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


Phase 1/Phase 2
18 Years
55 Years
Open (Enrolling)
Both
Chronic Myeloproliferative Disorders, Leukemia, Lymphoma, Multiple Myeloma and Plasma Cell Neoplasm, Myelodysplastic Syndromes

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Trial Information

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


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.

Inclusion Criteria


DISEASE CHARACTERISTICS:

- 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 WBC counts 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 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

- 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*:

- 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)

- AST ≤ 2 times ULN

- Creatinine clearance ≥ 50 mL/min

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- DLCO > 60% with no symptomatic pulmonary disease

- LVEF ≥ 50% by MUGA

- No 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

- No other serious illness that would limit survival to < 2 years

- No psychiatric condition that would preclude study compliance

- No uncontrolled diabetes mellitus or active serious infection

- No active second malignancy except for nonmelanomatous skin cancer

- No known hypersensitivity to E. coli-derived products

- No 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 CNS
recurrence within the past 4 weeks allowed (in high-risk patients)

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

One-year disease-free survival (DFS) rate at the maximum tolerated dose identified during phase I of the trial (target AUC 6912)

Outcome Time Frame:

One year post-transplant

Safety Issue:

No

Principal Investigator

Thomas C. Shea, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

UNC Lineberger Comprehensive Cancer Center

Authority:

United States: Food and Drug Administration

Study ID:

LCCC 0510

NCT ID:

NCT00448357

Start Date:

October 2005

Completion Date:

August 2013

Related Keywords:

  • Chronic Myeloproliferative Disorders
  • Leukemia
  • Lymphoma
  • Multiple Myeloma and Plasma Cell Neoplasm
  • Myelodysplastic Syndromes
  • 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
  • adult acute myeloid leukemia in remission
  • blastic phase chronic myelogenous leukemia
  • chronic eosinophilic leukemia
  • chronic neutrophilic leukemia
  • extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue
  • nodal marginal zone B-cell lymphoma
  • recurrent adult Burkitt lymphoma
  • recurrent adult diffuse large cell lymphoma
  • recurrent adult diffuse mixed cell lymphoma
  • recurrent adult diffuse small cleaved cell lymphoma
  • recurrent adult Hodgkin lymphoma
  • recurrent adult immunoblastic large cell lymphoma
  • recurrent adult lymphoblastic lymphoma
  • recurrent grade 1 follicular lymphoma
  • recurrent grade 2 follicular lymphoma
  • recurrent grade 3 follicular lymphoma
  • recurrent mantle cell lymphoma
  • recurrent marginal zone lymphoma
  • recurrent small lymphocytic lymphoma
  • stage III adult Burkitt lymphoma
  • stage III adult diffuse large cell lymphoma
  • stage III adult diffuse mixed cell lymphoma
  • stage III adult diffuse small cleaved cell lymphoma
  • stage III adult Hodgkin lymphoma
  • stage III adult immunoblastic large cell lymphoma
  • stage III adult lymphoblastic lymphoma
  • stage III grade 1 follicular lymphoma
  • stage III grade 2 follicular lymphoma
  • stage III grade 3 follicular lymphoma
  • stage III mantle cell lymphoma
  • stage III marginal zone lymphoma
  • stage III small lymphocytic lymphoma
  • 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)
  • primary myelofibrosis
  • chronic phase chronic myelogenous leukemia
  • de novo myelodysplastic syndromes
  • previously treated myelodysplastic syndromes
  • prolymphocytic leukemia
  • recurrent adult acute lymphoblastic leukemia
  • recurrent adult acute myeloid leukemia
  • refractory chronic lymphocytic leukemia
  • secondary myelodysplastic syndromes
  • stage III chronic lymphocytic leukemia
  • stage IV chronic lymphocytic leukemia
  • adult acute lymphoblastic leukemia in remission
  • polycythemia vera
  • essential thrombocythemia
  • splenic marginal zone lymphoma
  • recurrent mycosis fungoides/Sezary syndrome
  • recurrent cutaneous T-cell non-Hodgkin lymphoma
  • stage I multiple myeloma
  • recurrent adult grade III lymphomatoid granulomatosis
  • adult nasal type extranodal NK/T-cell lymphoma
  • Neoplasms
  • Leukemia
  • Lymphoma
  • Lymphoma, Non-Hodgkin
  • Multiple Myeloma
  • Neoplasms, Plasma Cell
  • Plasmacytoma
  • Myelodysplastic Syndromes
  • Preleukemia
  • Myeloproliferative Disorders
  • Lymphoma, Large-Cell, Immunoblastic

Name

Location

Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel HillChapel Hill, North Carolina  27599-7570