Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by Fred Hutchinson Cancer Research Center
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier:
NCT01028716
First received: December 8, 2009
Last updated: May 14, 2014
Last verified: May 2014
  Purpose

This phase II trial is studying how well donor peripheral blood stem cell (PBSC) transplant works in treating patients with hematologic malignancies. Cyclophosphamide when added to tacrolimus and mycophenolate mofetil is safe and effective in preventing severe graft-versus-host disease (GVHD) in most patients with hematologic malignancies undergoing transplantation of bone marrow from half-matched (haploidentical) donors. This approach has extended the transplant option to patients who do not have matched related or unrelated donors, especially for patients from ethnic minority groups. The graft contains cells of the donor's immune system which potentially can recognize and destroy the patient's cancer cells (graft-versus-tumor effect). Rejection of the donor's cells by the patient's own immune system is prevented by giving low doses of chemotherapy (fludarabine phosphate and cyclophosphamide) and total-body irradiation before transplant. Patients can experience low blood cell counts after transplant. Using stem cells and immune cells collected from the donor's circulating blood may result in quicker recovery of blood counts and may be more effective in therapy of the patient's disease than using bone marrow.


Condition Intervention Phase
Acute Undifferentiated Leukemia
Adult Acute Lymphoblastic Leukemia in Remission
Adult Acute Megakaryoblastic Leukemia (M7)
Adult Acute Myeloid Leukemia in Remission
Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
Adult Acute Myeloid Leukemia With t(15;17)(q22;q12)
Adult Erythroleukemia (M6a)
Adult Pure Erythroid Leukemia (M6b)
Recurrent Adult Burkitt Lymphoma
Recurrent Adult Diffuse Large Cell Lymphoma
Recurrent Adult Hodgkin Lymphoma
Recurrent Adult Immunoblastic Large Cell Lymphoma
Recurrent Adult Lymphoblastic Lymphoma
Recurrent Grade 1 Follicular Lymphoma
Recurrent Grade 2 Follicular Lymphoma
Recurrent Grade 3 Follicular Lymphoma
Recurrent Mantle Cell Lymphoma
Recurrent Marginal Zone Lymphoma
Refractory Multiple Myeloma
Stage II Multiple Myeloma
Stage III Multiple Myeloma
Drug: fludarabine phosphate
Drug: cyclophosphamide
Drug: tacrolimus
Drug: mycophenolate mofetil
Biological: filgrastim
Procedure: peripheral blood stem cell transplantation
Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation
Radiation: total-body irradiation
Procedure: laboratory biomarker analysis
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Nonmyeloablative Hematopoietic Cell Transplantation (HCT) for Patients With Hematologic Malignancies Using Related, HLA-Haploidentical Donors: A Phase II Trial of Peripheral Blood Stem Cells (PBSC) as the Donor Source

Resource links provided by NLM:


Further study details as provided by Fred Hutchinson Cancer Research Center:

Primary Outcome Measures:
  • Incidence of grades III/IV acute GVHD [ Time Frame: At day 84 ] [ Designated as safety issue: No ]
    Grading determined by organ system stages. Grade III/IV acute GVHD is defined as skin: stage IV, liver: stages II-IV, and/or gastrointestinal tract: stages II-IV.

  • Incidence of chronic GVHD [ Time Frame: Up to day 90 ] [ Designated as safety issue: No ]
    Scored according to the National Cancer Institute (NCI) criteria. The time to onset of limited and extensive chronic GVHD will be recorded.

  • Cumulative incidence of NRM, defined as death without evidence of disease progression [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]
  • Relapse of malignancy after transplantation [ Time Frame: Up to 7 years ] [ Designated as safety issue: No ]
    Defined by either morphological or cytogenetic evidence of acute leukemia consistent with pre-transplant features, or radiologic evidence of lymphoma progression. When in doubt, the diagnosis of recurrent or progressive lymphoma should be documented by tissue biopsy.


Secondary Outcome Measures:
  • Neutrophil recovery [ Time Frame: Up to day 84 ] [ Designated as safety issue: No ]
    Achievement of an ANC greater or equal to 500/mm^3 for three consecutive measurements on different days. The first of the three days will be designated the day of neutrophil recovery.

  • Primary graft failure [ Time Frame: Day 84 ] [ Designated as safety issue: No ]
    Defined as < 5% donor cluster of differentiation (CD)3 chimerism. Chimerism will be measured by short tandem repeat (STR)-polymerase chain reaction (PCR) on peripheral blood sorted into CD3 and CD33 cell fractions.

  • Secondary graft failure [ Time Frame: Up to day 84 ] [ Designated as safety issue: No ]
    Initial recovery followed by neutropenia with < 5% donor chimerism. If no chimerism assays were performed and ANC is less than 500/mm^3, then it will be counted as a secondary graft failure.

  • Platelet recovery [ Time Frame: Up to day 84 post-transplant ] [ Designated as safety issue: No ]
    The first day of a sustained platelet count > 20,000/mm^3 with no platelet transfusions in the preceding seven days.

  • Donor cell engraftment [ Time Frame: Up to day 84 ] [ Designated as safety issue: No ]
    Donor chimerism in the T-cell (CD3-positive) and granulocyte (CD33-positive) fractions of sorted peripheral blood greater or equal to 50%.

  • Progression-free survival [ Time Frame: Up to 7 years ] [ Designated as safety issue: No ]
    Defined as the minimum time interval to relapse/recurrence, to death or to last follow-up.

  • Infections [ Time Frame: Up to 7 years ] [ Designated as safety issue: No ]
    Reported by anatomic site, date of onset, organism and resolution, if any.

  • Toxicity of treatment regimen [ Time Frame: Up to day 90 ] [ Designated as safety issue: Yes ]
    Assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. The incidence of all adverse events greater or equal to grade 3 will be determined.


Estimated Enrollment: 50
Study Start Date: February 2010
Estimated Primary Completion Date: February 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (nonmyeloablative HCT, TBI)
Patients receive fludarabine IV over 30-60 minutes daily on days -6 through -2 and cyclophosphamide IV over 1-2 hours on days -6, -5, and 3-4. Patients undergo total-body irradiation on day -1. Patients undergo donor peripheral blood stem cell transplant on day 0. Patients then receive tacrolimus IV once daily or PO BID on days 5-180 (may be continued if active GvHD is present), mycophenolate mofetil IV or PO TID on days 5-35 (may be continued if GvHD present), and filgrastim IV or SC beginning on day 5 until the ANC is >= 1,000/mm^3 for three consecutive days.
Drug: fludarabine phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • Beneflur
  • Fludara
Drug: cyclophosphamide
Given IV
Other Names:
  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana
Drug: tacrolimus
Given IV or PO
Other Names:
  • FK 506
  • Prograf
Drug: mycophenolate mofetil
Given PO
Other Names:
  • Cellcept
  • MMF
Biological: filgrastim
Given IV or SC
Other Names:
  • G-CSF
  • Neupogen
Procedure: peripheral blood stem cell transplantation
Undergo PBSC
Other Names:
  • PBPC transplantation
  • PBSC transplantation
  • peripheral blood progenitor cell transplantation
  • transplantation, peripheral blood stem cell
Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation
Undergo PBSC
Radiation: total-body irradiation
Undergo total-body irradiation
Other Name: TBI
Procedure: laboratory biomarker analysis
Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

I. To demonstrate that use of PBSC in place of marrow as the source of lymphocytes and stem cells for nonmyeloablative transplants from related, haploidentical donors will not result in unacceptable rates of high-grade acute or chronic GVHD, non-relapse mortality (NRM) or relapse compared to historical data on nonmyeloablative transplants from unrelated donors.

SECONDARY OBJECTIVES:

I. Estimates of the rates of neutrophil and platelet recovery, number of red blood cell (RBC) and platelet transfusions, incidences of graft failure, transplant-related toxicities, disease-free survival and overall survival.

OUTLINE:

Patients receive fludarabine intravenously (IV) over 30-60 minutes daily on days -6 through -2 and cyclophosphamide IV over 1-2 hours on days -6, -5, and 3-4. Patients undergo total-body irradiation on day -1. Patients undergo donor peripheral blood stem cell transplant on day 0. Patients then receive tacrolimus IV once daily or orally (PO) twice daily (BID) on days 5-180 (may be continued if active GVHD is present), mycophenolate mofetil IV or PO thrice daily (TID) on days 5-35 (may be continued if GVHD present), and filgrastim IV or subcutaneously (SC) beginning on day 5 until the absolute neutrophil count (ANC) is >= 1,000/mm^3 for three consecutive days.

Treatment continues in the absence of disease progression or unacceptable toxicity.

  Eligibility

Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Molecular based human leukocyte antigen (HLA) typing will be performed for the HLA-A, -B, -Cw, -DRB1 and -DQB1 loci to the resolution adequate to establish haplo-identity; a minimum match of 5/10 is required
  • An unrelated donor search is not required for a patient to be eligible for this protocol if the clinical situation dictates an urgent transplant; clinical urgency is defined as 6-8 weeks from referral or low-likelihood of finding a matched, unrelated donor
  • Acute leukemias (includes T lymphoblastic lymphoma); remission is defined as < 5% blasts with no morphological characteristics of acute leukemia (e.g., Auer rods) in a bone marrow with > 20% cellularity, peripheral blood counts showing ANC > 1000/ul, including patients in complete remission with incomplete platelet recovery (CRp)
  • Acute lymphoblastic leukemia in high risk first complete remission (CR1) as defined by at least one of the following:

    • Adverse cytogenetics such as t(9;22), t(1;19), t(4;11), mixed lineage leukemia (MLL) rearrangements
    • White blood cell counts > 30,000/mcL
    • Patients over 30 years of age
    • Time to complete remission > 4 weeks
    • Presence of extramedullary disease
  • Acute myelogenous leukemia in high risk CR1 as defined by at least one of the following:

    • Greater than 1 cycle of induction therapy required to achieve remission
    • Preceding myelodysplastic syndrome (MDS)
    • Presence of fms-like tyrosine kinase receptor-3 (Flt3) abnormalities
    • French-American-British (FAB) M6 or M7 leukemia, or
    • Adverse cytogenetics for overall survival such as:

      • Those associated with MDS
      • Complex karyotype (>= 3 abnormalities); or
      • Any of the following: inv(3) or t(3;3), t(6;9), t(6;11), + 8 [alone or with other abnormalities except for t(8;21), t(9;11), inv(16) or t(16;16)], t(11;19)(q23;p13.1)]
  • Acute leukemias in 2nd or subsequent remission
  • Biphenotypic/undifferentiated leukemias in 1st or subsequent CR
  • High-risk MDS status-post cytotoxic chemotherapy
  • Burkitt's lymphoma: second or subsequent CR
  • Chemotherapy-sensitive (complete or partial response) large cell, mantle cell or Hodgkin's lymphomas that have failed at least 1 prior regimen of multi-agent chemotherapy and are ineligible for an autologous transplant
  • Marginal zone B-cell lymphoma or follicular lymphoma that has progressed after at least two prior therapies (excluding single agent Rituxan)
  • Multiple myeloma (MM) stage II or III patients who have progressed after an initial response to chemotherapy or autologous hematopoietic stem cell transplantation (HSCT) or MM patients with refractory disease who may benefit from tandem autologous-nonmyeloablative allogeneic transplant
  • Left ventricular ejection fraction at rest must be >= 35%
  • Bilirubin =< 2.5 mg/dL
  • Alanine aminotransferase (ALT) < 5 x upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) < 5 x ULN
  • Alkaline phosphatase < 5 x ULN
  • Serum creatinine within normal range for age, or if serum creatinine outside normal range for age, then renal function (creatinine clearance or glomerular filtration rate [GFR]) > 40 mL/min/1.73m^2
  • Forced expiratory volume in one second (FEV1), forced vital capacity (FVC), diffusion capacity of carbon monoxide (DLCO) (diffusion capacity) >= 40% predicted (corrected for hemoglobin); if unable to perform pulmonary function tests, then oxygen (O2) saturation > 92% on room air
  • Karnofsky/Lansky score >= 60%
  • Patients who have received a prior allogeneic HSCT and who have either rejected their grafts or who have become tolerant of their grafts with no active GVHD requiring immunosuppressive therapy
  • DONOR: Donors must be HLA-haploidentical first-degree relatives of the patient; eligible donors include biological parents, siblings, or children, or half-siblings
  • DONOR: Age >= 12 years
  • DONOR: Weight >= 40 kg
  • DONOR: Ability of donors < 18 years of age to undergo apheresis without use of a vascular access device; vein check must be performed and verified by an apheresis nurse prior to arrival at the Seattle Cancer Care Alliance (SCCA)
  • DONOR: Donors must meet the selection criteria as defined by the Foundation for the Accreditation of Cell Therapy (FACT) and will be screened per the American Association of Blood Banks (AABB) guidelines

Exclusion Criteria:

  • HLA-matched or single allele-mismatched donor able to donate
  • Pregnancy or breast-feeding
  • Current uncontrolled bacterial, viral or fungal infection (currently taking medication with evidence of progression of clinical symptoms or radiologic findings)
  • Patients with primary idiopathic myelofibrosis
  • DONOR: Positive anti-donor HLA antibody
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01028716

Locations
United States, Washington
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium Recruiting
Seattle, Washington, United States, 98109
Contact: Rachel B. Salit    206-667-1317      
Principal Investigator: Rachel B. Salit         
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center
Investigators
Principal Investigator: Rachel Salit Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
  More Information

No publications provided

Responsible Party: Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier: NCT01028716     History of Changes
Other Study ID Numbers: 2372.00, NCI-2009-01433, 2372.00, P30CA015704
Study First Received: December 8, 2009
Last Updated: May 14, 2014
Health Authority: United States: Federal Government

Additional relevant MeSH terms:
Congenital Abnormalities
Burkitt Lymphoma
Hodgkin Disease
Leukemia
Leukemia, Erythroblastic, Acute
Leukemia, Lymphoid
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Megakaryoblastic, Acute
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Lymphoma
Lymphoma, Follicular
Lymphoma, Non-Hodgkin
Multiple Myeloma
Neoplasms, Plasma Cell
Lymphoma, Large B-Cell, Diffuse
Lymphoma, Large-Cell, Immunoblastic
Lymphoma, B-Cell, Marginal Zone
Lymphoma, Mantle-Cell
Hematologic Neoplasms
Epstein-Barr Virus Infections
Herpesviridae Infections
DNA Virus Infections
Virus Diseases
Tumor Virus Infections
Neoplasms by Histologic Type
Neoplasms
Lymphoma, B-Cell
Neoplasms, Experimental
Lymphoproliferative Disorders

ClinicalTrials.gov processed this record on July 26, 2014