Clinical Trials /

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

NCT03128034

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.

Related Conditions:
  • Acute Lymphoblastic Leukemia
  • Acute Myeloid Leukemia
  • Chronic Myelomonocytic Leukemia
  • Mixed Phenotype Acute Leukemia
  • Refractory Anemia with Excess Blasts
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 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
  • Official Title: A Study Evaluating Escalating Doses of 211^At-Labeled Anti-CD45 MAb BC8-B10 (211^At-BC8-B10) Followed by Allogeneic Hematopoietic Cell Transplantation for High-Risk Acute Myeloid Leukemia (AML), Acute Lymphoblastic Leukemia (ALL), or Myelodysplastic Syndrome (MDS)

Clinical Trial IDs

  • ORG STUDY ID: 9595
  • SECONDARY ID: NCI-2017-00452
  • SECONDARY ID: 9595
  • SECONDARY ID: P01CA078902
  • SECONDARY ID: P30CA015704
  • SECONDARY ID: RG9217014
  • NCT ID: NCT03128034

Conditions

  • Acute Lymphoblastic Leukemia in Remission
  • Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome
  • Acute Myeloid Leukemia in Remission
  • High Risk Myelodysplastic Syndrome
  • Chronic Myelomonocytic Leukemia
  • Myelodysplastic Syndrome With Excess Blasts
  • Recurrent Acute Myeloid Leukemia
  • Refractory Acute Lymphoblastic Leukemia
  • Recurrent Acute Lymphoblastic Leukemia
  • Recurrent Mixed Phenotype Acute Leukemia
  • Refractory Acute Myeloid Leukemia
  • Refractory Mixed Phenotype Acute Leukemia

Interventions

DrugSynonymsArms
Cyclosporine27-400, Ciclosporin, CsA, Cyclosporin, Cyclosporin A, Gengraf, Neoral, OL 27-400, Sandimmun, Sandimmune, SangCyaTreatment (211^At-BC8-B10, PBSC)
Fludarabine Phosphate2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586Treatment (211^At-BC8-B10, PBSC)
Mycophenolate MofetilCellcept, MMFTreatment (211^At-BC8-B10, PBSC)
SirolimusAY 22989, RAPA, Rapamune, Rapamycin, SILA 9268A, WY-090217Treatment (211^At-BC8-B10, PBSC)

Purpose

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.

Detailed Description

      PRIMARY OBJECTIVES:

      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 Arms

NameTypeDescriptionInterventions
Treatment (211^At-BC8-B10, PBSC)ExperimentalPatients receive 211^At-BC8-B10 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 PBSC transplant on day 0. Patients also receive cyclosporine 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 QD on days -3 to 150 and then tapered to day 180.
  • Cyclosporine
  • Fludarabine Phosphate
  • Mycophenolate Mofetil
  • Sirolimus

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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Proportion of patients who develop grades III/IV Bearman regimen-related toxicity
Time Frame:Up to 100 days following hematopoietic cell transplantation
Safety Issue:
Description:The maximum tolerated dose will be defined as the dose of 211^At-BC8-B10 used in combination with the reduced-intensity hematopoietic cell transplantation conditioning regimen that is associated with a grade III/IV regimen-related toxicity or true dose limiting toxicity rate of 25%.the data, thereby generating a dose-response curve based on the observed toxicity rate at the various dose levels visited. Based on this fitted model, the maximum tolerated dose is estimated to be the dose that is associated with a toxicity rate of 25%.

Secondary Outcome Measures

Measure:Achievement of remission
Time Frame:Up to 2 years
Safety Issue:
Description:
Measure:Disease-free survival
Time Frame:Up to 100 days
Safety Issue:
Description:
Measure:Duration of remission
Time Frame:Up to 2 years
Safety Issue:
Description:
Measure:Non-relapse mortality
Time Frame:Up to 2 years
Safety Issue:
Description:
Measure:Overall survival
Time Frame:Up to 100 days
Safety Issue:
Description:
Measure:Rates of acute graft versus host disease
Time Frame:Up to day 180
Safety Issue:
Description:
Measure:Rates of chimerism
Time Frame:Up to day 84
Safety Issue:
Description:
Measure:Rates of engraftment
Time Frame:Up to day 100
Safety Issue:
Description:Sufficient evidence will be taken to be a lower limit of the appropriate 80% one-sided confidence interval associated with the estimated proportion of rejections in excess of 0.20.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Fred Hutchinson Cancer Research Center

Last Updated

August 9, 2019