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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

Complete 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

Research Study Number       2230.00
    
Principal Investigator       Brenda Sandmaier, MD
    
Phase       I/II

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Research Study Description

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.

Eligibility Criteria (must meet the following to participate in this study)

Genders Eligible for Study: Both

Accepts Healthy Volunteers: No

- 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 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

Other eligibility criteria may apply.

Exclusions (conditions that would prevent participation in this study)

- Patients with available HLA-matched related donors

- Patients eligible for a curative autologous HCT

- Significant organ dysfunction that would prevent compliance with conditioning, GHVD 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

Other exclusion criteria may apply.



Research Study Number       2230.00
    
Contact       Seattle Cancer Care Alliance Intake Office
    
Telephone       800-804-8824 / 206-288-1024
    
   

Keywords
Acute Lymphoid Leukemia (ALL); Acute Myeloid Leukemia (AML); Bone Marrow and Hematopoietic Stem Cell Transplant (BMT and HSCT); Chronic Lymphoid Leukemia (CLL); Chronic Myeloid Leukemia (CML); Hematologic Malignancies; Hodgkin's Lymphoma; Leukemia; Lympho

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  • Talk to your health care providers first before making decisions about your health care.
  • Whether you are eligible for a research study depends on many things. There are specific requirements to be in research studies. These requirements are different for each study.

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