- ICH GCP
- US Clinical Trials Registry
- Klinisk forsøg NCT00080925
T-Cell-Depleted Allogeneic Stem Cell Transplantation After Immunoablative Induction Chemotherapy and Reduced-Intensity Transplantation Conditioning in Treating Patients With Hematologic Malignancies
T-Cell Depleted, Reduced-Intensity Allogeneic Stem Cell Transplantation From Haploidentical Related Donors For Hematologic Malignancies
RATIONALE: Donor peripheral stem cell transplantation may be able to replace bone marrow and immune cells that were destroyed by chemotherapy. Sometimes the transplanted cells from a donor are rejected by the body's normal cells. Eliminating the T cells from the donor cells before transplanting them and giving cyclosporine may prevent this from happening.
PURPOSE: This phase I trial is studying the side effects of T-cell-depleted allogeneic stem cell transplantation after immunoablative induction chemotherapy and reduced-intensity transplantation conditioning (chemotherapy) in treating patients with hematologic malignancies.
Studieoversigt
Status
Betingelser
Intervention / Behandling
- Medicin: cyclophosphamid
- Medicin: prednison
- Medicin: cytarabin
- Medicin: etoposid
- Medicin: vincristinsulfat
- Biologisk: terapeutiske allogene lymfocytter
- Medicin: fludarabin fosfat
- Medicin: doxorubicin hydrochlorid
- Procedure: perifer blodstamcelletransplantation
- Biologisk: filgrastim
- Biologisk: rituximab
- Medicin: cyclosporin
- Biologisk: graft-versus-tumor-induktionsterapi
Detaljeret beskrivelse
OBJECTIVES:
Primary
- Determine engraftment in patients with hematologic malignancies treated with T-cell-depleted allogeneic stem cell transplantation after immunoablative induction chemotherapy and reduced-intensity transplantation conditioning.
Secondary
- Determine the incidence of acute graft-versus-host disease (GVHD), and nonrelapse mortality (within 100 days after transplantation) in these patients.
- Correlate levels of host immunosuppression before transplantation conditioning, as evaluated by peripheral blood CD4 counts, with graft rejection/failure within 100 days after transplantation and the level of donor hematopoietic chimerism 28 days after transplantation in these patients.
- Correlate donor-versus-recipient natural killer cell alloreactivity with graft rejection/failure, acute GVHD, and relapse of malignant disease in patients treated with this regimen.
- Determine the development of allospecific cytotoxic T-lymphocytes after transplantation in patients with myeloid or lymphoid leukemia.
- Correlate serum interleukin-7 and interleukin-15 levels with in vivo changes in host lymphocyte subpopulations in these patients during sequential immunoablative chemotherapy, before allogeneic stem cell transplantation, and during immune reconstitution after transplantation.
OUTLINE: This is a pilot study.
Induction chemotherapy: Patients receive 1 of 2 induction chemotherapy regimens according to diagnosis. Patients with partial response or better after prior therapy (i.e., already adequately immune depleted) proceed directly to the transplantation preparative regimen.
- Regimen A (Hodgkin's lymphoma, non-Hodgkin's lymphoma [except lymphoblastic lymphoma], chronic lymphocytic leukemia, prolymphocytic leukemia, or multiple myeloma): Patients receive rituximab IV (if they have CD20+ B-cell malignancies) on day 1; fludarabine IV over 30 minutes on days 1-4; etoposide, doxorubicin, and vincristine IV continuously on days 1-4; cyclophosphamide IV over 30 minutes on day 5; oral prednisone on days 1-5; and filgrastim (G-CSF) subcutaneously (SC) beginning on day 6 and continuing until blood counts recover.
- Regimen B (lymphoblastic lymphoma, acute myeloid leukemia, acute lymphoblastic leukemia, refractory anemia with excess blasts, myeloproliferative disorders, chronic myelomonocytic leukemia, or chronic myelogenous leukemia): Patients receive G-CSF SC beginning 24 hours before initiating induction chemotherapy and continuing until blood counts recover. Patients also receive fludarabine IV over 30 minutes and cytarabine IV over 4 hours on days 1-5.
For both regimens, treatment repeats every 21 days for 1-2 courses. Patients who achieve remission or who have responsive or stable disease after induction chemotherapy then proceed to transplantation preparative regimen chemotherapy.
- Transplantation preparative regimen chemotherapy: Patients receive fludarabine IV over 30 minutes and cyclophosphamide IV over 2 hours on days -6 to -3.
- Graft-versus-host disease (GVHD) prophylaxis: Patients receive cyclosporine IV over 2 hours twice daily beginning on day -1 and continuing IV or orally until day 100. Patients with no acute GVHD at day 100 taper cyclosporine over 12 weeks.
- Allogeneic stem cell transplantation (SCT): Patients undergo T-cell-depleted allogeneic peripheral blood SCT on day 0. Patients receive G-CSF SC beginning on day 0 and continuing until blood counts recover.
- Donor lymphocyte infusion (DLI): Patients with persistent or progressive malignant disease after transplantation or mixed chimerism that does not improve after tapering or discontinuing immunosuppression therapy may receive DLI. DLI may be administered alone or in combination with chemotherapy. DLI repeats every 4 weeks until adequate donor chimerism is achieved or until GVHD develops.
Patients are followed at 28 and 100 days and then at 6, 9, 12, 18, and 24 months.
PROJECTED ACCRUAL: A total of 6-20 patients will be accrued for this study within 2 years.
Undersøgelsestype
Tilmelding (Forventet)
Fase
- Fase 1
Kontakter og lokationer
Studiesteder
-
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Maryland
-
Bethesda, Maryland, Forenede Stater, 20892-1182
- Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office
-
-
Deltagelseskriterier
Berettigelseskriterier
Aldre berettiget til at studere
Tager imod sunde frivillige
Køn, der er berettiget til at studere
Beskrivelse
DISEASE CHARACTERISTICS:
Diagnosis of 1 of the following hematologic malignancies:
Acute myeloid leukemia (AML), meeting 1 of the following criteria:
In first complete remission (CR1), meeting 1 of the following criteria:
Adverse cytogenetics with minimal residual disease detectable by flow cytometry, cytogenetic analysis, fluorescence in situ hybridization (FISH), or polymerase chain reaction (PCR), defined as 1 of the following:
- Complex karyotype [≥ 3 abnormalities]
- inv(3) or t(3;3)
- t(6;9)
- t(6;11)
- Monosomy 7
- Trisomy 8, alone or with an abnormality other than t(8;21), t(9;11), inv(16), or t(16;16)
- t(11;19) (q23;p13.1)
- Failed to achieve CR after primary induction chemotherapy
- Secondary AML
- In second or subsequent remission (CR2 or greater)
Acute lymphoblastic leukemia, meeting 1 of the following criteria:
In CR1, meeting 1 of the following criteria:
Adverse cytogenetics with minimal residual disease detectable by flow cytometry, cytogenetic analysis, FISH, or PCR, defined as the following:
- Translocations involving 11q23, t(9;22), or bcr-abl rearrangement
- Failed to achieve CR after primary induction chemotherapy
- In CR2, if CR1 was < 12 months
- In CR3 or greater
Myelodysplastic syndromes (MDS)
- INT-2 or high-risk by International Prognostic Scoring System
- No MDS with Fanconi anemia
Chronic myelogenous leukemia (CML), meeting 1 of the following criteria:
- Accelerated phase with treatment failure after imatinib mesylate
- Blast phase
Myeloproliferative disorders, meeting 1 of the following criteria:
Agnogenic myeloid metaplasia with adverse-risk features, meeting at least 2 of the following criteria:
- Hemoglobin < 10 g/dL or > 10g/dL if transfusion-dependent
- WBC < 4,000/mm^3 OR > 30,000/mm^3 OR requires cytoreductive therapy to maintain WBC < 30,000/mm^3
- Abnormal cytogenetics, including +8, 12p-
- Polycythemia vera or essential thrombocythemia in transformation to secondary AML
Myelodysplastic/myeloproliferative disease
- Chronic myelomonocytic leukemia
Hodgkin's lymphoma or non-Hodgkin's lymphoma
- Refractory lymphoma with progressive disease during combination chemotherapy
- Relapse after OR ineligible for autologous stem cell transplantation (SCT)
Chronic lymphocytic leukemia
- Treatment failure* after fludarabine, chlorambucil, and at least 1 other salvage regimen
Prolymphocytic leukemia (PLL), meeting 1 of the following criteria:
T-PLL
- Treatment failure* after alemtuzumab and at least 1 other regimen
B-PLL
- Treatment failure* after fludarabine and at least 1 other salvage regimen
Multiple myeloma, meeting 1 of the following criteria:
- Relapse after autologous SCT
- Plasma cell leukemia
Adverse cytogenetics, defined as 1 of the following:
- del(13q) = 11q translocation NOTE: *Treatment failure is defined as relapse within 6 months OR failure to achieve remission
Less than 10% blasts in bone marrow and no circulating blasts in peripheral blood for the following diagnoses:
- Primary or secondary leukemia
- Refractory anemia with excess blasts
- CML
- Other eligible diagnosis in transformation to acute leukemia
- Expected survival of approximately 1 year or less with conventional therapy
No active CNS involvement by malignancy*
- Prior CNS involvement with no current evidence of CNS malignancy allowed NOTE: *Active CNS malignancy is defined by lymphoma: tumor mass on CT scan or leptomeningeal disease OR leukemia: blasts present on cerebrospinal fluid cytospin
Availability of a donor who is a sibling, parent, or offspring who shares 1 full haplotype (HLA-A, -B, or -DR)
- Recipient and donor must have at least a 2-antigen disparity in either the host-versus-graft or graft-versus-host direction
- Parent or offspring donor who is mismatched for a single HLA antigen (i.e., 5/6 HLA) is allowed
- No sibling donor who is 6/6 HLA-matched OR mismatched for a single HLA antigen (i.e., 5/6 HLA)
- No unrelated donor identified in a prior or current National Marrow Donor Program registry search
PATIENT CHARACTERISTICS:
Age
- 18 to 55
Performance status
- ECOG 0-2 OR
- Karnofsky 60-100%
Life expectancy
- At least 3 months
Hematopoietic
- See Disease Characteristics
- Absolute neutrophil count ≥ 1,000/mm^3*
- Platelet count ≥ 20,0000/mm^3* (without transfusion) NOTE: *Lower values may be accepted at the discretion of the principal investigator or study chairperson if due to bone marrow involvement by malignancy
Hepatic
- ALT and AST ≤ 2.5 times upper limit of normal (ULN)*
- Bilirubin ≤ 2.5 times ULN*
- Unconjugated hyperbilirubinemia consistent with Gilbert's syndrome allowed
No chronic active hepatitis B infection
- Hepatitis B core antibody positive allowed provided patient is surface antigen negative and has no evidence of active infection
No hepatitis C viral infection
- Seronegative for anti-hepatitis C antibody and detectable hepatitis C viral RNA by reverse transcriptase-polymerase chain reaction assay NOTE: *Higher levels may be accepted at the discretion of the principle investigator or study chairperson if such elevations are due to liver involvement by malignancy
Renal
- Creatinine ≤ 1.5 mg/dL OR
- Creatinine clearance ≥ 50 mL/min
Cardiovascular
- LVEF ≥ 45%
Pulmonary
- DLCO ≥ 50% of expected value (corrected for blood hemoglobin level and alveolar volume)
Other
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective contraception during and for 1 year after study participation
- HIV negative
- No active infection not responding to antimicrobial therapy
- No psychiatric disorder that would preclude study compliance or informed consent
PRIOR CONCURRENT THERAPY:
Biologic therapy
- See Disease Characteristics
- At least 2 weeks since prior monoclonal antibody therapy
Chemotherapy
- See Disease Characteristics
- At least 2 weeks since prior systemic chemotherapy
Endocrine therapy
- Not specified
Radiotherapy
- Not specified
Surgery
- Not specified
Other
- Recovered from all prior therapy
- No administration of tyrosine kinase (TK) inhibitors, including imatinib mesylate and dasatinib, during the conditioning regimen; TK inhibitor administration may resume 28 days after transplantation
Studieplan
Hvordan er undersøgelsen tilrettelagt?
Design detaljer
- Primært formål: Behandling
Samarbejdspartnere og efterforskere
Samarbejdspartnere
Efterforskere
- Studiestol: Michael R. Bishop, MD, National Cancer Institute (NCI)
Datoer for undersøgelser
Studer store datoer
Studiestart
Studieafslutning (Faktiske)
Datoer for studieregistrering
Først indsendt
Først indsendt, der opfyldte QC-kriterier
Først opslået (Skøn)
Opdateringer af undersøgelsesjournaler
Sidste opdatering sendt (Skøn)
Sidste opdatering indsendt, der opfyldte kvalitetskontrolkriterier
Sidst verificeret
Mere information
Begreber relateret til denne undersøgelse
Nøgleord
- primær myelofibrose
- tilbagevendende grad 3 follikulært lymfom
- tilbagevendende voksent diffust storcellet lymfom
- tilbagevendende voksen immunoblastisk storcellet lymfom
- recidiverende voksen Burkitt lymfom
- refraktær anæmi med overskydende blaster
- kronisk myelomonocytisk leukæmi
- de novo myelodysplastiske syndromer
- tidligere behandlede myelodysplastiske syndromer
- sekundære myelodysplastiske syndromer
- akut myeloid leukæmi hos voksne med 11q23 (MLL) abnormiteter
- akut myeloid leukæmi hos voksne med inv(16)(p13;q22)
- akut myeloid leukæmi hos voksne med t(15;17)(q22;q12)
- akut myeloid leukæmi hos voksne med t(16;16)(p13;q22)
- akut myeloid leukæmi hos voksne med t(8;21)(q22;q22)
- sekundær akut myeloid leukæmi
- kronisk fase kronisk myelogen leukæmi
- akut myeloid leukæmi hos voksne i remission
- recidiverende voksen Hodgkin lymfom
- recidiverende voksent diffust små spaltet celle lymfom
- recidiverende voksent diffust blandet celle lymfom
- recidiverende kronisk myelogen leukæmi
- stadium II myelomatose
- stadium III myelomatose
- tilbagevendende grad 1 follikulært lymfom
- tilbagevendende grad 2 follikulært lymfom
- tilbagevendende marginal zone lymfom
- tilbagevendende lille lymfocytisk lymfom
- ekstranodal marginal zone B-celle lymfom af slimhinde-associeret lymfoid væv
- nodal marginal zone B-celle lymfom
- milt marginal zone lymfom
- tilbagevendende lymfoblastisk lymfom hos voksne
- tilbagevendende kappecellelymfom
- refraktær kronisk lymfatisk leukæmi
- refraktær myelomatose
- polycytæmi vera
- essentiel trombocytæmi
- prolymfocytisk leukæmi
- accelereret fase kronisk myelogen leukæmi
- akut lymfatisk leukæmi hos voksne i remission
- myelodysplastisk/myeloproliferativ neoplasma, uklassificerbar
Yderligere relevante MeSH-vilkår
- Patologiske processer
- Hjerte-kar-sygdomme
- Karsygdomme
- Sygdomme i immunsystemet
- Neoplasmer efter histologisk type
- Lymfoproliferative lidelser
- Lymfesygdomme
- Immunproliferative lidelser
- Neoplasmer efter sted
- Sygdom
- Knoglemarvssygdomme
- Hæmatologiske sygdomme
- Hæmoragiske lidelser
- Hæmostatiske lidelser
- Paraproteinæmier
- Blodproteinforstyrrelser
- Forstadier til kræft
- Neoplasmer
- Lymfom
- Syndrom
- Myelodysplastiske syndromer
- Hæmatologiske neoplasmer
- Myelomatose
- Neoplasmer, Plasmacelle
- Leukæmi
- Præleukæmi
- Plasmacytom
- Myeloproliferative lidelser
- Myelodysplastisk-myeloproliferative sygdomme
- Lægemidlers fysiologiske virkninger
- Molekylære mekanismer for farmakologisk virkning
- Anti-infektionsmidler
- Antivirale midler
- Enzymhæmmere
- Anti-inflammatoriske midler
- Antirheumatiske midler
- Antimetabolitter, Antineoplastisk
- Antimetabolitter
- Antineoplastiske midler
- Immunsuppressive midler
- Immunologiske faktorer
- Tubulin modulatorer
- Antimitotiske midler
- Mitose modulatorer
- Glukokortikoider
- Hormoner
- Hormoner, hormonsubstitutter og hormonantagonister
- Antineoplastiske midler, hormonelle
- Antineoplastiske midler, Alkylering
- Alkyleringsmidler
- Myeloablative agonister
- Antineoplastiske midler, fytogene
- Topoisomerase II-hæmmere
- Topoisomerasehæmmere
- Antineoplastiske midler, immunologiske
- Dermatologiske midler
- Antibiotika, antineoplastisk
- Antifungale midler
- Calcineurin-hæmmere
- Cyclofosfamid
- Etoposid
- Rituximab
- Prednison
- Doxorubicin
- Liposomal doxorubicin
- Fludarabin
- Fludarabin phosphat
- Cytarabin
- Vincristine
- Cyclosporin
- Cyclosporiner
Andre undersøgelses-id-numre
- 040116
- 04-C-0116
- CDR0000357432
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