211At-BC8-B10 followed by Donor Stem Cell Transplant in Treating Participants with Relapsed or Refractory Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, or Myelodysplastic Syndrome

Status: Active

Description

This phase I / II trial studies the side effects and best dose of a radioactive agent linked to an antibody (211At-BC8-B10) followed by donor stem cell transplant in treating participants with acute myeloid leukemia, or acute lymphoblastic leukemia, or myelodysplastic syndrome that has come back or isn't responding to treatment. Monoclonal antibodies, such as 211At-BC8-B10, may interfere with the ability of cancer cells to grow and spread. Giving chemotherapy and total body irradiation before a stem cell transplant helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. When the healthy stem cells from a donor are infused into the participant, they may help the participant's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can attack the body's normal cells, called graft versus host disease. Giving cyclophosphamide, tacrolimus, mycophenolate mofetil, and sirolimus after a transplant may stop this from happening.

Eligibility Criteria

Inclusion Criteria

  • Patients must have advanced AML, ALL or high-risk MDS meeting one of the following descriptions: * AML or ALL beyond first remission (i.e., having relapsed at least one time after achieving remission in response to a treatment regimen); * AML or ALL representing primary refractory disease (i.e., having failed to achieve remission at any time following one or more prior treatment regimens); * AML evolved from myelodysplastic or myeloproliferative syndromes; * MDS expressed as refractory anemia with excess blasts (RAEB) * Chronic myelomonocytic leukemia (CMML) by French-American-British (FAB) criteria.
  • 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 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 by the following formula (Cockcroft-Gault). 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.
  • Eastern Cooperative Oncology Group (ECOG) < 2 or Karnofsky >= 70.
  • Patients must be free of uncontrolled infection.
  • Patients must not have an HLA-matched related donor or an HLA-matched unrelated donor who meets standard Seattle Cancer Care Alliance (SCCA) or National Marrow Donor Program (NMDP) or other donor center criteria for peripheral blood stem cell (PBSC) or bone marrow donation.
  • Patients must have a 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.
  • DONOR: Donors must meet HLA matching criteria as well as standard SCCA or NMDP or other donor center criteria for PBSC or bone marrow donation. Preference should be given to donors who are mismatched at the HLA-A, -B and –DRB1 loci.

Exclusion Criteria

  • 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 < 45%.
  • Corrected diffusion capacity of the lung for carbon monoxide (DLCO) < 35% 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 to be seropositive for human immunodeficiency virus (HIV).
  • Perceived inability to tolerate diagnostic or therapeutic procedures.
  • Active central nervous system (CNS) leukemia at time of treatment.
  • 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.
  • Inability to understand or give an informed consent.
  • Allergy to murine-based monoclonal antibodies.
  • Known contraindications to radiotherapy.

Locations & Contacts

Washington

Seattle
Fred Hutch / University of Washington Cancer Consortium
Status: Active
Contact: Phuong Vo
Phone: 206-667-2749

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose (MTD) of radiation delivered via 211At-BC8-B10 when combined with cyclophosphamide (CY), fludarabine (FLU) and total body irradiation (TBI) as a preparative regimen of an human leukocyte antigen (HLA)-haploidentical related donor hematopoietic cell transplantation (HCT) using post-transplantation immunosuppression with high dose CY, tacrolimus, sirolimus and mycophenolate mofetil (MMF) for patients aged >= 18 with advanced acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or high risk myelodysplastic syndrome (MDS).

SECONDARY OBJECTIVES:

I. To determine disease response and duration of remission.

II. To determine the rates of engraftment and donor chimerism resulting from this combined preparative regimen at day +84, and to correlate level of donor chimerism with amount of astatine 211At administered.

III. To determine rates of non-relapse mortality (NRM), immune reconstitution, incidence of grade II-IV acute and severe/moderate chronic graft-versus-host disease (GvHD).

IV. To determine overall survival through day 100.

OUTLINE: This is a dose-escalation study of astatine At 211 anti-CD45 monoclonal antibody BC8-B10.

PREPARATIVE REGIMEN: Participants receive astatine At 211 anti-CD45 monoclonal antibody BC8-B10 infusion on day -8, fludarabine intravenously (IV) over 30 minutes on days -6 to -2, and cyclophosphamide IV over 1 hour on days -6 and -5. Participants also undergo TBI on day -1.

TRANSPLANT: Participants undergo PBSC or bone marrow transplant on day 0.

GVHD PROPHYLAXIS: Participants receive cyclophosphamide IV over 1-2 hours on days 3-4, tacrolimus IV over 1-2 hours or orally (PO) on days 5-150 with a taper beginning on day 84, mycophenolate mofetil IV or PO on days 5-35, and sirolimus PO daily on days 5-180 with taper beginning on day 150. Participants also begin granulocyte colony-stimulating factor (G-CSF) IV or subcutaneously (SC) on day 5 to continue until absolute neutrophil count (ANC) > 1000/mm^3 X 3 days.

After completion of study treatment, participants are followed up at day 100, and at 6, 9, 12, 18, and 24 months.

Trial Phase & Type

Trial Phase

Phase I/II

Trial Type

Treatment

Lead Organization

Lead Organization
Fred Hutch / University of Washington Cancer Consortium

Principal Investigator
Phuong Vo

Trial IDs

Primary ID RG1003349
Secondary IDs NCI-2018-01788, 10060
Clinicaltrials.gov ID NCT03670966