211^At-BC8-B10 before Donor Stem Cell Transplant in Treating Patients with High-Risk Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Myelodysplastic Syndrome, or Mixed-Phenotype Acute Leukemia

Status: Active

Description

This phase I / II trial studies the side effects and best dose of 211^astatine(At)-BC8-B10 before donor stem cell transplant in treating patients with high-risk acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, or mixed-phenotype acute leukemia. Radioactive substances, such as astatine-211, linked to monoclonal antibodies, such as BC8, can bind to cancer cells and give off radiation which may help kill cancer cells and have less of an effect on healthy cells before donor stem cell transplant.

Eligibility Criteria

Inclusion Criteria

  • Patients must have advanced AML, ALL, high-risk MDS, or MPAL (also known as biphenotypic) meeting one of the following descriptions: * AML, ALL, or MPAL beyond first remission (i.e., having relapsed at least one time after achieving remission in response to a treatment regimen) * AML, ALL, or MPAL 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
  • 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
  • Patients must have normal hepatic function (bilirubin, 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 have an HLA-matched related 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) or bone marrow donation, as follows: * Related donor: related to the patient and genotypically or phenotypically identical for HLA-A, B, C, DRB1 and DQB1; phenotypic identity must be confirmed by high-resolution typing * Unrelated donor: ** Matched for HLA-A, B, C, DRB1 and DQB1 by high resolution typing; OR ** Mismatched for a single allele without antigen mismatching at HLA-A, B, or C as defined by high resolution typing but otherwise matched for HLA-A, B, C, DRB1 and DQB1 by high resolution typing ** Donors are excluded when preexisting immunoreactivity is identified that would jeopardize donor hematopoietic cell engraftment; the recommended procedure for patients with 10 of 10 HLA allele level (phenotypic) match is to obtain panel reactive antibody (PRA) screens to class I and class II antigens for all patients before hematopoietic cell transplant (HCT); if the PRA shows > 10% activity, then flow cytometric or B and T cell cytotoxic cross matches should be obtained; the donor should be excluded if any of the cytotoxic cross match assays are positive; for those patients with an HLA Class I allele mismatch, flow cytometric or B and T cell cytotoxic cross matches should be obtained regardless of the PRA results; a positive anti-donor cytotoxic crossmatch is an absolute donor exclusion * Patient and donor pairs homozygous at a mismatched allele in the graft rejection vector are considered a two-allele mismatch, i.e., the patient is A*0101 and the donor is A*0102, and this type of mismatch is not allowed

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 < 35%
  • Corrected diffusing capacity of the lungs 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 positive [beta-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: Brenda M. Sandmaier
Phone: 206-667-4961
Email: bsandmai@fredhutch.org

Trial Objectives and Outline

PRIMARY OBJECTIVE:

I. To estimate the maximum tolerated dose (MTD) of radiation delivered via 211^At-BC8-B10 when combined with fludarabine phosphate (FLU) and 2 or 3 gray (Gy) total body irradiation (TBI) as a preparative regimen for patients aged >= 18 with advanced acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), high risk myelodysplastic syndrome (MDS), or mixed-phenotype acute leukemia (MPAL).

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, and to correlate level of donor chimerism with amount of 211^At administered.

OUTLINE: This is a dose-escalation study of 211^At-BC8-B10.

Patients receive 211^At-BC8-B10 intravenously (IV) over 6-8 hours on day -7 and fludarabine phosphate IV over 30 minutes on days -4, -3 and -2. Patients undergo TBI and peripheral blood stem cell (PBSC) transplant on day 0. Patients also receive cyclosporine orally (PO) or IV every 12 hours on days -3 to 56 and then tapered to day 180, or continuing to day 96 and then tapered to day 150. Patients receive mycophenolate mofetil PO or IV (first dose to occur 4-6 hours after PBSC infusion) every 12 hours on days 0-27, or every 8 hours on day 0 and then reduced to every 12 hours on days 30-40. Patients with HLA-matched unrelated donors receive sirolimus PO once daily (QD) on days -3 to 150 and then tapered to day 180.

After completion of study treatment, patients are followed up at 100 days and then 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
Brenda M. Sandmaier

Trial IDs

Primary ID 9595
Secondary IDs NCI-2017-00452, RG9217014
Clinicaltrials.gov ID NCT03128034