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

• ClinicalTrials.gov Identifier: NCT00134004
• Recruitment Status: Completed
• First Posted: August 24, 2005
• Results First Posted: August 24, 2015
• Last Update Posted: October 6, 2015
• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Tracking Information

• First Submitted Date: August 22, 2005
• First Posted Date: 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: October 2004
• Actual Primary Completion Date: January 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (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: Not Provided

Current Secondary Outcome Measures (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: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Fludarabine, Cyclophosphamide, and Total-Body Irradiation in Treating Patients Who Are Undergoing a Donor Bone Marrow Transplant for Hematologic Cancer
• Official Title: 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: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Chronic Myeloproliferative Disorders
• Leukemia
• Lymphoma
• Multiple Myeloma and Plasma Cell Neoplasm
• Myelodysplastic Syndromes

Intervention

• 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

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 27, 2015): 210
• Original Enrollment: Not Provided
• Actual Study Completion Date: January 2015
• Actual Primary Completion Date: January 2015 (Final data collection date for primary outcome measure)

Eligibility Criteria

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, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT00134004
• Other Study ID Numbers: 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 at Johns Hopkins
• Study Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Collaborators: National Cancer Institute (NCI)

Investigators

• Study Chair: Ephraim J. Fuchs, MD; Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

• PRS Account: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Verification Date: September 2015