Trial document





This study has been imported from ClinicalTrials.gov without additional data checks.
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  DRKS00004002

Trial Description

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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

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Trial Acronym

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URL of the Trial

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Brief Summary in Lay Language

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.

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Brief Summary in Scientific Language

PRIMARY OBJECTIVES:

I. 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:

I. 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.

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Organizational Data

  •   DRKS00004002
  •   2013/06/06
  •   2004/03/08
  •   yes
  •   [---]*
  •   [---]*
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Secondary IDs

  •   NCT00078858  (ClinicalTrials.gov)
  •   1668.00  (Fred Hutchinson Cancer Research Center)
  •   NCI-2012-00668 
  •   1668.00 
  •   P30CA015704 
  •   P01CA018029 
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Health Condition or Problem studied

  •   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)
  •   Adult Acute Myeloid Leukemia With t(15;17)(q22;q12)
  •   Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
  •   Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)
  •   Adult Grade III Lymphomatoid Granulomatosis
  •   Adult Nasal Type Extranodal NK/T-cell Lymphoma
  •   Anaplastic Large Cell Lymphoma
  •   Angioimmunoblastic T-cell Lymphoma
  •   Childhood Acute Lymphoblastic Leukemia in Remission
  •   Childhood Acute Myeloid Leukemia in Remission
  •   Childhood Burkitt Lymphoma
  •   Childhood Chronic Myelogenous Leukemia
  •   Childhood Diffuse Large Cell Lymphoma
  •   Childhood Grade III Lymphomatoid Granulomatosis
  •   Childhood Immunoblastic Large Cell Lymphoma
  •   Childhood Myelodysplastic Syndromes
  •   Childhood Nasal Type Extranodal NK/T-cell Lymphoma
  •   Childhood Renal Cell Carcinoma
  •   Chronic Myelomonocytic Leukemia
  •   Chronic Phase Chronic Myelogenous Leukemia
  •   Clear Cell Renal Cell Carcinoma
  •   Contiguous Stage II Adult Burkitt Lymphoma
  •   Contiguous Stage II Adult Diffuse Large Cell Lymphoma
  •   Contiguous Stage II Adult Diffuse Mixed Cell Lymphoma
  •   Contiguous Stage II Adult Immunoblastic Large Cell Lymphoma
  •   Contiguous Stage II Adult Lymphoblastic Lymphoma
  •   Contiguous Stage II Grade 3 Follicular Lymphoma
  •   Contiguous Stage II Mantle Cell Lymphoma
  •   de Novo Myelodysplastic Syndromes
  •   Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue
  •   Hepatosplenic T-cell Lymphoma
  •   Juvenile Myelomonocytic Leukemia
  •   Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable
  •   Nodal Marginal Zone B-cell Lymphoma
  •   Noncontiguous Stage II Adult Burkitt Lymphoma
  •   Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma
  •   Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma
  •   Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma
  •   Noncontiguous Stage II Adult Lymphoblastic Lymphoma
  •   Noncontiguous Stage II Grade 3 Follicular Lymphoma
  •   Noncontiguous Stage II Mantle Cell Lymphoma
  •   Noncutaneous Extranodal Lymphoma
  •   Peripheral T-cell Lymphoma
  •   Post-transplant Lymphoproliferative Disorder
  •   Previously Treated Myelodysplastic Syndromes
  •   Recurrent Adult Acute Lymphoblastic Leukemia
  •   Recurrent Adult Acute Myeloid Leukemia
  •   Recurrent Adult Burkitt Lymphoma
  •   Recurrent Adult Diffuse Large Cell Lymphoma
  •   Recurrent Adult Diffuse Mixed Cell Lymphoma
  •   Recurrent Adult Diffuse Small Cleaved Cell Lymphoma
  •   Recurrent Adult Grade III Lymphomatoid Granulomatosis
  •   Recurrent Adult Hodgkin Lymphoma
  •   Recurrent Adult Immunoblastic Large Cell Lymphoma
  •   Recurrent Adult Lymphoblastic Lymphoma
  •   Recurrent Adult T-cell Leukemia/Lymphoma
  •   Recurrent Childhood Acute Lymphoblastic Leukemia
  •   Recurrent Childhood Acute Myeloid Leukemia
  •   Recurrent Childhood Anaplastic Large Cell Lymphoma
  •   Recurrent Childhood Grade III Lymphomatoid Granulomatosis
  •   Recurrent Childhood Large Cell Lymphoma
  •   Recurrent Childhood Lymphoblastic Lymphoma
  •   Recurrent Childhood Small Noncleaved Cell Lymphoma
  •   Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma
  •   Recurrent Grade 1 Follicular Lymphoma
  •   Recurrent Grade 2 Follicular Lymphoma
  •   Recurrent Grade 3 Follicular Lymphoma
  •   Recurrent Mantle Cell Lymphoma
  •   Recurrent Marginal Zone Lymphoma
  •   Recurrent Mycosis Fungoides/Sezary Syndrome
  •   Recurrent Renal Cell Cancer
  •   Recurrent Small Lymphocytic Lymphoma
  •   Recurrent/Refractory Childhood Hodgkin Lymphoma
  •   Refractory Anemia
  •   Refractory Anemia With Ringed Sideroblasts
  •   Refractory Chronic Lymphocytic Leukemia
  •   Refractory Hairy Cell Leukemia
  •   Refractory Multiple Myeloma
  •   Relapsing Chronic Myelogenous Leukemia
  •   Splenic Marginal Zone Lymphoma
  •   Stage I Adult Burkitt Lymphoma
  •   Stage I Adult Diffuse Large Cell Lymphoma
  •   Stage I Adult Diffuse Mixed Cell Lymphoma
  •   Stage I Adult Immunoblastic Large Cell Lymphoma
  •   Stage I Adult Lymphoblastic Lymphoma
  •   Stage I Adult T-cell Leukemia/Lymphoma
  •   Stage I Childhood Anaplastic Large Cell Lymphoma
  •   Stage I Childhood Large Cell Lymphoma
  •   Stage I Childhood Lymphoblastic Lymphoma
  •   Stage I Childhood Small Noncleaved Cell Lymphoma
  •   Stage I Grade 3 Follicular Lymphoma
  •   Stage I Mantle Cell Lymphoma
  •   Stage II Adult T-cell Leukemia/Lymphoma
  •   Stage II Childhood Anaplastic Large Cell Lymphoma
  •   Stage II Childhood Large Cell Lymphoma
  •   Stage II Childhood Lymphoblastic Lymphoma
  •   Stage II Childhood Small Noncleaved Cell Lymphoma
  •   Stage III Adult Burkitt Lymphoma
  •   Stage III Adult Diffuse Large Cell Lymphoma
  •   Stage III Adult Diffuse Mixed Cell Lymphoma
  •   Stage III Adult Immunoblastic Large Cell Lymphoma
  •   Stage III Adult Lymphoblastic Lymphoma
  •   Stage III Adult T-cell Leukemia/Lymphoma
  •   Stage III Childhood Anaplastic Large Cell Lymphoma
  •   Stage III Childhood Large Cell Lymphoma
  •   Stage III Childhood Lymphoblastic Lymphoma
  •   Stage III Childhood Small Noncleaved Cell Lymphoma
  •   Stage III Grade 3 Follicular Lymphoma
  •   Stage III Mantle Cell Lymphoma
  •   Stage IV Adult Burkitt Lymphoma
  •   Stage IV Adult Diffuse Large Cell Lymphoma
  •   Stage IV Adult Diffuse Mixed Cell Lymphoma
  •   Stage IV Adult Immunoblastic Large Cell Lymphoma
  •   Stage IV Adult Lymphoblastic Lymphoma
  •   Stage IV Adult T-cell Leukemia/Lymphoma
  •   Stage IV Childhood Anaplastic Large Cell Lymphoma
  •   Stage IV Childhood Large Cell Lymphoma
  •   Stage IV Childhood Lymphoblastic Lymphoma
  •   Stage IV Childhood Small Noncleaved Cell Lymphoma
  •   Stage IV Grade 3 Follicular Lymphoma
  •   Stage IV Mantle Cell Lymphoma
  •   Stage IV Renal Cell Cancer
  •   T-cell Large Granular Lymphocyte Leukemia
  •   Type 1 Papillary Renal Cell Carcinoma
  •   Type 2 Papillary Renal Cell Carcinoma
  •   Untreated Adult Acute Lymphoblastic Leukemia
  •   Untreated Adult Acute Myeloid Leukemia
  •   Untreated Childhood Acute Lymphoblastic Leukemia
  •   Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies
  •   Waldenström Macroglobulinemia
  •   C64 -  Malignant neoplasm of kidney, except renal pelvis
  •   T86.09 -  message.icd10.coding.redirected.en
  •   C95.9 -  Leukaemia, unspecified
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Interventions/Observational Groups

  •   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
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Characteristics

  •   Interventional
  •   [---]*
  •   Single arm study
  •   Open (masking not used)
  •   [---]*
  •   Uncontrolled/Single arm
  •   Treatment
  •   Single (group)
  •   I-II
  •   [---]*
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Primary Outcome

- Incidence of life-threatening GVHD in patients undergoing a modified taper of post-grafting immunosuppression after undergoing nonmyeloablative HSCT from matched unrelated donors; time frame: 1 year; 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.

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Secondary Outcome

- 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; time frame: 1 year
- Graft rejection; time frame: Up to day 365
- Incidence of acute and chronic GVHD; time frame: Up to 7 years
- Overall survival; time frame: Up to 7 years

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Countries of Recruitment

  •   United States
  •   Germany
  •   Italy
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Locations of Recruitment

  •  
  •  
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Recruitment

  •   [---]*
  •   2003/09/30
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  •   Multicenter trial
  •   International
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Inclusion Criteria

  •   Both, male and female
  •   no minimum age
  •   no maximum age
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Additional Inclusion Criteria

- 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

- 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

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Exclusion Criteria

- 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

- 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

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Addresses

  • start of 1:1-Block address primary-sponsor
    • Fred Hutchinson Cancer Research Center
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    •   [---]*
    •   [---]*
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  • start of 1:1-Block address other
    • National Heart, Lung, and Blood Institute (NHLBI)
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    •   [---]*
    •   [---]*
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  • start of 1:1-Block address other
    • National Cancer Institute (NCI)
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    •   [---]*
    •   [---]*
    •   [---]*
    •   [---]*
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  • start of 1:1-Block address scientific-contact
    • Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
    • Brenda Sandmaier 
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    •   [---]*
    •   [---]*
    •   [---]*
    •   [---]*
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  • start of 1:1-Block address public-contact
    • Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
    • Brenda Sandmaier 
    end of 1:1-Block address public-contact
    start of 1:1-Block address contact public-contact
    •   [---]*
    •   [---]*
    •   [---]*
    •   [---]*
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Sources of Monetary or Material Support

  • start of 1:1-Block address materialSupport
    • Bitte wenden Sie sich an den Sponsor / Please refer to primary sponsor
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    start of 1:1-Block address contact materialSupport
    •   [---]*
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    •   [---]*
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Status

  •   Recruiting complete, follow-up continuing
  •   [---]*
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Trial Publications, Results and other Documents

  • [---]*
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The parameters in ClinicalTrials.gov and DRKS are not identical. Therefore the data import from ClinicalTrials.gov required adjustments. For full details please see the DRKS FAQs .
  •   6
  •   2016/01/14


* This entry means the parameter is not applicable or has not been set.