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

Официальное название

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)

Обзор

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.

Подробное описание

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.

Вмешательства

• Биопрепарат Astatine At 211 Anti-CD45 Monoclonal Antibody BC8-B10
  Given via infusion
• Препарат Cyclophosphamide
  Given IV
• Лучевая терапия Total-Body Irradiation
  Undergo TBI
• Процедура Peripheral Blood Stem Cell Transplantation
  Undergo PBSC transplantation
• Процедура Bone Marrow Transplantation
  Undergo bone marrow transplant
• Препарат Mycophenolate Mofetil
  Given IV or PO
• Биопрепарат Recombinant Granulocyte Colony-Stimulating Factor
  Given IV or SC
• Препарат Fludarabine Phosphate
  Given IV
• Препарат Tacrolimus
  Given IV or PO
• Процедура Bone Marrow Aspiration and Biopsy
  Undergo bone marrow biopsy and aspiration

Первичные конечные точки

• Incidence of dose limiting toxicity (DLT) [Срок оценки: Up to 30 days post-transplant, with a review period for occurrence of veno-occlusive disease (VOD)/sinusoidal obstruction syndrome (SOS) extended to 60 days post-transplant]

Вторичные конечные точки (9)

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

Критерии участия

Критерии включения

• 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.
• Total bilirubin within normal limits
• 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.

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 1 центр

• Fred Hutch/University of Washington Cancer Consortium — Seattle

Идентификаторы

NCT: NCT03670966 · RG1003349 · 10060 · P30CA015704 · NCI-2018-01788 · P01CA078902

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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