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

Purpose

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.

Condition	Intervention	Phase
Leukemia Lymphoma Myelodysplastic Syndromes	Drug: busulfan Drug: cyclophosphamide Drug: fludarabine phosphate Drug: mycophenolate mofetil Drug: tacrolimus Procedure: allogeneic hematopoietic stem cell transplantation Procedure: peripheral blood stem cell transplantation	Phase 2

Study Type:	Interventional
Study Design:	Allocation: Non-Randomized Endpoint Classification: Safety Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	A Phase II Trial of Myeloablative Conditioning and Transplantation of Partially HLA-Mismatched Peripheral Blood Stem Cells for Patients With Hematologic Malignancies

Resource links provided by NLM:

Further study details as provided by Northside Hospital, Inc.:

Primary Outcome Measures:

Incidence of Graft Rejection for Patients at Day 100 [ Time Frame: Day 100 ] [ Designated as safety issue: Yes ]
Number of patients who experienced graft rejection by Day 100
Number of Patients Who Experienced Severe Graft-versus-host Disease (GVHD)(Grade 3 or 4) [ Time Frame: Day 100 ] [ Designated as safety issue: Yes ]
Number of patients who experienced post-transplant complication (GVHD) as seen by clinical evidence

Secondary Outcome Measures:

Overall Survival at Day 100 [ Time Frame: Day 100 ] [ Designated as safety issue: No ]
Overall survival is assessed, without regard to disease status, post-transplant, at Day 100.
Non-relapse Mortality at 1 Year After Peripheral Blood Stem Cell Transplantation (PBSCT) [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
Non-relapse mortality refers to whether a patient dies of causes related to something other than the primary disease.
Achievement of >90% (Full) Donor Chimerism in the T-Cell Lineage as Measured by PCR at Day 30 Post-transplantation [ Time Frame: Day 30 ] [ Designated as safety issue: No ]
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.
Non-relapse Mortality at Day 100 After Peripheral Blood Stem Cell Transplantation (PBSCT) [ Time Frame: Day 100 ] [ Designated as safety issue: Yes ]
Achievement of >90% (Full) Donor Chimerism in the T-Cell Lineage as Measured by PCR at Day 60 Post-transplantation [ Time Frame: Day 60 ] [ Designated as safety issue: No ]
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.
Achievement of >90% (Full) Donor Chimerism in the T-Cell Lineage as Measured by PCR at Day 90 Post-transplantation [ Time Frame: Day 90 ] [ Designated as safety issue: No ]
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.
Overall Survival at 12 Months [ Time Frame: 12 months ] [ Designated as safety issue: No ]
Overall survival, defined as a patient being alive after transplant, is without regard to disease status.
Disease Free Survival at 12 Months [ Time Frame: 12 months ] [ Designated as safety issue: No ]
Disease free survival refers to patients with no evidence of disease after transplant, at the 12 month time point.
Disease Free Survival at Day 100 [ Time Frame: Day 100 ] [ Designated as safety issue: No ]
Disease free survival refers to patients with no evidence of disease after transplant, at the Day 100 time point.

Enrollment:	20
Study Start Date:	October 2008
Study Completion Date:	April 2012
Primary Completion Date:	April 2011 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Myeloablative Haploidentical Transplant All patients will receive treatment using Fludarabine, Busulfan and Cyclophosphamide prior to receiving a haploidentical transplant followed by post-transplant cyclosphosphamide.	Drug: busulfan 110 mg/m2 infused over 3 hours once daily on 4 consecutive days (Days -7, -6, -5, -4) Drug: cyclophosphamide 14.5 mg/kg infused over 1-2 hours once daily on 2 consecutive days (days -3,-2). Drug: fludarabine phosphate 30mg/m2 infused over 30 minutes once daily on three consecutive days (days -5, -4, -3) Drug: 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. Other Name: CellCept Drug: 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. Other Name: Prograf, FK-506 Procedure: allogeneic hematopoietic stem cell transplantation Patients to received unmanipulated PBSCs on Day 0 Other Name: Allo HSCT Procedure: peripheral blood stem cell transplantation patients to receive unmanipulated PBSCs on day 0 Other Name: allogeneic hematopoietic stem cell transplant

Arms

Assigned Interventions

Experimental: Myeloablative Haploidentical Transplant

All patients will receive treatment using Fludarabine, Busulfan and Cyclophosphamide prior to receiving a haploidentical transplant followed by post-transplant cyclosphosphamide.

Drug: busulfan

110 mg/m2 infused over 3 hours once daily on 4 consecutive days (Days -7, -6, -5, -4)

Drug: cyclophosphamide

14.5 mg/kg infused over 1-2 hours once daily on 2 consecutive days (days -3,-2).

Drug: fludarabine phosphate

30mg/m2 infused over 30 minutes once daily on three consecutive days (days -5, -4, -3)

Drug: 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.

Other Name: CellCept

Drug: 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.

Other Name: Prograf, FK-506

Procedure: allogeneic hematopoietic stem cell transplantation

Patients to received unmanipulated PBSCs on Day 0

Other Name: Allo HSCT

Procedure: peripheral blood stem cell transplantation

patients to receive unmanipulated PBSCs on day 0

Other Name: allogeneic hematopoietic stem cell transplant

Detailed 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.

Eligibility

Ages Eligible for Study:	18 Years to 60 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

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 ≥ 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)

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00782379

Locations

United States, Georgia
Blood and Marrow Transplant Group of Georgia
Atlanta, Georgia, United States, 30342

Sponsors and Collaborators

Northside Hospital, Inc.

Investigators

Principal Investigator:	Scott R. Solomon, MD	Blood and Marrow Transplant Group of Georgia
Principal Investigator:	H. Kent Holland, MD	Blood and Marrow Transplant Group of Georgia
Principal Investigator:	Asad Bashey, MD, PhD	Blood and Marrow Transplant Group of Georgia
Principal Investigator:	Lawrence E. Morris, MD	Blood and Marrow Transplant Group of Georgia

More Information

No publications provided

Responsible Party:	Northside Hospital, Inc.
ClinicalTrials.gov Identifier:	NCT00782379 History of Changes
Other Study ID Numbers:	CDR0000617648, BMTGG-NSH-864
Study First Received:	October 29, 2008
Results First Received:	March 18, 2013
Last Updated:	March 18, 2013
Health Authority:	United States: Food and Drug Administration

Keywords provided by Northside Hospital, Inc.:

stage III adult diffuse large cell lymphoma
stage III adult diffuse mixed cell lymphoma
stage III adult diffuse small cleaved cell lymphoma
stage III adult Hodgkin lymphoma
stage III adult lymphoblastic lymphoma
stage III grade 1 follicular lymphoma
stage III grade 2 follicular lymphoma
stage III grade 3 follicular lymphoma
stage III mantle cell lymphoma
stage IV adult diffuse large cell lymphoma
stage IV adult diffuse mixed cell lymphoma
stage IV adult diffuse small cleaved cell lymphoma
stage IV adult Hodgkin lymphoma
stage IV adult lymphoblastic lymphoma
stage IV grade 1 follicular lymphoma

stage IV grade 2 follicular lymphoma
stage IV grade 3 follicular lymphoma
stage IV mantle cell lymphoma
recurrent adult diffuse large cell lymphoma
recurrent adult diffuse mixed cell lymphoma
recurrent adult diffuse small cleaved cell lymphoma
recurrent adult Hodgkin lymphoma
recurrent grade 1 follicular lymphoma
recurrent grade 2 follicular lymphoma
recurrent grade 3 follicular lymphoma
recurrent mantle cell lymphoma
noncontiguous stage II adult diffuse large cell lymphoma
noncontiguous stage II adult diffuse mixed cell lymphoma
noncontiguous stage II adult diffuse small cleaved cell lymphoma
noncontiguous stage II adult lymphoblastic lymphoma

Additional relevant MeSH terms:

Leukemia
Lymphoma
Lymphoma, Non-Hodgkin
Myelodysplastic Syndromes
Preleukemia
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Busulfan

Cyclophosphamide
Mycophenolate mofetil
Fludarabine monophosphate
Tacrolimus
Fludarabine
Mycophenolic Acid
Vidarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents

ClinicalTrials.gov processed this record on May 16, 2013