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

Tracking Information
First Submitted Date ICMJE	August 22, 2005
First Posted Date ICMJE	August 24, 2005
Results First Submitted Date	June 26, 2015
Results First Posted Date	August 24, 2015
Last Update Posted Date	October 6, 2015
Study Start Date ICMJE	October 2004
Actual Primary Completion Date	January 2015 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: September 2, 2015)	Transplant-related Mortality [ Time Frame: 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 [ Time Frame: Cumulative incidence for the entire study, up to 11 years ]Percentage of participants who experience disease relapse.; Progression-free Survival [ Time Frame: 2 years ]Percentage of participants who do not experience disease relapse, disease progression, or death.
Original Primary Outcome Measures ICMJE	Not Provided
Change History	Complete list of historical versions of study NCT00134004 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: September 2, 2015)	Graft Failure Rate [ Time Frame: 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 [ Time Frame: 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.
Original Secondary Outcome Measures ICMJE	Not Provided
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	Fludarabine, Cyclophosphamide, and Total-Body Irradiation in Treating Patients Who Are Undergoing a Donor Bone Marrow Transplant for Hematologic Cancer
Official Title ICMJE	A Phase II Trial of Non-Myeloablative Conditioning and Transplantation of Partially HLA-Mismatched Bone Marrow for Patients With Hematologic Malignancies
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 Type ICMJE	Interventional
Study Phase	Phase 2
Study Design ICMJE	Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition ICMJE	Chronic Myeloproliferative Disorders; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes
Intervention ICMJE	Drug: cyclophosphamide; Drug: fludarabine phosphate; Drug: mycophenolate mofetil; Drug: tacrolimus; Procedure: allogeneic bone marrow transplantation; Radiation: radiation therapy
Study Arms	Experimental: Mini-haplo Transplant; 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.; Interventions: Drug: cyclophosphamide; Drug: fludarabine phosphate; Drug: mycophenolate mofetil; Drug: tacrolimus; Procedure: allogeneic bone marrow transplantation; Radiation: radiation therapy
Publications *	Not Provided
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Completed
Actual Enrollment ICMJE; (submitted: July 27, 2015)	210
Original Enrollment ICMJE	Not Provided
Actual Study Completion Date	January 2015
Actual Primary Completion Date	January 2015 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	DISEASE CHARACTERISTICS: Diagnosis of 1 of the following hematologic malignancies: Acute leukemia In second or subsequent complete remission (CR), as defined by absence of abnormal blast population by flow cytometry In first CR with any of the following poor-risk cytogenetic features: Alteration of chromosome 5 or 7 Multiple abnormalities Philadelphia chromosome positive Chronic phase chronic myelogenous leukemia (CML) In first chronic phase and refractory to interferon alfa or imatinib mesylate In second or subsequent chronic phase Chronic lymphocytic leukemia, meeting 1 of the following criteria: Received prior chemotherapy with a nucleoside analog and had remission lasting < 6 months Received 1 prior therapy and has any of the following high-risk features: Cytogenetic abnormalities of 17p, 11q Mutations of the Zap70 gene Somatically unmutated immunoglobulin heavy chain variable region genes Hodgkin's lymphoma Ineligible for autologous stem cell transplantation (SCT) due to any of the following exclusion factors: LVEF < 45% FEV_1 or FVC < 50% of predicted (75% of predicted in patients with prior thoracic or mantle radiotherapy) Total bilirubin > 2.0 mg/dL (unless documented Gilbert's disease) Creatinine > 2.0 mg/dL Non-Hodgkin's lymphoma (NHL) Low-grade NHL allowed provided patient had a remission duration of < 1 year after administration of any established, multi-agent chemotherapy regimen (e.g., CVP, CHOP, or rituximab in combination with CHOP) Intermediate- or high-grade NHL allowed provided patient is ineligible for autologous SCT according to the criteria listed above Multiple myeloma Myelodysplastic syndromes Paroxysmal nocturnal hemoglobinuria Chronic myeloproliferative disorders other than CML, including any of the following: Chronic myelomonocytic leukemia Agnogenic myeloid metaplasia (or myeloid metaplasia with myelofibrosis), with hemoglobin < 10 g/dL OR WBC < 4,000/mm^3 or > 30,000/mm^3 Polycythemia vera or essential thrombocythemia in "spent" phase, with a history of 2 of the following: Marrow fibrosis Splenomegaly Cytopenia (i.e., absolute neutrophil count < 1,500/mm^3, platelet count < 100,000/mm^3, hemoglobin < 10 g/dL) Polycythemia vera or essential thrombocythemia with transformation to myelodysplastic syndromes or acute myeloid leukemia (requires treatment to achieve < 20% blasts in marrow); No smoldering myeloma; Patients with acute myeloid leukemia or myelodysplastic syndromes must have had comprehensive cytogenetic evaluation of bone marrow specimen during active disease; Ineligible for or refused bone marrow transplantation from an HLA-matched sibling or unrelated donor; Ineligible for or refused autologous SCT; Must have an HLA mismatched (i.e., 3/6, 4/6, or 5/6) related (first-degree relative)* donor available Donor ≥ 18 years of age NOTE: *Patients with an inherited recombinant HLA haplotype may receive marrow from the parent in whose gamete the recombination occurred NOTE: A new classification scheme for adult non-Hodgkin's 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. PATIENT CHARACTERISTICS: Age; 6 months to 74 years Performance status; ECOG 0-1 Life expectancy; Not specified Hematopoietic; See Disease Characteristics Hepatic; See Disease Characteristics; Bilirubin < 3.1 mg/dL Renal; See Disease Characteristics Cardiovascular; See Disease Characteristics; LVEF ≥ 35% Pulmonary; See Disease Characteristics; FEV_1 or FVC ≥ 40% of predicted in patients without prior thoracic or mantle radiotherapy (60% of predicted in patients with prior thoracic or mantle radiotherapy) Other; Not pregnant or nursing; Negative pregnancy test; Fertile patients must use effective contraception; HIV negative; Geographically accessible; No debilitating medical or psychiatric illness that would preclude giving informed consent or receiving optimal treatment or follow-up PRIOR CONCURRENT THERAPY: Biologic therapy; See Disease Characteristics; No prior transfusions from donor Chemotherapy; See Disease Characteristics Endocrine therapy; Not specified Radiotherapy; See Disease Characteristics Surgery; Not specified
Sex/Gender	Sexes Eligible for Study: All
Ages	6 Months to 74 Years (Child, Adult, Senior)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	United States
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT00134004
Other Study ID Numbers ICMJE	J0457 CDR0000440990; P01CA015396 ( U.S. NIH Grant/Contract ); P30CA006973 ( U.S. NIH Grant/Contract ); JHOC-J0457 ( Other Identifier: Johns Hopkins SKCCC ); JHOC-04072704
Has Data Monitoring Committee	Not Provided
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Not Provided
Responsible Party	Sidney Kimmel Comprehensive Cancer Center
Study Sponsor ICMJE	Sidney Kimmel Comprehensive Cancer Center
Collaborators ICMJE	National Cancer Institute (NCI)
Investigators ICMJE	Study Chair: Ephraim J. Fuchs, MD Sidney Kimmel Comprehensive Cancer Center
PRS Account	Sidney Kimmel Comprehensive Cancer Center
Verification Date	September 2015
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP