211At-BC8-B10 Followed by Donor Stem Cell Transplant in Treating Patients With Relapsed or Refractory High-Risk Acute Leukemia or Myelodysplastic Syndrome

A Phase I/II Study Evaluating Escalating Doses of 211At-Labeled Anti-CD45 MAb BC8-B10 (211At-BC8-B10) Followed by Related Haplo-Identical Allogeneic Hematopoietic Cell Transplantation for High-Risk Acute Leukemia or Myelodysplastic Syndrome (MDS)

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 patients with high-risk acute leukemia or myelodysplastic syndrome that has come back (recurrent) or isn't responding to treatment (refractory). 211At-BC8-B10 is a monoclonal antibody that 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 patient, they may help the patient'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, mycophenolate mofetil, and tacrolimus after a transplant may stop this from happening.

Study Overview

• Status: Recruiting
• Conditions: Hematopoietic and Lymphoid Cell Neoplasm; Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Chronic Myelomonocytic Leukemia; Recurrent Acute Myeloid Leukemia; Refractory Acute Myeloid Leukemia; Myelodysplastic Syndrome With Excess Blasts; Recurrent Acute Lymphoblastic Leukemia; Refractory Acute Lymphoblastic Leukemia; Recurrent Mixed Phenotype Acute Leukemia; Refractory Mixed Phenotype Acute Leukemia; Acute Myeloid Leukemia in Remission; Acute Lymphoblastic Leukemia in Remission
• Intervention / Treatment: Procedure: Biospecimen Collection; Drug: Cyclophosphamide; Radiation: Total-Body Irradiation; Procedure: Peripheral Blood Stem Cell Transplantation; Drug: Fludarabine Phosphate; Drug: Tacrolimus; Procedure: Bone Marrow Aspiration and Biopsy; Drug: Mycophenolate Mofetil; Biological: Astatine At 211 Anti-CD45 Monoclonal Antibody BC8-B10; Procedure: Bone Marrow Transplantation; Biological: Recombinant Granulocyte Colony-Stimulating Factor

Detailed Description

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

PREPARATIVE REGIMEN: Patients receive astatine At 211 anti-CD45 monoclonal antibody BC8-B10 infusion over 6-8 hours 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. Patients also undergo TBI on day -1.

TRANSPLANT: Patients undergo peripheral blood stem cell (PBSC) or bone marrow transplant on day 0.

GVHD PROPHYLAXIS: Patients receive cyclophosphamide IV over 1-2 hours on days 3-4, mycophenolate mofetil IV or PO three times daily (TID) on days 5-35, and tacrolimus IV over 1-2 hours (changed to PO once tolerated) on days 5-180 with taper beginning on day 84 per physician discretion. Patients 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.

Patients undergo bone marrow biopsy and aspiration and blood sample collection throughout the study.

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

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Phuong Vo; Phone Number: 206-667-2749; Email: ptvo@fredhutch.org

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98109
      • Recruiting
      • Fred Hutch/University of Washington Cancer Consortium
      • Contact: Phuong Vo; Phone Number: 206-667-2749; Email: ptvo@fredhutch.org
      • Principal Investigator: Phuong Vo

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients must have 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.
• 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 with prior non-myeloablative or reduced-intensity conditioning allogeneic-HCT must have no evidence of ongoing GVHD and be off all 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 magnetic resonance imaging (MRI).
• Patients should have an official gastrointestinal (GI) consult prior to the transplant for full evaluation.
• 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 Seattle Cancer Care Alliance (SCCA) 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. When pulmonary function tests (PFTs) 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 [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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (211At-BC8-B10, chemotherapy, TBI, MMF, G-CSF); PREPARATIVE REGIMEN: Patients receive astatine At 211 anti-CD45 monoclonal antibody BC8-B10 infusion over 6-8 hours on day -8, fludarabine IV over 30 minutes on days -6 to -2, and cyclophosphamide IV over 1 hour on days -6 and -5. Patients also undergo TBI on day -1. TRANSPLANT: Patients undergo PBSC or bone marrow transplant on day 0. GVHD PROPHYLAXIS: Patients receive cyclophosphamide IV over 1-2 hours on days 3-4, mycophenolate mofetil IV or PO TID on days 5-35, and tacrolimus IV over 1-2 hours (changed to PO once tolerated) on days 5-180 with taper beginning on day 84 per physician discretion. Patients also begin G-CSF IV or SC on day 5 to continue until ANC > 1000/mm^3 x 3 days. Patients undergo bone marrow biopsy and aspiration and blood sample collection throughout the study.

Procedure: Biospecimen Collection; Undergo blood sample collection; Other Names: Biological Sample Collection; Drug: Cyclophosphamide; Given IV; Other Names: (-)-Cyclophosphamide; Asta B 518; B-518; WR-138719; Radiation: Total-Body Irradiation; Undergo TBI; Other Names: Total Body Irradiation; TBI; SCT_TBI; Whole Body Irradiation; Whole-Body Irradiation; Procedure: Peripheral Blood Stem Cell Transplantation; Undergo PBSC transplantation; Other Names: PBPC transplantation; Drug: Fludarabine Phosphate; Given IV; Other Names: 2-F-ara-AMP; Beneflur; Fludara; SH T 586; Fludarabine-5''-Monophosphate; Drug: Tacrolimus; Given IV or PO; Other Names: Prograf; FK 506; Protopic; FK-506; Tacforius; Procedure: Bone Marrow Aspiration and Biopsy; Undergo bone marrow biopsy and aspiration; Drug: Mycophenolate Mofetil; Given IV or PO; Other Names: Cellcept; MMF; 115007-34-6; Biological: Astatine At 211 Anti-CD45 Monoclonal Antibody BC8-B10; Given via infusion; Other Names: At 211 MAb BC8-B10; APAMISTAMAB-B10-ASTATINE AT-211; Procedure: Bone Marrow Transplantation; Undergo bone marrow transplant; Other Names: BMT; Bone Marrow Grafting; Biological: Recombinant Granulocyte Colony-Stimulating Factor; Given IV or SC; Other Names: rhG-CSF; Recombinant Colony-Stimulating Factor 3; 143011-72-7

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Toxicity: Proportion of patients who develop grades III/IV Bearman regimen-related toxicity	Proportion of patients who develop grades III/IV Bearman regimen-related toxicity.	Up 100 days after hematopoietic cell transplantation (HCT)

Secondary Outcome Measures

Outcome Measure	Time Frame
Achievement of remission	Up to 2 years
Rate of engraftment	Up to 2 years
Donor chimerism	At days 28, 56, 84, 180, and at 1 year
Non-relapse mortality (NRM)	Up to 2 years
Number of patients experiencing Immune reconstitution	Up to 2 years
Number of patients experiencing Number of Grade II-IV acute graft versus host disease (GVHD)	Up to 2 years
Number of patients experiencing Moderate/severe chronic GVHD	Up to 2 years
Overall survival	Up to 100 days
Disease-free survival	Up to day 100

Collaborators and Investigators

• Sponsor: Fred Hutchinson Cancer Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Phuong Vo, Fred Hutchinson Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): July 10, 2019
• Primary Completion (Estimated): June 28, 2025
• Study Completion (Estimated): March 20, 2027

Study Registration Dates

• First Submitted: September 12, 2018
• First Submitted That Met QC Criteria: September 12, 2018
• First Posted (Actual): September 14, 2018

Study Record Updates

• Last Update Posted (Actual): March 18, 2024
• Last Update Submitted That Met QC Criteria: March 15, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Lymphoid Leukemia; Myeloid and Monocytic Leukemia; Other Hematopoietic
• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; Disease; Bone Marrow Diseases; Hematologic Diseases; Anemia; Precancerous Conditions; Myelodysplastic-Myeloproliferative Diseases; Anemia, Refractory; Chronic Disease; Syndrome; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Recurrence; Preleukemia; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Acute Disease; Anemia, Refractory, with Excess of Blasts; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Anti-Bacterial Agents; Adjuvants, Immunologic; Antibiotics, Antineoplastic; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Cyclophosphamide; Antibodies; Lenograstim; Antibodies, Monoclonal; Fludarabine; Fludarabine phosphate; Tacrolimus; Mycophenolic Acid
• Other Study ID Numbers: RG1003349; P30CA015704 (U.S. NIH Grant/Contract); P01CA078902 (U.S. NIH Grant/Contract); 10060 (Other Identifier: Fred Hutch/University of Washington Cancer Consortium); NCI-2018-01788 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No