Accelerated Phase Chronic Myelogenous LeukemiaPhase 1/2NCT00078858
Mycophenolate Mofetil and Cyclosporine in Reducing Graft-Versus-Host Disease in Patients With Hematologic Malignancies or Metastatic Kidney Cancer Undergoing Donor Stem Cell Transplant
A Phase 1/2 study testing fludarabine phosphate, total-body irradiation and nonmyeloablative allogeneic hematopoietic stem cell transplantation in people with Accelerated Phase Chronic Myelogenous Leukemia and Adult Acute Lymphoblastic Leukemia in Remission, run by Fred Hutchinson Cancer Center at 10 sites in 3 countries.
Trial summary
This phase I/II trial studies whether stopping cyclosporine before mycophenolate mofetil is better at reducing the risk of life-threatening graft-versus-host disease (GVHD) than the previous approach where mycophenolate mofetil was stopped before cyclosporine. Read more about this study
- Who is it for?
- Any age
- Conditions the study is for
- Accelerated Phase Chronic Myelogenous Leukemia, Adult Acute Lymphoblastic Leukemia in Remission, Adult Acute Myeloid Leukemia in Remission
- What is being tested?
- fludarabine phosphate, total-body irradiation and nonmyeloablative allogeneic hematopoietic stem cell transplantation
- Type of treatment
- Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 37 participants
- Where
- 10 sitesin 3 countries
- Study dates
- Sep 2003to Jan 2006
- Phase
- Phase 1/2
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 Any age
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- Ages > 50 years with hematologic malignancies treatable by unrelated HCT
- Ages =< 50 years of age with hematologic diseases treatable by allogeneic HCT who through pre-existing medical conditions or prior therapy are considered to be at high risk for regimen related toxicity associated with a conventional transplant (> 40% risk of transplant-related mortality [TRM]) or those patients who refuse a conventional HCT; transplants must be approved for these inclusion criteria by both the participating institution's patient review committee such as the Patient Care Conference (PCC at the Fred Hutchinson Cancer Research Center [FHCRC]) and by the principal investigator at the collaborating center; patients =< 50 years of age who have received previous high-dose transplantation do not require patient review committee approval; all children < 12 years must be discussed with the FHCRC primary investigator (PI) prior to registration
- Patients with metastatic renal cell carcinoma with the histologic subtypes of clear cell, papillary and medullary may be accepted regardless of age
- The following diseases will be permitted although other diagnoses can be considered if approved by PCC or the participating institution's patient review committees and the principal investigator:
- Aggressive non-Hodgkin lymphomas (NHLs) and other histologies such as diffuse large B cell NHL-not eligible for autologous hematopoietic stem cell transplant (HSCT), not eligible for conventional myeloablative HSCT, or after failed autologous HSCT
- Low grade NHL- with < 6 month duration of complete remission (CR) between courses of conventional therapy
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- Mantle cell NHL-may be treated in first CR
- Chronic lymphocytic leukemia (CLL)- Must be refractory to fludarabine; patients who fail to have a complete or partial response after therapy with a regimen containing fludarabine (or another nucleoside analog, e.g. 2-cladribine [CDA], pentostatin) or experience disease relapse within 12 months after completing therapy with a regimen containing fludarabine (or another nucleoside analog)
- Hodgkin disease (HD)- must have received and failed frontline therapy
- Multiple myeloma (MM)- must have received prior chemotherapy; consolidation of chemotherapy by autografting prior to nonmyeloablative HCT is permitted
- Acute myeloid leukemia (AML)- must have < 5% marrow blasts at the time of transplant.
- Acute lymphocytic leukemia (ALL)- must have < 5% marrow blasts at the time of transplant
- Chronic myelogenous leukemia (CML)- Patients will be accepted in chronic phase or accelerated phase; patients who have received prior autografts after high dose therapy or have undergone intensive chemotherapy with filgrastim (G-CSF)-mobilized peripheral blood mononuclear cells (G-PBMC) autologous or conventional HCT for advanced CML may be enrolled provided they are in CR or CP and have < 5% marrow blasts at time of transplant
- Myelodysplastic syndrome (MDS)/myeloproliferative disorder (MPD)- Only patients with MDS/refractory anemia (RA) or MDS/refractory anemia with ringed sideroblasts (RARS) will be eligible for this protocol; additionally patients with myeloproliferative syndromes (MPS) will be eligible; those patients with MDS or MPS with > 5% marrow blasts (including those with transformation to AML) must receive cytotoxic chemotherapy and achieve < 5% marrow blasts at time of transplant
- Renal cell carcinoma- Must have evidence of disease not amenable to surgical cure or history of or active metastatic disease by radiological and histologic criteria
- DONOR: FHCRC matching allowed will be grade 1.0 to 2.1: Unrelated donors who are prospectively:
- Matched for human leukocyte antigen (HLA)-A, B, C, major histocompatibility complex, class II, DR beta 1 (DRB1) and major histocompatibility complex, class II, DQ beta 1 (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
- DONOR: A positive anti-donor cytotoxic crossmatch is an absolute donor exclusion
- 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*0201, and this type of mismatch is not allowed
- DONOR: G-PBMC only will be permitted as a HSC source on this protocol
Who cannot join
- Patients with rapidly progressive intermediate or high grade NHL
- Renal cell carcinoma patients
- With expected survival of less than 6 months
- Disease resulting in severely limited performance status (< 70%)
- Any vertebral instability
- History of brain metastases
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- Central nervous system (CNS) involvement with disease refractory to intrathecal chemotherapy
- Fertile men or women unwilling to use contraceptive techniques during and for 12 months following treatment
- Females who are pregnant
- Patients with non-hematological tumors except renal cell carcinoma
- Fungal infections with radiological progression after receipt of amphotericin B or active triazole for greater than 1 month
- Cardiac ejection fraction < 35%; ejection fraction is required if there is a history of anthracycline exposure or history of cardiac disease
- Diffusing capacity of the lung for carbon monoxide (DLCO) < 40% and/or receiving supplementary continuous oxygen
- The FHCRC PI of the study must approve of enrollment of all patients with pulmonary nodules
- Patients with clinical or laboratory evidence of liver disease would be evaluated for the cause of liver disease, its clinical severity in terms of liver function, and the degree of portal hypertension; patients will be excluded if they are 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, bridging fibrosis, bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin > 3 mg/dL, and symptomatic biliary disease
- Karnofsky scores < 60 (except renal cell carcinoma [RCC])
- Patients with > grade II hypertension by Common Toxicity Criteria (CTC)
- Human immunodeficiency virus (HIV) positive patients
- The addition of cytotoxic agents for "cytoreduction" with the exception of hydroxyurea and imatinib mesylate will not be allowed within two weeks of the initiation of conditioning
- DONOR: Marrow donors
- DONOR: Donors who are HIV-positive and/or, medical conditions that would result in increased risk for G-CSF mobilization and harvest of G-PBMC
Trial locations and contacts
10 sites in 3 countries.
10 sites in 3 countries
United States7 sites
Emory University/Winship Cancer Institute
Atlanta, Georgia, 30322
Rocky Mountain Cancer Centers-Midtown
Denver, Colorado, 80218
Froedtert Memorial Lutheran Hospital, Medical College of Wisconsin
Milwaukee, Wisconsin, 53226
OHSU Knight Cancer Institute
Portland, Oregon, 97239
Huntsman Cancer Institute/University of Utah
Salt Lake City, Utah, 84112
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
Seattle, Washington, 98109
Stanford University Hospitals and Clinics
Stanford, California, 94305
Germany2 sites
Universitaet Leipzig
Leipzig, D-04103
University of Tuebingen-Germany
Tübingen, D-72076
About this study
Official title: Prolonged Mycophenolate Mofetil and Truncated Cyclosporine Postgrafting Immunosuppression to Reduce Life-Threatening GVHD After Unrelated Donor Peripheral Blood Cell Transplantation Using Nonmyeloablative Conditioning for Patients With Hematologic Malignancies and Renal Cell Carcinoma - A Multi-Center Trial
This phase I/II trial studies whether stopping cyclosporine before mycophenolate mofetil is better at reducing the risk of life-threatening graft-versus-host disease (GVHD) than the previous approach where mycophenolate mofetil was stopped before cyclosporine. The other reason this study is being done because at the present time there are no curative therapies known outside of stem cell transplantation for these types of cancer. Because of age or underlying health status, patients may have a higher likelihood of experiencing harm from a conventional blood stem cell transplant. This study tests whether this new blood stem cell transplant method can be made safer by changing the order and length of time that immune suppressing drugs are given after transplant.
Read the detailed description
PRIMARY OBJECTIVES:
- To determine whether the incidence of life-threatening GVHD can be reduced after unrelated donor peripheral blood mononuclear cell (PBMC) hematopoietic cell transplantation (HCT) using nonmyeloablative conditioning with earlier discontinuation of cyclosporine (CSP) and extended administration of mycophenolate mofetil (MMF) in patients with hematologic malignancies and metastatic renal cell carcinoma.
SECONDARY OBJECTIVES:
- To compare the incidence of acute and chronic GVHD to protocols 1463 and 1641.
II. To compare the utilization of corticosteroids to protocols 1463 and 1641.
III. To compare survival to that achieved under protocol 1463 and 1641.
OUTLINE:
CONDITIONING: Patients receive fludarabine phosphate intravenously (IV) over 30 minutes on days -4 to -2, and undergo total-body irradiation (TBI) on day 0.
TRANSPLANTATION: Patients undergo allogeneic PBMC transplant on day 0.
IMMUNOSUPPRESSION: Patients receive cyclosporine orally (PO) twice daily (BID) on days -3 to 80 with taper to day 150 and mycophenolate mofetil PO or IV thrice daily (TID) on days 0-30, BID on days 31-150, and then taper to day 180. Treatment continues in the absence of unacceptable toxicity.
After completion of study treatment, patients are followed up periodically for 24 months and then yearly for 5 years.
- Conditions
- Accelerated Phase Chronic Myelogenous Leukemia, Adult Acute Lymphoblastic Leukemia in Remission, Adult Acute Myeloid Leukemia in Remission, Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Del(5q), Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
- Being tested
- fludarabine phosphate, total-body irradiation, nonmyeloablative allogeneic hematopoietic stem cell transplantation, peripheral blood stem cell transplantation, cyclosporine
- Medical subject headings
- Leukemia, Myeloid, Accelerated Phase, Congenital Abnormalities, Lymphoma, Extranodal NK-T-Cell, Lymphoma, Large-Cell, Anaplastic, Immunoblastic Lymphadenopathy, Burkitt Lymphoma, Lymphoma, Large B-Cell, Diffuse, Leukemia, Myelomonocytic, Chronic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Also called 2-F-ara-AMP, Beneflur, Fludara
Given IV
total-body irradiationRadiation
Also called TBI
Undergo TBI
nonmyeloablative allogeneic hematopoietic stem cell transplantationProcedure or surgery
Undergo allogeneic PBMC 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 allogeneic PBMC transplantation
cyclosporineDrug
Also called ciclosporin, cyclosporin, cyclosporin A, CYSP
Given PO
Also called Cellcept, MMF
Given PO or IV
laboratory biomarker analysisOther
Correlative studies
| Study group | Role | What they receive |
|---|---|---|
| Treatment (prolonged MMF and truncated CSP) | Experimental | CONDITIONING: Patients receive fludarabine phosphate IV over 30 minutes on days -4 to -2, and undergo TBI on day 0.
TRANSPLANTATION: Patients undergo allogeneic PBMC transplant on day 0.
IMMUNOSUPPRESSION: Patients receive cyclosporine PO BID on days -3 to 80 with taper to day 150 and mycophenolate mofetil PO or IV TID on days 0-30, BID on days 31-150, and then taper to day 180. Treatment continues in the absence of unacceptable toxicity. Receives: Drug: fludarabine phosphate; Radiation: total-body irradiation; Procedure: nonmyeloablative 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.
Incidence of life-threatening GVHD in patients undergoing a modified taper of post-grafting immunosuppression after undergoing nonmyeloablative HSCT from matched unrelated donors
Life-threatening GVHD defined as (1) death related to GVHD or its treatment, (2) disability caused by GVHD or its treatment (3) 3 or more major infections in a calendar year or (4) suicidal ideation because of GVHD.
Measured: 1 year
Secondary outcomes (4)
Need for corticosteroid treatment, defined as more than 1 mg/kg or equivalent of prednisone for more than 3 days at any time after transplant
Measured: 1 year
Graft rejection
Measured: Up to day 365
Incidence of acute and chronic GVHD
Measured: Up to 7 years
Overall survival
Measured: Up to 7 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Mar 2004 (estimated)
- Study startSep 2003
- Primary completionJan 2006
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Accelerated Phase Chronic Myelogenous LeukemiaStudies of the same condition, open and under way.
- 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 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 37 participants (actual)
Sponsor and investigators
- Lead sponsor
- Fred Hutchinson Cancer Center
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Brenda Sandmaier, Principal investigator, Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00078858
- Sponsor's protocol ID
- 1668.00
- Other IDs
- NCI-2012-00668, 1668.00, P30CA015704, P01CA018029
- Status last verified
- Feb 2019
- First submitted
- 8 Mar 2004
- Last updated
- 18 Jan 2020
- Results posted
- No
- 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 32499241