|Phase II, Phase I||Biomarker/Laboratory analysis, Treatment||Active||18 to 69||NCI||070195|
07-C-0195, NCI-07-C-0195, NCT00520130
Major problems with stem cell transplantation (SCT) for cancer treatment are a lack of suitable donors for patients without an HLA tissue-matched sibling and graft-versus-host disease (GVHD), a serious side effects of immune-suppressing chemotherapy that is given to bring the cancer under control before SCT. In GVHD, the patient's immune system attacks the transplanted donor cells.
This study will try to improve the results of SCT from unrelated HLA-matched donors using targeted immune-depleting chemotherapy to bring the cancer under control before transplantation and to lower the chance of graft rejection, followed by reduced-intensity transplant chemotherapy to make the procedure less toxic.
To evaluate the safety and effectiveness of targeted immune-depleting chemotherapy followed by reduced-intensity transplant chemotherapy in patients with advanced cancers of the blood and immune system.
To evaluate the safety and effectiveness of two different drug combinations to prevent GVHD. Both regimens have been successful in preventing GVHD, but they work by different mechanisms and affect the rebuilding of the immune system after the transplant.
People 18 to 69 years of age with advanced or high-risk cancers of the blood and immune system who do not have a suitable HLA-matched sibling.
All patients receive chemotherapy before transplant to treat the cancer and suppress immune function.
All patients receive a conditioning regimen of cyclophosphamide for 4 days and fludarabine for 4 days before SCT to prepare for the transplant.
Patients are randomly assigned to one of two combination drug treatments to prevent GHVD as follows:
- Group 1: Tacrolimus starting 3 days before SCT and continuing for 6 months, plus methotrexate on days 1, 3, 6, and 11 post-SCT, plus sirolimus starting 3 days before the SCT and continuing through day 14 following SCT.
- Group 2: Alemtuzumab for 4 days starting 8 days before SCT, plus cyclosporine starting 1 day before SCT and continuing for 6 months.
Patients receive the donor's stem cells and immune cells 2 days after the conditioning regimen.
Patients are followed at the clinic regularly for the first 6 months after SCT, and then less often for at least 5 years. Some visits may include bone marrow aspirates and biopsies, blood draws, and other tests to monitor disease status.
A skin biopsy, oral mucosa biopsy, and saliva collection are done to study chronic GVHD.
Further Study Information
- The major limitations to the broader applicability of allogeneic hematopoietic stem cell transplantation (HSCT) for the treatment of malignancies are lack of suitable donors and therapy-related toxicities which include delayed and incomplete immune reconstitution and graft-versus-host disease (GVHD). Based on the theory that the rapid establishment of donor chimerism was essential for an optimal graft-versus-tumor effect, we have employed a strategy of targeted immunedepleting chemotherapy prior to reduced-intensity allogeneic HSCT. It is our intent to investigate this approach in the setting of HLA-matched unrelated donors in a pilot manner.
- A clearly superior GVHD prophylaxis regimen has not been established in the unrelated donor transplant setting. The best results that have been reported are with the combination of alemtuzumab plus cyclosporine [AC] and the combination of tacrolimus, methotrexate, and sirolimus [TMS]. These two regimens work by mechanisms which are biologically distinct and potentially have markedly different effects upon immune reconstitution that have not been well studied. In addition neither of these regimens has been assessed for their affects on chronic GVHD using the NIH Consensus Conference Criteria. It is our intent to study the effects that these two regimens have on immune reconstitution and chronic GVHD in the setting sequential targeted immune-depleting chemotherapy and reduced-intensity allogeneic HSCT from HLA-matched unrelated donors.
- Primary objectives:
1. to assess the effects of two biologically distinct GVHD prophylaxis regimens, TMS and AC, on immune reconstitution in patients receiving targeted-immune depletion and reduced-intensity allogeneic HSCT from HLA-matched unrelated donors. As part of a comprehensive assessment of immune reconstitution, the primary immunologic endpoint will be the determination of CD4+ T cell receptor V BETA repertoire by CDR3 spectratyping at 3 months post-transplant.
2. to assess overall safety of these two regimens in this setting, as determined by engraftment, acute GVHD, early and late treatment-related mortality, and overall survival.
3. to 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 those tools for use in clinical practice and trials (Pavletic, Imanguli, and Cowen).
- Secondary objectives include further assessment of immune reconstitution, study of engraftment kinetics, and assessment of those patients who receive higher doses of anthracyclines for long and short term toxicities
- Adults (18 - 74 years) with advanced or high risk hematologic malignancies including AML, ALL, MDS, CLL, NHL, HL,CML, multiple myeloma, and MPD who lack a suitable HLA-matched sibling.
- An unrelated donor matched at a minimum of 7 of 8 alleles (HLA-A,-B,-C, and DRB1) by highresolution typing, identified through the National Marrow Donor Program.
- Life expectancy of at least 3 months, ECOG less than or equal to 2 and relatively normal major organ functions.
- Patients will receive disease-specific induction chemotherapy (EPOCH-F/R or FLAG) prior to transplant for disease control and immune depletion. If disease is controlled (greater than PR) and immune depletion objectives have been met, patients may forgo induction chemotherapy and move forward to the transplant conditioning regimen.
- All patients will receive an identical conditioning regimen consisting of cyclophosphamide 1200 mg/m(2)/day IV for 4 days and fludarabine 30 mg/m(2)/day for 4 days.
- Patients will be stratified according to degree of HLA-match and randomized at the time of enrollment to one of two GHVD prophylaxis regimens:
- Arm A (TMS): Tacrolimus, starting day -3 before transplant, given initially at 0.02 mg/kg/day CIV and then an equivalent oral dose for six months, methotrexate 5 mg/m(2) IV on days +1, +3, +6, and +11 post-transplant, and sirolimus given as an initial loading dose of 12 mg p.o. on day -3 pre-transplant and subsequently 4 mg daily through day +63 post transplant.
- Arm B (AC): Alemtuzumab at 20 mg/day IV over 8 h on days -8 to -4 pre-transplant and cyclosporine, starting day -1 before transplant, given initially at 2mg/kg IV every 12 hours and then an equivalent oral dose for six months and.
- A maximum of 105 patients will be enrolled and randomly assigned to the two arms in order to yield 44 patients per arm (88 total patients) who are able to be evaluated for development of severe chronic GVHD. This represents an increase of 20 patients over the number permitted prior to this amendment: 25 patients (50 total) randomly assigned to each arm within the 8/8 match group and 13/arm (26 total) within the 7/8 match group (maximum study enrollment = 76 transplanted patients from among up to 85 patients registered).
- INCLUSION CRITERIA:
RECIPIENT ON STANDARD CARE THERAPY:
- The patient is 18 - 74 years of age.
- The patient has a potentially suitable 8/8 donor if they are between the ages of 69-74years of age or a potentially suitable 8/8 or 7/8 unrelated donor(s) in the National MarrowRegistry or Other Available Registry if they are between the ages of 18-74.
- The patient currently does not meet the protocol's eligibility/enrollment criteria for any reason.
- There is a high likelihood that the patient, in the opinion of the PI or LAI, will meet the protocol's eligibility/enrollment criteria to proceed to transplant after standard therapy is completed.
- The patient or legal guardian is able to give informed consent.
RECIPIENT ON STANDARD CARE THERAPY:
- HIV infection. There is theoretical concern that the degree of immune suppression associated with the treatment may result in progression of HIV infection.
- Pregnant or lactating. Patients of childbearing potential must use an effective method of contraception (section 4.4). The effects of the chemotherapy, the subsequent transplant and the medications used after the transplant are highly likely to be harmful to a fetus. The effects upon breast milk are also unknown and may be harmful to the infant.
Inclusion Criteria - Recipient:
Disease: B-Chronic Lymphocytic Leukemia (CLL) Small Lympho(plasma)cytic Lymphoma (B-SLL, B-LPL).
Disease Status: a) Relapse/progression after fludarabine and at least one other salvage regimen. (Section 2.1.7) b) Relapse/progression after autologous HSCT.
Disease: Prolymphocytic Leukemia (PLL) T-CLL.
Disease Status: a) T-PLL: Treatment failure after Campath-1H and at least one other regimen (Section 2.1.7) b) B-PLL: Treatment failure after fludarabine and at least one other salvage regimen (Section 2.1.7).
Disease: Hodgkin's Lymphoma.
Disease Status: a) Primary treatment failure ineligible for autologous HSCT. Relapse/progression after autologous HSCT.
Disease: Follicular Lymphoma, Marginal Zone Lymphomas (splenic, nodal, or extranodal/MALT type).
Disease Status: a) Chemotherapy-refractory disease b) Relapse after greater than or equal to 2 prior regimens c) Relapse/progression after autologous HSCT.
Disease: Burkitt or Acute Lymphoblastic Lymphomas.
Disease Status: a) High-risk disease in remission b) Primary refractory disease c) Recurrent disease d) Relapse/progression after autologous HSCT.
Disease: Diffuse Large B-cell Lymphoma, Follicular Large cell Lymphoma, Peripheral T-cell Lymphoma, mantle cell lymphoma, Anaplastic Large Cell Lymphoma.
Disease Status: a) Primary refractory disease. b) Relapse/progression after autologous HSCT after autologous HSCT c) Stable disease or better response to last therapy.
Disease: Cutaneous T-cell Lymphomas (Mycosis Fungoides, Sezary Syndrome)
Disease Status: a) greater than or equal to Stage III b) Disease progression greater than or equal to 2 prior regimens, including at least one systemic therapy.
Disease: Multiple Myeloma
Disease Status: a) Relapse/progression after autologous HSCT. b) Plasma cell leukemia c) Adverse cytogenetics: del(13q) or 11q translocation.
Disease: Acute Myelogenous Leukemia
Disease Status: a) In first complete Remission with high-risk cytogenetics, b) Primary induction failure. c) In second or greater complete remission. d) Secondary AML. (Section 220.127.116.11) e) In first complete Remission with hyperleukocytosis at diagnosis as defined in 18.104.22.168.
Disease: Acute Lymphocytic Leukemia.
Disease Status: a) First Complete Remission, with high-risk cytogenetics. b) Primary induction failure. c) Second or greater complete remission.
Disease: Myelodysplastic Syndrome
Disease Status: a) RAEB I or II. b) High-risk ISS. c) Secondary MDS
Disease: Myeloproliferative disorders (Idiopathic myelofibrosis, polycythemia vera, essential thrombocytosis, chronic myelomonocytic leukemia, agnogenic myeloid metaplasia).
Disease Status: a) Agnogenic myeloid metaplasia with adverse-risk features (Section 2.1.5) b) Polycythemia vera or essential thrombocythemia in transformation to secondary AML.
Disease: Chronic Myelogenous Leukemia
Disease Status: Chronic phase CML (Section 2.1.10)
Accelerated phase CML
Not eligible for myeloablative allogeneic HSCT.
Disease: NK Cell Neoplasms
Disease Status: a) First CR for patients with high risk natural killer cell neoplasms including myeloid/NK cell precursor acute leukemia, blastic NK-cell lymphoma, aggressive NK-cell leukemia and nasal-type extranodal NK-cell lymphoma in first complete remission. b) Primary induction failure. c) Second or greater CR.
Disease: Adult T-Cell leukemia/lymphoma, hepatosplenic T-Cell lymphoma, and enteropathy associated T-Cell Lymphoma
Disease Status: a) First CR. b) Chemotherapy-refractory disease. c) Relapse after greater than or equal to 1 prior regimen.
2.1.1 - Diagnosis of hematologic malignancy and at least one of the criteria in the Disease Status column as specified in the table above.
2.1.2 - Recipients with AML in CR1 must have one of the following:
22.214.171.124 - Adverse cytogenetics with residual disease detectable by flow cytometry, cytogenetic analysis, FISH, or PCR. Adverse cytogenetics in AML are defined as complex karyotype (greater than or equal to 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); or t(11;19)(q23;p13.1)
126.96.36.199 - Primary induction failure, defined as failure to achieve CR with primary induction chemotherapy.
188.8.131.52 - Secondary AML, defined as AML related to antecedent MDS, MPD, or cytotoxic chemotherapy.
184.108.40.206 - Hyperleukocytosis, WBC greater than or equal to 100,000, at diagnosis.
220.127.116.11 - Mutations in the FMS-like tyrosine kinase 3 (FLT3) gene (FLT3-LM; FLT-ITDs).
2.1.3 - Recipients with ALL in CR1 must have one of the following:
18.104.22.168 - Adverse cytogenetics or residual disease detectable by flow cytometry, cytogenetic analysis, FISH, or PCR. Adverse cytogenetics in ALL are defined as translocations involving t(4;11), t(1;19), t(8;14), 11q23, t(9;22) or bcr-abl rearrangement or complex cytogenetic abnormalities.
22.214.171.124 - Primary induction failure, defined as failure to achieve CR with primary induction chemotherapy.
2.1.4 - Patients with Cutaneous T-cell Lymphomas (e.g. mycosis fungoides, Sezary syndrome) must have:
126.96.36.199 - Stage III or greater disease
188.8.131.52 - Disease which has progressed on or failed to respond to at least 2 therapies including one systemic therapy.
2.1.5 - Recipients with agnogenic myeloid metaplasia must have at least 2 of the following features:
184.108.40.206 - Hemoglobin less than 10 g/dl, or greater than 10 g/dl with transfusion dependence.
220.127.116.11 - WBC less than 4,000 or greater than 30,000/mm(3) or requires cytoreductive therapy to maintain.
18.104.22.168 - WBC less than 30,000/mm.
22.214.171.124 - Abnormal cytogenetics including plus 8, 12p-.
2.1.6 - Recipients with primary or secondary acute leukemia, refractory anemia with excess blasts (RAEB), CML, or other eligible diagnosis in transformation to acute leukemia must have less than or equal to 5 percent blasts in bone marrow and no circulating blasts in peripheral blood at study entry. Recipients 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.
2.1.7 - For recipients with CLL or PLL, treatment failure for a specified therapy is defined as relapse within 6 months or failure to achieve remission.
126.96.36.199 - Recipients who are ineligible for a specified therapy (e.g., due to refractory cytopenias) may be considered for enrollment in this protocol.
188.8.131.52 - Recipients who have a 17p/p53 deletion who have never received fludarabine will be eligible.
184.108.40.206 - Recipients who have had Richter's transformation who have not received prior chemotherapy for their CLL will be eligible.
2.1.8 - For patient with NK cell neoplasms: 1) Patients with high risk natural killer cell neoplasms including myeloid/NK cell precursor acute leukemia, blastic NK-cell lymphoma, aggressive NK-cell leukemia and nasal-type extranodal NK-cell lymphoma in first complete remission. 2) All NK cell neoplasms can be transplanted in: a) Primary induction failure or b) Second or greater complete remission.
2.1.9 - For patients with T-Cell Neoplasms including adult T-cell leukemia/lymphoma, heptosplenic T-Cell lymphoma and enteropathy associated T-cell lymphoma.
220.127.116.11 First CR
18.104.22.168 Chemotherapy-refractory disease.
22.214.171.124 Relapse after greater than or equal to 1 prior regimen.
2.1.10 - For patients with non-Hodgkin's lymphoma, must be determined to have at least stable disease to last therapy.
2.1.11 - For patients with chronic phase chronic myelogenous leukemia, patient's disease must have evidence of never responded to or progressed after receiving a tyrosine-kinase inhibitor (e.g. imatinib mesylate).
2.1.12 - Patients with accelerated phase chronic myelogenous leukemia, may have less than or equal to 10 percent blasts in the peripheral smear or bone marrow at study entry.
2.1.13 - Patients 18 - 74 years of age.
2.1.14 - Patient or legal guardian must be able to give informed consent.
2.1.15 - All previous cytotoxic chemotherapy must be completed at least 2 weeks prior to study entry. Any grade 3 or 4 non-hematologic toxicity of any previous therapy must have resolved to grade 2 or less, unless specified elsewhere in Section 2.1.
2.1.16 - ECOG performance status equal to 0, 1, or 2, and Karnofsky performance status greater than or equal to 60 percent.
2.1.17 - Life expectancy of at least 3 months.
2.1.18 - Patients with acute leukemia or myelodysplastic syndrome or chronic myelomonocytic leukemia must be in hematologic remission, defined as less than 5 percent blasts present in both blood and bone marrow to be referred for evaluation. Should a patient have greater than 5 percent blasts or a donor not be available by the time the patient is ready for enrollment, the patient will be referred back to their primary hematologist-oncologist for treatment. Patients with diseases other than acute leukemia including but not limited to Hodgkin's and Non-Hodgkin;s lymphoma, CLL/SLL, NKTCL, PTCL, must have stable disease to their most recent regimen received within 8 weeks if chemo/radiotherapy or within 12 weeks after prior autologous stem cell transplantation. Should a patient in either of these scenarios have progressive disease or a donor not be available after enrollment, the patient will be referred back to their primary hematologist-oncologist for treatment. If either of these scenarios are not in the best interest of the patient according to the clinical judgement of the PI/LAI, then the patient may receive standard treatment for the malignant disease under the current study. If under either of these settings, it becomes apparent that thte patient will not be able to proceed to transplant, then he/she must come off study. Recipient-Subjects receiving a standard therapy will be told about the therapy, associated risks, benefits alternatives of the proposed therapy, and availability of receiving the same treatment elsewhere, outside of a research protocol.
2.1.19 -Left ventricular ejection fraction greater than 45 percent by either MUGA or 2-D echo, obtained within 28 days of enrollment. Patients who have a prior cumulative anthracycline dose greater than 450 mg/m(2) will also have a cardiology consult to determine if further anthrracycline administration is an absolute contraindication in patients who may require induction chemotherapy with EPOCH-F.
2.1.20 - DLCO greater than 50 percent of the expected value when corrected for Hb, obtained within 28 days of enrollment.
2.1.21 - Creatinine less than or equal to 1.5 mg/dl and creatinine clearance greater than or equal to 50 ml/min/1.73 m(2).
2.1.22 - Serum total bilirubin less than 2.5 mg/dl, and serum ALT and AST values less than or equal to 2.5 times the upper limit of normal. Patients with elevations of serum total bilirubin up to 10 mg/dl and/or ALT or AST up to 10 times the upper limit of normal may be considered for participation if such elevations are thought to be due to liver involvement by malignancy. However, in these latter patients, if these values do not decrease to less than or equal to 2.5 times the upper limit of normal during induction chemotherapy, such patients will not be eligible for the transplant phase of the protocol, and will thus be taken off study.
2.1.23 - Minimum absolute neutrophil count of 1,000 cells/microliter and minimum platelet count (without transfusion) of 20,000/mm(3). Values below these levels may be accepted at the discretion of the PI or study chairperson, if thought to be due to bone marrow involvement by malignancy.
2.2 - Exclusion Criteria - Recipient
2.2.1 - Active infection that is not responding to antimicrobial therapy.
2.2.2 - Active CNS involvement by malignancy (patients with known positive CSF cytology or parenchymal lesions visible by CT or MRI).
2.2.3 - Progressive disease within 8 weeks of prior therapy or within 12 weeks after prior autologous stem cell transplantation.
2.2.4 - Active or recent second malignancies unless they have undergone potentially curative therapy for that malignancy and (1) have had no evidence of that disease for 5 years, and/or (2) be deemed at low risk for recurrence (less than or equal to 20 percent at 5 years).
2.2.5 - HIV infection. There is theoretical concern that the degree of immune suppression associated with the treatment may result i...
Trial Lead Organizations/Sponsors
National Cancer Institute
|Steven Zivko Pavletic||Principal Investigator|
|Ashley E Carpenter||Ph: (301) 594-5525|
|NIH - Warren Grant Magnuson Clinical Center|
|For more information at the NIH Clinical Center contact National Cancer Institute Referral Office||Ph: (888) NCI-1937|
Link to the current ClinicalTrials.gov record.
NLM Identifer NCT00520130
Information obtained from ClinicalTrials.gov on May 05, 2013
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