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211^At-BC8-B10 Before Donor Stem Cell Transplant in Treating Patients With High-Risk Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, or Myelodysplastic Syndrome

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ClinicalTrials.gov Identifier: NCT03128034
Recruitment Status : Recruiting
First Posted : April 25, 2017
Last Update Posted : April 17, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research 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, or myelodysplastic syndrome. 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.

Condition or disease Intervention/treatment Phase
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 Adult Acute Myeloid Leukemia Refractory Adult Acute Lymphoblastic Leukemia Recurrent Adult Acute Lymphoblastic Leukemia Drug: Cyclosporine Drug: Fludarabine Phosphate Other: Laboratory Biomarker Analysis Drug: Mycophenolate Mofetil Procedure: Peripheral Blood Stem Cell Transplantation Other: Pharmacological Study Radiation: Pretargeted Radioimmunotherapy Drug: Sirolimus Radiation: Total-Body Irradiation Phase 1 Phase 2

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), 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, 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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : October 24, 2017
Estimated Primary Completion Date : June 30, 2021
Estimated Study Completion Date : March 22, 2023


Arm Intervention/treatment
Experimental: Treatment (211^At-BC8-B10, PBSC)
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, 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.
Drug: Cyclosporine
Given PO or IV
Other Names:
  • 27-400
  • Ciclosporin
  • CsA
  • Cyclosporin
  • Cyclosporin A
  • Gengraf
  • Neoral
  • OL 27-400
  • Sandimmun
  • Sandimmune
  • SangCya

Drug: Fludarabine Phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-
  • Beneflur
  • Fludara
  • SH T 586

Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Mycophenolate Mofetil
Given PO or IV
Other Names:
  • Cellcept
  • MMF

Procedure: Peripheral Blood Stem Cell Transplantation
Undergo allogeneic PBSC transplant
Other Names:
  • PBPC transplantation
  • PBSCT
  • Peripheral Blood Progenitor Cell Transplantation
  • Peripheral Stem Cell Support
  • Peripheral Stem Cell Transplant
  • Peripheral Stem Cell Transplantation

Other: Pharmacological Study
Correlative studies

Radiation: Pretargeted Radioimmunotherapy
Given 211^At-BC8-B10 IV

Drug: Sirolimus
Given PO
Other Names:
  • AY 22989
  • RAPA
  • Rapamune
  • Rapamycin
  • SILA 9268A
  • WY-090217

Radiation: Total-Body Irradiation
Undergo TBI
Other Names:
  • Total Body Irradiation
  • Whole-Body Irradiation




Primary Outcome Measures :
  1. Proportion of patients who develop grades III/IV Bearman regimen-related toxicity [ Time Frame: 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 :
  1. Achievement of remission [ Time Frame: Up to 2 years ]
  2. Disease-free survival [ Time Frame: Up to 100 days ]
  3. Duration of remission [ Time Frame: Up to 2 years ]
  4. Non-relapse mortality [ Time Frame: Up to 2 years ]
  5. Overall survival [ Time Frame: Up to 100 days ]
  6. Rates of acute graft versus host disease [ Time Frame: Up to day 180 ]
  7. Rates of chimerism [ Time Frame: Up to day 84 ]
  8. Rates of engraftment [ Time Frame: 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.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03128034


Locations
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United States, Washington
Fred Hutch/University of Washington Cancer Consortium Recruiting
Seattle, Washington, United States, 98109
Contact: Brenda M. Sandmaier    206-667-4961    bsandmai@fredhutch.org   
Principal Investigator: Brenda M. Sandmaier         
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Brenda Sandmaier Fred Hutch/University of Washington Cancer Consortium

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier: NCT03128034     History of Changes
Other Study ID Numbers: 9595
NCI-2017-00452 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
9595 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
P01CA078902 ( U.S. NIH Grant/Contract )
P30CA015704 ( U.S. NIH Grant/Contract )
First Posted: April 25, 2017    Key Record Dates
Last Update Posted: April 17, 2019
Last Verified: April 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Syndrome
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Preleukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Leukemia, Myelomonocytic, Chronic
Leukemia, Myelomonocytic, Juvenile
Anemia, Refractory, with Excess of Blasts
Disease
Pathologic Processes
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Myelodysplastic-Myeloproliferative Diseases
Anemia, Refractory
Anemia
Fludarabine
Fludarabine phosphate
Sirolimus
Everolimus
Mycophenolic Acid