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

NCT00789776 | Completed Phase 1 Results DMC

• 4 other identifiers: 2230.00NCI-2010-00106P01CA078902P30CA015704
• Study Type: interventional
• Target: 41
• Locations: 1 country
• Sites: 3

Brief Summary

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.

Conditions

Acute Lymphoblastic Leukemia; Acute Myeloid Leukemia; Aggressive Non-Hodgkin Lymphoma; Diffuse Large B-Cell Lymphoma; Previously Treated Myelodysplastic Syndrome; Recurrent Chronic Lymphocytic Leukemia; Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Recurrent Indolent Adult Non-Hodgkin Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Plasma Cell Myeloma; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hodgkin Lymphoma; Refractory Plasma Cell Myeloma; Refractory Small Lymphocytic Lymphoma; Waldenstrom Macroglobulinemia

Outcome Measures

Primary Outcomes (5)

• Number of Participants With Dose Limiting Toxicities

  Defined as having at least one of the following adverse events, independent of the attribution to the Natural Killer cell infusion: grade IV infusional toxicity (based on the Adapted Common Toxicity Criteria); grade IV regimen-related toxicity (based on Adapted Common Toxicity Criteria); grade IV acute Graft-Versus-Host Disease; non-relapse mortality.

  Day 35 (28 days after NK cell infusion)

• Number of Participants With Relapsed Disease

  CML New cytogenetic abnormality and/or development of accelerated phase or blast crisis. The criteria for accelerated phase will be defined as unexplained fever greater than 38.3°C, new clonal cytogenetic abnormalities in addition to a single Ph-positive chromosome, marrow blasts and promyelocytes \>20%. AML, ALL \>5% marrow blasts by morphologic or flow cytometric, or appearance of extramedullary disease. CLL ≥1 of: Physical exam/Imaging studies (nodes, liver, and/or spleen) ≥50% increase or new, circulating lymphocytes by morphology and/or flow cytometry ≥50% increase, and lymph node biopsy w/ Richter's transformation. NHL \>25% increase in the sum of the products of the perpendicular diameters of marker lesions, or the appearance of new lesions. MM ≥100% increase of the serum myeloma protein from its lowest level, or reappearance of myeloma peaks that had disappeared w/ treatment; or definite increase in the size or number of plasmacytomas or lytic bone lesions.

  At 1 year

• Number of Participants With Grades III-IV Acute GVHD

  Number of patients who developed acute GVHD post-transplant. aGVHD Stages Skin: a maculopapular eruption involving \< 25% BSA a maculopapular eruption involving 25 - 50% BSA generalized erythroderma generalized erythroderma with bullous formation and often with desquamation Liver: bilirubin 2.0 - 3.0 mg/100 mL bilirubin 3 - 5.9 mg/100 mL bilirubin 6 - 14.9 mg/100 mL bilirubin \> 15 mg/100 mL Gut: Diarrhea is graded 1 - 4 in severity. Nausea and vomiting and/or anorexia caused by GVHD is assigned as 1 in severity. The severity of gut involvement is assigned to the most severe involvement noted. Patients with visible bloody diarrhea are at least stage 2 gut and grade 3 overall. aGVHD Grades Grade III: Stage 2 - 4 gut involvement and/or stage 2 - 4 liver involvement Grade IV: Pattern and severity of GVHD similar to grade 3 with extreme constitutional symptoms or death

  Day 100

• Number of Non-relapse Participant Mortalities

  Defined as death in any patient for whom there has not been a diagnosis of relapse or disease progression.

  Day 200

• Number of Participants Who Experienced Graft Failure

  Graft failure is defined as grade IV thrombocytopenia and neutropenia after Day +21 that lasts \>2 weeks and is refractory to growth factor support.

  Day 100

Secondary Outcomes (2)

• Number of Subjects Surviving Post-transplant.

  Up to 1 year

• Number of Participants Who Experienced Chronic Extensive GVHD

  Up to 1 year

Study Arms (1)

Treatment (non-myeloablative transplant)

EXPERIMENTAL

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.

Procedure: Allogeneic Bone Marrow Transplantation; Drug: Cyclophosphamide; Drug: Fludarabine Phosphate; Other: Laboratory Biomarker Analysis; Drug: Mycophenolate Mofetil; Biological: Natural Killer Cell Therapy; Drug: Tacrolimus; Radiation: Total-Body Irradiation

Interventions

Allogeneic Bone Marrow Transplantation PROCEDURE

Undergo donor bone marrow transplantation

Also known as: Allo BMT, Allogeneic BMT

Treatment (non-myeloablative transplant)

Cyclophosphamide DRUG

Given IV

Also known as: (-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719

Treatment (non-myeloablative transplant)

Fludarabine Phosphate DRUG

Given IV

Also known as: 2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, Oforta, SH T 586

Treatment (non-myeloablative transplant)

Laboratory Biomarker Analysis OTHER

Correlative studies

Treatment (non-myeloablative transplant)

Mycophenolate Mofetil DRUG

Given PO

Also known as: Cellcept, MMF

Treatment (non-myeloablative transplant)

Natural Killer Cell Therapy BIOLOGICAL

Given IV

Treatment (non-myeloablative transplant)

Tacrolimus DRUG

Given IV or PO

Also known as: FK 506, Fujimycin, Hecoria, Prograf, Protopic

Treatment (non-myeloablative transplant)

Total-Body Irradiation RADIATION

Undergo total-body irradiation

Also known as: TOTAL BODY IRRADIATION, Whole-Body Irradiation

Treatment (non-myeloablative transplant)

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• \) 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)
• \) Failed FLU- CY (cyclophosphamide)-rituximab (FCR) combination chemotherapy at any time point; or
• \) 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

You may not qualify if:

• 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:
• \) 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
• \) 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
• \) 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
• 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

Sponsors & Collaborators

• Fred Hutchinson Cancer Center: lead
• National Cancer Institute (NCI): collaborator
• The Wayne D. Kuni and Joan E. Kuni Foundation: collaborator

Study Sites (3)

Fred Hutch/University of Washington Cancer Consortium

Seattle, Washington, 98109, United States

Location

Children's Hospital of Wisconsin

Milwaukee, Wisconsin, 53201, United States

Location

Froedtert and the Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

MeSH Terms

Conditions

Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myeloid, Acute; Lymphoma, Large B-Cell, Diffuse; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Lymphoma, Mantle-Cell; Multiple Myeloma; Hodgkin Disease; Waldenstrom Macroglobulinemia

Interventions

Cyclophosphamide; fludarabine phosphate; Mycophenolic Acid; Tacrolimus; Whole-Body Irradiation

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Leukemia, Myeloid; Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Lymphoma; Leukemia, B-Cell; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Myeloproliferative Disorders; Bone Marrow Diseases; Neoplasms, Plasma Cell; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hemorrhagic Disorders

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids; Macrolides; Lactones; Radiotherapy; Therapeutics; Investigative Techniques

Results Point of Contact

• Title: Dr. Brenda M. Sandmaier
• Organization: Fred Hutchinson Cancer Research Center

bsandmai@fredhutch.org

(206) 667-4961

Study Officials

• Brenda Sandmaier

  Fred Hutch/University of Washington Cancer Consortium

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: November 12, 2008
• First Posted: November 13, 2008
• Study Start: October 13, 2008
• Primary Completion: May 1, 2017
• Study Completion: May 1, 2017
• Last Updated: January 31, 2020
• Results First Posted: July 12, 2018

Record last verified: 2020-01

Locations

US (3)