Clinical trial NCT00119366: Iodine I 131 Monoclonal Antibody BC8, Fludarabine Phosphate, Total Body Irradiation, and Donor Stem Cell Transplant Followed by Cyclosporine and Mycophenolate Mofetil in Treating Patients With Advanced Acute Myeloid Leukemia or Myelodysplastic Syndrome
Official title: A Phase II Trial Combining Radiolabeled BC8 (Anti-CD45) Antibody With Fludarabine and Low Dose TBI Followed by Related or Unrelated PBSC Infusion and Post-Transplant Immunosuppression for Patients With Advanced AML or High Risk Myelodysplastic Syndrome
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
Adult Acute Myeloid Leukemia With Del(5q)
Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
Adult Acute Myeloid Leukemia With t(15;17)(q22;q12)
Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)
Childhood Myelodysplastic Syndromes
Chronic Myelomonocytic Leukemia
Previously Treated Myelodysplastic Syndromes
Recurrent Adult Acute Myeloid Leukemia
Recurrent Childhood Acute Myeloid Leukemia
Refractory Anemia With Excess Blasts
Refractory Anemia With Excess Blasts in Transformation
Refractory Anemia With Ringed Sideroblasts
Refractory Cytopenia With Multilineage Dysplasia
Secondary Acute Myeloid Leukemia
Secondary Myelodysplastic Syndromes
Lead sponsor: Fred Hutchinson Cancer Center
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2005-07-13
Enrollment: 18
Sex: ALL
Minimum age (years): 16
Maximum age (years): 50
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: This study will assess the feasibility and safety of patients with advanced AML or high-risk MDS treated with Iodine-131 BC8 antibody at a starting dose of 22 Gy delivered to the normal organ receiving the highest dose combined with fludarabine and 2 Gy total body irradiation (TBI), plus cyclosporine (CSP)/mycophenolate mofetil (MMF), followed by matched related or unrelated allogeneic hematopoietic stem cell transplantation (HSCT). Determination of the maximum tolerated dose (MTD) will be the major study endpoint.

Dose-escalation/de-escalation of radiolabeled BC8 antibody (I-131-BC8) is conducted using a "two-stage" approach. Under this plan, dose levels during the first stage are increased (or decreased) for individual patients until a dose-limiting toxicity (DLT) is observed, at which point the second stage proceeds with each dose level administered to a cohort of four patients.
Primary purpose: TREATMENT

Brief summary: This phase II trial studies the side effects and best dose of iodine I 131 monoclonal antibody BC8 when given together with fludarabine phosphate, total-body irradiation, and donor stem cell transplant followed by cyclosporine and mycophenolate mofetil in treating patients with acute myeloid leukemia or myelodysplastic syndrome that has spread to other places in the body and usually cannot be cured or controlled with treatment. Giving chemotherapy drugs, such as fludarabine phosphate, and total-body irradiation before a donor peripheral blood stem cell 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 fludarabine phosphate and total-body irradiation before the transplant together with cyclosporine and mycophenolate mofetil after the transplant may stop this from happening. Giving a radiolabeled monoclonal antibody together with donor stem cell transplant, cyclosporine, and mycophenolate mofetil may be an effective treatment for advanced acute myeloid leukemia or myelodysplastic syndromes.

Detailed description: PRIMARY OBJECTIVES:

I. To evaluate the maximum tolerated dose (MTD) and the transplant-related mortality (TRM) and toxicity of delivering 131I-BC8 (iodine I 131 monoclonal antibody BC8) (anti-cluster of differentiation \[CD\]45 antibody) at a starting dose of 22 Gy to the normal organ receiving the highest dose in combination with the non-myeloablative regimen of fludarabine (fludarabine phosphate) (FLU), 2 Gy total body irradiation (TBI), cyclosporine (CSP), mycophenolate mofetil (MMF), and human leukocyte antigen (HLA)-matched related or unrelated allogeneic hematopoietic stem cell transplant (HSCT) in patients 16 to 50 years old who have advanced acute myeloid leukemia (AML) or high risk myelodysplastic syndrome (MDS).

II. To estimate rates of donor chimerism resulting from this combined preparative regimen and to correlate level of donor chimerism with estimated radiation doses delivered to hematopoietic tissues via antibody.

III. To determine rates of disease relapse, graft vs. host disease, and 2-year disease-free survival in patients receiving 131I-BC8 antibody combined with FLU, 2 Gy TBI, CSP, MMF, and HLA-matched related or unrelated allogeneic HSCT.

OUTLINE: This is a dose-escalation study of iodine I 131 monoclonal antibody BC8.

RADIOIMMUNOTHERAPY: Patients receive therapeutic iodine I 131 monoclonal antibody BC8 intravenously (IV) on day -12.

CONDITIONING: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0.

TRANSPLANTATION: After completion of TBI, patients undergo allogeneic peripheral blood stem cell (PBSC) transplant on day 0.

IMMUNOSUPPRESSION: Patients with a matched related donor receive cyclosporine IV or orally (PO) twice daily (BID) on days -3 to 56 followed by a taper to day 180 in the absence of graft-versus-host disease. Beginning 4-6 hours after PBSC transplant, these patients also receive mycophenolate mofetil PO BID on days 0 to 27. Patients with a matched unrelated donor receive cyclosporine IV or PO BID on days -3 to 100 followed by a taper to day 180. Beginning 4-6 hours after PBSC transplant, these patients also receive mycophenolate mofetil PO thrice daily (TID) on days 0 to 40 followed by a taper to day 96.

After completion of study treatment, patients are followed up at 6, 9, 12, 18, and 24 months and then annually thereafter.

Eligibility criteria: Inclusion Criteria:

* Patients with advanced AML 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 anemia with excess blasts in transformation (RAEBT), refractory cytopenia with multilineage dysplasia (RCMD), RCMD with ringed sideroblasts (RCMD-RS), or chronic myelomonocytic leukemia (CMML)
* Patients not in remission must have CD45-expressing leukemic blasts or myelodysplastic cells; 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 an estimated creatinine clearance greater than 50/ml per minute (serum creatinine value must be within 28 days prior to registration)
* 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 an HLA-identical sibling donor or an HLA-matched unrelated donor who meets standard Seattle Cancer Care Alliance (SCCA) and/or National Marrow Donor Program (NMDP) or other donor center criteria for peripheral blood stem cell (PBSC) donation; related donors should be matched by molecular methods at the intermediate resolution level at HLA-A, B, C, and developmentally regulated RNA binding protein 1 (DRB1) according to Fred Hutchinson Cancer Research Center (FHCRC) Standard Practice Guidelines and to the allele level at DQB1; unrelated donors should be identified using matching criteria that follows the FHCRC Standard Practice Guidelines limiting the study to eligible donors that are allele matched for HLA-A, B, C, DRB1, and DQB1 (grade 1), and accepting up to one allele mismatch as per Standard Practice grade 2.1 for HLA-A, B, or C
* DONOR: Donors must meet HLA matching criteria as well as standard SCCA and/or NMDP or other donor center criteria for PBSC donation

Exclusion Criteria:

* Circulating antibody against mouse immunoglobulin (human anti-mouse antibody \[HAMA\])
* Prior radiation to maximally tolerated levels to any normal organ
* Patients may not have symptomatic coronary artery disease and may not be on cardiac medications for anti-arrhythmic or inotropic effects
* Inability to understand or give an informed consent
* Patients who are seropositive for human immunodeficiency virus (HIV)
* Perceived inability to tolerate diagnostic or therapeutic procedures, particularly treatment in radiation isolation
* Patients who have previously undergone autologous or allogeneic HSCT

Primary outcomes:
measure: Number of Participants With Dose-limiting Toxicities (DLT) 100 Days After Transplant
timeFrame: Up to 100 days post-transplant
Secondary outcomes:
measure: Number of Participants With Transplant Related Mortality Within 100 Days After Transplant
timeFrame: Up to 100 days post-transplant
measure: Participant Disease Response Within 4 Weeks After Transplant
timeFrame: 4 weeks after transplant
measure: Severity of Acute GVHD in Patients Who Completed the Study Treatment
timeFrame: 100 days after transplant
measure: Number of Participants With 100% Donor Chimerism at Day 28 and Day 84
timeFrame: Day 28 and Day 80 after transplant
measure: Two-year Disease-free Survival of Study Participants Who Completed the Study Regimen
timeFrame: 2 years post transplant
Other outcomes:
Locations:
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
state: Washington
Study officials:
affiliation: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
name: Johnnie Orozco
role: PRINCIPAL_INVESTIGATOR
References: