Combination Chemotherapy, Donor Stem Cell Transplant, Tacrolimus, Mycophenolate Mofetil, and Cyclophosphamide in Treating Patients With Hematologic Cancer

Lymphoma Clinical Trial

Official title:

A Phase II Trial of Myeloablative Conditioning and Transplantation of Partially HLA-Mismatched Peripheral Blood Stem Cells for Patients With Hematologic Malignancies

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00782379
• Other study ID #: CDR0000617648
• Secondary ID: BMTGG-NSH-864
• Status: Completed
• Phase: Phase 2
• First received: October 29, 2008
• Last updated: October 28, 2013
• Start date: October 2008
• Est. completion date: April 2012

Study information

• Verified date: March 2013
• Source: Northside Hospital, Inc.
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

RATIONALE: Giving chemotherapy, such as fludarabine, busulfan, and cyclophosphamide, before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells and helps stop the patient's immune system from rejecting the donor's stem cells. When the healthy 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 make an immune response against the body's normal cells. Giving high-dose cyclophosphamide together with tacrolimus and mycophenolate mofetil after transplant may stop this from happening.

PURPOSE: This phase II trial is studying how well combination chemotherapy works when given together with a donor stem cell transplant, followed by tacrolimus, mycophenolate mofetil, and high-dose cyclophosphamide, in treating patients with high-risk hematologic cancer.

Description:

OBJECTIVES:

Primary

• To estimate the incidence of graft rejection and severe graft-versus-host disease after myeloablative HLA-mismatched peripheral blood stem cell transplantation (PBSCT) from first-degree relatives in patients with high-risk hematologic malignancies.

Secondary

• To estimate overall survival, relapse, non-relapse mortality, and event-free survival in these patients.

• To characterize additional hematologic and non-hematologic toxicities of myeloablative haploidentical PBSCT.

• To characterize donor hematopoietic chimerism in peripheral blood stem cells after PBSCT.

OUTLINE:

• Preparative regimen: Patients receive fludarabine phosphate IV over 30 minutes on days -7 to -2, busulfan IV over 3 hours on days -7 to -4, and cyclophosphamide IV over 1-2 hours on days -3 and -2.

• Allogeneic peripheral blood stem cell transplantation (PBSCT): Patients undergo infusion of unmanipulated peripheral blood stem cells on day 0.

• Post-transplant regimen: Patients receive high-dose cyclophosphamide IV over 1-2 hours on days 3 and 4, tacrolimus IV over 24 hours or orally twice daily on days 5-180, and oral mycophenolate mofetil 3 times daily on days 5-34 followed by a taper to day 90. Treatment continues in the absence of disease progression or clinically significant graft-vs-host disease.

After completion of PBSCT, patients are followed periodically for 1 year.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 20
• Est. completion date: April 2012
• Est. primary completion date: April 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 60 Years

Eligibility

DISEASE CHARACTERISTICS:

• Diagnosis of one of the following high-risk hematologic malignancies:

• Chronic myelogenous leukemia meeting one of the following criteria:

• Disease in chronic phase and resistant to available tyrosine kinase inhibitors

• Disease in accelerated phase

• Disease with blast crisis that has entered into a second chronic phase after induction chemotherapy

• Acute myelogenous leukemia meeting the following criteria:

• Marrow blasts < 5% but persistence of minimal residual disease by flow cytometry, cytogenetics, or FISH

• Must meet one of the following criteria:

• Disease in second or subsequent complete remission

• Primary induction chemotherapy failure with disease subsequently entering complete remission

• Disease in first complete remission with poor-risk cytogenetics or arising from preceding hematological disease

• Myelodysplastic syndrome meeting at least one of the following criteria:

• Treatment-related

• Monosomy 7 or complex cytogenetics

• International prognostic scoring system score = 1.5

• Chronic myelomonocytic leukemia

• Acute lymphocytic leukemia or lymphoblastic lymphoma meeting the following criteria:

• Marrow blasts < 5% but persistence of minimal residual disease by flow cytometry, cytogenetics, or FISH

• Must meet one of the following criteria:

• Disease in second or subsequent complete remission

• Acute lymphocytic leukemia with poor-risk karyotype [e.g., t(9;22) or bcr-abl fusion, t(4;11), or other MLL translocation] and in first complete remission

• Chronic lymphocytic leukemia or prolymphocytic leukemia meeting both of the following criteria:

• Previously treated disease that has either relapsed or failed to respond adequately to conventional-dose therapy including purine analogs

• In the opinion of the transplant physician, unlikely to benefit from reduced intensity transplantation due to the presence of one or more high-risk features (i.e., bulky tumor masses, B symptoms, and/or inadequate response to salvage chemotherapy)

• Hodgkin or non-Hodgkin lymphoma (including low-grade, mantle cell, and intermediate-grade/diffuse disease) meeting the following criteria:

• Previously treated disease that has either relapsed or failed to respond adequately to conventional-dose therapy or autologous transplantation

• In the opinion of the transplant physician, unlikely to benefit from reduced intensity transplantation due to the presence of one or more high-risk features (i.e., bulky tumor masses, B symptoms, and/or inadequate response to salvage chemotherapy) NOTE: A new classification scheme for adult non-Hodgkin lymphoma has been adopted by PDQ. The terminology of "indolent" or "aggressive" lymphoma will replace the former terminology of "low", "intermediate", or "high" grade lymphoma. However, this protocol uses the former terminology.

• No available matched related or unrelated donor OR a matched related or unrelated donor will not be available in the time frame necessary to perform a transplant

• Availability of a first-degree relative (parent, child, sibling) matched at 3/6-5/6 loci (HLA-A, -B, -DR)

• Donor must be willing to donate mobilized peripheral blood stem cells

• No positive HLA crossmatch in the host-vs-graft direction or high titer donor-specific antibodies

PATIENT CHARACTERISTICS:

• Karnofsky performance status 70-100%

• Bilirubin < 2 mg/dL (unless due to hemolysis, Gilbert syndrome, or primary malignancy)

• Creatinine < 2 mg/dL OR creatinine clearance = 40 mL/min

• Not pregnant

• Fertile patients must use effective contraception

• LVEF (Left ventriculr ejection fraction) = 45%

• FEV_1 and forced vital capacity = 50% predicted

• No HIV positivity

• No debilitating medical or psychiatric illness that would preclude giving informed consent or receiving optimal treatment and follow-up

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics

• No immunosuppressive agents = 24 hours after completion of post-transplant cyclophosphamide (including steroids as antiemetics)

Study Design

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Leukemia
• Lymphoma
• Myelodysplastic Syndromes
• Preleukemia

Intervention

Drug:
• busulfan
110 mg/m2 infused over 3 hours once daily on 4 consecutive days (Days -7, -6, -5, -4)
• cyclophosphamide
14.5 mg/kg infused over 1-2 hours once daily on 2 consecutive days (days -3,-2).
• fludarabine phosphate
30mg/m2 infused over 30 minutes once daily on three consecutive days (days -5, -4, -3)
• mycophenolate mofetil
15 mg/kg po three times a daily with a maximum dose of 3gm/day starting D+5. To be discontinued on Day +35 in the absence of clinically significant GVHD.
• tacrolimus
0.03 mg/kg/day infuse over 24 hours starting on day +5 (adjusted to maintain trough level of 5-15 ng/ml). Switch to oral (twice daily divided dose) on day +21 or when able to tolerate PO. Discontinue on day +180 in the absence of clinically significant GVHD.

Procedure:
• allogeneic hematopoietic stem cell transplantation
Patients to received unmanipulated PBSCs on Day 0
• peripheral blood stem cell transplantation
patients to receive unmanipulated PBSCs on day 0

Locations

Country	Name	City	State
United States	Blood and Marrow Transplant Group of Georgia	Atlanta	Georgia

Sponsors (1)

Lead Sponsor	Collaborator
Northside Hospital, Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of Graft Rejection for Patients at Day 100	Number of patients who experienced graft rejection by Day 100	Day 100	Yes
Primary	Number of Patients Who Experienced Severe Graft-versus-host Disease (GVHD)(Grade 3 or 4)	Number of patients who experienced post-transplant complication (GVHD) as seen by clinical evidence	Day 100	Yes
Secondary	Overall Survival at Day 100	Overall survival is assessed, without regard to disease status, post-transplant, at Day 100.	Day 100	No
Secondary	Non-relapse Mortality at 1 Year After Peripheral Blood Stem Cell Transplantation (PBSCT)	Non-relapse mortality refers to whether a patient dies of causes related to something other than the primary disease.	1 year	Yes
Secondary	Achievement of >90% (Full) Donor Chimerism in the T-Cell Lineage as Measured by PCR at Day 30 Post-transplantation	Chimerism analysis of peripheral blood mononuclear cells using PCR (polymerase chain reaction) for STR/VNTR (short tandme repeat/variable number tandem repeat) will be performed post transplant. On each occasion, the peripheral blood will be separated into the T-cell component (using e.g. CD3 selection) and the myeloid component (using e.g.CD14/15 selection) before assessment of chimerism.	Day 30	No
Secondary	Non-relapse Mortality at Day 100 After Peripheral Blood Stem Cell Transplantation (PBSCT)		Day 100	Yes
Secondary	Achievement of >90% (Full) Donor Chimerism in the T-Cell Lineage as Measured by PCR at Day 60 Post-transplantation	Chimerism analysis of peripheral blood mononuclear cells using PCR for STR/VNTR will be performed post transplant. On each occasion, the peripheral blood will be separated into the T-cell component (using e.g. CD3 selection) and the myeloid component (using e.g.CD14/15 selection) before assessment of chimerism.	Day 60	No
Secondary	Achievement of >90% (Full) Donor Chimerism in the T-Cell Lineage as Measured by PCR at Day 90 Post-transplantation	Chimerism analysis of peripheral blood mononuclear cells using PCR for STR/VNTR will be performed post transplant. On each occasion, the peripheral blood will be separated into the T-cell component (using e.g. CD3 selection) and the myeloid component (using e.g.CD14/15 selection) before assessment of chimerism.	Day 90	No
Secondary	Overall Survival at 12 Months	Overall survival, defined as a patient being alive after transplant, is without regard to disease status.	12 months	No
Secondary	Disease Free Survival at 12 Months	Disease free survival refers to patients with no evidence of disease after transplant, at the 12 month time point.	12 months	No
Secondary	Disease Free Survival at Day 100	Disease free survival refers to patients with no evidence of disease after transplant, at the Day 100 time point.	Day 100	No