of carbon monoxide (DLCO) < 35% and/or receiving supplemental continuous oxygen
- Liver abnormalities: fulminant liver failure, cirrhosis of the liver with evidence of portal hypertension, alcoholic hepatitis, esophageal varices, hepatic encephalopathy, uncorrectable hepatic synthetic dysfunction as evidenced by prolongation of the prothrombin time, ascites related to portal hypertension, bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis, or symptomatic biliary disease
- Patients who are known seropositive for human immunodeficiency virus (HIV)
- Perceived inability to tolerate diagnostic or therapeutic procedures, particularly treatment in radiation isolation
- Central nervous system (CNS) involvement with disease refractory to intrathecal chemotherapy and/or standard cranial-spinal radiotherapy
- Women of childbearing potential who are pregnant (beta-human chorionic gonadotropin positive [b-HCG+]) or breast feeding
- Fertile men and women unwilling to use contraceptives during and for 12 months post-transplant
- Inability to understand or give an informed consent
Study Plan
How is the study designed?
Design Details
- Primary Purpose: TREATMENT
- Allocation: NA
- Interventional Model: SINGLE_GROUP
- Masking: NONE
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
EXPERIMENTAL: Treatment (chemo, TBI, transplant, immunosuppression)
RADIOIMMUNOTHERAPY: Patients receive therapeutic iodine I 131 monoclonal antibody BC8 via central line on day -14. NONMYELOABLATIVE CONDITIONING: Patients receive FLU IV over 30 minutes on days -6 to -2 and CY IV over 1 hour on days -6 and -5. Patients undergo TBI on day -1. TRANSPLANTATION: Patients undergo allogeneic bone marrow transplantation on day 0. POST-TRANSPLATATION IMMUNOSUPPRESSION: Patients receive CY IV over 1-2 hours on day 3, MMF IV or PO TID on days 4 to 35, and tacrolimus IV over 1-2 hours or PO on days 4 to 180 with taper on day 84. |
Correlative studies
Given IV
Other Names:
Undergo TBI
Other Names:
Given IV
Other Names:
Given IV or PO
Other Names:
Given IV or PO
Other Names:
Given via central line
Other Names:
Given IV (dosimetry dose) or via central line (therapeutic dose)
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Number of Participants With Dose-limiting Toxicities (DLT) 30 Days After Transplant
Time Frame: Up to 30 days post-transplant
|
The criteria of Grade III/IV regimen-related toxicity (Bearman) or dose-limiting toxicity (DLT) are as follows: Grade 1 Development of transient chemical abnormalities which are not of major clinical consequence and which reverse without requiring major medical interventions. In general, the intent of this toxicity scale is to observe transient target organ toxicity which is reversible. Grade 2 Development of chemical or laboratory abnormalities that are persistent and which may represent target organ damage that may not be readily reversed. It is anticipated that at this dose of the drug, the toxicity obtained would be manageable by clinical methods but may interfere with other therapies. Grade 3 Development of major clinical, chemical or laboratory abnormalities which represent maximum toxicities without being fatal. This grade of toxicity is designed to be the dose-limiting toxicity. Grade 4 Fatal |
Up to 30 days post-transplant
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Number of Participants With Transplant-Related Mortality Within 100 Days After Transplant
Time Frame: Up to 100 days post-transplant
|
Number of Participants that received and completed study treatment who died within 100 days after transplant
|
Up to 100 days post-transplant
|
Participant Disease Response Within 90 Days After Transplant
Time Frame: Up to 90 days after transplant
|
The number of participants that are in complete remission or relapsed within 90 days after transplant Complete Remission is defined as the complete resolution of all signs of leukemia for at least 90 days with all of the following:
Relapse is measured as follows:
|
Up to 90 days after transplant
|
Severity of Acute GVHD in Patients Who Completed the Study Treatment
Time Frame: 100 days after transplant
|
The severity of acute GVHD is measured based on Graft vs Host Disease: Grade I +1 to +2 skin rash No gut or liver involvement Grade II +3 skin rash or
Grade III +2 to +4 gastrointestinal involvement and/or
Grade IV Pattern and severity of GVHD similar to grade 3 with extreme constitutional symptoms or death |
100 days after transplant
|
Number of Participants With 100% Donor Chimerism at Day 84
Time Frame: Day 84 after transplant
|
Post-transplant bone marrow and peripheral blood samples were collected on day 84 after transplant for DNA Chimerism Analysis
|
Day 84 after transplant
|
Two-Year Disease-free Survival of Study Participants Who Completed the Study Regimen
Time Frame: 2 years post-transplant
|
Survival and complete resolution of all signs of leukemia 2 years after transplant with all of the following: 1, Normal bone marrow with blasts <5% with normal cellularity, normal megakaryopoiesis, more than 15% erythropoiesis, and more than 25% granulocytopoiesis. 2. Normalization of blood counts (no basts, platelets >100,000/mm3, granulocytes >1,500/mm3) 3. No extramedullary disease. |
2 years post-transplant
|
Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Johnnie Orozco, Fred Hutch/University of Washington Cancer Consortium
Study record dates
Study Major Dates
Study Start (ACTUAL)
Primary Completion (ACTUAL)
Study Completion (ACTUAL)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (ESTIMATE)
Study Record Updates
Last Update Posted (ESTIMATE)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Pathologic Processes
- Immune System Diseases
- Neoplasms by Histologic Type
- Neoplasms
- Lymphoproliferative Disorders
- Lymphatic Diseases
- Immunoproliferative Disorders
- Disease
- Bone Marrow Diseases
- Hematologic Diseases
- Blood Platelet Disorders
- Precancerous Conditions
- Myelodysplastic-Myeloproliferative Diseases
- Leukocyte Disorders
- Syndrome
- Myelodysplastic Syndromes
- Leukemia
- Leukemia, Myeloid
- Leukemia, Myeloid, Acute
- Preleukemia
- Leukemia, Myelomonocytic, Chronic
- Leukemia, Myelomonocytic, Juvenile
- Precursor Cell Lymphoblastic Leukemia-Lymphoma
- Leukemia, Lymphoid
- Anemia
- Thrombocytopenia
- Leukopenia
- Anemia, Refractory, with Excess of Blasts
- Anemia, Refractory
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Anti-Infective Agents, Local
- Anti-Infective Agents
- Enzyme Inhibitors
- Antirheumatic Agents
- Antimetabolites, Antineoplastic
- Antimetabolites
- Antineoplastic Agents
- Immunosuppressive Agents
- Immunologic Factors
- Antineoplastic Agents, Alkylating
- Alkylating Agents
- Myeloablative Agonists
- Trace Elements
- Micronutrients
- Anti-Bacterial Agents
- Antibiotics, Antineoplastic
- Antitubercular Agents
- Antibiotics, Antitubercular
- Calcineurin Inhibitors
- Cyclophosphamide
- Antibodies
- Immunoglobulins
- Antibodies, Monoclonal
- Iodine
- Cadexomer iodine
- Antineoplastic Agents, Immunological
- Fludarabine
- Fludarabine phosphate
- Tacrolimus
- Mycophenolic Acid
Other Study ID Numbers
- 2186.00 (OTHER: Fred Hutch/University of Washington Cancer Consortium)
- P01CA044991 (U.S. NIH Grant/Contract)
- NCI-2010-00404 (REGISTRY: CTRP (Clinical Trial Reporting Program))
- 2186.00p
- RG1707019 (OTHER: Fred Hutch/University of Washington Cancer Consortium)
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