Fludarabine, Cyclophosphamide, and Total-Body Irradiation in Treating Patients Who Are Undergoing a Donor Bone Marrow Transplant for Hematologic Cancer

Phase 2

Completed

• Conditions: Chronic Myeloproliferative Disorders; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes
• Interventions: Drug: cyclophosphamide; Drug: fludarabine phosphate; Drug: mycophenolate mofetil; Drug: tacrolimus; Procedure: allogeneic bone marrow transplantation; Radiation: radiation therapy

• Registration Number: NCT00134004
• Lead Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Brief Summary

RATIONALE: Giving low doses of chemotherapy, such as fludarabine and cyclophosphamide, and radiation therapy before a donor bone marrow transplant helps stop the growth of cancer cells. Giving chemotherapy or radiation therapy before or after transplant also stops the patient's immune system from rejecting the donor's bone marrow stem cells. The donated stem cells may replace the patient's immune system cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving tacrolimus and mycophenolate mofetil after the transplant may stop this from happening.

PURPOSE: This phase II trial is studying how well giving fludarabine and cyclophosphamide together with total-body irradiation works in treating patients who are undergoing a donor bone marrow transplant for hematologic cancer.

Detailed Description

OBJECTIVES:

* Determine transplant-related mortality, risk of relapse, and progression-free survival of patients with standard- or high-risk hematologic malignancies undergoing nonmyeloablative conditioning comprising fludarabine, cyclophosphamide, and total-body irradiation followed by HLA-haploidentical allogeneic bone marrow transplantation.

* Determine donor hematopoietic chimerism in patients' peripheral blood at 30, 60, and 180 days after transplantation.

* Determine hematologic and nonhematologic toxic effects of this regimen in these patients.

* Determine, when feasible, surface expression of HLA molecules and death receptors, sensitivity to cytotoxic lymphocytes, and expression of anti-apoptotic genes (e.g., Bcl-2, Bcl-xL, X-IAP, and c-FLIP) in cancer cells from patients who relapse after treatment with this regimen.

OUTLINE: This is a multicenter study. Patients are stratified according to risk of relapse (standard \[defined as ≤ 30% risk\] vs high \[defined as ≥ 70% risk\]).

* Nonmyeloablative conditioning regimen: Patients receive fludarabine IV over 30 minutes on days -6 to -2 and cyclophosphamide IV over 1-2 hours on days -6 and -5. Patients undergo total body irradiation on day -1.

* Allogeneic bone marrow transplantation: Patients undergo donor bone marrow infusion on day 0.

* Post-transplantation therapy: Patients receive cyclophosphamide IV over 1-2 hours on days 3 and 4.

* Graft-vs-host disease prophylaxis: Beginning on day 5, patients receive oral mycophenolate mofetil 3 times daily until day 35 and tacrolimus IV (then changing to orally) twice daily until day 180.

Treatment continues in the absence of disease progression.

After completion of study transplantation, patients are followed on days 30, 60, 100, and 180; at 1 year; and then annually for 4 additional years.

PROJECTED ACCRUAL: A total of 75-100 patients will be accrued for this study within 3-4 years.

Study Timeline

• Study Start: 2004-10
• Study First Submitted: 2005-08-22
• Study First Submitted QC: 2005-08-22
• Study First Posted: 2005-08-24
• Primary Completion: 2015-01
• Study Completion: 2015-01
• Results First Submitted: 2015-06-26
• Results First Submitted QC: 2015-07-27
• Results First Posted: 2015-08-24
• Status Verified: 2015-09
• Last Update Submitted: 2015-09-02
• Last Update Posted: 2015-10-06

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 210

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Mini-haplo Transplant	cyclophosphamide	Non-myeloablative haploidentical bone marrow transplant with a fludarabine, cyclophosphamide (Cy), TBI (total body irradiation) preparative regimen and post-transplant Cy, mycophenolate mofetil (MMF), and tacrolimus as GVHD prophylaxis.
Mini-haplo Transplant	mycophenolate mofetil	Non-myeloablative haploidentical bone marrow transplant with a fludarabine, cyclophosphamide (Cy), TBI (total body irradiation) preparative regimen and post-transplant Cy, mycophenolate mofetil (MMF), and tacrolimus as GVHD prophylaxis.
Mini-haplo Transplant	allogeneic bone marrow transplantation	Non-myeloablative haploidentical bone marrow transplant with a fludarabine, cyclophosphamide (Cy), TBI (total body irradiation) preparative regimen and post-transplant Cy, mycophenolate mofetil (MMF), and tacrolimus as GVHD prophylaxis.
Mini-haplo Transplant	radiation therapy	Non-myeloablative haploidentical bone marrow transplant with a fludarabine, cyclophosphamide (Cy), TBI (total body irradiation) preparative regimen and post-transplant Cy, mycophenolate mofetil (MMF), and tacrolimus as GVHD prophylaxis.
Mini-haplo Transplant	fludarabine phosphate	Non-myeloablative haploidentical bone marrow transplant with a fludarabine, cyclophosphamide (Cy), TBI (total body irradiation) preparative regimen and post-transplant Cy, mycophenolate mofetil (MMF), and tacrolimus as GVHD prophylaxis.
Mini-haplo Transplant	tacrolimus	Non-myeloablative haploidentical bone marrow transplant with a fludarabine, cyclophosphamide (Cy), TBI (total body irradiation) preparative regimen and post-transplant Cy, mycophenolate mofetil (MMF), and tacrolimus as GVHD prophylaxis.

Primary Outcome Measures

Name	Time	Method
Transplant-related Mortality	Cumulative incidence for the entire study, up to 11 years	Percentage of participants who die for any reason other than recurrence of disease.
Relapse Rate	Cumulative incidence for the entire study, up to 11 years	Percentage of participants who experience disease relapse.
Progression-free Survival	2 years	Percentage of participants who do not experience disease relapse, disease progression, or death.

Secondary Outcome Measures

Name	Time	Method
Graft Failure Rate	Cumulative incidence for the entire study, up to 11 years	Percentage of participants who experienced failure to engraft (also called graft failure or graft rejection). Failure to engraft is defined as \<5% donor chimerism and absence of relapse or any other reason for that chimerism value. All participants who met this criterion were included in this outcome measure.
Hematologic and Non-hematologic Toxicities as Measured by NCI Common Toxicity Criteria for Adverse Events, v 3.0 Weekly Until 1 Year After Transplantation	1 year	Percentage of study participants who experienced a serious adverse event (SAE) within 1 year of bone marrow transplant. Complete data is provided in the Adverse Event tables.

Trial Locations

Locations (3)

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; 🇺🇸 Baltimore, Maryland, United States

Blood and Marrow Transplant Program at Northside Hospital; 🇺🇸 Atlanta, Georgia, United States

Hahnemann University Hospital; 🇺🇸 Philadelphia, Pennsylvania, United States