Chronic Myeloproliferative DisordersPhase 2NCT00134004
Fludarabine, Cyclophosphamide, and Total-Body Irradiation in Treating Patients Who Are Undergoing a Donor Bone Marrow Transplant for Hematologic Cancer
A Phase 2 study testing cyclophosphamide, fludarabine phosphate and mycophenolate mofetil in people with Chronic Myeloproliferative Disorders and Leukemia, run by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins at 3 sites in United States.
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. Read more about this study
- Who is it for?
- Ages 6 months to 74 years
- Conditions the study is for
- Chronic Myeloproliferative Disorders, Leukemia, Lymphoma
- What is being tested?
- cyclophosphamide, fludarabine phosphate and mycophenolate mofetil
- Type of treatment
- Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 210 participants
- Where
- 3 sitesUnited States
- Study dates
- Oct 2004to Jan 2015
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 6 months to 74 years
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
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
Trial locations and contacts
3 sites in 1 country.
United States3 sites
Blood and Marrow Transplant Program at Northside Hospital
Atlanta, Georgia, 30342
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Baltimore, Maryland, 21231-2410
Hahnemann University Hospital
Philadelphia, Pennsylvania, 19102-1192
About this study
Official title: A Phase II Trial of Non-Myeloablative Conditioning and Transplantation of Partially HLA-Mismatched Bone Marrow for Patients With Hematologic Malignancies
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.
Read the 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.
- Conditions
- Chronic Myeloproliferative Disorders, Leukemia, Lymphoma, Multiple Myeloma and Plasma Cell Neoplasm, Myelodysplastic Syndromes
- Being tested
- cyclophosphamide, fludarabine phosphate, mycophenolate mofetil, tacrolimus, allogeneic bone marrow transplantation
- Keywords
- adult acute lymphoblastic leukemia in remission, adult acute myeloid leukemia in remission, childhood acute lymphoblastic leukemia in remission, childhood acute myeloid leukemia in remission, childhood chronic myelogenous leukemia, chronic phase chronic myelogenous leukemia, refractory chronic lymphocytic leukemia, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, adult acute myeloid leukemia with 11q23 (MLL) abnormalities, adult acute myeloid leukemia with inv(16)(p13;q22), adult acute myeloid leukemia with t(15;17)(q22;q12), adult acute myeloid leukemia with t(16;16)(p13;q22), adult acute myeloid leukemia with t(8;21)(q22;q22), chronic idiopathic myelofibrosis, chronic myelomonocytic leukemia, de novo myelodysplastic syndromes, previously treated myelodysplastic syndromes, noncontiguous stage II adult Burkitt lymphoma, noncontiguous stage II adult diffuse large cell lymphoma, noncontiguous stage II adult diffuse mixed cell lymphoma
- Medical subject headings
- Myeloproliferative Disorders, Leukemia, Lymphoma, Multiple Myeloma, Neoplasms, Plasma Cell, Myelodysplastic Syndromes, Leukemia, Myeloid, Chronic-Phase, Leukemia, Lymphocytic, Chronic, B-Cell
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
cyclophosphamideDrug
tacrolimusDrug
allogeneic bone marrow transplantationProcedure or surgery
radiation therapyRadiation
| Study group | Role | What they receive |
|---|---|---|
| Mini-haplo Transplant | Experimental | 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. Receives: Drug: cyclophosphamide; Drug: fludarabine phosphate; Drug: mycophenolate mofetil; Drug: tacrolimus; Procedure: allogeneic bone marrow transplantation; Radiation: radiation therapy |
What is being measured
The primary outcome is the main question the study is designed to answer.
Transplant-related Mortality
Percentage of participants who die for any reason other than recurrence of disease.
Measured: Cumulative incidence for the entire study, up to 11 years
Relapse Rate
Percentage of participants who experience disease relapse.
Measured: Cumulative incidence for the entire study, up to 11 years
Progression-free Survival
Percentage of participants who do not experience disease relapse, disease progression, or death.
Measured: 2 years
Secondary outcomes (2)
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.
Measured: Cumulative incidence for the entire study, up to 11 years
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.
Measured: 1 year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Aug 2005 (estimated)
- Study startOct 2004
- Primary completionJan 2015
- Study completionJan 2015
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Chronic Myeloproliferative DisordersStudies of the same condition, open and under way.
- More trials run by Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 210 participants (actual)
Sponsor and investigators
- Sponsor type
- University, hospital or other
- Collaborators
- National Cancer Institute (NCI)
- Responsible party
- Sponsor
- Investigators
- Ephraim J. Fuchs, MD, Study chair, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00134004
- Sponsor's protocol ID
- J0457 CDR0000440990
- Other IDs
- P01CA015396, P30CA006973, JHOC-J0457, JHOC-04072704
- Status last verified
- Sep 2015
- First submitted
- 22 Aug 2005
- Last updated
- 6 Oct 2015
- Results posted
- Yes, on ClinicalTrials.gov
Study at a glance
From the registry record, last updated by the sponsor on 6 Oct 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase II Trial of Non-Myeloablative Conditioning and Transplantation of Partially HLA-Mismatched Bone Marrow for Patients With Hematologic Malignancies
- ClinicalTrials.gov ID
- NCT00134004
- Acronym / sponsor ID
- J0457 CDR0000440990
- Conditions
- Chronic Myeloproliferative Disorders, Leukemia, Lymphoma, Multiple Myeloma and Plasma Cell Neoplasm, Myelodysplastic Syndromes
- Keywords
- adult acute lymphoblastic leukemia in remission, adult acute myeloid leukemia in remission, childhood acute lymphoblastic leukemia in remission, childhood acute myeloid leukemia in remission, childhood chronic myelogenous leukemia, chronic phase chronic myelogenous leukemia, refractory chronic lymphocytic leukemia, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 210 participants (actual)
- Lead sponsor
- Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsUniversity, hospital or other
- Collaborators
- National Cancer Institute (NCI)
- Study start
- Oct 2004
- Primary completion
- Jan 2015 (actual)
- Study completion
- Jan 2015 (actual)
- First posted
- 24 Aug 2005 (estimated)
- Results
- Posted 24 Aug 2015
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Mini-haplo Transplant | Experimental | Drug: cyclophosphamide, Drug: fludarabine phosphate, Drug: mycophenolate mofetil, Drug: tacrolimus, Procedure: allogeneic bone marrow transplantation, Radiation: radiation therapyNon-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. |
Who may qualify
- Ages
- 6 months to 74 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| cyclophosphamide | Drug | Mini-haplo Transplant |
| fludarabine phosphate | Drug | Mini-haplo Transplant |
| mycophenolate mofetil | Drug | Mini-haplo Transplant |
| tacrolimus | Drug | Mini-haplo Transplant |
| allogeneic bone marrow transplantation | Procedure or surgery | Mini-haplo Transplant |
| radiation therapy | Radiation | Mini-haplo Transplant |
Primary outcome
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.
2 secondary outcomes
Graft Failure Rate
Time frame: Cumulative incidence for the entire study, up to 11 years
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
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Oct 2015.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ephraim J. Fuchs, MD study chair
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing cyclophosphamide, fludarabine phosphate and mycophenolate mofetil in people with Chronic Myeloproliferative Disorders and Leukemia, run by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins at 3 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 6 Oct 2015. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 24 Aug 2015). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Transplant-related Mortality (time frame: Cumulative incidence for the entire study, up to 11 years). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Oct 2015.