Tacrolimus, Methotrexate, and Sirolimus or Alemtuzumab and Cyclosporine in Preventing Graft-Versus-Host Disease in Patients with Leukemia, Lymphoma, or Pre-malignant Blood Disorders Undergoing Donor Peripheral Blood Stem Cell Transplant

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Basic Trial Information

PhaseTypeAgeTrial IDs
Phase IIBiomarker/Laboratory analysis, Treatment18 to 6907-C-0195
NCI-2013-01439, P07161, NCI-07-C-0195, NCT00520130

Trial Description

Summary

This randomized, pilot phase II trial studies the side effects and how well tacrolimus, methotrexate, and sirolimus or alemtuzumab and cyclosporine work in preventing graft-versus-host disease in patients with leukemia, lymphoma, or pre-malignant disorders undergoing donor peripheral blood stem cell transplant. Giving chemotherapy before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. When the health 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. Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells (called graft-versus-host disease). Giving tracolimus, methotrexate, sirolimus or alemtuzumab and cyclophosphamide before and after the transplant may stop this from happening. It is not yet known whether tacrolimus, methotrexate, and sirolimus are more effective than alemtuzumab and cyclosporine in preventing graft-versus-host disease.

Further Study Information

PRIMARY OBJECTIVES:

I. To assess in a pilot manner the effects of two biologically distinct graft-versus-host disease (GVHD) prophylaxis regimens (tacrolimus/methotrexate/sirolimus [TMS] and alemtuzumab/cyclosporine [AC]) on immune reconstitution in patients receiving targeted-immune depletion and reduced-intensity allogeneic hematopoietic stem cell transplantation (HSCT) from human leukocyte antigen (HLA)-matched unrelated donors.

II. To assess in a pilot manner the overall safety, as determined by engraftment, severe (grade III-IV) acute GVHD, early and late treatment-related mortality, and overall survival, of targeted sequential immune-depleting chemotherapy followed by reduced-intensity allogeneic HSCT from HLA-matched unrelated donors in the treatment of patients with advanced hematologic malignancies.

II. To determine and monitor incidence, organ severity and overall severity of chronic GVHD prospectively using the National Institutes of Health (NIH) Consensus Conference diagnosis and staging criteria and preliminarily validate those tools for use in clinical practice and trials.

SECONDARY OBJECTIVES:

I. To assess effects of two different GVHD prophylaxis regimens, TMS and AC, on cluster of differentiation (CD)4+ T cell receptor V beta repertoire by complementary determining region 3 (CDR3) spectratyping at 1, 3, 6, and 12 months post-transplant.

II. To assess effects of two different GVHD prophylaxis regimens, TMS and AC, on CD8+ T cell receptor V beta repertoire by CDR3 spectratyping at 1, 3, 6, and 12 months post-transplant.

III. To assess effects of two different GVHD prophylaxis regimens, TMS and AC, on the kinetics of CD4+ and CD8+ T-cells and natural killer (NK) cell depletion and recovery following the use of two different GVHD prophylaxis regimens, TMS and AC, in the setting of reduced-intensity allogeneic HSCT from HLA-matched unrelated donors.

IV. To correlate serum interleukin-7 and interleukin-15 levels during early immune reconstitution after two different GVHD prophylaxis regimens, TMS and AC, in the setting of sequential targeted immune-depleting chemotherapy followed by reduced-intensity allogeneic HSCT from HLA-matched unrelated donors.

V. To characterize the pattern of post-transplant CD14+ monocyte production of inflammatory cytokines interleukin (IL)-1-alpha and tumor necrosis factor (TNF)-alpha following the use of two different GVHD prophylaxis regimens, TMS and AC, in the setting of reduced-intensity allogeneic HSCT from HLA-matched unrelated donors.

VI. To assess the impact of two different GVHD prophylaxis regimens (TMS and AC) on donor/recipient chimerism in the setting of sequential targeted immune-depleting chemotherapy followed by reduced-intensity allogeneic HSCT from HLA-matched unrelated donors.

VII. To determine the incidence and severity of acute GVHD following sequential targeted immune-depleting chemotherapy and reduced-intensity allogeneic HSCT from HLA-matched unrelated donors using two different GVHD prophylaxis regimens, TMS and AC.

VIII. To evaluate the feasibility of isolating and expanding clinically relevant numbers of tumor derived lymphocytes from patients’ bone marrow or lymph nodes.

IX. To 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.

X. To prospectively assess long and short term cardiac toxicities of etoposide, vincristine sulfate, doxorubicin hydrochloride, prednisone, cyclophosphamide, and fludarabine phosphate (EPOCH-F) in patients who have received greater than 450 mg/m^2 of anthracyclines prior to study enrollment.

OUTLINE:

INDUCTION CHEMOTHERAPY: Patients with Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL) (except lymphoblastic lymphoma), chronic lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL), or multiple myeloma (MM) receive EPOCH-F/R comprising rituximab intravenously (IV) on day 1 (patients with CD20+ B-cell malignancies only); fludarabine phosphate IV over 30 minutes, etoposide IV continuously over 24 hours, doxorubicin hydrochloride continuously IV over 24 hours, and vincristine sulfate continuously IV over 24 hours on days 1-4; and cyclophosphamide IV over 30 minutes on day 5. Treatment with EOPCH-F/R repeats every 21 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. Patients with acute myelogenous leukemia (AML), secondary AML, acute lymphocytic leukemia (ALL), lymphoblastic lymphoma, myelodysplastic syndrome (MDS), chronic myelogenous leukemia (CML), or myeloproliferative disorder (MPD) receive FLAG comprising fludarabine phosphate IV over 30 minutes and cytarabine IV over 4 hours on days 1-5. Treatment with FLAG repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity.

PREPARATIVE REGIMEN: Patients achieving responsive or stable disease, or remission, receive fludarabine phosphate IV and cyclophosphamide IV on days -6 to -3.

GVHD PROPHYLAXIS: Patients are randomized to 1 of 2 treatment arms.

ARM TMS: Patients receive tacrolimus IV continuously or orally (PO) on days -3 to 63 with taper to day 180. Patients also receive methotrexate IV over 15 minutes on days 1, 3, 6, and 11 and sirolimus PO on days -3 to 63 with taper to day 180.

ARM AC: Patients receive cyclosporine IV over 2 hours twice daily (BID) or PO on days -1 to 100 with taper to day 180. Patients also receive alemtuzumab IV over 8 hours on days -8 to -4.

TRANSPLANT: Patients undergo allogeneic peripheral blood stem cell transplant (PBSCT) on day 0.

Treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at days 28 and 100, 6, 9, 12, 18, and 24 months, and then annually thereafter.

Eligibility Criteria

Inclusion Criteria:

Minimum absolute neutrophil count of 1,000 cells/ul and minimum platelet count (without transfusion) of 20,000/mm^3; values below these levels may be accepted at the discretion of the PI, if thought to be due to bone marrow involvement by malignancy

DONOR: Donors must be human immunodeficiency virus (HIV) negative, hepatitis B surface antigen negative, and hepatitis C antibody negative

Patients with acute leukemia or myelodysplastic syndrome or chronic myelomonocytic leukemia must be in a hematologic remission, defined as < 5% blasts present in both blood and marrow to be referred for evaluation; should a patient have > 5% 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, natural killer T-cell lymphoma (NKTCL), peripheral T-cell lymphoma (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 judgment of the PI, 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 the 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

All previous cytotoxic chemotherapy must be completed at least 2 weeks prior to study entry, with the exception of the tyrosine kinase inhibitors imatinib, nilotinib and dasatinib which may be continued through induction therapy; any grade 3 or 4 nonhematologic toxicity of any previous therapy must have resolved to grade 2 or less, unless specified elsewhere

Recipients with AML in first complete remission (CR1) must have one of the following:

Adverse cytogenetics with residual disease detectable by flow cytometry, cytogenetic analysis, fluorescence in situ hybridization (FISH), or polymerase chain reaction (PCR); adverse cytogenetics in AML are defined as complex karyotype (>= 3 abnormalities); inversion (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)

Primary induction failure, defined as failure to achieve CR with primary induction chemotherapy

Secondary AML, defined as AML related to antecedent MDS, MPD, or cytotoxic chemotherapy

Hyperleukocytosis, white blood cells (WBC) >= 100,000, at diagnosis

Mutations in the FMS-like tyrosine kinase 3 (FLT3) gene (FLT3-LM; FLT internal tandem duplication [ITD]s)

Recipients with ALL in CR1 must have one of the following:

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

Primary induction failure, defined as failure to achieve CR with primary induction chemotherapy

Acute myelogenous leukemia

In first complete remission with high-risk cytogenetics

Primary induction failure

In second or greater complete remission

Secondary AML

In first complete remission with hyperleukocytosis at diagnosis

Diffuse large B-cell lymphoma, follicular large cell lymphoma, peripheral T-cell lymphoma, mantle cell lymphoma, anaplastic large cell lymphoma

Primary refractory disease

Relapse/progression after autologous HSCT after autologous HSCT

Stable disease or better response to last therapy

There is a high likelihood that the patient, in the opinion of the principal investigator (PI) will meet the protocol’s eligibility/enrollment criteria to proceed to transplant after standard therapy is completed

ELIGIBILITY CRITERIA – RECIPIENT ON STANDARD CARE THERAPY

INCLUSION CRITERIA - RECIPIENT

DONOR: The evaluation of donors shall be in accordance with existing NMDP Standard Policies and Procedures

DONOR: Age 18 years or older

DONOR: General donor inclusion criteria specified in the National Marrow Donor Program (NMDP) Standards (20th edition)

DONOR: Ability to give informed consent

DONOR: Volunteer unrelated donor matched at a minimum of seven of eight loci (HLA-A, B, C, DRB1), by high resolution typing (> 7/8 allele match) are acceptable donors

The preferred donor-recipient pair would be matched at all eight loci (8/8 allele match)

When an 8/8 allele-matched unrelated donor is not available, a single mismatch at HLA-A, -B, -C, or DRB1 will be acceptable in patients who meet all eligibility criteria and are 18-69 years of age

  • In the situation where more than one 7/8 match is available donor recipient pairs matched at HLA-DQ will be used

The patient or legal guardian is able to give informed consent

For patients with T-cell neoplasms including adult T-cell leukemia/lymphoma, hepatosplenic T-cell lymphoma and enteropathy associated T-cell lymphoma

First CR

Chemotherapy-refractory disease

Relapse after greater than or equal to 1 prior regimen

For patients with non-Hodgkin’s lymphoma, they must be determined to have at least stable disease to last therapy

The patient has a potentially suitable 8/8 donor if they are between the ages of 69-74 years of age or a potentially suitable 8/8 or 7/8 unrelated donor(s) in the National Marrow Registry 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

Life expectancy of at least 3 months

Left ventricular ejection fraction > 45% by either multigated acquisition scan (MUGA) or 2-dimensional (2-D) echocardiogram (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 anthracycline administration is an absolute contraindication in patients who may require induction chemotherapy with EPOCH-F

Creatinine =< 1.5 mg/dl and creatinine clearance >= 50 ml/min/1.73 m^2

Patients with cutaneous T-cell lymphomas (e.g. mycosis fungoides, Sezary syndrome) must have:

Stage III or greater disease

Disease which has progressed on or failed to respond to at least 2 therapies including one systemic therapy

Recipients with agnogenic myeloid metaplasia must have at least 2 of the following features:

Hemoglobin < 10 g/dl, or > 10 g/dl with transfusion dependence

WBC < 4,000 or > 30,000/mm^3 or requires cytoreductive therapy to maintain

WBC < 30,000/mm

Abnormal cytogenetics including +8, 12p-

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 =< 5% 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

For recipients with CLL or PLL, treatment failure for a specified therapy is defined as relapse within 6 months or failure to achieve remission

Recipients who are ineligible for a specified therapy (e.g., due to refractory cytopenias) may be considered for enrollment in this protocol

Recipients who have a 17p/p53 deletion who have never received fludarabine will be eligible

Recipients who have had Richter’s transformation who have not received prior chemotherapy for their CLL will be eligible

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

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)

Patient or legal guardian must be able to give informed consent

Diffusion capacity of the lung for carbon monoxide (DLCO) > 50% of the expected value when corrected for hemoglobin (Hb), obtained within 28 days of enrollment

Diagnosis of hematologic malignancy and at least one of the criteria as specified above

Patients with accelerated phase chronic myelogenous leukemia may have =< 10% blasts in the peripheral smear or bone marrow at study entry

Eastern Cooperative Oncology Group (ECOG) performance status equal to 0, 1, or 2, and Karnofsky performance status greater than or equal to 60%

B-chronic lymphocytic leukemia (CLL), small lympho(plasma)cytic lymphoma (B-SLL, B-LPL)

Relapse/progression after fludarabine (fludarabine phosphate) and at least one other salvage regimen or 2 standard regimens

If 17p deletion present, one standard regimen is sufficient

Prolymphocytic Leukemia (PLL), T-cell chronic lymphocytic lymphoma (T-CLL)

T-PLL: treatment failure after Campath-1H and at least one other regimen

B-PLL: treatment failure after fludarabine and at least one other salvage regimen

Hodgkin’s lymphoma

Primary treatment failure ineligible for autologous HSCT; relapse/progression after autologous HSCT

Burkitt or acute lymphoblastic lymphomas

High-risk disease in remission

Primary refractory disease

Recurrent disease

Relapse/progression after autologous HSCT

Cutaneous T-cell lymphomas (mycosis fungoides, Sezary syndrome)

>= Stage III

Disease progression >= 2 prior regimens, including at least one systemic therapy

Serum total bilirubin less than 2.5 mg/dl; patients with elevations of serum total bilirubin up to 10 mg/dl 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

Follicular lymphoma, marginal zone lymphomas (splenic, nodal, or extranodal/mucosa-associated lymphoid tissue [MALT] type)

Chemotherapy-refractory disease

Relapse after >= 2 prior regimens

Relapse/progression after autologous HSCT

Chronic myelogenous leukemia (CML)

Chronic phase CML

Accelerated phase CML

Not eligible for myeloablative allogeneic HSCT

NK cell neoplasms

First complete remission (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

Primary induction failure

Second or greater CR

Multiple myeloma

Relapse/progression after autologous HSCT

Plasma cell leukemia

Adverse cytogenetics: del(13q) or 11q translocation

Acute lymphocytic leukemia

First complete remission, with high-risk cytogenetics

Primary induction failure

Second or greater complete remission

Myelodysplastic syndrome

Refractory anemia with excess blasts (RAEB) I or II

High-risk International Prognostic Scoring System (IPSS)

Secondary MDS

Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) values less than or equal to 2.5 times the upper limit of normal; patients with elevations of 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

Myeloproliferative disorders (idiopathic myelofibrosis, polycythemia vera, essential thrombocytosis, chronic myelomonocytic leukemia, agnogenic myeloid metaplasia)

Agnogenic myeloid metaplasia with adverse-risk features

Polycythemia vera or essential thrombocythemia in transformation to secondary AML

T-cell neoplasm: adult T-cell leukemia/lymphoma, hepatosplenic T-cell lymphoma, and enteropathy associated T-cell lymphoma

First CR

Chemotherapy-refractory disease

Relapse after greater than or equal to 1 prior regimen

Exclusion Criteria:

Human immunodeficiency virus (HIV) infection; there is theoretical concern that the degree of immune suppression associated with the treatment may result in progression of HIV infection

Chronic active hepatitis B; patients may be hepatitis B core antibody positive; for patients with concomitant positive hepatitis B surface antigen, patient will require a hepatology consultation; the risk/benefit profile of transplant and hepatitis B will be discussed with the patient and eligibility determined by the principal investigator

No available suitably HLA- matched unrelated donor

Pregnant or lactating

DONOR: Presence of sickle hemoglobin as demonstrated by appropriate testing such as hemoglobin electrophoresis

EXCLUSION CRITERIA – RECIPIENT ON STANDARD CARE THERAPY

Pregnant or lactating; patients of childbearing potential must use an effective method of contraception

History of psychiatric disorder which may compromise compliance with transplant protocol, or which does not allow for appropriate informed consent (as determined by principal investigator or lead associate investigator)

Available suitably HLA- matched unrelated donor is unwilling to donate peripheral blood stem cells (PBSC), and no alternate donor is found

EXCLUSION CRITERIA - RECIPIENT

DONOR: In addition to NMDP donor exclusion criteria, for the purposes of this protocol, donors who are unwilling to donate PBSC and only wish to pursue a bone marrow donation will be excluded; an alternate donor will be selected if possible, but in the event that no alternate donor is available, the patient will be removed from the trial

DONOR: Current treatment with lithium

Hepatitis C infection; patient may have a hepatitis C infection; however, each patient will require a hepatology consultation; the risk/benefit profile of transplant and hepatitis C will be discussed with the patient and eligibility determined by the principal investigator and lead associate investigator

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% at 5 years)

DONOR: Donor exclusion will be in accordance with existing NMDP Standards (20th edition)

Active infection that is not responding to antimicrobial therapy

Active central nervous system (CNS) involvement by malignancy (patients with known positive cerebrospinal fluid [CSF] cytology or parenchymal lesions visible by computed tomography [CT] or magnetic resonance imaging [MRI])

Progressive disease within 8 weeks of prior therapy or within 12 weeks after prior autologous stem cell transplantation

HIV infection; there is theoretical concern that the degree of immune suppression associated with the treatment may result in progression of HIV infection

Trial Contact Information

Trial Lead Organizations / Sponsors / Collaborators

NCI - Center for Cancer Research

  • National Cancer Institute
Steven Zivko Pavletic, Principal Investigator

Trial Sites

U.S.A.

Maryland
Bethesda

Mark O Hatfield-Warren Grant Magnuson Clinical Center

Steven Zivko Pavletic
Ph: 301-402-4899
Email: pavletis@mail.nih.gov

Steven Zivko Pavletic
Principal Investigator

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT00520130

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