Trial document

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Trial Description

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Low-Dose TBI and Fludarabine Followed by Nonmyeloablative Unrelated Donor Peripheral Blood Stem Cell Transplantation Using Enhanced Postgrafting Immunosuppression 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 a new kind of blood stem cell (bone marrow)
transplant, that may be less toxic, is able to treat underlying blood cancer. Stem cells are
"seed cells" necessary to make blood cells. Researchers want to see if using less radiation
and less chemotherapy with new immune suppressing drugs will enable a stem cell transplant
to work. Researchers are hoping to see a mixture of recipient and donor stem cells after
transplant. This mixture of donor and recipient stem cells is called "mixed-chimerism".
Researchers hope to see these donor cells eliminate tumor cells. This is called a
"graft-versus-leukemia" response.

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Brief Summary in Scientific Language


I. To determine whether stable unrelated peripheral blood stem cell (PBSC) grafts can be
safely established using nonmyeloablative pretransplant conditioning with intensified
post-grafting immunosuppression and with every (q) 8 hours (hr) and possibly q 6 hr
mycophenolate mofetil (MMF) dosing in patients with hematologic malignancies and renal cell

II. To determine if the incidence and severity of acute grades II-IV graft-versus-host
disease (GVHD) can be reduced in patients with sustained engraftment with the use of q 8 hr
MMF dosing.


I. To determine if engraftment can be maintained in patients with low chimerism and high
risk of rejection with the use of a single dose of fludarabine (fludarabine phosphate)
followed by donor lymphocyte infusion (DLI) on continued MMF/cyclosporine (CSP).

II. To compare survival and disease free survival to those achieved under protocol 1463.


REDUCED-INTENSITY CONDITIONING: Patients receive fludarabine phosphate intravenously (IV) on
days -4, -3, and -2 and undergo total-body irradiation (TBI) on day 0.

TRANSPLANT: Patients undergo allogeneic peripheral blood stem cell transplant (PBSCT) on day

IMMUNOSUPPRESSION: Patients receive cyclosporine orally (PO) twice daily (BID) on days -3 to
100 with taper to day 177 and mycophenolate mofetil PO every 8 hours on days 0-40 with taper
to day 96.

After completion of study treatment, patients are followed up at 6 months, 1 year, 1.5
years, 2 years, and then annually thereafter.

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Organizational Data

  •   DRKS00006513
  •   2015/03/16
  •   2001/12/07
  •   yes
  •   [---]*
  •   [---]*
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Secondary IDs

  •   NCT00027820  (
  •   1641.00  (Fred Hutchinson Cancer Research Center)
  •   NCI-2012-00591 
  •   P01CA018029 
  •   P01CA018029 
  •   1641.00 
  •   P30CA015704 
  •   P01CA018029 
  •   P01CA018029 
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Health Condition or Problem studied

  •   Adult Acute Myeloid Leukemia in Remission
  •   Childhood Acute Lymphoblastic Leukemia in Remission
  •   Childhood Acute Myeloid Leukemia in Remission
  •   Childhood Myelodysplastic Syndrome
  •   Childhood Renal Cell Carcinoma
  •   Chronic Myelomonocytic Leukemia
  •   Clear Cell Renal Cell Carcinoma
  •   de Novo Myelodysplastic Syndrome
  •   Metastatic Renal Cell Cancer
  •   Previously Treated Myelodysplastic Syndrome
  •   Progression of Multiple Myeloma or Plasma Cell Leukemia
  •   Recurrent Adult Acute Lymphoblastic Leukemia
  •   Recurrent Adult Acute Myeloid Leukemia
  •   Recurrent Adult Hodgkin Lymphoma
  •   Recurrent Adult Lymphoblastic Lymphoma
  •   Recurrent Adult Non-Hodgkin Lymphoma
  •   Recurrent Childhood Acute Lymphoblastic Leukemia
  •   Recurrent Childhood Acute Myeloid Leukemia
  •   Recurrent Childhood Lymphoblastic Lymphoma
  •   Recurrent Childhood Non-Hodgkin Lymphoma
  •   Refractory Anemia
  •   Refractory Anemia With Ringed Sideroblasts
  •   Refractory Childhood Hodgkin Lymphoma
  •   Refractory Chronic Lymphocytic Leukemia
  •   Renal Medullary Carcinoma
  •   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
  •   C81-C96 -  Malignant neoplasms, stated or presumed to be primary, of lymphoid, haematopoietic and related tissue
  •   C64 -  Malignant neoplasm of kidney, except renal pelvis
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Interventions/Observational Groups

  •   Drug: Fludarabine Phosphate
  •   Radiation: Total-Body Irradiation
  •   Procedure: Peripheral Blood Stem Cell Transplantation
  •   Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation
  •   Drug: Cyclosporine
  •   Drug: Mycophenolate Mofetil
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  •   Interventional
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  •   Single arm study
  •   Open (masking not used)
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  •   Uncontrolled/Single arm
  •   Treatment
  •   Single (group)
  •   I-II
  •   [---]*
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Primary Outcome

- Risk of true graft rejection in patients with and without preceding chemotherapy; time frame: Up to 5 years; The goal is to reduce the risk in patients without preceding chemotherapy to < 20% and with preceding chemotherapy to < 10%.
- Risk of grades II-IV acute GVHD in those patients with sustained engraftment; time frame: Up to 5 years; The goal is to reduce the incidence of grades II-IV acute GVHD from 50% to less than 35% in patients with sustained engraftment by increasing the dosing of MMF to every 8 hours. The impact of the enhanced post-grafting immunosuppression on objective measures of GVHD will be described. These include doses and duration of immunosuppression (in particular corticosteroids) and number of GVHD treatment regimens used within the first year. These parameters will be compared to the results of protocol 1463.

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Secondary Outcome

- Incidence of reversing impending graft rejection (less than 40% donor cluster of differentiation [CD]3+ T cell chimerism); time frame: Up to 5 years; The secondary objective of reversing pending graft rejection with fludarabine phosphate and DLI will be evaluated in the context of overall engraftment. The number of patients given DLI in this context is expected to be small. The response to DLI will be followed and reported in a descriptive manner. The effect of this intervention on adverse outcomes will be followed.
- Overall survival; time frame: Up to 5 years
- Progression-free survival; time frame: Up to 5 years

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Countries of Recruitment

  •   United States
  •   Germany
  •   Italy
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Locations of Recruitment

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  •   2001/08/31
  •   150
  •   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 hematopoietic
stem cell transplantation (HSCT)

- Ages =< 50 years of age with hematologic diseases treatable by allogeneic HSCT 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 HSCT; 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 autologous transplantation do not require patient review
committee approval; all children < 12 years must be discussed with the FHCRC
principal 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:

- Intermediate or high grade non-Hodgkin lymphoma (NHL) - not eligible for
autologous HSCT or after failed autologous HSCT

- Low grade NHL - with < 6 month duration of complete remission (CR) between
courses of conventional therapy

- Chronic lymphocytic leukemia (CLL) - must have failed two lines of conventional
therapy and be refractory to fludarabine

- Hodgkin's 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 HSCT is permitted

- Acute myeloid leukemia (AML) - must have < 5% marrow blasts at the time of

- Acute lymphoblastic leukemia - must have < 5% 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 PBSC autologous or
conventional HSCT for advanced CML may be enrolled provided they are in CR or
chronic phase (CP) and have < 5% marrow blasts at time of transplant

- Myelodysplastic syndromes (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

- Renal cell carcinoma - must have evidence of disease not amenable to surgical
cure or history of or active metastatic disease by radiological and histologic

- DONOR: FHCRC matching allowed will be grade 1.0 to 2.1; unrelated donors who are

- Matched for human leukocyte antigen (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

- DONOR: A positive anti-donor cytotoxic crossmatch is an absolute donor exclusion

- DONOR: Patient and donor pairs homozygous at a mismatched allele 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: PBSC only will be permitted as a hematopoietic stem cell (HSC) source on this

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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

- 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

- Diffusion 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

- 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,
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 filgrastim (G-CSF) mobilization and harvest of PBSC

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  • start of 1:1-Block address primary-sponsor
    • Fred Hutchinson Cancer Research Center
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    • National Heart, Lung, and Blood Institute (NHLBI)
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    •   [---]*
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    • National Cancer Institute (NCI)
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    • Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
    • Brenda Sandmaier 
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    • Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
    • Brenda Sandmaier 
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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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  •   Recruiting complete, follow-up continuing
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Trial Publications, Results and other Documents

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Additional Trial Attributes

  • Urological disease 
  • If other, please specify 
  • Study recommendations 
  • If other, please specify 
  • German director of clinical investigation 
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  • Further contact 
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  • Function of contact 
  • Non-interventional study 
  • Stage 
  • If other, please specify 
  • Onset of therapy 
  • If other, please specify 
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The parameters in and DRKS are not identical. Therefore the data import from required adjustments. For full details please see the DRKS FAQs .
  •   2
  •   2015/06/25
* This entry means the parameter is not applicable or has not been set.