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Adult Acute Myeloid Leukemia With 11q23 (MLL) AbnormalitiesPhase 2NCT00119366

Iodine I 131 Monoclonal Antibody BC8, Fludarabine Phosphate, Total Body Irradiation, and Donor Stem Cell Transplant Followed by Cyclosporine and Mycophenolate Mofetil in Treating Patients With Advanced Acute Myeloid Leukemia or Myelodysplastic Syndrome

A Phase 2 study testing iodine I 131 monoclonal antibody BC8, fludarabine phosphate and total-body irradiation in people with Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities and Adult Acute Myeloid Leukemia With Del(5q), run by Fred Hutchinson Cancer Center at 1 site in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record

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Trial summary

This phase II trial studies the side effects and best dose of iodine I 131 monoclonal antibody BC8 when given together with fludarabine phosphate, total-body irradiation, and donor stem cell transplant followed by cyclosporine and mycophenolate mofetil in treating patients with acute myeloid leukemia or… Read more about this study

Who is it for?
Ages 16 to 50 years
What is being tested?
iodine I 131 monoclonal antibody BC8, fludarabine phosphate and total-body irradiation
Could I receive a placebo?
No, everyone receives an active treatment
How many people
18 participants
Where
1 siteUnited States
Study dates
May 2003to 8 May 2019
Phase
Phase 2

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 16 to 50 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

  • Patients with advanced AML defined as beyond first remission, primary refractory disease, or evolved from myelodysplastic or myeloproliferative syndromes; or patients with MDS expressed as refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEBT), refractory cytopenia with multilineage dysplasia (RCMD), RCMD with ringed sideroblasts (RCMD-RS), or chronic myelomonocytic leukemia (CMML)
  • Patients not in remission must have CD45-expressing leukemic blasts or myelodysplastic cells; 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 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 (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
Show all 10Show fewer
  • Karnofsky score >= 70 or Eastern Cooperative Oncology Group (ECOG) =< 2
  • Patients must have an expected survival of > 60 days and must be free of active infection
  • Patients must have an HLA-identical sibling 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) donation; related donors should be matched by molecular methods at the intermediate resolution level at HLA-A, B, C, and developmentally regulated RNA binding protein 1 (DRB1) according to Fred Hutchinson Cancer Research Center (FHCRC) Standard Practice Guidelines and to the allele level at DQB1; unrelated donors should be identified using matching criteria that follows the FHCRC Standard Practice Guidelines limiting the study to eligible donors that are allele matched for HLA-A, B, C, DRB1, and DQB1 (grade 1), and accepting up to one allele mismatch as per Standard Practice grade 2.1 for HLA-A, B, or C
  • DONOR: Donors must meet HLA matching criteria as well as standard SCCA and/or NMDP or other donor center criteria for PBSC donation

Who cannot join

  • Circulating antibody against mouse immunoglobulin (human anti-mouse antibody [HAMA])
  • Prior radiation to maximally tolerated levels to any normal organ
  • Patients may not have symptomatic coronary artery disease and may not be on cardiac medications for anti-arrhythmic or inotropic effects
  • Inability to understand or give an informed consent
  • Patients who are seropositive for human immunodeficiency virus (HIV)
  • Perceived inability to tolerate diagnostic or therapeutic procedures, particularly treatment in radiation isolation
  • Patients who have previously undergone autologous or allogeneic HSCT

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

    Seattle, Washington, 98109

Other trials in United States

About this study

Official title: A Phase II Trial Combining Radiolabeled BC8 (Anti-CD45) Antibody With Fludarabine and Low Dose TBI Followed by Related or Unrelated PBSC Infusion and Post-Transplant Immunosuppression for Patients With Advanced AML or High Risk Myelodysplastic Syndrome

This phase II trial studies the side effects and best dose of iodine I 131 monoclonal antibody BC8 when given together with fludarabine phosphate, total-body irradiation, and donor stem cell transplant followed by cyclosporine and mycophenolate mofetil in treating patients with acute myeloid leukemia or myelodysplastic syndrome that has spread to other places in the body and usually cannot be cured or controlled with treatment. Giving chemotherapy drugs, such as fludarabine phosphate, and total-body irradiation before a donor peripheral blood stem cell transplant helps stop the growth of cancer or abnormal cells and helps stop the patient's immune system from rejecting the donor's stem cells. Also, radiolabeled monoclonal antibodies, such as iodine I 131 monoclonal antibody BC8, can find cancer cells and carry cancer-killing substances to them without harming normal 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 make an immune response against the body's normal cells. Giving fludarabine phosphate and total-body irradiation before the transplant together with cyclosporine and mycophenolate mofetil after the transplant may stop this from happening. Giving a radiolabeled monoclonal antibody together with donor stem cell transplant, cyclosporine, and mycophenolate mofetil may be an effective treatment for advanced acute myeloid leukemia or myelodysplastic syndromes.

Read the detailed description

PRIMARY OBJECTIVES:

  1. To evaluate the maximum tolerated dose (MTD) and the transplant-related mortality (TRM) and toxicity of delivering 131I-BC8 (iodine I 131 monoclonal antibody BC8) (anti-cluster of differentiation [CD]45 antibody) at a starting dose of 22 Gy to the normal organ receiving the highest dose in combination with the non-myeloablative regimen of fludarabine (fludarabine phosphate) (FLU), 2 Gy total body irradiation (TBI), cyclosporine (CSP), mycophenolate mofetil (MMF), and human leukocyte antigen (HLA)-matched related or unrelated allogeneic hematopoietic stem cell transplant (HSCT) in patients 16 to 50 years old who have advanced acute myeloid leukemia (AML) or high risk myelodysplastic syndrome (MDS).

II. To estimate rates of donor chimerism resulting from this combined preparative regimen and to correlate level of donor chimerism with estimated radiation doses delivered to hematopoietic tissues via antibody.

III. To determine rates of disease relapse, graft vs. host disease, and 2-year disease-free survival in patients receiving 131I-BC8 antibody combined with FLU, 2 Gy TBI, CSP, MMF, and HLA-matched related or unrelated allogeneic HSCT.

OUTLINE: This is a dose-escalation study of iodine I 131 monoclonal antibody BC8.

RADIOIMMUNOTHERAPY: Patients receive therapeutic iodine I 131 monoclonal antibody BC8 intravenously (IV) on day -12.

CONDITIONING: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0.

TRANSPLANTATION: After completion of TBI, patients undergo allogeneic peripheral blood stem cell (PBSC) transplant on day 0.

IMMUNOSUPPRESSION: Patients with a matched related donor receive cyclosporine IV or orally (PO) twice daily (BID) on days -3 to 56 followed by a taper to day 180 in the absence of graft-versus-host disease. Beginning 4-6 hours after PBSC transplant, these patients also receive mycophenolate mofetil PO BID on days 0 to 27. Patients with a matched unrelated donor receive cyclosporine IV or PO BID on days -3 to 100 followed by a taper to day 180. Beginning 4-6 hours after PBSC transplant, these patients also receive mycophenolate mofetil PO thrice daily (TID) on days 0 to 40 followed by a taper to day 96.

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

Being tested
iodine I 131 monoclonal antibody BC8, fludarabine phosphate, total-body irradiation, allogeneic hematopoietic stem cell transplantation, peripheral blood stem cell transplantation
Medical subject headings
Congenital Abnormalities, Leukemia, Myelomonocytic, Chronic, Leukemia, Myeloid, Acute, Anemia, Refractory, with Excess of Blasts

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • iodine I 131 monoclonal antibody BC8Radiation

    Also called I 131 MOAB BC8, I 131 Monoclonal Antibody BC8, iodine I 131 MOAB BC8

    Given IV

  • fludarabine phosphateDrug

    Also called 2-F-ara-AMP, Beneflur, Fludara

    Given IV

  • total-body irradiationRadiation

    Also called TBI

    Undergo TBI

  • allogeneic hematopoietic stem cell transplantationProcedure or surgery

    Undergo PBSC transplantation

  • peripheral blood stem cell transplantationProcedure or surgery

    Also called PBPC transplantation, PBSC transplantation, peripheral blood progenitor cell transplantation, transplantation, peripheral blood stem cell

    Undergo PBSC transplantation

  • cyclosporineDrug

    Also called ciclosporin, cyclosporin, cyclosporin A, CYSP

    Given IV or PO

  • mycophenolate mofetilDrug

    Also called Cellcept, MMF

    Given PO

  • laboratory biomarker analysisOther

    Correlative studies

Study groups in NCT00119366
Study groupRoleWhat they receive
Dose Level 1: 12 Gy iodine-131 monoclonal antibody BC8ExperimentalRADIOIMMUNOTHERAPY: Patients receive therapeutic iodine I 131 monoclonal antibody BC8 IV on day -12. CONDITIONING: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0. TRANSPLANTATION: After completion of TBI, patients undergo allogeneic PBSC transplant on day 0. IMMUNOSUPPRESSION: Patients with a matched related donor receive cyclosporine IV or PO BID on days -3 to 56 followed by a taper to day 180 in the absence of graft-versus-host disease. Beginning 4-6 hours after PBSC transplant, these patients also receive mycophenolate mofetil PO 2 BID on days 0 to 27. Patients with a matched unrelated donor receive cyclosporine IV or PO BID on days -3 to 100 followed by a taper to day 180. Beginning 4-6 hours after PBSC transplant, these patients also receive mycophenolate mofetil PO TID on days 0 to 40 followed by a taper to day 96.
Receives: Radiation: iodine I 131 monoclonal antibody BC8; Drug: fludarabine phosphate; Radiation: total-body irradiation; Procedure: allogeneic hematopoietic stem cell transplantation; Procedure: peripheral blood stem cell transplantation; Drug: cyclosporine; Drug: mycophenolate mofetil; Other: laboratory biomarker analysis
Dose Level 7: 22 Gy iodine-131 monoclonal antibody BC8ExperimentalRADIOIMMUNOTHERAPY: Patients receive therapeutic iodine I 131 monoclonal antibody BC8 IV on day -12. CONDITIONING: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0. TRANSPLANTATION: After completion of TBI, patients undergo allogeneic PBSC transplant on day 0. IMMUNOSUPPRESSION: Patients with a matched related donor receive cyclosporine IV or PO BID on days -3 to 56 followed by a taper to day 180 in the absence of graft-versus-host disease. Beginning 4-6 hours after PBSC transplant, these patients also receive mycophenolate mofetil PO 2 BID on days 0 to 27. Patients with a matched unrelated donor receive cyclosporine IV or PO BID on days -3 to 100 followed by a taper to day 180. Beginning 4-6 hours after PBSC transplant, these patients also receive mycophenolate mofetil PO TID on days 0 to 40 followed by a taper to day 96.
Receives: Radiation: iodine I 131 monoclonal antibody BC8; Drug: fludarabine phosphate; Radiation: total-body irradiation; Procedure: allogeneic hematopoietic stem cell transplantation; Procedure: peripheral blood stem cell transplantation; Drug: cyclosporine; Drug: mycophenolate mofetil; Other: laboratory biomarker analysis
Dose Level 8: 24 Gy iodine-131 monoclonal antibody BC8ExperimentalRADIOIMMUNOTHERAPY: Patients receive therapeutic iodine I 131 monoclonal antibody BC8 IV on day -12. CONDITIONING: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0. TRANSPLANTATION: After completion of TBI, patients undergo allogeneic PBSC transplant on day 0. IMMUNOSUPPRESSION: Patients with a matched related donor receive cyclosporine IV or PO BID on days -3 to 56 followed by a taper to day 180 in the absence of graft-versus-host disease. Beginning 4-6 hours after PBSC transplant, these patients also receive mycophenolate mofetil PO 2 BID on days 0 to 27. Patients with a matched unrelated donor receive cyclosporine IV or PO BID on days -3 to 100 followed by a taper to day 180. Beginning 4-6 hours after PBSC transplant, these patients also receive mycophenolate mofetil PO TID on days 0 to 40 followed by a taper to day 96.
Receives: Radiation: iodine I 131 monoclonal antibody BC8; Drug: fludarabine phosphate; Radiation: total-body irradiation; Procedure: allogeneic hematopoietic stem cell transplantation; Procedure: peripheral blood stem cell transplantation; Drug: cyclosporine; Drug: mycophenolate mofetil; Other: laboratory biomarker analysis
Dose Level 9: 26 Gy iodine-131 monoclonal antibody BC8ExperimentalRADIOIMMUNOTHERAPY: Patients receive therapeutic iodine I 131 monoclonal antibody BC8 IV on day -12. CONDITIONING: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0. TRANSPLANTATION: After completion of TBI, patients undergo allogeneic PBSC transplant on day 0. IMMUNOSUPPRESSION: Patients with a matched related donor receive cyclosporine IV or PO BID on days -3 to 56 followed by a taper to day 180 in the absence of graft-versus-host disease. Beginning 4-6 hours after PBSC transplant, these patients also receive mycophenolate mofetil PO 2 BID on days 0 to 27. Patients with a matched unrelated donor receive cyclosporine IV or PO BID on days -3 to 100 followed by a taper to day 180. Beginning 4-6 hours after PBSC transplant, these patients also receive mycophenolate mofetil PO TID on days 0 to 40 followed by a taper to day 96.
Receives: Radiation: iodine I 131 monoclonal antibody BC8; Drug: fludarabine phosphate; Radiation: total-body irradiation; Procedure: allogeneic hematopoietic stem cell transplantation; Procedure: peripheral blood stem cell transplantation; Drug: cyclosporine; Drug: mycophenolate mofetil; Other: laboratory biomarker analysis
Dose Level 10: 28 Gy iodine-131 monoclonal antibody BC8ExperimentalRADIOIMMUNOTHERAPY: Patients receive therapeutic iodine I 131 monoclonal antibody BC8 IV on day -12. CONDITIONING: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0. TRANSPLANTATION: After completion of TBI, patients undergo allogeneic PBSC transplant on day 0. IMMUNOSUPPRESSION: Patients with a matched related donor receive cyclosporine IV or PO BID on days -3 to 56 followed by a taper to day 180 in the absence of graft-versus-host disease. Beginning 4-6 hours after PBSC transplant, these patients also receive mycophenolate mofetil PO 2 BID on days 0 to 27. Patients with a matched unrelated donor receive cyclosporine IV or PO BID on days -3 to 100 followed by a taper to day 180. Beginning 4-6 hours after PBSC transplant, these patients also receive mycophenolate mofetil PO TID on days 0 to 40 followed by a taper to day 96.
Receives: Radiation: iodine I 131 monoclonal antibody BC8; Drug: fludarabine phosphate; Radiation: total-body irradiation; Procedure: allogeneic hematopoietic stem cell transplantation; Procedure: peripheral blood stem cell transplantation; Drug: cyclosporine; Drug: mycophenolate mofetil; Other: laboratory biomarker analysis

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Number of Participants With Dose-limiting Toxicities (DLT) 100 Days After Transplant

    The criteria of Grade III/IV regimen-related toxicity (Bearman) or dose-limiting toxicity (DLT) are as follows:

    Grade 1 Development of transient chemical abnormalities which are not of major clinical consequence and which reverse without requiring major medical interventions. In general, the intent of this toxicity scale is to observe transient target organ toxicity which is reversible.

    Grade 2 Development of chemical or laboratory abnormalities that are persistent and which may represent target organ damage that may not be readily reversed. It is anticipated that at this dose of the drug, the toxicity obtained would be manageable by clinical methods but may interfere with other therapies.

    Grade 3 Development of major clinical, chemical or laboratory abnormalities which represent maximum toxicities without being fatal. This grade of toxicity is designed to be the dose-limiting toxicity.

    Measured: Up to 100 days post-transplant

Secondary outcomes (5)

  1. Number of Participants With Transplant Related Mortality Within 100 Days After Transplant

    Number of participants that received and completed study treatment who died within 100 days after transplant

    Measured: Up to 100 days post-transplant

  2. Participant Disease Response Within 4 Weeks After Transplant

    The number of participants that are in complete remission (CR) or relapsed within 4 weeks after transplant.

    Complete Remission is defined as complete resolution of all signs of leukemia for at least four weeks with all of the following:

    • Normal bone marrow with blasts <5% with normal cellularity, normal megakarypoiesis, more than 15% erythropoiesis and more than 25% granulocytopoiesis.
    • Normalization of blood counts (no blasts, platelets >100,000/mm3, granulocytes >1,500/mm3).
    • No extramedullary disease.

    Relapse is measured as follows:

    • After CR: >5% blasts in the bone marrow and/or peripheral blood.
    • Confirmation of relapse by bone marrow analysis with more than 10% blasts.
    • Extramedullary disease confirmed cytologically or histologically.

    Measured: 4 weeks after transplant

  3. Severity of Acute GVHD in Patients Who Completed the Study Treatment

    The severity of acute GVHD is measured based on Graft-vs-Host Disease:

    Severity of GVHD Grade I +1 to +2 skin rash No gut or liver involvement

    Grade II +3 skin rash or

    • 1 gastrointestinal involvement and/or +1 liver involvement

    Grade III +2 to +4 gastrointestinal involvement and/or

    • 2 to +4 liver involvement with or without a rash

    Grade IV Pattern and severity of GVHD similar to grade 3 with extreme constitutional symptoms or death

    Measured: 100 days after transplant

  4. Number of Participants With 100% Donor Chimerism at Day 28 and Day 84

    Post-transplant bone marrow samples were collected on day 28 and day 84 after transplant for DNA Chimerism Analysis

    Measured: Day 28 and Day 80 after transplant

  5. Two-year Disease-free Survival of Study Participants Who Completed the Study Regimen

    Survival and complete resolution of all signs of leukemia for 2 years after transplant with all of the following:

    1. Normal bone marrow with blasts <5% with normal cellularity, normal megakarypoiesis, more than 15% erythropoiesis and more than 25% granulocytopoiesis.
    2. Normalization of blood counts (no blasts, platelets >100,000/mm3, granulocytes >1,500/mm3).
    3. No extramedullary disease.

    Measured: 2 years post transplant

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted13 Jul 2005 (estimated)
  2. Study startMay 2003
  3. Primary completionAug 2014
  4. Study completion8 May 2019

Why it stopped: Funding ended before target accrual was reached; participants are no longer being examined or receiving intervention.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Sequential
Model description
This study will assess the feasibility and safety of patients with advanced AML or high-risk MDS treated with Iodine-131 BC8 antibody at a starting dose of 22 Gy delivered to the normal organ receiving the highest dose combined with fludarabine and 2 Gy total body irradiation (TBI), plus cyclosporine (CSP)/mycophenolate mofetil (MMF), followed by matched related or unrelated allogeneic hematopoietic stem cell transplantation (HSCT). Determination of the maximum tolerated dose (MTD) will be the major study endpoint. Dose-escalation/de-escalation of radiolabeled BC8 antibody (I-131-BC8) is conducted using a "two-stage" approach. Under this plan, dose levels during the first stage are increased (or decreased) for individual patients until a dose-limiting toxicity (DLT) is observed, at which point the second stage proceeds with each dose level administered to a cohort of four patients.
Masking
None (open label)
Enrolment
18 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00119366
Sponsor's protocol ID
1809.00
Other IDs
NCI-2010-00234, 1809.00, P30CA015704
Status last verified
Dec 2022
First submitted
12 Jul 2005
Last updated
12 Dec 2022
Data monitoring committee
No

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