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

Phase 1

Suspended

• Conditions: Acute Lymphoblastic Leukemia; Recurrent Acute Lymphoblastic Leukemia; Chronic Myelomonocytic Leukemia; Myelodysplastic Syndrome With Excess Blasts; Recurrent Acute Myeloid Leukemia; Refractory Acute Myeloid Leukemia; Mixed Phenotype Acute Leukemia; Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Acute Myeloid Leukemia; Refractory Acute Lymphoblastic Leukemia
• Interventions: Drug: Cyclosporine; Drug: Fludarabine Phosphate; Other: Laboratory Biomarker Analysis; Drug: Mycophenolate Mofetil; Procedure: Peripheral Blood Stem Cell Transplantation; Other: Pharmacological Study; Radiation: Pretargeted Radioimmunotherapy; Radiation: Total-Body Irradiation

• Registration Number: NCT03128034
• Lead Sponsor: Fred Hutchinson Cancer Center

Brief Summary

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

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 (for patients with related donors), or continuing to day 96 and then tapered to day 150 (for patients with unrelated donors). Patients receive mycophenolate mofetil PO or IV (first dose to occur 4-6 hours after PBSC infusion) every 12 hours on days 0-27 (for patients with related donors) or every 8 hours on day 0 and then reduced to every 12 hours on days 30-150 then tapered to day 180 (for patients with unrelated donors).

After completion of study treatment, patients are followed up at 100 days and then at 6, 9, 12, 18 and 24 months.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2017-04-13
• Study First Submitted QC: 2017-04-20
• Study First Posted: 2017-04-25
• Study Start: 2017-10-24
• Primary Completion: 2023-01-13
• Disposition First Submitted: 2023-12-21
• Disposition First Posted: 2024-01-18
• Status Verified: 2024-06
• Last Update Submitted: 2024-06-26
• Last Update Posted: 2024-06-28
• Study Completion: 2027-03-31

Recruitment & Eligibility

• Status: SUSPENDED
• Sex: All
• Target Recruitment: 75

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 in first remission with evidence of measurable residual disease (MRD) by flow cytometry
  • 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 (because in remission patients, virtually all antibody binding is to non-malignant cells which make up >= 95% of nucleated cells in the marrow)

• Patients must be >= 18 and =< 75 years of age

• 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 within normal limits, aspartate aminotransferase [AST] and alanine aminotransferase [ALT] < 2 times the upper limit of normal) within 2 months prior to the astatine-211 infusion date (with the exception of patients that are known to have Gilbert's disease)

• Eastern Cooperative Oncology Group (ECOG) < 2 or Karnofsky >= 70

• Patients must be free of uncontrolled infection

• Patients with prior non-myeloablative or reduced-intensity conditioning allogeneic-hematopoietic cell transplant (HCT) must have no evidence of ongoing GVHD and be off GVHD treatment immunosuppression for at least 6 weeks at time of enrollment

• Patients must have normal elastography

• If ferritin is elevated, patient must have less than 7 mg/g liver iron concentration on liver T2* MRI

• Patients should have an official gastrointestinal (GI) consult prior to the transplant for full evaluation

• Patients must have an HLA-matched related donor or an HLA-matched unrelated donor who meets standard Fred Hutch 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 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

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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; when pulmonary function test (PFT)s cannot be obtained, the 6-minute walk test (6MWT, also known as exercise oximetry) will be used: Any patient with oxygen saturation on room air of < 89% during a 6MWT will be excluded
• 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
• Patients with prior myeloablative allogeneic-HCT
• 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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (211^At-BC8-B10, PBSC)	Pharmacological Study	Patients 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 (for patients with related donors) or every 8 hours on day 0 and then reduced to every 12 hours on days 30-150 then tapered to day 180 (for patients with unrelated donors).
Treatment (211^At-BC8-B10, PBSC)	Total-Body Irradiation	Patients 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 (for patients with related donors) or every 8 hours on day 0 and then reduced to every 12 hours on days 30-150 then tapered to day 180 (for patients with unrelated donors).
Treatment (211^At-BC8-B10, PBSC)	Peripheral Blood Stem Cell Transplantation	Patients 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 (for patients with related donors) or every 8 hours on day 0 and then reduced to every 12 hours on days 30-150 then tapered to day 180 (for patients with unrelated donors).
Treatment (211^At-BC8-B10, PBSC)	Laboratory Biomarker Analysis	Patients 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 (for patients with related donors) or every 8 hours on day 0 and then reduced to every 12 hours on days 30-150 then tapered to day 180 (for patients with unrelated donors).
Treatment (211^At-BC8-B10, PBSC)	Pretargeted Radioimmunotherapy	Patients 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 (for patients with related donors) or every 8 hours on day 0 and then reduced to every 12 hours on days 30-150 then tapered to day 180 (for patients with unrelated donors).
Treatment (211^At-BC8-B10, PBSC)	Cyclosporine	Patients 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 (for patients with related donors) or every 8 hours on day 0 and then reduced to every 12 hours on days 30-150 then tapered to day 180 (for patients with unrelated donors).
Treatment (211^At-BC8-B10, PBSC)	Mycophenolate Mofetil	Patients 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 (for patients with related donors) or every 8 hours on day 0 and then reduced to every 12 hours on days 30-150 then tapered to day 180 (for patients with unrelated donors).
Treatment (211^At-BC8-B10, PBSC)	Fludarabine Phosphate	Patients 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 (for patients with related donors) or every 8 hours on day 0 and then reduced to every 12 hours on days 30-150 then tapered to day 180 (for patients with unrelated donors).

Primary Outcome Measures

Name	Time	Method
Proportion of patients who develop grades III/IV Bearman regimen-related toxicity	Up to 100 days following hematopoietic cell transplantation	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

Name	Time	Method
Disease-free survival	Up to 100 days
Achievement of remission	Up to 2 years
Duration of remission	Up to 2 years
Rates of engraftment	Up to day 100	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.
Non-relapse mortality	Up to 2 years
Overall survival	Up to 100 days
Rates of acute graft versus host disease	Up to day 180
Rates of chimerism	Up to day 84

Trial Locations

Locations (1)

Fred Hutch/University of Washington Cancer Consortium; 🇺🇸 Seattle, Washington, United States