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Chronic Myeloproliferative DisordersPhase 1/2LCCC0510NCT00448357

Allogeneic Hematopoietic Cell Transplantation for Patients With Busulfex-based Regimen

A Phase 1/2 study testing rabbit anti-thymocyte globulin (ATG), therapeutic allogeneic lymphocytes and busulfan in people with Chronic Myeloproliferative Disorders and Leukemia, run by UNC Lineberger Comprehensive Cancer Center at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

RATIONALE: Giving chemotherapy, such as fludarabine and busulfan, before a donor peripheral stem cell transplant helps stop the growth of cancer or abnormal cells. It also helps stop the patient's immune system from rejecting the donor's stem cells. Read more about this study

Who is it for?
Ages 18 to 55 years
What is being tested?
rabbit anti-thymocyte globulin (ATG), therapeutic allogeneic lymphocytes and busulfan
Could I receive a placebo?
No, everyone receives an active treatment
How many people
54 participants
Where
1 siteUnited States
Study dates
Oct 2005to Nov 2015
Phase
Phase 1/2
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 18 to 55 years
  • All sexes
  • No healthy volunteers
  • Adult

Who may be able to join

  • Histologically confirmed diagnosis of any of the following:
  • Chronic lymphocytic leukemia or prolymphocytic leukemia Chemotherapy-refractory or advanced disease after ≥ 3 prior treatments Chronic myelogenous leukemia Diagnosis based on t(9;22) or related t(9;12) cytogenetic abnormalities AND characterized by elevated white blood counts (WBC) in peripheral blood or marrow Patients with progressive disease on imatinib mesylate or other protein tyrosine kinase inhibitors; less than a major cytogenetic or fluorescent in situ hybridization (FISH) complete response (CR) after a minimum of 6 months of targeted therapy; or less than a complete FISH or cytogenetic response after 12 months of targeted therapy are eligible Patients with other cytogenetic abnormalities, such as t(9;12), that are associated with an aggressive clinical course are eligible Non-Hodgkin's lymphoma (NHL) or Hodgkin's lymphoma Any World Health Organization (WHO) classification histologic subtype allowed Must have advanced disease as defined by relapse after initial CR or failure to achieve CR OR deemed to have less than a 30% likelihood of durable response with an autologous stem cell transplant Refractory low-grade NHL histologies or any intermediate or aggressive large cell or mantle cell lymphoma allowed Acute myeloid leukemia (AML) High-risk disease in first CR (CR1) OR evidence of any recurrent disease beyond CR1 High-risk individuals are those requiring more than 1 course of induction therapy to achieve remission; those with extra-medullary disease at presentation; or those with high-risk cytogenetic abnormalities (abnormalities of chromosomes 5, 7, 2, trisomy 8, or 3) or > 2 cytogenetic abnormalities
  • Multiple myeloma
  • Myelodysplastic syndromes (MDS) Must have MDS defined by WHO criteria with > 5% blasts or high-risk cytogenetic abnormalities (abnormalities of chromosomes 5, 7, 2, trisomy 8, or 3)
  • Acute lymphoblastic leukemia (ALL) High-risk disease in CR1 OR beyond CR1 High-risk disease includes the following: t(9;22) or t(4;11); WBC > 30,000/mm³ at presentation; non-T-cell phenotype; or more than 30 years of age
  • Myelofibrosis/agnogenic myeloid metaplasia
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  • Patients must be transfusion dependant or have evidence of evolving AML as evidenced by an excess of blasts or a state of marrow failure/fibrosis
  • Myeloproliferative disorders with advanced disease (e.g., progressive or spent phase polycythemia vera, myelofibrosis, or essential thrombocythemia)
  • Any of the following categories of donors are acceptable*:
  • Human Leucocyte Antigen (HLA)-identical or 1 antigen-mismatched sibling (5/6, 6/6, or 8/10) donor
  • Minimal serologic typing required for class I (A, B); molecular typing required for class II (DRB1)
  • 8/10 matched unrelated donor (MUD)
  • Molecular analysis at HLA-A, -B, -C, -DRB1 and -DQB1 (8/10 match) by high resolution typing is required
  • 5/6 MUD
  • Molecular analysis at HLA-A, -B, and -DRB1 required Note: *No syngeneic donors
  • PATIENT CHARACTERISTICS:
  • Performance status 0-2
  • Bilirubin ≤ 2 times upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) ≤ 2 times ULN
  • Creatinine clearance ≥ 50 mL/min
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • Diffusing capacity of the lungs for carbon monoxide (DLCO) > 60% with no symptomatic pulmonary disease
  • Left ventricular ejection fraction (LVEF) ≥ 50% by multigated acquisition (MUGA) scan
  • EXCLUSION CRITERIA Uncontrolled or severe cardiovascular disease, pulmonary disease, or infection that, in the opinion of the treating physician, would make this study unreasonably hazardous to the patient Other serious illness that would limit survival to < 2 years Psychiatric condition that would preclude study compliance Uncontrolled diabetes mellitus or active serious infection Active second malignancy except for nonmelanomatous skin cancer Known hypersensitivity to E. coli-derived products HIV positivity
  • PRIOR CONCURRENT THERAPY:
  • See Disease Characteristics
  • More than 4 weeks since prior chemotherapy, radiotherapy, or surgery
  • Cranial radiotherapy or intrathecal therapy as prophylaxis against central nervous system (CNS) recurrence within the past 4 weeks allowed (in high-risk patients)

Who cannot join

None listed.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill

    Chapel Hill, North Carolina, 27599-7295

Other trials in United States

About this study

Official title: Allogeneic Hematopoietic Cell Transplantation for Patients With Hematologic Disorders Who Are Undergoing Dose-Adjusted Treatment With A Maximally Intensive Busulfex-Based Therapeutic Regimen

RATIONALE: Giving chemotherapy, such as fludarabine and busulfan, before a donor peripheral stem cell transplant helps stop the growth of cancer or abnormal cells. It also helps stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving a monoclonal antibody, alemtuzumab, before the transplant and tacrolimus after the transplant may stop this from happening.

PURPOSE: The phase I portion of this trial identified the maximum tolerated dose of busulfan after treating 40 patients on a dose-escalation scheme. We are now treating an additional 26 patients on the phase II portion of the trial at a Pharmacokinetic (PK)-directed dose of total area under curve (AUC) 6912 micrometer (uM)-min/24 hours. We transitioned to the Phase II portion of the study in October 2009.

Read the detailed description

OBJECTIVES:

Primary

  • Phase I Objective: To identify the maximum tolerated dose of continuous infusion IV busulfan based on blood levels derived from a test dose in conjunction with fludarabine, ATG and methotrexate plus tacrolimus for GVHD prophylaxis
  • Phase II Objective: To determine the one-year disease-free survival (DFS) rate at the maximum tolerated dose identified during Phase I of the trial (target AUC 6912)

Secondary

  • Determine the overall and disease-free survival of patients treated with this regimen.
  • Determine the dose-limiting toxicities of this regimen in these patients.
  • Determine the capacity of test dosing of busulfan that would result in the desired area under the curve concentration exposure of patients receiving a full-dose busulfan regimen.
  • Determine the incidence of graft-vs-host disease and DNA chimerism between 1 month and 2 years post-transplantation in these patients.
  • Compare the overall survival (OS) and disease-free survival (DFS) rates for patients treated with Campath vs. patients treated with ATG/Methotrexate for GVHD control

OUTLINE: This is a non-randomized, open-label, parallel group study of busulfan. Patients are stratified according to donor relationship - matched related donor (MRD) vs matched unrelated donor (MUD).

  • Conditioning regimen: Patients receive fludarabine phosphate IV over 30 minutes on days -7 to -3 and busulfan IV over 2 hours once within days -15 to -10 and then IV continuously over 90 hours on days -7 to -4. Patients with a MRD also receive Methotrexate (MTX) on Days +1, +3, and +6. Patients with a MUD receive ATG on Days -3 and -2 and MTX on Days +1, +3 and +6.

Phase I portion only: Cohorts of 3-6 patients receive escalating doses of busulfan until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

  • Allogeneic peripheral blood stem cell transplantation: Patients undergo allogeneic peripheral blood stem cell transplantation on day 0. Patients then receive sargramostim (GM-CSF) subcutaneously beginning on day 5 and continuing until blood counts recover.
  • Graft-vs-host disease (GVHD) prophylaxis: Patients receive oral tacrolimus twice daily on days -1 to 180 or days -1 to 240.
  • Donor lymphocyte infusion (DLI): Patients who do not achieve CR, do not have GVHD, and have been off immunosuppressants for at least 30 days may receive up to 3 DLIs, at least 8 weeks apart, after completion of tacrolimus.

After the completion of study treatment, patients are followed periodically for up to 5 years.

Being tested
rabbit anti-thymocyte globulin (ATG), therapeutic allogeneic lymphocytes, busulfan, fludarabine phosphate, tacrolimus
Keywords
refractory multiple myeloma, relapsing chronic myelogenous leukemia, secondary acute myeloid leukemia, stage II multiple myeloma, stage III multiple myeloma, stage IV adult Burkitt lymphoma, stage IV adult diffuse large cell lymphoma, stage IV adult diffuse mixed cell lymphoma, stage IV adult diffuse small cleaved cell lymphoma, stage IV adult immunoblastic large cell lymphoma, stage IV adult lymphoblastic lymphoma, stage IV adult Hodgkin lymphoma, stage IV grade 1 follicular lymphoma, stage IV grade 2 follicular lymphoma, stage IV grade 3 follicular lymphoma, stage IV mantle cell lymphoma, stage IV marginal zone lymphoma, stage IV small lymphocytic lymphoma, Waldenstrom macroglobulinemia, accelerated phase chronic myelogenous leukemia
Medical subject headings
Myeloproliferative Disorders, Leukemia, Lymphoma, Multiple Myeloma, Neoplasms, Plasma Cell, Myelodysplastic Syndromes, Burkitt Lymphoma, Lymphoma, Large B-Cell, Diffuse

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • rabbit anti-thymocyte globulin (ATG)Biological

    .5 mg/kg on day -3 and 2.5 mg/kg on day -2

  • therapeutic allogeneic lymphocytesBiological

    minimum total cluster of differentiation (CD34+) cells of 3 x 10^6 cells/kg and a maximum of 8 x 10^6 cells/kg will be infused on day 0

  • busulfanDrug

    PK-targeted continuous IV infusion over 90 hours on Days -7 to -4.

  • fludarabine phosphateDrug

    30 mg/m^2/day x 5 days intravenous piggyback (IVPB) over 30 minutes on Days -7 through -3

  • tacrolimusDrug

    The suggested starting dose is 0.03 mg/kg po bid starting on day -1

  • allogeneic hematopoietic stem cell transplantationProcedure or surgery

    A minimum total CD34+ cell dose of 3 x 10^6 cells/kg and maximum of 8 x 10^6 cells/kg will be infused on day 0

  • peripheral blood stem cell transplantationProcedure or surgery

    minimum total CD34+ cell dose of 3 x 10^6 cells/kg and a maximum of 8 x 10^6 cells/kg will be infused on day 0

  • methotrexateDrug

    5 mg/m^2 on days +1, +3 and +6

Study groups in NCT00448357
Study groupRoleWhat they receive
GVHD prophylaxisExperimentalSubjects with matched-related donors (MRDs) were treated with tacrolimus and methotrexate with or without alemtuzumab for graft vs host disease prophylaxis Subjects also receive busulfan and fludarabine . Matched unrelated donor (MUD) or mismatched related donor (MMRD) subjects receive GVHD prophylaxis with rabbit anti-thymocyte globulin (ATG) + Methotrexate Subjects also receive busulfan, fludarabine, and tacrolimus.
Receives: Biological: rabbit anti-thymocyte globulin (ATG); Biological: therapeutic allogeneic lymphocytes; Drug: busulfan; Drug: fludarabine phosphate; Drug: tacrolimus; Procedure: allogeneic hematopoietic stem cell transplantation; Procedure: peripheral blood stem cell transplantation; Drug: methotrexate

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Three-year Relapse-free Survival (RFS) Rate at the Maximum Tolerated Dose Identified During Phase I of the Trial (Target AUC 6912)

    Relapse is defined as new or increased sites of disease or positive one marrow after a complete response (CR). The RFS was calculated as the percentage of patients who were alive and without relapse at 3 years

    Measured: Three years post-transplant

  2. Number of Participants With Dose Limiting Toxicities (DLTs)

    Dose limiting toxicity will be defined as any irreversible grade 3 or any grade 4 non-hematologic toxicity that is related to busulfan infusion and not graft vs host disease or late infection after recovery from the initial period of myelosuppression. The maximum tolerated dose (MTD) is defined as the dose with probability of dose limiting toxicity (DLT) of 0.25. The dose of continuous infusion IV busulfan based on blood levels derived from a test dose in conjunction with fludarabine and alemtuzumab plus tacrolimus for GVHD prophylaxis.

    Measured: first 6 weeks or 42 days following stem cell infusion

Secondary outcomes (4)

  1. Capacity of Test Dosing of Busulfan That Would Result in the Desired Area Under the Curve Concentration Exposure of Patients Receiving a Full-dose Busulfan Regimen

    Test doses of busulfan were administered and plasma levels were measured to determine a targeted AUC dosing estimate. The capacity is reported as the precision with which these test dose goals predicted the actual 90-hour mean AUC levels.Dose targeting precision was estimated by root mean squared error.

    Measured: Day -15 to Day -11

  2. Incidence of Graft vs Host Disease in Patients Between One Month and Two Years Post Transplant

    GVHD can be mild, moderate or severe depending on the differences in tissue type between patient and donor. GVHD can be acute or chronic. Its symptoms can include:

    • Rashes, which include burning and redness, that erupt on the palms or soles and may spread to the trunk and eventually to the entire body
    • Blistering, causing the exposed skin surface to flake off in severe cases
    • Nausea, vomiting, abdominal cramps, diarrhea and loss of appetite, which can indicate that the gastrointestinal (digestive) tract is affected
    • Jaundice, or a yellowing of the skin, which can indicate liver damage
    • Excessive dryness of the mouth and throat, leading to ulcers
    • Dryness of the lungs, vagina and other surfaces

    Measured: 100 days post transplant

  3. Incidence of DNA Chimerism in Patients Between One Month Post Transplant

    Deoxyribonucleic acid (DNA) chimerism is a measure identifying the genetic profiles of the transplant recipient and of the donor and then evaluating the extent of mixture in the recipient's blood, bone marrow, or other tissue.

    Measured: 30 days post transplant

  4. Overall Survival

    Percentage of participants alive at 3 years post transplant

    Measured: Three years post-transplant

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted16 Mar 2007 (estimated)
  2. Study startOct 2005
  3. Primary completionNov 2015
  4. Study completionNov 2015

Resources

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 1/2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
54 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00448357
Sponsor's protocol ID
LCCC 0510
Other IDs
P30CA016086
Acronym
LCCC0510
Status last verified
Jun 2017
First submitted
14 Mar 2007
Last updated
17 Jul 2017
Data monitoring committee
Yes
Individual data sharing
No

Publications

  • Shea TC, Walko C, Chung Y, Ivanova A, Sheets J, Rao K, Gabriel D, Comeau T, Wood W, Coghill J, Armistead P, Sarantopoulos S, Serody J. Phase I/II Trial of Dose-Escalated Busulfan Delivered by Prolonged Continuous Infusion in Allogeneic Transplant Patients. Biol Blood Marrow Transplant. 2015 Dec;21(12):2129-2135. doi: 10.1016/j.bbmt.2015.07.016. Epub 2015 Jul 22.

    PubMed 26210442

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing rabbit anti-thymocyte globulin (ATG), therapeutic allogeneic lymphocytes and busulfan in people with Chronic Myeloproliferative Disorders and Leukemia, run by UNC Lineberger Comprehensive Cancer Center at 1 site 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?

The sponsor lists 30 inclusion and 0 exclusion criteria. 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 17 Jul 2017. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site 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 combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

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 17 Jul 2017). 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?

Three-year Relapse-free Survival (RFS) Rate at the Maximum Tolerated Dose Identified During Phase I of the Trial (Target AUC 6912) (time frame: Three years post-transplant). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00448357, which also lists 1 linked publication.

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 17 Jul 2017.

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