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Autologous Peripheral Blood Stem Cell Transplant Followed by Donor Bone Marrow Transplant in Treating Patients With High-Risk Hodgkin Lymphoma, Non-Hodgkin Lymphoma, Multiple Myeloma, or Chronic Lymphocytic Leukemia

NCT01008462

Description:

This phase II trial studies autologous peripheral blood stem cell transplant followed by donor bone marrow transplant in treating patients with high-risk Hodgkin lymphoma, non-Hodgkin lymphoma, multiple myeloma, or chronic lymphocytic leukemia. Autologous stem cell transplantation uses the patient's stem cells and does not cause graft versus host disease (GVHD) and has a very low risk of death, while minimizing the number of cancer cells. Peripheral blood stem cell (PBSC) transplant uses stem cells from the patient or a donor and may be able to replace immune cells that were destroyed by chemotherapy. These donated stem cells may help destroy cancer cells. Bone marrow transplant known as a nonmyeloablative transplant uses stem cells from a haploidentical family donor. Autologous peripheral blood stem cell transplant followed by donor bone marrow transplant may work better in treating patients with high-risk Hodgkin lymphoma, non-Hodgkin lymphoma, multiple myeloma, or chronic lymphocytic leukemia.

Related Conditions:
  • Chronic Lymphocytic Leukemia
  • Lymphoma
  • Multiple Myeloma
  • Plasma Cell Leukemia
  • Small Lymphocytic Lymphoma
  • T-Cell Prolymphocytic Leukemia
  • Waldenstrom Macroglobulinemia
Recruiting Status:

Completed

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Autologous Peripheral Blood Stem Cell Transplant Followed by Donor Bone Marrow Transplant in Treating Patients With High-Risk Hodgkin Lymphoma, Non-Hodgkin Lymphoma, Multiple Myeloma, or Chronic Lymphocytic Leukemia
  • Official Title: Sequential Autologous HCT / Nonmyeloablative Allogeneic HCT Using Related, HLA-Haploidentical Donors for Patients With High-Risk Lymphoma, Multiple Myeloma, or Chronic Lymphocytic Leukemia

Clinical Trial IDs

  • ORG STUDY ID: 2241.00
  • SECONDARY ID: NCI-2009-01334
  • SECONDARY ID: 2241.00
  • SECONDARY ID: P30CA015704
  • NCT ID: NCT01008462

Conditions

  • B-Cell Prolymphocytic Leukemia
  • Hypodiploidy
  • Loss of Chromosome 17p
  • Plasma Cell Leukemia
  • Progression of Multiple Myeloma or Plasma Cell Leukemia
  • Recurrent Adult Hodgkin Lymphoma
  • Recurrent Adult Non-Hodgkin Lymphoma
  • Recurrent Childhood Hodgkin Lymphoma
  • Recurrent Childhood Non-Hodgkin Lymphoma
  • Recurrent Chronic Lymphocytic Leukemia
  • Recurrent Plasma Cell Myeloma
  • Recurrent Small Lymphocytic Lymphoma
  • Refractory Childhood Hodgkin Lymphoma
  • Refractory Chronic Lymphocytic Leukemia
  • Refractory Non-Hodgkin Lymphoma
  • Refractory Plasma Cell Myeloma
  • Refractory Small Lymphocytic Lymphoma
  • t(14;16)
  • t(4;14)
  • T-Cell Prolymphocytic Leukemia
  • Waldenstrom Macroglobulinemia

Interventions

DrugSynonymsArms
CarmustineBCNU, Becenum, Becenun, BiCNU, Bis(chloroethyl) Nitrosourea, Bis-Chloronitrosourea, Carmubris, Carmustin, Carmustinum, FDA 0345, Gliadel, N,N'-Bis(2-chloroethyl)-N-nitrosourea, Nitrourean, Nitrumon, SK 27702, SRI 1720, WR-139021Treatment (autologous HCT, donor HCT)
Cyclophosphamide(-)-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- 138719Treatment (autologous HCT, donor HCT)
Cytarabine.beta.-Cytosine arabinoside, 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-.beta.-D-Arabinofuranosylcytosine, 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-Beta-D-arabinofuranosylcytosine, 1.beta.-D-Arabinofuranosylcytosine, 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-, 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-, Alexan, Ara-C, ARA-cell, Arabine, Arabinofuranosylcytosine, Arabinosylcytosine, Aracytidine, Aracytin, Aracytine, Beta-cytosine Arabinoside, CHX-3311, Cytarabinum, Cytarbel, Cytosar, Cytosine Arabinoside, Cytosine-.beta.-arabinoside, Cytosine-beta-arabinoside, Erpalfa, Starasid, Tarabine PFS, U 19920, U-19920, Udicil, WR-28453Treatment (autologous HCT, donor HCT)
EtoposideDemethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, Lastet, Toposar, Vepesid, VP 16-213, VP-16, VP-16-213Treatment (autologous HCT, donor HCT)
Fludarabine Phosphate2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586Treatment (autologous HCT, donor HCT)
MelphalanAlanine Nitrogen Mustard, CB-3025, L-PAM, L-Phenylalanine Mustard, L-sarcolysin, L-Sarcolysin Phenylalanine mustard, L-Sarcolysine, Melphalanum, Phenylalanine Mustard, Phenylalanine nitrogen mustard, Sarcoclorin, Sarkolysin, WR-19813Treatment (autologous HCT, donor HCT)
Mycophenolate MofetilCellcept, MMFTreatment (autologous HCT, donor HCT)
TacrolimusFK 506, Fujimycin, Hecoria, Prograf, ProtopicTreatment (autologous HCT, donor HCT)

Purpose

This phase II trial studies autologous peripheral blood stem cell transplant followed by donor bone marrow transplant in treating patients with high-risk Hodgkin lymphoma, non-Hodgkin lymphoma, multiple myeloma, or chronic lymphocytic leukemia. Autologous stem cell transplantation uses the patient's stem cells and does not cause graft versus host disease (GVHD) and has a very low risk of death, while minimizing the number of cancer cells. Peripheral blood stem cell (PBSC) transplant uses stem cells from the patient or a donor and may be able to replace immune cells that were destroyed by chemotherapy. These donated stem cells may help destroy cancer cells. Bone marrow transplant known as a nonmyeloablative transplant uses stem cells from a haploidentical family donor. Autologous peripheral blood stem cell transplant followed by donor bone marrow transplant may work better in treating patients with high-risk Hodgkin lymphoma, non-Hodgkin lymphoma, multiple myeloma, or chronic lymphocytic leukemia.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Event-free survival (EFS) at 1-year after autograft.

      SECONDARY OBJECTIVES:

      I. Relapse rates at 1-year after autograft.

      II. Overall survival (OS) at 1-year after autograft.

      III. Incidence of grades II-IV acute GVHD and chronic extensive GVHD.

      IV. Non-relapse mortality (NRM) at 200 days and 1 year after allograft.

      V. Donor engraftment at day +84.

      VI. Incidence of infections.

      OUTLINE:

      CONDITIONING REGIMEN 1 (lymphoma, Waldenstrom macroglobulinemia, or chronic lymphocytic
      leukemia [CLL] with no dose limiting radiation or significant comorbidities: Patients receive
      cyclophosphamide intravenously (IV) on days -6 and -5. Patients undergo high-dose total body
      irradiation (TBI) twice daily (BID) on days -3 to -1.

      CONDITIONING REGIMEN 2 (lymphoma, Waldenstrom Macroglobulinemia, CLL, with prior
      dose-limiting radiation, or significant comorbidities): Patients receive carmustine IV on day
      -7, etoposide IV BID on days -6 to -3, cytarabine IV BID on days -6 to -3, and melphalan IV
      on day -2.

      CONDITIONING REGIMEN 3 (multiple myeloma or plasma cell leukemia, with no significant renal
      insufficiency or other significant comorbidities): Patients receive high-dose melphalan IV on
      day -2.

      CONDITIONING REGIMEN 4 (multiple myeloma or plasma cell leukemia, with significant renal
      insufficiency or other significant comorbidities): Patients receive lessened dose of
      melphalan IV on day -2.

      PBSC TRANSPLANTATION: All patients undergo autologous PBSC transplantation on day 0.

      WAITING INTERVAL: Between 40 and 120 days.

      NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV once daily
      (QD) on days -6 to -2 and cyclophosphamide IV QD on days -6 to -5 and day 3. Patients infused
      with donor's peripheral blood stem cells will additionally receive cyclophosphamide IV on day
      4. Patients undergo low-dose TBI on day -1.

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

      GRAFT VERSUS HOST DISEASE PROPHYLAXIS: Beginning on day 4, patients receive tacrolimus orally
      (PO) or IV and taper beginning on day 86 if no graft-versus-host disease. Patients also
      receive mycophenolate mofetil PO thrice daily (TID) on days 4 - 35.

      PERIPHERAL BLOOD COUNT SUPPORT: Patients receive filgrastim (G-CSF) IV or subcutaneously (SC)
      beginning from day 4 and continue till blood counts recover.

      ALLOGENEIC PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMC) TRANSPLANTATION: Patients undergo donor
      PBMC transplantation on day 0.

      GRAFT VERSUS HOST DISEASE PROPHYLAXIS: Beginning on day 5, patients receive tacrolimus orally
      (PO) or IV and taper beginning on day 86 if no graft-versus-host disease. Patients also
      receive mycophenolate mofetil PO thrice daily (TID) on days 5 - 35.

      PERIPHERAL BLOOD COUNT SUPPORT: Patients receive filgrastim IV or SC beginning from day 5 and
      continue till blood counts recover.

      After completion of study treatment, patients are followed up annually for 5 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (autologous HCT, donor HCT)ExperimentalSee Detailed Description
  • Carmustine
  • Cyclophosphamide
  • Cytarabine
  • Etoposide
  • Fludarabine Phosphate
  • Melphalan
  • Mycophenolate Mofetil
  • Tacrolimus

Eligibility Criteria

        Inclusion Criteria:

          -  Must have the capacity to give informed consent

          -  Detectable tumor prior to mobilization regimen

          -  Patients with stored autologous stem cells will be allowed

          -  Stem cells from an identical donor could be used for autologous hematopoietic cell
             transplant (HCT)

          -  Marrow is the preferred source of stem cells from the HLA-haploidentical donor,
             however, peripheral blood mononuclear cells (PBMC) could be used as stem cell source,
             after clearance with the Fred Hutchinson Cancer Research Center (FHCRC) principal
             investigator, in the case of difficulties or contraindications to bone marrow harvest
             from the donor

          -  Cross-over to other tandem autologous-allogeneic research protocol (#1409 or other
             appropriate protocol) will be allowed if a suitable HLA-matched related or unrelated
             donor is identified before receiving the allogeneic transplantation and if the patient
             meets the eligibility criteria of the subsequent study

          -  Cross-over from other tandem autologous-allogeneic research protocol (#1409 or other
             appropriate protocol) will be allowed if the patient loses the suitable HLA-matched
             related or unrelated donor but has an available HLA-haploidentical donor before
             receiving the allogeneic transplantation and if the patient meets the eligibility
             criteria of the subsequent study

          -  Lymphoma: patients with

               -  Diagnosis of non-Hodgkin lymphoma (NHL) or Hodgkin's lymphoma (HL), of any
                  histological grade

               -  Refractory or relapsed disease after standard chemotherapy

               -  High risk of early relapse following autograft alone

          -  Waldenstrom's macroglobulinemia: must have failed 2 courses of therapy

          -  CLL:

               -  Patients with either a:

                    -  Diagnosis of T-cell CLL or T-cell prolymphocytic leukemia (PLL) who have
                       failed initial chemotherapy, patients with T cell CLL or PLL or

                    -  Diagnosis of B-cell CLL, B-cell small lymphocytic lymphoma, or B-cell CLL
                       that progressed to PLL who either:

                         1. Failed to meet National Cancer Institute (NCI) Working Group criteria
                            for complete or partial response after therapy with a regimen
                            containing fludarabine (or another nucleoside analog, e.g.
                            2-chlorodeoxyadenosine [CDA], pentostatin) or experience disease
                            relapse within 12 months after completing therapy with a regimen
                            containing fludarabine (or another nucleoside analog)

                         2. Failed any aggressive chemotherapy regimen, such as fludarabine,
                            cyclophosphamide and rituximab (FCR), at any time point

                         3. Have "17p deletion" cytogenetic abnormality and relapsed at any time
                            point after initial chemotherapy

               -  Harvesting criteria for autologous HCT:

                    -  Previously collected PBMC may be used

                    -  Circulating CLL cells < 5000

               -  Marrow involvement with CLL cells < 50%

          -  Multiple myeloma (MM): patients who

               -  Have received induction therapy for a minimum of 4 cycles

               -  In addition, patients must meet at least one of the following criteria I-IX
                  (I-VII at time of diagnosis or pre-autograft):

                    -  Any abnormal karyotype by metaphase analysis except for isolated t(11,14),

                    -  Fluorescent in situ hybridization (FISH) translocation 4:14,

                    -  FISH translocation 14:16,

                    -  FISH deletion 17p,

                    -  Beta2 (B2)-microglobulin > 5.5 mg/ml,

                    -  Cytogenetic hypodiploidy

                    -  Plasmablastic morphology (>= 2%)

                    -  Recurrent or non-responsive (less than partial remission [PR]) MM after at
                       least two different lines of conventional chemotherapy

                    -  Progressive MM after a previous autograft (provided stored autologous
                       cluster of differentiation [CD]34 cells are available)

          -  Plasma cell leukemia: after induction chemotherapy

          -  DONOR: Related donors who are genotypically identical for one HLA haplotype and who
             may be mismatched at the HLA-A, -B, -C or DRB1 loci of the unshared haplotype with the
             exception of single HLA-A, -B or -C allele mismatches

          -  DONOR: Marrow is the preferred source of stem cells from the HLA-haploidentical donor,
             however PBMC could be used as stem cell source, after clearance with the FHCRC
             principal investigator, in the case of difficulties or contraindications to bone
             marrow harvest from the donor

          -  DONOR: In the case that PBMC will be used as stem cell source, 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: Age >= 12 years of age

        Exclusion Criteria:

          -  Life expectancy severely limited by disease other than malignancy

          -  Seropositive for the human immunodeficiency virus

          -  Female patients who are pregnant or breastfeeding

          -  Fertile men or women unwilling to use contraceptive techniques during and for 12
             months following treatment

          -  Central nervous system (CNS) involvement with disease refractory to intrathecal
             chemotherapy

          -  Patients with active non-hematological malignancies (except non-melanoma skin cancers)
             or those with non-hematological 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 5 years

               -  This exclusion does not apply to patients with non-hematologic malignancies that
                  do not require therapy

          -  Patients with fungal infection and radiological progression after receipt of
             amphotericin B or active triazole for greater than 1 month

          -  Symptomatic coronary artery disease or ejection fraction < 40% or other cardiac
             failure requiring therapy (or, if unable to obtain ejection fraction, shortening
             fraction of < 26%); ejection fraction is required if the patient has a history of
             anthracyclines or history of cardiac disease; patients with a shortening fraction <
             26% may be enrolled if approved by a cardiologist

          -  Corrected diffusion capacity of the lungs for carbon monoxide (DLCO) < 50% of
             predicted, forced expiratory volume in one second (FEV1) < 50% of predicted, and/or
             receiving supplementary continuous oxygen; the FHCRC principal investigator (PI) of
             the study must approve of enrollment of all patients with pulmonary nodules

          -  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, and symptomatic biliary disease

          -  Karnofsky score < 50% for adult patients

          -  Lansky play-performance score < 40 for pediatric patients

          -  Patient with poorly controlled hypertension despite multiple antihypertensives

          -  DONOR: Donor-recipient pairs in which the HLA-mismatch is only in the
             host-versus-graft (HVG) direction

          -  DONOR: Infection with human immunodeficiency virus (HIV)

          -  DONOR: Weight < 20 kg

          -  DONOR: A positive anti-donor cytotoxic crossmatch
      
Maximum Eligible Age:75 Years
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-free survival (PFS)
Time Frame:From the date of autologous transplant until the time of death, assessed up to 1 year
Safety Issue:
Description:An observed 1-year PFS of >= 50% would be considered efficacious and worthy of further study.

Secondary Outcome Measures

Measure:Early non-relapse mortality (NRM)
Time Frame:At 200 days
Safety Issue:
Description:Recorded and reported on clinical reporting forms. Every effort will be made to determine the exact cause of death for all patients as they occur. Reasonable evidence will be taken to mean that the lower bound of a one-sided 80% confidence interval for the true rate of NRM is above 0.30.
Measure:Early non-relapse mortality (NRM)
Time Frame:At 1 year
Safety Issue:
Description:Recorded and reported on clinical reporting forms. Every effort will be made to determine the exact cause of death for all patients as they occur. Reasonable evidence will be taken to mean that the lower bound of a one-sided 80% confidence interval for the true rate of NRM is above 0.30.
Measure:Immune reconstitution after allografting
Time Frame:Up to 1 year
Safety Issue:
Description:
Measure:Incidence of acute and chronic graft versus host disease (GVHD)
Time Frame:Up to 84 days
Safety Issue:
Description:Skin involvement should be assessed by punch biopsy. The percentage of body surface area involved will be recorded. Gastrointestinal symptoms suspicious for GVHD should be evaluated by endoscopy and biopsy as indicated. Time to onset of GVHD will be recorded.
Measure:Incidence of engraftment failure or rejection
Time Frame:Up to 1 year
Safety Issue:
Description:
Measure:Incidence of infections
Time Frame:Up to 1 year
Safety Issue:
Description:
Measure:Overall survival
Time Frame:At 1 year
Safety Issue:
Description:Estimated by the method of Kaplan and Meier. Confidence intervals will also be estimated.
Measure:Rates of relapse, defined by presence of malignant cells in marrow, peripheral blood or extramedullary sites detectable by morphologic, flow cytometric, cytogenetic or molecular assays not evident at the time of transplant
Time Frame:At 1 year
Safety Issue:
Description:Summarized using cumulative incidence estimates. Confidence intervals will also be estimated.
Measure:Reconstitution of lymphocyte subsets in peripheral blood
Time Frame:Up to 84 days
Safety Issue:
Description:Absolute counts of B-cells (CD19+), T-cell subsets (determined by differential expression of CD4, CD8 or CD45 isoforms on CD3+ cells) and natural killer cells (CD16+/CD56+) in peripheral blood should be compared to pre-transplant lymphocyte.
Measure:Severity of acute and chronic graft versus host disease (GVHD)
Time Frame:Up to 84 days
Safety Issue:
Description:Skin involvement should be assessed by punch biopsy. The percentage of body surface area involved will be recorded. Gastrointestinal symptoms suspicious for GVHD should be evaluated by endoscopy and biopsy as indicated. Time to onset of GVHD will be recorded.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Completed
Lead Sponsor:Fred Hutchinson Cancer Research Center

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