Fludarabine Phosphate, Cyclophosphamide, Total-Body Irradiation, and Donor Bone Marrow Transplant Followed by Donor Natural Killer Cell Therapy, Mycophenolate Mofetil, and Tacrolimus in Treating Patients With Hematologic Cancer

This study is currently recruiting participants. (see Contacts and Locations)
Verified January 2015 by Fred Hutchinson Cancer Research Center
Sponsor:
Collaborators:
Wayne D. Kuni and Joan E. Kuni Foundation
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier:
NCT00789776
First received: November 12, 2008
Last updated: January 30, 2015
Last verified: January 2015
  Purpose

This phase I/II trial studies the side effects and best dose of donor natural killer (NK) cell therapy and to see how well it works when given together with fludarabine phosphate, cyclophosphamide, total-body irradiation, donor bone marrow transplant, mycophenolate mofetil, and tacrolimus in treating patients with hematologic cancer. Giving chemotherapy, such as fludarabine phosphate and cyclophosphamide, and total-body irradiation before a donor bone marrow transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Giving an infusion of the donor's T cells (donor lymphocyte infusion) may help the patient's immune system see any remaining cancer cells as not belonging in the patient's body and destroy them (called graft-versus-tumor effect). Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving mycophenolate mofetil and tacrolimus after the transplant may stop this from happening.


Condition Intervention Phase
Adult Acute Lymphoblastic Leukemia
Adult Acute Myeloid Leukemia
Adult Nasal Type Extranodal NK/T-Cell Lymphoma
Aggressive Adult Non-Hodgkin Lymphoma
Aggressive Non-Hodgkin Lymphoma
Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative
Childhood Acute Lymphoblastic Leukemia
Childhood Acute Myeloid Leukemia
Childhood Burkitt Lymphoma
Childhood Diffuse Large B -Cell Lymphoma
Childhood Immunoblastic Lymphoma
Childhood Myelodysplastic Syndrome
Childhood Nasal Type Extranodal NK/T-Cell Lymphoma
Chronic Myelomonocytic Leukemia
de Novo Myelodysplastic Syndrome
Juvenile Myelomonocytic Leukemia
Myelodysplastic Syndrome With Isolated Del(5q)
Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable
Previously Treated Myelodysplastic Syndrome
Recurrent Adult Burkitt Lymphoma
Recurrent Adult Diffuse Large Cell Lymphoma
Recurrent Adult Diffuse Mixed Cell Lymphoma
Recurrent Adult Grade III Lymphomatoid Granulomatosis
Recurrent Adult Hodgkin Lymphoma
Recurrent Adult Immunoblastic Lymphoma
Recurrent Adult Lymphoblastic Lymphoma
Recurrent Adult T-Cell Leukemia/Lymphoma
Recurrent Aggressive Adult Non-Hodgkin Lymphoma
Recurrent Childhood Anaplastic Large Cell Lymphoma
Recurrent Childhood Grade III Lymphomatoid Granulomatosis
Recurrent Childhood Lymphoblastic Lymphoma
Recurrent Chronic Lymphocytic Leukemia
Recurrent Cutaneous T-Cell Non-Hodgkin Lymphoma
Recurrent Grade 1 Follicular Lymphoma
Recurrent Grade 2 Follicular Lymphoma
Recurrent Grade 3 Follicular Lymphoma
Recurrent Indolent Adult Non-Hodgkin Lymphoma
Recurrent Mantle Cell Lymphoma
Recurrent Marginal Zone Lymphoma
Recurrent Mycosis Fungoides and Sezary Syndrome
Recurrent Plasma Cell Myeloma
Recurrent Small Lymphocytic Lymphoma
Refractory Adult T-Cell Leukemia/Lymphoma
Refractory Childhood Hodgkin Lymphoma
Refractory Chronic Lymphocytic Leukemia
Refractory Mantle Cell Lymphoma
Refractory Plasma Cell Myeloma
Waldenstrom Macroglobulinemia
Drug: Fludarabine Phosphate
Drug: Cyclophosphamide
Radiation: Total-Body Irradiation
Drug: Mycophenolate Mofetil
Drug: Tacrolimus
Procedure: Allogeneic Bone Marrow Transplantation
Biological: Natural Killer Cell Therapy
Other: Laboratory Biomarker Analysis
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I/II Study Evaluating the Safety and Efficacy of Adding a Single Prophylactic Donor Lymphocyte Infusion (DLI) of Natural Killer Cells Early After Nonmyeloablative, HLA-Haploidentical Hematopoietic Cell Transplantation - A Multi Center Trial

Resource links provided by NLM:

Genetic and Rare Diseases Information Center resources: Acute Lymphoblastic Leukemia Acute Lymphoblastic Leukemia, Childhood Acute Monoblastic Leukemia Acute Myeloblastic Leukemia Type 5 Acute Myelocytic Leukemia Acute Myeloid Leukemia, Adult Acute Myeloid Leukemia, Childhood Acute Non Lymphoblastic Leukemia Anaplastic Large Cell Lymphoma B-cell Lymphomas Burkitt Lymphoma Chronic Lymphocytic Leukemia Chronic Myeloid Leukemia Chronic Myelomonocytic Leukemia Chronic Myeloproliferative Disorders Cutaneous T-cell Lymphoma Follicular Lymphoma Hodgkin Lymphoma Hodgkin Lymphoma, Childhood Juvenile Myelomonocytic Leukemia Leukemia, B-cell, Chronic Leukemia, Myeloid Leukemia, T-cell, Chronic Lymphoblastic Lymphoma Lymphoma, Large-cell Lymphoma, Large-cell, Immunoblastic Lymphomatoid Granulomatosis Lymphosarcoma Mantle Cell Lymphoma Multiple Myeloma Mycosis Fungoides Myelodysplastic Syndromes Myelodysplastic/myeloproliferative Disease Plasmablastic Lymphoma Sezary Syndrome Small Non-cleaved Cell Lymphoma Squamous Cell Carcinoma of the Head and Neck Waldenstrom Macroglobulinemia
U.S. FDA Resources

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

Primary Outcome Measures:
  • Dose-limiting toxicity (Phase I) [ Time Frame: Day 35 (28 days after NK cell infusion) ] [ Designated as safety issue: Yes ]
    Defined as having at least one of the following adverse events, independent of the attribution to the NK cell infusion: grade IV infusional toxicity (based on the Adapted Common Toxicity Criteria or CTC); grade IV regimen-related toxicity (based on Adapted CTC); grade IV acute GVHD; non-relapse mortality.


Secondary Outcome Measures:
  • Non-relapse mortality (Phase II) [ Time Frame: Day 200 ] [ Designated as safety issue: No ]
    Defined as death in any patient for whom there has not been a diagnosis of relapse or disease progression.

  • Relapse (Phase II) [ Time Frame: At 1 year ] [ Designated as safety issue: No ]
    Defined as presence of malignant cells in marrow (> 5% blasts by morphology), peripheral blood (circulating blasts), or extramedullary sites (enlarging lymphadenopathy, soft tissue masses) not evident at the time of HCT.

  • Progression (Phase II) [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Defined as advancement of malignancy after HCT despite previous achievement of stable disease.

  • Acute GvHD (Phase II) [ Time Frame: Day 100 ] [ Designated as safety issue: No ]
  • Chronic extensive GvHD (Phase II) [ Time Frame: At 1 year ] [ Designated as safety issue: No ]
  • Engraftment (Phase II) [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
  • Evaluation of rejection (Phase II) [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
  • Overall survival (Phase II) [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
  • Contribution of KIR ligand alloreactivity to relapse (Phase II) [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
  • NK cell infusion on post-transplant immune reconstitution (Phase II) [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]

Estimated Enrollment: 40
Study Start Date: October 2008
Estimated Primary Completion Date: October 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (non-myeloablative transplant)

CONDITIONING: Patients receive fludarabine IV over 30 minutes on days -6 to -2 and cyclophosphamide IV over 1 hour on days -6 and -5. Patients undergo total-body irradiation on day -1.

DONOR BONE MARROW TRANSPLANTATION: Patients undergo donor bone marrow transplantation on day 0.

POST-TRANSPLANTATION IMMUNOSUPPRESSION: Patients receive cyclophosphamide IV over 1 hour on day 3 and mycophenolate mofetil PO TID on days 4 to 40, followed by a taper until day 84 in the absence of GVHD. Patients also receive tacrolimus IV continuously or IV QD over 1-2 hours or PO BID on days 4 to 84, followed by a taper until day 180 in the absence of GVHD.

NK CELL INFUSION: Patients undergo donor lymphocyte infusion of NK cells on day 7.

Drug: Fludarabine Phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • Beneflur
  • SH T 586
Drug: Cyclophosphamide
Given IV
Radiation: Total-Body Irradiation
Undergo total-body irradiation
Other Names:
  • TBI
  • Total Body Irradiation
  • Whole-Body Irradiation
Drug: Mycophenolate Mofetil
Given PO
Other Names:
  • Cellcept
  • MMF
Drug: Tacrolimus
Given IV or PO
Other Names:
  • Advagraf
  • FK 506
Procedure: Allogeneic Bone Marrow Transplantation
Undergo donor bone marrow transplantation
Other Names:
  • Allo BMT
  • Allogeneic BMT
Biological: Natural Killer Cell Therapy
Given IV
Other: Laboratory Biomarker Analysis
Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

I. Identification of the maximal feasible dose of NK cells that can be infused one week after nonmyeloablative, human leukocyte antigen (HLA)-haploidentical hematopoietic cell transplant (HCT). (Phase I)

SECONDARY OBJECTIVES:

Once the maximal feasible dose has been identified, accrual will be limited to the cohort containing this cell dose to determine:

I. Incidence of relapse. (Phase II)

II. Incidence of grades III-IV acute graft-versus-host disease (GVHD). (Phase II)

III. Incidence of non-relapse mortality. (Phase II)

OUTLINE: This is a phase I, dose-escalation study of donor NK cell therapy followed by a phase II study.

CONDITIONING: Patients receive fludarabine intravenously (IV) over 30 minutes on days -6 to -2 and cyclophosphamide IV over 1 hour on days -6 and -5. Patients undergo total-body irradiation on day -1.

DONOR BONE MARROW TRANSPLANTATION: Patients undergo donor bone marrow transplantation on day 0.

POST-TRANSPLANTATION IMMUNOSUPPRESSION: Patients receive cyclophosphamide IV over 1 hour on day 3 and mycophenolate mofetil orally (PO) thrice daily (TID) on days 4 to 40, followed by a taper until day 84 in the absence of GVHD. Patients also receive tacrolimus IV continuously or IV once daily (QD) over 1-2 hours or PO twice daily (BID) on days 4 to 84, followed by a taper until day 180 in the absence of GVHD.

DONOR NK CELL INFUSION: Patients undergo donor lymphocyte infusion of NK cells on day 7.

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

  Eligibility

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

Inclusion Criteria:

  • Patients with the following hematologic malignancies will be permitted although other diagnoses can be considered if approved by Patient Care Conference (PCC) and the principal investigators:
  • Aggressive non-Hodgkin lymphomas (NHL) and other histologies such as diffuse large B cell (DLBC) NHL - a) not eligible for autologous HCT, b) not eligible for high-dose HCT, c) after failed autologous HCT, or d) be part of a tandem auto-allo approach for high risk patients
  • Mantle cell NHL must be beyond first complete response (CR)
  • Low-grade NHL with < 6 month duration of CR between courses of conventional therapy
  • Chronic lymphocytic leukemia (CLL) must have either

    • 1) Failed to meet National Cancer Institute (NCI) Working Group criteria for complete or partial response after therapy with a regimen containing FLU (fludarabine phosphate) (or another nucleoside analog, e.g. 2-chlorodeoxyadenosine [2-CDA], pentostatin) or experience disease relapse within 12 months after completing therapy with a regimen containing FLU (or another nucleoside analog)
    • 2) Failed FLU- CY (cyclophosphamide)-rituximab (FCR) combination chemotherapy at any time point; or
    • 3) Have "17p deletion" cytogenetic abnormality and relapsed at any time point after any initial chemotherapy
  • Hodgkin lymphoma - must have received and a) failed frontline therapy, b) not be eligible for autologous HCT, or c) or be part of a tandem auto-allo approach for high risk patients
  • Multiple myeloma or plasma cell leukemia must have received more than one line of 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 HCT
  • Acute lymphocytic leukemia (ALL) must have < 5% marrow blasts at the time of HCT
  • Chronic myeloid leukemia (CML) accepted if they are beyond chronic phase (CP)1 and if they have received previous myelosuppressive chemotherapy or HCT and have < 5% marrow blasts at time of transplant
  • Myelodysplasia (MDS)/myeloproliferative syndrome (MPS) - (> intermediate 1 [int-1] per International Prognostic Scoring System [IPSS]) after > or = 1 prior cycle of induction chemotherapy; must have < 5% marrow blasts at time of transplant
  • Waldenstrom's macroglobulinemia must have failed 2 courses of therapy
  • Patients must be expected to have disease controlled for at least 60 days after HCT
  • Patients for whom HLA-matched unrelated donor search could not be initiated or completed due to insurance reasons, concerns of rapidly progressive disease, and/or discretion of attending physician are eligible for this protocol
  • DONOR: Related, HLA-haploidentical donors who are identical for one HLA haplotype and mismatched for any number of HLA-A, -B, -C, DRB1 or DQB1 loci of the unshared haplotype
  • DONOR: Marrow will be the only allowed hematopoietic stem cell source
  • DONOR: Haploidentical donor selection will be based on standard institutional criteria, otherwise no specific prioritization will be made amongst the suitable available donors; donors will not be selected based on killer cell immunoglobulin-like receptor (KIR) status

Exclusion Criteria:

  • Patients with available HLA-matched related donors
  • Patients eligible for a curative autologous HCT
  • Significant organ dysfunction that would prevent compliance with conditioning, GVHD prophylaxis, or would severely limit the probability of survival:

    • 1) Symptomatic coronary artery disease or ejection fraction < 35% or other cardiac failure requiring therapy (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
    • 2) Diffusion capacity of the lung for carbon monoxide (DLCO) < 40% total lung capacity (TLC) < 40%, forced expiratory volume in one second (FEV1) < 40% and/or receiving supplementary continuous oxygen; the Fred Hutchinson Cancer Research Center (FHCRC) study PI must approve enrollment of all patients with pulmonary nodules
    • 3) 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 > 3 mg/dL, or symptomatic biliary disease
  • Human immunodeficiency virus (HIV) seropositive patients
  • Patients with poorly controlled hypertension despite multiple antihypertensive medications
  • Fertile females who are unwilling to use contraceptive techniques during and for the twelve months following treatment, as well as females who are pregnant or actively breast feeding
  • Fertile males who are unwilling to use contraceptive techniques during and for the twelve months following treatment
  • Patients with active non-hematologic malignancies (except non-melanoma skin cancers) or those with non-hematologic malignancies (except non-melanoma skin cancers) who have been rendered with no evidence of disease, but have a greater than 20% chance of having disease recurrence within five years; this exclusion does not apply to patients with non-hematologic malignancies that do not require therapy
  • Active infectious disease concerns
  • Karnofsky performance score < 60 Lansky performance score < 60
  • Life expectancy severely limited by diseases other than malignancy
  • Patients with a diagnosis of chronic myelomonocytic leukemia (CMML)
  • Central nervous system (CNS) involvement with disease refractory to intrathecal chemotherapy
  • Patients with AML, MDS, ALL, or CML must not have presence of circulating leukemic blasts detected by standard pathology
  • Patients with aggressive lymphomas (such as DLBC) must not have bulky, rapidly progressive disease immediately prior to HCT
  • Patients who have received a prior allogeneic HCT must have no active GVHD requiring immunosuppressive therapy for at least 21 days prior to start of conditioning
  • DONOR: Children less than 12 years of age.
  • DONOR: Children greater than or equal to 12 years of age who have not provided informed assent in the presence of a parent and an attending physician who is not a member of the recipient's care team
  • DONOR: Children greater than or equal to 12 years of age who have inadequate peripheral vein access to safely undergo apheresis
  • DONOR: Donors unable or unwilling to undergo marrow harvest for the initial HCT, storage of autologous blood prior to marrow harvest or apheresis one week after marrow harvest
  • DONOR: Donors who are not expected to meet the minimum target dose of marrow cells (1 x 10^8 nucleated cells/kg recipient ideal body weight [IBW]) for the initial HCT; the average nucleated cell content of harvested marrow is 22 x 10^6 nucleated cells/mL or 220 x 10^8 nucleated cells/Liter
  • DONOR: HIV-positive donors
  • DONOR: Donors who are cross-match positive with recipient
  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: NCT00789776

Locations
United States, Washington
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium Recruiting
Seattle, Washington, United States, 98109
Contact: Brenda M. Sandmaier    206-667-4961      
Principal Investigator: Brenda M. Sandmaier         
United States, Wisconsin
Children's Hospital of Wisconsin Recruiting
Milwaukee, Wisconsin, United States, 53201
Contact: Monica S. Thakar    414-456-7546      
Principal Investigator: Monica S. Thakar         
Froedtert and the Medical College of Wisconsin Recruiting
Milwaukee, Wisconsin, United States, 53226
Contact: Parameswaran Hari    414-805-4600      
Principal Investigator: Parameswaran Hari         
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center
Wayne D. Kuni and Joan E. Kuni Foundation
Investigators
Principal Investigator: Brenda Sandmaier 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: NCT00789776     History of Changes
Other Study ID Numbers: 2230.00, NCI-2010-00106, 2230.00, P30CA015704, P01CA078902
Study First Received: November 12, 2008
Last Updated: January 30, 2015
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative
Aggression
Burkitt Lymphoma
Hodgkin Disease
Leukemia
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Lymphoid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Leukemia, Myelomonocytic, Acute
Leukemia, Myelomonocytic, Chronic
Leukemia, Myelomonocytic, Juvenile
Leukemia, T-Cell
Leukemia-Lymphoma, Adult T-Cell
Lymphoma
Lymphoma, B-Cell
Lymphoma, B-Cell, Marginal Zone
Lymphoma, Extranodal NK-T-Cell
Lymphoma, Follicular
Lymphoma, Large B-Cell, Diffuse
Lymphoma, Large-Cell, Anaplastic
Lymphoma, Large-Cell, Immunoblastic
Lymphoma, Mantle-Cell
Lymphoma, Non-Hodgkin
Lymphoma, T-Cell
Lymphoma, T-Cell, Cutaneous
Lymphomatoid Granulomatosis
Multiple Myeloma
Mycosis Fungoides

ClinicalTrials.gov processed this record on April 16, 2015