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Allogeneic Bone Marrow Transplantation Using Less Intensive Therapy


Phase 2
N/A
75 Years
Open (Enrolling)
Both
Kidney Cancer, Leukemia, Lymphoma, Multiple Myeloma, Plasma Cell Neoplasm, Myelodysplastic Syndromes

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Trial Information

Allogeneic Bone Marrow Transplantation Using Less Intensive Therapy


OBJECTIVES:

- Determine if a nonmyeloablative regimen comprising cyclophosphamide, fludarabine, and
radiotherapy followed by cyclosporine and mycophenolate mofetil provides a prompt and
durable donor engraftment in patients with hematologic malignancies or kidney cancer
who are undergoing allogeneic stem cell transplantation.

- Determine the safety of this nonmyeloablative transplantation regimen in these
patients.

- Determine the risk of graft-versus-host-disease in patients treated with this regimen.

- Determine the antineoplastic potency of nonmyeloablative stem cell transplantation in
patients treated with this regimen.

- Determine the effect of lower doses of daily fludarabine on treatment-related mortality
(TRM) OUTLINE: Patients are stratified according to risk (standard vs high).

- Preparative regimen*: Patients receive cyclophosphamide intravenously (IV) over 2 hours
on day -6 and fludarabine IV over 1 hour on days -6 to -2. Patients undergo total body
irradiation on day -1. Some patients also receive anti-thymocyte globulin (ATG)** IV
every 12 hours on days -6 to -4. Patients who receive ATG* include the following:

- Related donor recipients who have not received combination chemotherapy within the
past 6 months

- Unrelated donor recipients who have not received combination chemotherapy within
the past 3 months

- Unrelated donor recipients who have received only 1 induction course for the
treatment of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML),
myelodysplastic syndromes (MDS), or blastic phase chronic myelogenous leukemia
(CML) NOTE: **Patients who underwent prior autologous stem cell transplantation in
the past year do not receive ATG.

- Allogeneic peripheral blood stem cell transplantation (PBSCT): Patients undergo
allogeneic PBSCT on day 0.

- Graft-versus-host-disease prophylaxis: Patients receive cyclosporine IV over 2 hours
beginning on day -3 and continuing until at least day 100. Patients also receive
mycophenolate mofetil IV or orally twice daily on days -3 to 30.

- Donor lymphocyte infusion (DLI): Patients without active GVHD but deteriorating donor
chimerism may receive DLI IV over 2 hours.

After completion of study treatment, patients are followed periodically for 2 years.

PROJECTED ACCRUAL: A total of 300 patients will be accrued for this study.


Inclusion Criteria:



Standard patients will be enrolled into Arms 1-6. High risk patients (transplant with
aplasia) will be considered separately in Arm 7.

- Age and Graft criteria (all patients)

- Patient's < or = 75 years old with a 5/6 or 6/6 related donor match are
eligible.

- Patient's < or = 75 years who have a 7-8/8 HLA-A,B,C,DRB1 allele matched
unrelated volunteer marrow and/or peripheral blood stem cell (PBSC) donor match
are eligible.

- Disease Criteria (standard risk patients)

- Acute myelogenous leukemia— high risk CR1 (as evidenced by preceding
myelodysplastic syndrome [MDS], high risk cytogenetics such as those associated
with MDS or complex karyotype, or > 2 cycles to obtain CR); second or greater
complete remission (CR). Must be in remission by morphology. Patients in
morphologic relapse/ persistent disease defined as > 5% blasts in normocellular
bone marrow OR any % blasts if blasts have unique morphologic markers (eg auer
rods) or associated cytogenetic markers that allows morphologic relapse to be
distinguished are not eligible for arms 2 or 3.

Note cytogenetic evidence of disease alone without morphologic relapse is acceptable. Also
a small percentage of blasts that is equivocal between marrow regeneration vs early
relapse is acceptable provided there are no associated cytogenetic markers consistent with
relapse.

- Acute lymphocytic leukemia-- high risk CR1 as evidenced by high risk cytogenetics (eg
t(9;22) or complex cytogenetic abnormalities) or > 1 cycle to obtain CR; second or
greater CR. Must be in remission by morphology. Patients in morphologic relapse/
persistent disease defined as > 5% blasts in normocellular bone marrow OR any %
blasts if blasts have unique morphologic markers or associated cytogenetic markers
that allows morphologic relapse to be distinguished are not eligible for arms 2 or 3.
Note cytogenetic relapse or persistent disease without morphologic relapse is
acceptable. Also a small percentage of blasts that is equivocal between marrow
regeneration vs early relapse is acceptable provided there are no associated
cytogenetic markers consistent with relapse.

- Chronic myelogenous leukemia all types except blast crisis (note treated blast crisis
in chronic phase is eligible).

- Non-Hodgkins lymphoma (NHL), Hodgkins, chronic lymphocytic leukemia, multiple myeloma
demonstrating chemosensitive disease

- Acquired bone marrow failure syndromes

- Myelodysplastic syndrome of all subtypes including refractory anemia (RA) or all IPSS
categories if severe pancytopenia, transfusion requirements not responsive to
therapy, or high risk cytogenetics. Blasts must be less than 5%. If >5% requires
therapy (induction or Hypomethylating agents) pre-transplant to decrease disease
burden.

- Renal cell cancer,

- Chronic myeloproliferative disorder, i.e. myelofibrosis

- Disease Criteria (High risk patients on Arm 7)

- Patients with refractory leukemia or MDS may be taken to transplant in aplasia after
induction or re-induction chemotherapy or radiolabeled antibody. These high risk
patients will be analyzed separately in Arm 7.

- Adequate organ function and performance status (all patients):

- Cardiac: No decompensated congestive heart failure (CHF), or uncontrolled arrythmia;
ejection fraction > 35%

- Pulmonary: DLCO > 30% predicted, No oxygen requirements

- Liver: Transaminases < 5.0 x upper limit of normal (ULN); Bilirubin < 3 x ULN

- Renal: Creatinine < 2.0 mg/dl (adults) or creatinine clearance > 40 ml/min. ). All
adults with a creatinine > 1.2 or a history of renal dysfunction must have creatinine
clearance (must be > 40 ml/min).

- Second bone marrow transplant (BMT): must be > 3 months after prior myeloablative
transplant

- Defined as Karnofsky > 60 (adults) or Lansky >/= 50.

- If recent mold infection (e.g. aspergillus) must have minimum of 30 days of therapy
and responsive disease and be cleared by Infectious Disease.

- Albumin > 2.5

Exclusion Criteria:

- Pregnancy or breast feeding

- Evidence of HIV infection or known HIV positive serology

- Active serious infection

- Congenital bone marrow failure syndrome

- Previous irradiation that precludes the safe administration of an additional dose of
200 cGy of total body irradiation (TBI)

- Chronic myelogenous leukemia (CML) in refractory blast crisis

- Intermediate or high grade NHL, mantle cell NHL, and Hodgkins disease that is
progressive on salvage therapy. Stable disease is acceptable to move forward provided
it is non-bulky.

- Multiple Myeloma progressive on salvage chemotherapy.

DONOR ELIGIBILITY

- Related will undergo apheresis - if donor is unable to undergo apheresis, a bone
marrow harvest is acceptable; unrelated volunteer donors must be able to undergo bone
marrow harvest or apheresis.

- All donors must be able to give informed consent.

- Donors weighing less than 40 kg (children) will need evaluation by a pediatrician for
suitability of the apheresis procedure. Informed consent must be obtained from parent
or guardian as applicable for minors.

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:

Neutrophil and Donor Cell Engraftment

Outcome Description:

Successful sustained engraftment is defined as primary neutrophil engraftment by day 42 and e90% donor cells at day 100, with or without DLI. Engraftment based on absolute neutrophil count of donor origin > 0.5 x 10e9 /L for 3 days by day 42

Outcome Time Frame:

Day 42 and Day 100

Safety Issue:

No

Principal Investigator

Erica Warlick, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Masonic Cancer Center, University of Minnesota

Authority:

United States: Food and Drug Administration

Study ID:

2001LS058

NCT ID:

NCT00303719

Start Date:

March 2002

Completion Date:

January 2015

Related Keywords:

  • Kidney Cancer
  • Leukemia
  • Lymphoma
  • Multiple Myeloma
  • Plasma Cell Neoplasm
  • Myelodysplastic Syndromes
  • leukemia
  • lymphoma
  • myeloma
  • Neoplasms
  • Carcinoma, Renal Cell
  • Kidney Neoplasms
  • Leukemia
  • Lymphoma
  • Multiple Myeloma
  • Neoplasms, Plasma Cell
  • Plasmacytoma
  • Myelodysplastic Syndromes
  • Preleukemia

Name

Location

Masonic Cancer Center at University of MinnesotaMinneapolis, Minnesota  55455