Donor Peripheral Blood Stem Cell Transplant and Pretargeted Radioimmunotherapy in Treating Patients With High-Risk Advanced Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, or Myelodysplastic Syndrome

Fred Hutchinson Cancer Center (FHCC)

Status and phase

Completed

Phase 1

Conditions

Refractory Anemia With Excess Blasts

Refractory Cytopenia With Multilineage Dysplasia

Previously Treated Myelodysplastic Syndrome

Secondary Acute Myeloid Leukemia

Recurrent Adult Acute Lymphoblastic Leukemia

Recurrent Adult Acute Myeloid Leukemia

Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable

Chronic Myelomonocytic Leukemia

Refractory Cytopenia With Multilineage Dysplasia and Ringed Sideroblasts

Treatments

Drug: Fludarabine Phosphate

Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation

Biological: Pretargeted Radioimmunotherapy

Radiation: Total-Body Irradiation

Drug: Cyclosporine

Procedure: Peripheral Blood Stem Cell Transplantation

Drug: Mycophenolate Mofetil

Other: Laboratory Biomarker Analysis

Other: Pharmacological Study

Study type

Interventional

Funder types

Other

NIH

Identifiers

NCT00988715

P01CA044991 (U.S. NIH Grant/Contract)

NCI-2009-01294 (Registry Identifier)

P30CA015704 (U.S. NIH Grant/Contract)

2309.00 (Other Identifier)

Details and patient eligibility

About

This phase I trial studies pretargeted radioimmunotherapy and donor peripheral blood stem cell transplant employing fludarabine phosphate and total-body irradiation (TBI) to treat patients with high-risk acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome. Giving chemotherapy drugs, such as fludarabine phosphate, and TBI before a donor peripheral blood stem cell transplant helps stop the patient's immune system from rejecting the donor's stem cells. Radiolabeled monoclonal antibodies can be combined with fludarabine phosphate and TBI to find cancer cells and kill them without harming normal cells. Pretargeted radioimmunotherapy (PRIT) allows for further improved targeting of tumor cells over standard directly labeled antibodies.

Full description

PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose (MTD) of radiation delivered via PRIT using BC8-SA (BC8 antibody-streptavidin conjugate) when combined with fludarabine (FLU) (fludarabine phosphate), 2 Gy total body irradiation (TBI), cyclosporine (CSP), mycophenolate mofetil (MMF), and allogeneic hematopoietic cell transplant (HCT) in patients who have advanced acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or high risk myelodysplastic syndromes (MDS).

SECONDARY OBJECTIVES:

I. To estimate rates of immune reconstitution, engraftment, and donor chimerism resulting from this combined preparative regimen.

II. To estimate rates of disease relapse, acute graft-versus-host disease (GvHD), and day-100 disease-free survival in patients receiving PRIT using BC8-SA combined with FLU, 2 Gy TBI, CSP, MMF, and allogeneic HCT.

III. To assess biodistribution, serum half-life, urinary excretion, tissue localization, and clearance of BC8-SA conjugate and DOTA-biotin.

IV. To assess the feasibility of yttrium y 90 (90Y)-DOTA-biotin to bind to BC8-SA conjugate localized to hematolymphoid tissues.

OUTLINE:

Patients undergo pretargeted radioimmunotherapy comprising a test dose of BC8-SA conjugate intravenously (IV) on day -22 and indium In 111(111In)-DOTA-biotin IV on day -20, followed by a therapy dose of BC8-SA conjugate IV on day -14 and 90Y-DOTA-biotin IV on day -12. Patients receive fludarabine phosphate IV on days -4 to -2. Patients undergo TBI and then peripheral blood stem cell transplantation on day 0. Patients with matched related donors receive cyclosporine IV on days -3 to 56 and taper to day 180 and mycophenolate mofetil orally (PO) twice daily (BID) on days 0-27. Patients with matched unrelated donors receive cyclosporine IV on days -3 to 100 and taper to day 180 and mycophenolate mofetil PO thrice daily (TID) on days 0-40 and 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.

Enrollment

17 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

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 CD45-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 nonmalignant 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
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 human leukocyte antigen (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 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; PBSC is the only permitted stem cell source
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 human anti-mouse antibody (HAMA) or human anti-streptavidin antibody (HASA)
Prior radiation to maximally tolerated levels to any critical normal organ
Patients may not have symptomatic coronary artery disease and may not be on cardiac medications for anti-arrhythmic or inotropic effects
Patients with the following organ dysfunction:
- Left ventricular ejection fraction < 35%
- Corrected diffusion capacity of the lung for 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
Active central nervous system (CNS) leukemia
Women of childbearing potential who are pregnant (beta-human chorionic gonadotropin [b-HCG] +) or breast feeding
Fertile men and women unwilling to use contraceptives during and for 12 months post-transplant
Patients may not use vitamin supplements containing biotin from the time of 1 week prior to treatment until 1 week after completion of treatment with all PRIT components
Inability to understand or give an informed consent

Trial design

Primary purpose

Treatment

Allocation

N/A

Interventional model

Single Group Assignment

Masking

None (Open label)

17 participants in 1 patient group

Treatment (PRIT, transplant)

Experimental group

Description:

Patients undergo pretargeted radioimmunotherapy comprising a test dose of BC8-SA conjugate IV on day -22 and 111In-DOTA-biotin IV on day -20, followed by a therapy dose of BC8-SA conjugate IV on day -14 and 90Y-DOTA-biotin IV on day -12. Patients receive fludarabine phosphate IV on days -4 to -2. Patients undergo TBI and then peripheral blood stem cell transplant on day 0. Patients with matched related donors receive cyclosporine IV on days -3 to 56 and taper to day 180 and mycophenolate mofetil PO BID on days 0-27. Patients with matched unrelated donors receive cyclosporine IV on days -3 to 100 and taper to day 180 and mycophenolate mofetil PO TID on days 0-40 and taper to day 96.

Treatment: