Atypical Chronic Myeloid Leukemia, BCR-ABL1 NegativePhase 2NCT00397813
Fludarabine Phosphate and Total Body Irradiation Followed by a Donor Peripheral Stem Cell Transplant in Treating Patients With Myelodysplastic Syndromes or Myeloproliferative Disorders
A Phase 2 study testing Cyclosporine, Fludarabine Phosphate and Laboratory Biomarker Analysis in people with Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative and Chronic Myelomonocytic Leukemia, run by Fred Hutchinson Cancer Center at 3 sites in United States.
Trial summary
This phase II trial studies the side effects and best dose of total-body irradiation when given together with fludarabine phosphate followed by a donor peripheral stem cell transplant in treating patients with myelodysplastic syndromes (MDS) or myeloproliferative disorders (MPD). Read more about this study
- Who is it for?
- Ages 50 to 75 years
- Conditions the study is for
- Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative, Chronic Myelomonocytic Leukemia, de Novo Myelodysplastic Syndrome
- What is being tested?
- Cyclosporine, Fludarabine Phosphate and Laboratory Biomarker Analysis
- Type of treatment
- Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 77 participants
- Where
- 3 sitesUnited States
- Study dates
- Jan 2006to Mar 2018
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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 50 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Patients aged >= 50 and < 75 years (yrs) with CMML, or previously untreated MDS or MPD
- Patients aged < 50 yrs at high risk for regimen related toxicity using standard high dose regimens; factors considered high risk include pre-existing conditions such as a chronic disease affecting kidneys, liver, lungs, or heart or previous failed HCT
- An human leukocyte antigen (HLA)-identical related or an HLA-matched unrelated donor (Fred Hutchinson Cancer Research Center [FHCRC] matching allowed will be Grade 1.0 to 2.1) is available
- Recovery from the effects of previous chemotherapy, with a minimum of 21 days from initiation of last therapy; hydroxyurea or anagrelide may be used to manage elevated cell counts in patients up to the time they begin therapy under this protocol
- Patients < 12 yrs of age must be discussed on a case by case basis with the primary investigator (PI) of the protocol prior to registration
- A signed informed consent form or minor assent form
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- MDS: MDS classifiable by the World Health Organization (WHO) system as RA, RARS, refractory cytopenia with multilineage dysplasia (RCMD), RCMD and ringed sideroblasts (RCMD-RS) or RAEB
- MDS: No previous myelosuppressive therapy; for the purpose of this protocol myelosuppressive chemotherapy will be defined as chemotherapy given with the intent of inducing a complete remission (e.g., standard 7+3, high dose intermittent ARA-C [HIDAC], or Mylotarg)
- MDS: Patients must have < 10% marrow blasts; fewer than 10% marrow blasts must be documented by marrow examination within 3 weeks of initiation of conditioning
- CMML: Patients with CMML1 who have not received myelosuppressive therapy must have < 10% marrow blasts; fewer than 10% marrow blasts must be documented by marrow examination within 3 weeks of initiation of conditioning; OR patients with CMML who have progressed beyond CMML1 and have received myelosuppressive chemotherapy must have < 5% marrow blasts; fewer than 5% marrow blasts must be documented by marrow examination within 3 weeks of initiation of conditioning
- MPD: Patients with polycythemia vera with persistent thrombotic or hemorrhagic complications despite conventional therapy, or who have progressed to postpolycythemic marrow fibrosis
- MPD: Patients with essential thrombocythemia with persistent thrombotic or hemorrhagic complications despite conventional therapy, or who have progressed to myelofibrosis
- MPD: Chronic idiopathic myelofibrosis with peripheral blood cytopenias
- MPD: Patients must have < 10% marrow blasts; fewer than 10% marrow blasts must be documented by marrow examination within 3 weeks of initiation of conditioning
- MPD: No previous myelosuppressive therapy; for the purpose of this protocol myelosuppressive chemotherapy will be defined as chemotherapy given with the intent of inducing a complete remission (e.g., standard 7+3, HIDAC, or Mylotarg)
- Atypical chronic myeloid leukemia (CML): Philadelphia chromosome-negative patients with a diagnosis of atypical CML
- Atypical CML: Patients must have < 10% marrow blasts; fewer than 10% marrow blasts must be documented by marrow examination within 3 weeks of initiation of conditioning
- Atypical CML: No previous myelosuppressive therapy; for the purpose of this protocol myelosuppressive chemotherapy will be defined as chemotherapy given with the intent of inducing a complete remission (e.g., standard 7+3, HIDAC, or Mylotarg)
- Paroxysmal nocturnal hemoglobinuria (PNH): Patients with the non-aplastic form of PNH (cellular bone marrow) who have had a history of life-threatening complications of their disease including thrombotic events, severe hemolysis or Budd Chiari syndrome are eligible; other patients may be considered following approval at PCC and approval by the Principal investigator
- Matched Related Donor: Related to the patient and is genotypically or phenotypically HLA-identical
- Matched Related Donor: Donor age < 75 yrs unless cleared by institutional PI
- Matched Related Donor: Capable of giving written, informed consent
- Matched Related Donor: Donor must consent to PBSC mobilization with G-CSF and apheresis
- Unrelated Donor: FHCRC matching allowed will be grades 1.0 to 2.1: Unrelated donors who are prospectively:
- Matched for HLA-A, B, C, DRB1 and DQB1 by high resolution typing;
- Only a single allele disparity will be allowed for HLA-A, B, or C as defined by high resolution typing
- Unrelated Donor: 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
- HLA Matched Related Donor: G-CSF mobilized peripheral blood mononuclear cell (PBMC) only will be permitted as a hematopoietic stem cell (HSC) source on this protocol
- HLA Matched Unrelated Donor: Donor must consent to PBSC mobilization with G-CSF and apheresis; bone marrow unrelated donors are not eligible for this protocol
Who cannot join
- Organ dysfunction as defined by the following:
- Symptomatic coronary artery disease or cardiac ejection fraction < 35% (or, if unable to obtain ejection fraction, shortening fraction of < 26%); if shortening fraction is < 26% a cardiology consult is required with the principal investigator (PI) having final approval of eligibility; ejection fraction is required if age > 50 years or there is a history of anthracycline exposure or history of cardiac disease
- Diffusing capacity of the lung for carbon monoxide (DLCO) < 35%, TLC < 35%, forced expiratory volume (FEV)1 < 35% and/or receiving supplementary continuous oxygen; the FHCRC PI of the study must approve of enrollment of all patients with pulmonary nodules
- Liver function abnormalities: Patient with clinical or laboratory evidence of liver disease will be evaluated for the cause of liver disease, its clinical severity in terms of liver function, bridging fibrosis, and the degree of portal hypertension; the patient will be excluded if he/she is found to have fulminant liver failure, cirrhosis of the liver with evidence of portal hypertension, alcoholic hepatitis, esophageal varices, a history of bleeding esophageal varices, hepatic encephalopathy, uncorrectable hepatic synthetic dysfunction evinced by prolongation of the prothrombin time, ascites related to portal hypertension, bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin > 3mg/dL, or symptomatic biliary disease
- Bone marrow documenting blast count >= 10% or >= 5% in CMML patients who have progressed beyond CMML1 and received myelosuppressive chemotherapy
- Patients with active non-hematologic malignancies (except non-melanoma skin cancers); this exclusion does not apply to patients with non-hematologic malignancies that do not require therapy
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- Patients with a history of non-hematologic malignancies (except non-melanoma skin cancers) currently in a complete remission, who are less than 5 years from the time of complete remission, and have a > 20% risk of disease recurrence
- Presence of >= 5% circulating leukemic blasts (in the peripheral blood) detected by standard pathology
- Active central nervous system (CNS) involvement of disease
- Karnofsky performance score < 70% or Lansky-Play Performance score < 70 for pediatric patients
- Life expectancy severely limited by diseases other than malignancy
- Fungal infections with radiological progression after receipt of amphotericin product or active triazole for > 1 month
- Active bacterial infection
- Patients of fertile age who refuse contraception for a twelve month period post-transplant
- Females who are pregnant or breastfeeding
- Human immunodeficiency virus (HIV) seropositivity
- Severe psychological illness such as major psychosis (e.g. schizophrenia), major bipolar depression, or suicidal situational depression
- Matched Related Donor: Identical twin
- Matched Related Donor: Any contra-indication to the administration of subcutaneous G-CSF at a dose of 16mg/kg/d for five consecutive days
- Matched Related Donor: Serious medical or psychological illness
- Matched Related Donor: Pregnant or lactating females
- Matched Related Donor: Prior malignancy within the preceding five yrs, with the exception of non-melanoma skin cancers
- Matched Related Donor: HIV seropositivity
- Unrelated Donor: A positive anti-donor cytotoxic crossmatch is an absolute donor exclusion; donors are excluded when preexisting immunoreactivity is identified that would jeopardize donor hematopoietic cell engraftment; this determination is based on the standard practice of the individual institution; the recommended procedure for patients with 10 of 10 HLA allele level (phenotypic) match is to obtain a 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
- Unrelated Donor: Marrow donors
- Unrelated Donor: Donors who are HIV-positive and/or medical conditions that would result in increased risk to the donor G-CSF mobilization and G-PBMC collections
- Unrelated Donor: Serious medical or psychological illness
- Unrelated Donor: Pregnant or lactating females
- Unrelated Donor: Prior malignancy within the preceding five yrs, with the exception of non-melanoma skin cancers
- Unrelated Donor: HIV seropositivity
Trial locations and contacts
3 sites in 1 country.
United States3 sites
LDS Hospital
Salt Lake City, Utah, 84143
Veterans Administration Center-Seattle
Seattle, Washington, 98108
Fred Hutch/University of Washington Cancer Consortium
Seattle, Washington, 98109
About this study
Official title: Low-Dose TBI Dose Escalation to Decrease Risks of Progression and Graft Rejection After Hematopoietic Cell Transplantation With Nonmyeloablative Conditioning as Treatment for Untreated Myelodysplastic Syndrome or Myeloproliferative Disorders - A Multi-Center Trial
This phase II trial studies the side effects and best dose of total-body irradiation when given together with fludarabine phosphate followed by a donor peripheral stem cell transplant in treating patients with myelodysplastic syndromes (MDS) or myeloproliferative disorders (MPD). Giving low doses of chemotherapy, such as fludarabine phosphate, and total-body irradiation before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells. Giving chemotherapy or radiation therapy before or after transplant also stops the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving cyclosporine and mycophenolate mofetil after the transplant may stop this from happening.
Read the detailed description
PRIMARY OBJECTIVES:
- Decrease the incidence of day-200 hematopoietic cell transplantation (HCT) failure to < 20% in patients with MDS-Refractory anemia (RA)-(ringed sideroblasts [RS])/MPD and in patients with chronic myelomonocytic leukemia (CMML)/refractory anemia with excess blasts (RAEB).
SECONDARY OBJECTIVES:
- The rate of relapse/progression in patients with MPD or MDS-RA and those with CMML or MDS-RAEB.
II. The probability of progression free survival (PFS) in patients with MPD or MDS-RA and those with CMML or MDS-RAEB.
III. The kinetics of donor engraftment.
IV. The incidence of infections.
OUTLINE: This is a dose-escalation study of total body irradiation (TBI).
NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate intravenously (IV) on days -4 to -2 and undergo TBI on day 0.
PERIPHERAL BLOOD STEM CELL (PBSC) TRANSPLANTATION: Patients undergo filgrastim (G-CSF)-mobilized PBSC infusion after TBI on day 0.
IMMUNOSUPPRESSION:
Matched Related Donor: Patients receive cyclosporine orally (PO) twice daily (BID) on days -3 to 56, followed by a taper until day 180. Patients also receive mycophenolate mofetil (MMF) PO BID beginning 4-6 hours after transplantation on day 0 and continue until day 27.
Unrelated Donor: Patients receive cyclosporine PO BID on days -3 to 100, followed by a taper until day 180. Patients also receive MMF PO three times daily beginning 4-6 hours after transplantation on day 0 and continue until day 40, followed by a taper until day 96.
After completion of study treatment, patients are followed periodically.
- Conditions
- Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative, Chronic Myelomonocytic Leukemia, de Novo Myelodysplastic Syndrome, Essential Thrombocythemia, Myeloproliferative Neoplasm, Paroxysmal Nocturnal Hemoglobinuria
- Being tested
- Cyclosporine, Fludarabine Phosphate, Laboratory Biomarker Analysis, Mycophenolate Mofetil, Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation
- Medical subject headings
- Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative, Leukemia, Myelomonocytic, Chronic, Thrombocythemia, Essential, Myeloproliferative Disorders, Hemoglobinuria, Paroxysmal, Polycythemia Vera, Primary Myelofibrosis, Anemia, Refractory
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
CyclosporineDrug
Also called 27-400, Ciclosporin, CsA, Cyclosporin
Given PO
Also called 2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara
Given IV
Laboratory Biomarker AnalysisOther
Correlative studies
Also called Cellcept, MMF
Given PO
Nonmyeloablative Allogeneic Hematopoietic Stem Cell TransplantationProcedure or surgery
Also called Non-myeloablative allogeneic transplant, Nonmyeloablative Stem Cell Transplantation, NST
Undergo transplantation
Peripheral Blood Stem Cell TransplantationProcedure or surgery
Also called PBPC transplantation, Peripheral Blood Progenitor Cell Transplantation, Peripheral Stem Cell Support, Peripheral Stem Cell Transplantation
Undergo PBSC transplant
Total-Body IrradiationRadiation
Also called TOTAL BODY IRRADIATION, Whole-Body Irradiation
Undergo TBI
| Study group | Role | What they receive |
|---|---|---|
| Arm A - Dose Level 1 | Experimental | Arm A - patients with MPD or MDS-RA/RARS Dose Level 1 - 300 cGy TBI
NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0.
PBSC TRANSPLANTATION: Patients undergo filgrastim-mobilized PBSC infusion after TBI on day 0.
IMMUNOSUPPRESSION:
Matched Related Donor: Patients receive cyclosporine PO BID on days -3 to 56, followed by a taper until day 180. Patients also receive MMF PO BID beginning 4-6 hours after transplantation on day 0 and continue until day 27.
Unrelated Donor: Patients receive cyclosporine PO BID on days -3 to 100, followed by a taper until day 180. Patients also receive MMF PO three times daily beginning 4-6 hours after transplantation on day 0 and continue until day 40, followed by a taper until day 96. Receives: Drug: Cyclosporine; Drug: Fludarabine Phosphate; Other: Laboratory Biomarker Analysis; Drug: Mycophenolate Mofetil; Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation; Procedure: Peripheral Blood Stem Cell Transplantation; Radiation: Total-Body Irradiation |
| Arm A - Dose Level 2 | Experimental | Arm A - patients with MPD or MDS-RA/RARS Dose Level 2 - 400 cGy TBI
NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0.
PBSC TRANSPLANTATION: Patients undergo filgrastim-mobilized PBSC infusion after TBI on day 0.
IMMUNOSUPPRESSION:
Matched Related Donor: Patients receive cyclosporine PO BID on days -3 to 56, followed by a taper until day 180. Patients also receive MMF PO BID beginning 4-6 hours after transplantation on day 0 and continue until day 27.
Unrelated Donor: Patients receive cyclosporine PO BID on days -3 to 100, followed by a taper until day 180. Patients also receive MMF PO three times daily beginning 4-6 hours after transplantation on day 0 and continue until day 40, followed by a taper until day 96. Receives: Drug: Cyclosporine; Drug: Fludarabine Phosphate; Other: Laboratory Biomarker Analysis; Drug: Mycophenolate Mofetil; Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation; Procedure: Peripheral Blood Stem Cell Transplantation; Radiation: Total-Body Irradiation |
| Arm A - Dose Level 3 | Experimental | Arm A - patients with MPD or MDS-RA/RARS Dose Level 3 - 450 cGy TBI
NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0.
PBSC TRANSPLANTATION: Patients undergo filgrastim-mobilized PBSC infusion after TBI on day 0.
IMMUNOSUPPRESSION:
Matched Related Donor: Patients receive cyclosporine PO BID on days -3 to 56, followed by a taper until day 180. Patients also receive MMF PO BID beginning 4-6 hours after transplantation on day 0 and continue until day 27.
Unrelated Donor: Patients receive cyclosporine PO BID on days -3 to 100, followed by a taper until day 180. Patients also receive MMF PO three times daily beginning 4-6 hours after transplantation on day 0 and continue until day 40, followed by a taper until day 96. Receives: Drug: Cyclosporine; Drug: Fludarabine Phosphate; Other: Laboratory Biomarker Analysis; Drug: Mycophenolate Mofetil; Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation; Procedure: Peripheral Blood Stem Cell Transplantation; Radiation: Total-Body Irradiation |
| Arm B - Dose Level 1 | Experimental | Arm B - patients with MDS-RAEB or CMML Dose Level 1 - 300 cGy TBI
NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0.
PBSC TRANSPLANTATION: Patients undergo filgrastim-mobilized PBSC infusion after TBI on day 0.
IMMUNOSUPPRESSION:
Matched Related Donor: Patients receive cyclosporine PO BID on days -3 to 56, followed by a taper until day 180. Patients also receive MMF PO BID beginning 4-6 hours after transplantation on day 0 and continue until day 27.
Unrelated Donor: Patients receive cyclosporine PO BID on days -3 to 100, followed by a taper until day 180. Patients also receive MMF PO three times daily beginning 4-6 hours after transplantation on day 0 and continue until day 40, followed by a taper until day 96. Receives: Drug: Cyclosporine; Drug: Fludarabine Phosphate; Other: Laboratory Biomarker Analysis; Drug: Mycophenolate Mofetil; Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation; Procedure: Peripheral Blood Stem Cell Transplantation; Radiation: Total-Body Irradiation |
| Arm B - Dose Level 2 | Experimental | Arm B - patients with MDS-RAEB or CMML Dose Level 2 - 400 cGy TBI
NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0.
PBSC TRANSPLANTATION: Patients undergo filgrastim-mobilized PBSC infusion after TBI on day 0.
IMMUNOSUPPRESSION:
Matched Related Donor: Patients receive cyclosporine PO BID on days -3 to 56, followed by a taper until day 180. Patients also receive MMF PO BID beginning 4-6 hours after transplantation on day 0 and continue until day 27.
Unrelated Donor: Patients receive cyclosporine PO BID on days -3 to 100, followed by a taper until day 180. Patients also receive MMF PO three times daily beginning 4-6 hours after transplantation on day 0 and continue until day 40, followed by a taper until day 96. Receives: Drug: Cyclosporine; Drug: Fludarabine Phosphate; Other: Laboratory Biomarker Analysis; Drug: Mycophenolate Mofetil; Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation; Procedure: Peripheral Blood Stem Cell Transplantation; Radiation: Total-Body Irradiation |
| Arm B - Dose Level 3 | Experimental | Arm B - patients with MDS-RAEB or CMML Dose Level 3 - 450 cGy TBI
NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0.
PBSC TRANSPLANTATION: Patients undergo filgrastim-mobilized PBSC infusion after TBI on day 0.
IMMUNOSUPPRESSION:
Matched Related Donor: Patients receive cyclosporine PO BID on days -3 to 56, followed by a taper until day 180. Patients also receive MMF PO BID beginning 4-6 hours after transplantation on day 0 and continue until day 27.
Unrelated Donor: Patients receive cyclosporine PO BID on days -3 to 100, followed by a taper until day 180. Patients also receive MMF PO three times daily beginning 4-6 hours after transplantation on day 0 and continue until day 40, followed by a taper until day 96. Receives: Drug: Cyclosporine; Drug: Fludarabine Phosphate; Other: Laboratory Biomarker Analysis; Drug: Mycophenolate Mofetil; Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation; Procedure: Peripheral Blood Stem Cell Transplantation; Radiation: Total-Body Irradiation |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Patients With HCT Failure.
HCT failure will be defined as graft rejection (defined as < 5% donor T-cell chimerism) or disease progression within 200 days of transplant.
Measured: 200 days
Secondary outcomes (4)
Number of Patients Who Had Infections
Number of patients who experienced bacterial, fungal, or viral infections.
Measured: 1 year
Number of Patients Who Engrafted
Continued engraftment will be defined as the detection of donor T-cells (CD3+) as a proportion of the total T-cell of greater than 5%.
Measured: 1 year
Number of Patients With Progression-free Survival
Evidence of disease progression will be an indication for therapeutic intervention. Defined as any evidence by morphologic or flow cytometric evaluation of the bone marrow aspirate of an incremental increase in 5% blasts in MDS/CMML; defined as any evidence of blastic transformation in agnogenic myeloid metaplasia/atypical CML; and defined as progressive erythrocytosis, thrombocytosis, or evidence of leukemic transformation in polycythemia vera and essential thrombocythemia.
Measured: 1 year
Number of Patients With Relapse/Progression
Evidence of disease progression will be an indication for therapeutic intervention. Defined as any evidence by morphologic or flow cytometric evaluation of the bone marrow aspirate of an incremental increase in 5% blasts in MDS/CMML; defined as any evidence of blastic transformation in agnogenic myeloid metaplasia/atypical CML; and defined as progressive erythrocytosis, thrombocytosis, or evidence of leukemic transformation in polycythemia vera and essential thrombocythemia.
Measured: 1 year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Nov 2006 (estimated)
- Study startJan 2006
- Primary completionSep 2017
- Study completionMar 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Atypical Chronic Myeloid Leukemia, BCR-ABL1 NegativeStudies of the same condition, open and under way.
- More trials run by Fred Hutchinson Cancer CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
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
- Single group
- Masking
- None (open label)
- Enrolment
- 77 participants (actual)
Sponsor and investigators
- Lead sponsor
- Fred Hutchinson Cancer Center
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Brenda Sandmaier, Fred Hutchinson Cancer Center
- Investigators
- Brenda Sandmaier, Principal investigator, Fred Hutch/University of Washington Cancer Consortium
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00397813
- Sponsor's protocol ID
- 2056.00
- Other IDs
- NCI-2010-00237, 2056.00, P01CA018029, P30CA015704
- Status last verified
- Jan 2020
- First submitted
- 9 Nov 2006
- Last updated
- 31 Jan 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
Cooper JP, Storer BE, Granot N, Gyurkocza B, Sorror ML, Chauncey TR, Shizuru J, Franke GN, Maris MB, Boyer M, Bruno B, Sahebi F, Langston AA, Hari P, Agura ED, Lykke Petersen S, Maziarz RT, Bethge W, Asch J, Gutman JA, Olesen G, Yeager AM, Hubel K, Hogan WJ, Maloney DG, Mielcarek M, Martin PJ, Flowers MED, Georges GE, Woolfrey AE, Deeg JH, Scott BL, McDonald GB, Storb R, Sandmaier BM. Allogeneic hematopoietic cell transplantation with non-myeloablative conditioning for patients with hematologic malignancies: Improved outcomes over two decades. Haematologica. 2021 Jun 1;106(6):1599-1607. doi: 10.3324/haematol.2020.248187.
PubMed 32499241Monaco F, Scott BL, Chauncey TR, Petersen FB, Storer BE, Baron F, Flowers ME, Deeg HJ, Maloney DG, Storb R, Sandmaier BM. Total body irradiation dose escalation decreases risk of progression and graft rejection after hematopoietic cell transplantation for myelodysplastic syndromes or myeloproliferative neoplasms. Haematologica. 2019 Jun;104(6):1221-1229. doi: 10.3324/haematol.2018.199398. Epub 2019 Jan 10.
PubMed 30630975
Study at a glance
From the registry record, last updated by the sponsor on 31 Jan 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Low-Dose TBI Dose Escalation to Decrease Risks of Progression and Graft Rejection After Hematopoietic Cell Transplantation With Nonmyeloablative Conditioning as Treatment for Untreated Myelodysplastic Syndrome or Myeloproliferative Disorders - A Multi-Center Trial
- ClinicalTrials.gov ID
- NCT00397813
- Acronym / sponsor ID
- 2056.00
- Conditions
- Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative, Chronic Myelomonocytic Leukemia, de Novo Myelodysplastic Syndrome, Essential Thrombocythemia, Myeloproliferative Neoplasm, Paroxysmal Nocturnal Hemoglobinuria
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 77 participants (actual)
- Lead sponsor
- Fred Hutchinson Cancer CenterUniversity, hospital or other
- Collaborators
- National Cancer Institute (NCI), National Heart, Lung, and Blood Institute (NHLBI)
- Study start
- Jan 2006 (actual)
- Primary completion
- Sep 2017 (actual)
- Study completion
- Mar 2018 (actual)
- First posted
- 10 Nov 2006 (estimated)
- Results
- Posted 24 Oct 2018
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This phase II trial studies the side effects and best dose of total-body irradiation when given together with fludarabine phosphate followed by a donor peripheral stem cell transplant in treating patients with myelodysplastic syndromes (MDS) or myeloproliferative disorders (MPD). Giving low doses of chemotherapy, such as fludarabine phosphate, and total-body irradiation before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells. Giving chemotherapy or radiation therapy before or after transplant also stops the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving cyclosporine and mycophenolate mofetil after the transplant may stop this from happening.
Detailed description
PRIMARY OBJECTIVES:
- Decrease the incidence of day-200 hematopoietic cell transplantation (HCT) failure to < 20% in patients with MDS-Refractory anemia (RA)-(ringed sideroblasts [RS])/MPD and in patients with chronic myelomonocytic leukemia (CMML)/refractory anemia with excess blasts (RAEB).
SECONDARY OBJECTIVES:
- The rate of relapse/progression in patients with MPD or MDS-RA and those with CMML or MDS-RAEB.
II. The probability of progression free survival (PFS) in patients with MPD or MDS-RA and those with CMML or MDS-RAEB.
III. The kinetics of donor engraftment.
IV. The incidence of infections.
OUTLINE: This is a dose-escalation study of total body irradiation (TBI).
NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate intravenously (IV) on days -4 to -2 and undergo TBI on day 0.
PERIPHERAL BLOOD STEM CELL (PBSC) TRANSPLANTATION: Patients undergo filgrastim (G-CSF)-mobilized PBSC infusion after TBI on day 0.
IMMUNOSUPPRESSION:
Matched Related Donor: Patients receive cyclosporine orally (PO) twice daily (BID) on days -3 to 56, followed by a taper until day 180. Patients also receive mycophenolate mofetil (MMF) PO BID beginning 4-6 hours after transplantation on day 0 and continue until day 27.
Unrelated Donor: Patients receive cyclosporine PO BID on days -3 to 100, followed by a taper until day 180. Patients also receive MMF PO three times daily beginning 4-6 hours after transplantation on day 0 and continue until day 40, followed by a taper until day 96.
After completion of study treatment, patients are followed periodically.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 6
| Arm | Type | Receives |
|---|---|---|
| Arm A - Dose Level 1 | Experimental | Drug: Cyclosporine, Drug: Fludarabine Phosphate, Other: Laboratory Biomarker Analysis, Drug: Mycophenolate Mofetil, Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation, Procedure: Peripheral Blood Stem Cell Transplantation, Radiation: Total-Body IrradiationArm A - patients with MPD or MDS-RA/RARS Dose Level 1 - 300 cGy TBI NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0. PBSC TRANSPLANTATION: Patients undergo filgrastim-mobilized PBSC infusion after TBI on day 0. IMMUNOSUPPRESSION: Matched Related Donor: Patients receive cyclosporine PO BID on days -3 to 56, followed by a taper until day 180. Patients also receive MMF PO BID beginning 4-6 hours after transplantation on day 0 and continue until day 27. Unrelated Donor: Patients receive cyclosporine PO BID on days -3 to 100, followed by a taper until day 180. Patients also receive MMF PO three times daily beginning 4-6 hours after transplantation on day 0 and continue until day 40, followed by a taper until day 96. |
| Arm A - Dose Level 2 | Experimental | Drug: Cyclosporine, Drug: Fludarabine Phosphate, Other: Laboratory Biomarker Analysis, Drug: Mycophenolate Mofetil, Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation, Procedure: Peripheral Blood Stem Cell Transplantation, Radiation: Total-Body IrradiationArm A - patients with MPD or MDS-RA/RARS Dose Level 2 - 400 cGy TBI NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0. PBSC TRANSPLANTATION: Patients undergo filgrastim-mobilized PBSC infusion after TBI on day 0. IMMUNOSUPPRESSION: Matched Related Donor: Patients receive cyclosporine PO BID on days -3 to 56, followed by a taper until day 180. Patients also receive MMF PO BID beginning 4-6 hours after transplantation on day 0 and continue until day 27. Unrelated Donor: Patients receive cyclosporine PO BID on days -3 to 100, followed by a taper until day 180. Patients also receive MMF PO three times daily beginning 4-6 hours after transplantation on day 0 and continue until day 40, followed by a taper until day 96. |
| Arm A - Dose Level 3 | Experimental | Drug: Cyclosporine, Drug: Fludarabine Phosphate, Other: Laboratory Biomarker Analysis, Drug: Mycophenolate Mofetil, Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation, Procedure: Peripheral Blood Stem Cell Transplantation, Radiation: Total-Body IrradiationArm A - patients with MPD or MDS-RA/RARS Dose Level 3 - 450 cGy TBI NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0. PBSC TRANSPLANTATION: Patients undergo filgrastim-mobilized PBSC infusion after TBI on day 0. IMMUNOSUPPRESSION: Matched Related Donor: Patients receive cyclosporine PO BID on days -3 to 56, followed by a taper until day 180. Patients also receive MMF PO BID beginning 4-6 hours after transplantation on day 0 and continue until day 27. Unrelated Donor: Patients receive cyclosporine PO BID on days -3 to 100, followed by a taper until day 180. Patients also receive MMF PO three times daily beginning 4-6 hours after transplantation on day 0 and continue until day 40, followed by a taper until day 96. |
| Arm B - Dose Level 1 | Experimental | Drug: Cyclosporine, Drug: Fludarabine Phosphate, Other: Laboratory Biomarker Analysis, Drug: Mycophenolate Mofetil, Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation, Procedure: Peripheral Blood Stem Cell Transplantation, Radiation: Total-Body IrradiationArm B - patients with MDS-RAEB or CMML Dose Level 1 - 300 cGy TBI NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0. PBSC TRANSPLANTATION: Patients undergo filgrastim-mobilized PBSC infusion after TBI on day 0. IMMUNOSUPPRESSION: Matched Related Donor: Patients receive cyclosporine PO BID on days -3 to 56, followed by a taper until day 180. Patients also receive MMF PO BID beginning 4-6 hours after transplantation on day 0 and continue until day 27. Unrelated Donor: Patients receive cyclosporine PO BID on days -3 to 100, followed by a taper until day 180. Patients also receive MMF PO three times daily beginning 4-6 hours after transplantation on day 0 and continue until day 40, followed by a taper until day 96. |
| Arm B - Dose Level 2 | Experimental | Drug: Cyclosporine, Drug: Fludarabine Phosphate, Other: Laboratory Biomarker Analysis, Drug: Mycophenolate Mofetil, Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation, Procedure: Peripheral Blood Stem Cell Transplantation, Radiation: Total-Body IrradiationArm B - patients with MDS-RAEB or CMML Dose Level 2 - 400 cGy TBI NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0. PBSC TRANSPLANTATION: Patients undergo filgrastim-mobilized PBSC infusion after TBI on day 0. IMMUNOSUPPRESSION: Matched Related Donor: Patients receive cyclosporine PO BID on days -3 to 56, followed by a taper until day 180. Patients also receive MMF PO BID beginning 4-6 hours after transplantation on day 0 and continue until day 27. Unrelated Donor: Patients receive cyclosporine PO BID on days -3 to 100, followed by a taper until day 180. Patients also receive MMF PO three times daily beginning 4-6 hours after transplantation on day 0 and continue until day 40, followed by a taper until day 96. |
| Arm B - Dose Level 3 | Experimental | Drug: Cyclosporine, Drug: Fludarabine Phosphate, Other: Laboratory Biomarker Analysis, Drug: Mycophenolate Mofetil, Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation, Procedure: Peripheral Blood Stem Cell Transplantation, Radiation: Total-Body IrradiationArm B - patients with MDS-RAEB or CMML Dose Level 3 - 450 cGy TBI NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo TBI on day 0. PBSC TRANSPLANTATION: Patients undergo filgrastim-mobilized PBSC infusion after TBI on day 0. IMMUNOSUPPRESSION: Matched Related Donor: Patients receive cyclosporine PO BID on days -3 to 56, followed by a taper until day 180. Patients also receive MMF PO BID beginning 4-6 hours after transplantation on day 0 and continue until day 27. Unrelated Donor: Patients receive cyclosporine PO BID on days -3 to 100, followed by a taper until day 180. Patients also receive MMF PO three times daily beginning 4-6 hours after transplantation on day 0 and continue until day 40, followed by a taper until day 96. |
Who may qualify
- Ages
- 50 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (29 listed)
- Patients aged >= 50 and < 75 years (yrs) with CMML, or previously untreated MDS or MPD
- Patients aged < 50 yrs at high risk for regimen related toxicity using standard high dose regimens; factors considered high risk include pre-existing conditions such as a chronic disease affecting kidneys, liver, lungs, or heart or previous failed HCT
- An human leukocyte antigen (HLA)-identical related or an HLA-matched unrelated donor (Fred Hutchinson Cancer Research Center [FHCRC] matching allowed will be Grade 1.0 to 2.1) is available
- Recovery from the effects of previous chemotherapy, with a minimum of 21 days from initiation of last therapy; hydroxyurea or anagrelide may be used to manage elevated cell counts in patients up to the time they begin therapy under this protocol
- Patients < 12 yrs of age must be discussed on a case by case basis with the primary investigator (PI) of the protocol prior to registration
Key exclusion criteria (30 listed)
- Organ dysfunction as defined by the following:
- Bone marrow documenting blast count >= 10% or >= 5% in CMML patients who have progressed beyond CMML1 and received myelosuppressive chemotherapy
- Patients with active non-hematologic malignancies (except non-melanoma skin cancers); this exclusion does not apply to patients with non-hematologic malignancies that do not require therapy
- Patients with a history of non-hematologic malignancies (except non-melanoma skin cancers) currently in a complete remission, who are less than 5 years from the time of complete remission, and have a > 20% risk of disease recurrence
- Presence of >= 5% circulating leukemic blasts (in the peripheral blood) detected by standard pathology
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| CyclosporineAlso: 27-400, Ciclosporin, CsA, CyclosporinGiven PO | Drug | Arm A - Dose Level 1, Arm A - Dose Level 2, Arm A - Dose Level 3, Arm B - Dose Level 1, Arm B - Dose Level 2, Arm B - Dose Level 3 |
| Fludarabine PhosphateAlso: 2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, FludaraGiven IV | Drug | Arm A - Dose Level 1, Arm A - Dose Level 2, Arm A - Dose Level 3, Arm B - Dose Level 1, Arm B - Dose Level 2, Arm B - Dose Level 3 |
| Laboratory Biomarker AnalysisCorrelative studies | Other | Arm A - Dose Level 1, Arm A - Dose Level 2, Arm A - Dose Level 3, Arm B - Dose Level 1, Arm B - Dose Level 2, Arm B - Dose Level 3 |
| Mycophenolate MofetilAlso: Cellcept, MMFGiven PO | Drug | Arm A - Dose Level 1, Arm A - Dose Level 2, Arm A - Dose Level 3, Arm B - Dose Level 1, Arm B - Dose Level 2, Arm B - Dose Level 3 |
| Nonmyeloablative Allogeneic Hematopoietic Stem Cell TransplantationAlso: Non-myeloablative allogeneic transplant, Nonmyeloablative Stem Cell Transplantation, NSTUndergo transplantation | Procedure or surgery | Arm A - Dose Level 1, Arm A - Dose Level 2, Arm A - Dose Level 3, Arm B - Dose Level 1, Arm B - Dose Level 2, Arm B - Dose Level 3 |
| Peripheral Blood Stem Cell TransplantationAlso: PBPC transplantation, Peripheral Blood Progenitor Cell Transplantation, Peripheral Stem Cell Support, Peripheral Stem Cell TransplantationUndergo PBSC transplant | Procedure or surgery | Arm A - Dose Level 1, Arm A - Dose Level 2, Arm A - Dose Level 3, Arm B - Dose Level 1, Arm B - Dose Level 2, Arm B - Dose Level 3 |
| Total-Body IrradiationAlso: TOTAL BODY IRRADIATION, Whole-Body IrradiationUndergo TBI | Radiation | Arm A - Dose Level 1, Arm A - Dose Level 2, Arm A - Dose Level 3, Arm B - Dose Level 1, Arm B - Dose Level 2, Arm B - Dose Level 3 |
Primary outcome
Number of Patients With HCT Failure.
Time frame: 200 days
HCT failure will be defined as graft rejection (defined as < 5% donor T-cell chimerism) or disease progression within 200 days of transplant.
4 secondary outcomes
Number of Patients Who Had Infections
Time frame: 1 year
Number of Patients Who Engrafted
Time frame: 1 year
Number of Patients With Progression-free Survival
Time frame: 1 year
Number of Patients With Relapse/Progression
Time frame: 1 year
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 31 Jan 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 32499241Cooper JP, Storer BE, Granot N, Gyurkocza B, Sorror ML, Chauncey TR, Shizuru J, Franke GN, Maris MB, Boyer M, Bruno B, Sahebi F, Langston AA, Hari P, Agura ED, Lykke Petersen S, Maziarz RT, Bethge W, Asch J, Gutman JA, Olesen G, Yeager AM, Hubel K, Hogan WJ, Maloney DG, Mielcarek M, Martin PJ, Flowers MED, Georges GE, Woolfrey AE, Deeg JH, Scott BL, McDonald GB, Storb R, Sandmaier BM. Allogeneic hematopoietic cell transplantation with non-myeloablative conditioning for patients with hematologic malignancies: Improved outcomes over two decades. Haematologica. 2021 Jun 1;106(6):1599-1607. doi: 10.3324/haematol.2020.248187.
- Derived from this study: PubMed 30630975Monaco F, Scott BL, Chauncey TR, Petersen FB, Storer BE, Baron F, Flowers ME, Deeg HJ, Maloney DG, Storb R, Sandmaier BM. Total body irradiation dose escalation decreases risk of progression and graft rejection after hematopoietic cell transplantation for myelodysplastic syndromes or myeloproliferative neoplasms. Haematologica. 2019 Jun;104(6):1221-1229. doi: 10.3324/haematol.2018.199398. Epub 2019 Jan 10.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Brenda Sandmaier principal investigator
Fred Hutch/University of Washington Cancer Consortium
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Cyclosporine, Fludarabine Phosphate and Laboratory Biomarker Analysis in people with Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative and Chronic Myelomonocytic Leukemia, run by Fred Hutchinson Cancer Center at 3 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 29 inclusion and 30 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 31 Jan 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 24 Oct 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Patients With HCT Failure. (time frame: 200 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00397813, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 31 Jan 2020.