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Phase I/II Randomized Pilot Study of Targeted Immune-Depleting Chemotherapy, Reduced-Intensity Allogeneic Hematopoietic Stem Cell Transplantation from an HLA-Matched Unrelated Donor, and Graft-Versus-Host Disease Prophylaxis Comprising Tacrolimus, Methotrexate, and Sirolimus Versus Alemtuzumab and Cyclosporine in Patients With High-Risk Advanced Hematologic Malignancies or Other Diseases
Alternate Title Basic Trial Information Objectives Entry Criteria Expected Enrollment Outcomes Outline Trial Contact Information Registry Information
Alternate Title
Chemotherapy, Donor Stem Cell Transplant, and Graft-Versus-Host Disease Prevention in Treating Patients With Advanced Hematologic Cancer or Other Disease
Basic Trial Information
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Protocol IDs
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Phase II, Phase I
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Biomarker/Laboratory analysis, Treatment
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Active
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18 to 69
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NCI
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NCI-07-C-0195 07-C-0195, NCT00520130
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Special Category:
NIH Clinical Center trial Objectives Primary - Assess the effects of two biologically distinct graft-vs-host disease (GVHD) prophylaxis regimens (tacrolimus/methotrexate/sirolimus [TMS] and alemtuzumab/cyclosporine [AC]) on immune reconstitution in patients with high-risk advanced hematologic malignancies or other disorders receiving targeted immune-depleting chemotherapy and reduced-intensity allogeneic hematopoietic stem cell transplantation (HSCT) from HLA-matched unrelated donors.
- Assess the overall safety of this therapy, as determined by engraftment, severe (grade III-IV) acute GVHD, early and late treatment-related mortality, and overall survival, in these patients.
Secondary - Assess the effects of two different GVHD prophylaxis regimens (TMS and AC) on CD4+ T-cell receptor Vβ repertoire by CDR3 spectratyping at 1, 6, and 12 months post-transplantation.
- Assess the effects of these regimens on CD8+ T-cell receptor Vβ repertoire by CDR3 spectratyping at 1, 3, 6, and 12 months post-transplantation.
- Assess the effects of these regimens on the kinetics of CD4+ and CD8+ T cells and NK-cell depletion and recovery.
- Correlate serum interleukin (IL)-7 and IL-15 levels during early immune reconstitution after administration of these regimens.
- Characterize the pattern of post-transplant CD14+ monocyte production of inflammatory cytokines IL-1-α and TNF-α.
- Assess the impact of these regimens on donor/recipient chimerism.
- Determine the incidence and severity of acute GVHD following sequential targeted immune-depleting chemotherapy and reduced-intensity allogeneic HSCT from HLA-matched unrelated donors.
- Determine and monitor incidence, organ severity, and overall severity of chronic GVHD prospectively using the newly developed NIH Consensus Conference diagnosis and staging criteria and preliminarily validate these tools for use in clinical practice and trials.
- Evaluate the feasibility of isolating and expanding clinically relevant numbers of tumor-derived lymphocytes from patients' bone marrow or lymph nodes.
- Detect post-transplant antibodies that selectively recognize tumor cell surface antigens.
- Prospectively evaluate the pathogenesis of chronic GVHD by examining the immune cell reconstitution in the target tissues and cellular and molecular events preceding and coinciding with the clinical onset of chronic GVHD.
- Prospectively assess long and short term cardiac toxicities of etoposide, doxorubicin hydrochloride, vincristine, cyclophosphamide, and fludarabine (EPOCH-F) regimen in
patients who have received greater than 450 mg/m² of anthracyclines prior to
study enrollment.
Entry Criteria Disease Characteristics:
- Patient must have one of the following diagnoses:
- Patients with primary or secondary acute leukemia, RAEB, CML, or other eligible diagnosis in transformation to acute leukemia must have ≤ 10% blasts in bone marrow and no circulating blasts in peripheral blood
- Patients who do not meet these criteria may be re-evaluated for study eligibility after receiving standard induction therapy for acute leukemia and determined to be in remission
- Patients with non-Hodgkin lymphoma must have at least stable disease after the last therapy
- Has a 10/10 allele-matched unrelated donor available
- Unrelated donor matched at HLA-A, B, C, DRB1, and DQ loci by high-resolution typing (10/10 allele match)
- No active CNS involvement by malignancy (i.e., known positive CSF cytology or parenchymal lesions visible by CT scan or MRI)
- No progressive disease within 8 weeks after prior therapy or within 12 weeks after prior autologous HSCT
Prior/Concurrent Therapy:
- See Disease Characteristics
- Recovered from prior therapy (nonhematologic toxicity ≤ grade 2)
- At least 2 weeks since prior cytotoxic chemotherapy
Patient Characteristics:
- ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100%
- Life expectancy ≥ 3 months
- Absolute neutrophil count ≥ 1,000/μL* (without transfusion)
- Platelet count ≥ 20,000/mm³* (without transfusion)
- Serum total bilirubin < 2.5 mg/dL (≤ 10 mg/dL if thought to be due to liver involvement by malignancy)
- Serum ALT and AST ≤ 2.5 times upper limit of normal (ULN) (≤ 10 times ULN if thought to be due to liver involvement by malignancy)
- Creatinine ≤ 1.5 mg/dL
- Creatinine clearance ≥ 50 mL/min
- LVEF > 45% by MUGA or 2D-echo
- Patients who have received a prior cumulative anthracycline dose > 450 mg/m² will have a cardiology consult to determine if further anthracycline administration is an absolute contradindication in patients who may require induction chemotherapy with EPOCH-F
- DLCO > 50% of the expected value when corrected for hemoglobin
- No chronic active hepatitis B
- Hepatitis B core antibody positivity allowed provided patient is hepatitis B surface antigen negative with no evidence of active infection
- No hepatitis C infection with evidence of cirrhosis
- No HIV infection
- No active infection that is not responding to antimicrobial therapy
- No active or recent second malignancy unless it has been treated with potentially curative therapy and meets ≥ 1 of the following criteria:
- Patient has had no evidence of that disease for ≥ 5 years
- Deemed to be at low risk for recurrence (≤ 20% at 5 years)
- No history of psychiatric disorder that may compromise compliance with transplant protocol or that does not allow for appropriate informed consent
- Not pregnant or lactating
- Fertile patients must use an effective method of contraception
[Note: * Values below these levels may be accepted at the discretion of the principal investigator or study chairperson, if thought to be due to bone marrow involvement by malignancy] Expected Enrollment 20Outcomes Primary Outcome(s)Change in the CD4+ T-cell repertoire diversity determined by spectratype complexity index within a Vβ family at 3 months post-transplant Overall safety Graft rejection based on CD3+ chimerism Acute graft-vs-host disease Treatment-related mortality (early and at 1 year) Overall survival at 1 year
Secondary Outcome(s)Immune reconstitution parameters
Outline Patients with persistent or progressive malignancy post-HSCT or mixed chimerism that does not improve after tapering or discontinuing immune suppression may receive donor lymphocyte infusions (DLIs). DLI may be administered alone or after chemotherapy every 4 weeks provided GVHD is not present. Blood samples are obtained at baseline and then periodically before and after HSCT. To determine T-cell receptor Vβ repertoire, samples are examined by reverse transcriptase-PCR and Vβ spectratype analysis. Peripheral blood monocytes are analyzed by flow cytometry for expression of markers of T cell proliferation, cytokine production and gene expression, cytotoxic T lymphocyte generation, and antigen-presenting cell function. To correlate monocyte cytokine expression patterns with GVHD, cytokine capture flow cytometry is used to evaluate markers of T1 (interleukin [IL]-2 and interferon-γ) and T2 (IL-4 and IL-10) cytokine excretion. Punch biopsies of skin and buccal mucosa and whole saliva samples are collected at day 63 and at 6 months (or at the development of GVHD) post-transplant and examined by immunofluorescence, confocal microscopy, gene expression profiles, and protein-based assays.
After completion of study therapy, patients are followed periodically for 2 years.
Trial Contact Information
Trial Lead Organizations NCI - Center for Cancer Research | | | Michael Bishop, MD, Protocol chair | | | | Steven Pavletic, MD, Protocol co-chair | | | | Trial Sites
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U.S.A. |
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Maryland |
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Bethesda |
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| | | | | | | | Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office |
| | Clinical Trials Office - Warren Grant Magnusen Clinical Center - NCI Clinical Trials Referral Office | |
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Registry Information | | Official Title | | Pilot Trial of Targeted Immune-Depleting Chemotherapy and Reduced-Intensity Allogeneic hematopoietic Stem Cell Transplantation Using HLA-Matched Unrelated Donors and Utilizing Two Graft-Versus-Host Disease Prophylaxis Regimens for the Treatment of Leukemias, Lymphomas, and Pre-Malignant Blood Disorders | | Trial Start Date | | 2007-07-23 | | Registered in ClinicalTrials.gov | | NCT00520130 | | Date Submitted to PDQ | | 2007-07-23 | | Information Last Verified | | 2008-07-28 |
Note: The purpose of most clinical trials listed in this database is to test new cancer treatments, or new methods of diagnosing, screening, or preventing cancer. Because all potentially harmful side effects are not known before a trial is conducted, dose and schedule modifications may be required for participants if they develop side effects from the treatment or test. The therapy or test described in this clinical trial is intended for use by clinical oncologists in carefully structured settings, and may not prove to be more effective than standard treatment. A responsible investigator associated with this clinical trial should be consulted before using this protocol. Back to Top |
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