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

Lymphoma Clinical Trial

Official title:

A Phase II Trial of Non-Myeloablative Conditioning and Transplantation of Partially HLA-Mismatched Bone Marrow for Patients With Hematologic Malignancies

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00134004
• Other study ID #: J0457 CDR0000440990
• Secondary ID: P01CA015396P30CA
• Status: Completed
• Phase: Phase 2
• First received: August 22, 2005
• Last updated: September 2, 2015
• Start date: October 2004
• Est. completion date: January 2015

Study information

• Verified date: September 2015
• Source: Sidney Kimmel Comprehensive Cancer Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 210
• Est. completion date: January 2015
• Est. primary completion date: January 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 6 Months to 74 Years

Eligibility

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

Study Design

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Chronic Myeloproliferative Disorders
• Leukemia
• Lymphoma
• Multiple Myeloma
• Multiple Myeloma and Plasma Cell Neoplasm
• Myelodysplastic Syndromes
• Myeloproliferative Disorders
• Neoplasms, Plasma Cell
• Plasmacytoma
• Preleukemia

Intervention

Drug:
• cyclophosphamide

• fludarabine phosphate

• mycophenolate mofetil

• tacrolimus

Procedure:
• allogeneic bone marrow transplantation

Radiation:
• radiation therapy

Locations

Country	Name	City	State
United States	Blood and Marrow Transplant Program at Northside Hospital	Atlanta	Georgia
United States	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	Baltimore	Maryland
United States	Hahnemann University Hospital	Philadelphia	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
Sidney Kimmel Comprehensive Cancer Center	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Transplant-related Mortality	Percentage of participants who die for any reason other than recurrence of disease.	Cumulative incidence for the entire study, up to 11 years	No
Primary	Relapse Rate	Percentage of participants who experience disease relapse.	Cumulative incidence for the entire study, up to 11 years	No
Primary	Progression-free Survival	Percentage of participants who do not experience disease relapse, disease progression, or death.	2 years	No
Secondary	Graft Failure Rate	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.	Cumulative incidence for the entire study, up to 11 years	No
Secondary	Hematologic and Non-hematologic Toxicities as Measured by NCI Common Toxicity Criteria for Adverse Events, v 3.0 Weekly Until 1 Year After Transplantation	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.	1 year	Yes