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

Chronic Myelomonocytic Leukemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00589316
• Other study ID #: 2186.00
• Secondary ID: NCI-2010-0040421
• Status: Terminated
• Phase: Phase 1
• Start date: October 5, 2007
• Est. completion date: October 1, 2021

Study information

• Verified date: January 2023
• Source: Fred Hutchinson Cancer Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This phase I trial studies the side effects and best dose of iodine I 131monoclonal antibody BC8 when given together with fludarabine phosphate, cyclophosphamide, total-body irradiation, and donor bone marrow transplant, and to see how well they work in treating patients with acute myeloid leukemia or acute lymphoblastic leukemia that has spread to nearby or other places in the body (advanced), or high-risk myelodysplastic syndrome. Giving chemotherapy drugs, such as fludarabine phosphate and cyclophosphamide, and total-body irradiation before a donor bone marrow transplant helps stop the growth of cancer or abnormal cells and helps stop the patient's immune system from rejecting the donor's stem cells. Also, radiolabeled monoclonal antibodies, such as iodine I 131 monoclonal antibody BC8, can find cancer cells and carry cancer-killing substances to them without harming normal cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving cyclophosphamide together with mycophenolate mofetil and tacrolimus after the transplant may stop this from happening. Giving a radiolabeled monoclonal antibody together with donor stem cell transplant, fludarabine phosphate, cyclophosphamide, mycophenolate mofetil, and tacrolimus may be an effective treatment for advanced acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndromes.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 26
• Est. completion date: October 1, 2021
• Est. primary completion date: October 1, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome
• Adult Acute Lymphoblastic Leukemia in Remission
• Adult Acute Myeloid Leukemia in Remission
• Anemia
• Anemia, Refractory, with Excess of Blasts
• CD45-Positive Neoplastic Cells Present
• Chronic Myelomonocytic Leukemia
• Leukemia
• Leukemia, Lymphoid
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Leukemia, Myelomonocytic, Chronic
• Leukemia, Myelomonocytic, Juvenile
• Leukopenia
• Myelodysplastic Syndromes
• Precursor Cell Lymphoblastic Leukemia-Lymphoma
• Preleukemia
• Previously Treated Myelodysplastic Syndrome
• Refractory Anemia With Excess Blasts
• Refractory Anemia With Ring Sideroblasts
• Refractory Cytopenia With Multilineage Dysplasia
• Refractory Cytopenia With Multilineage Dysplasia and Ring Sideroblasts
• Syndrome
• Thrombocytopenia

Intervention

Procedure:
• Allogeneic Bone Marrow Transplantation
Given via central line

Drug:
• Cyclophosphamide
Given IV
• Fludarabine Phosphate
Given IV

Radiation:
• Iodine I 131 Monoclonal Antibody BC8
Given IV (dosimetry dose) or via central line (therapeutic dose)

Other:
• Laboratory Biomarker Analysis
Correlative studies

Drug:
• Mycophenolate Mofetil
Given IV or PO
• Tacrolimus
Given IV or PO

Radiation:
• Total-Body Irradiation
Undergo TBI

Locations

Country	Name	City	State
United States	Fred Hutch/University of Washington Cancer Consortium	Seattle	Washington

Sponsors (2)

Lead Sponsor	Collaborator
Fred Hutchinson Cancer Center	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Dose-limiting Toxicities (DLT) 30 Days After 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	Number of Participants With Transplant-Related Mortality Within 100 Days After Transplant	Number of Participants that received and completed study treatment who died within 100 days after transplant	Up to 100 days post-transplant
Secondary	Participant Disease Response Within 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: Normal bone marrow with blasts <5% with normal cellularity, normal megakarypoiesis, more than 15% erythropoiesis, and more than 25% granulocytopoiesis.; Normalization of blood counts (no blasts, platelets > 100000/mm3, granulocytes >1500/mm3); No extramedullary disease; Relapse is measured as follows: After CR: >5% blasts in the bone marrow and/or peripheral blood. Confirmation of relapse by bone marrow analysis with more than 10% blasts.; After PR: increase of blast cells in the marrow to >50% of those during PR.; Extramedullary disease confirmed cytologically or histologically.	Up to 90 days after transplant
Secondary	Severity of Acute GVHD in Patients Who Completed the Study Treatment	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; 1 gastrointestinal involvement and/or +1 liver involvement; Grade III +2 to +4 gastrointestinal involvement and/or; 2 to +4 liver involvement with or without a rash; Grade IV Pattern and severity of GVHD similar to grade 3 with extreme constitutional symptoms or death	100 days after transplant
Secondary	Number of Participants With 100% Donor Chimerism at Day 84	Post-transplant bone marrow and peripheral blood samples were collected on day 84 after transplant for DNA Chimerism Analysis	Day 84 after transplant
Secondary	Two-Year Disease-free Survival of Study Participants Who Completed the Study Regimen	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