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A Phase I/II Dose Escalation Trial of Clofarabine, in Addition to Melphalan and Thiotepa as Myeloablative Regimen Followed by an Allogeneic Unmodified Hematopoietic Stem Cell Transplant From HLA-Compatible Related or Unrelated Donors for the Treatment of High Risk and/or Advanced Hematologic Malignancies


Phase 1/Phase 2
N/A
54 Years
Open (Enrolling)
Both
Graft Versus Host Disease, Leukemia, Myelodysplastic Syndromes

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Trial Information

A Phase I/II Dose Escalation Trial of Clofarabine, in Addition to Melphalan and Thiotepa as Myeloablative Regimen Followed by an Allogeneic Unmodified Hematopoietic Stem Cell Transplant From HLA-Compatible Related or Unrelated Donors for the Treatment of High Risk and/or Advanced Hematologic Malignancies


OBJECTIVES:

Primary

- Determine the maximum tolerated dose of clofarabine when administered with melphalan
and thiotepa followed by allogeneic stem cell transplantation in patients with
high-risk and/or advanced hematologic malignancies. (Phase I)

- Determine the 1-year disease-free survival of patients treated with this regimen.
(Phase II)

- Determine the efficacy of this regimen, in terms of antileukemic potential and relapse
rate, in these patients.

Secondary

- Evaluate the incidence and severity of nonhematologic toxicity of this regimen in these
patients.

- Evaluate the incidence and severity of graft-versus-host disease in patients treated
with this regimen.

OUTLINE: This is a phase I, dose-escalation study of clofarabine followed by an open-label,
phase II study. Patients are stratified according to HLA-compatible donor type (related vs
unrelated).

- Cytoreductive therapy: Patients receive clofarabine IV over 2 hours once daily on days
-9 to -5, thiotepa IV over 4 hours on day -4, and melphalan IV over 30 minutes once
daily on days -3 and -2.

Cohorts of 3-6 patients receive escalating doses of clofarabine 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.

- Graft-versus-host disease (GVHD) prophylaxis: Patients who undergo bone marrow or
peripheral blood stem cell transplantation receive tacrolimus IV continuously over 24
hours or orally every 8-12 hours beginning on day -3 and methotrexate IV on days 1, 3,
6, and 11. Patients who undergo UCB transplantation receive tacrolimus IV continuously
over 24 hours or orally every 8-12 hours beginning on day -3 and mycophenolate mofetil
(MMF) IV or orally 2 or 3 times daily on days -3 to 45 followed by a taper until day
100 (unless there are signs of acute GVHD). Patients who undergo UCB transplantation
without GVHD continue tacrolimus for 6 months followed by a taper and discontinued 1
year after transplantation.

- Allogeneic hematopoietic stem cell transplantation (HSCT) or allogeneic umbilical cord
blood (UCB) transplantation: Patients undergo allogeneic HSCT (bone marrow or
peripheral blood stem cells) or double UCB transplantation on day 0. Patients also
receive filgrastim (G-CSF) IV or subcutaneously beginning on day 7 and continuing until
blood counts recover.

- Maintenance therapy: Approximately 2 months after transplantation patients with ALL, M4
or M5 AML, and those transplanted with AML in bone marrow relapse receive cytarabine
intrathecally (IT) monthly for up to 5 doses. Patients with a history of CNS leukemia
receive cytarabine IT once monthly during months 2-12 after HSCT.

After completion of study therapy, patients are followed periodically for at least 4 years.

PROJECTED ACCRUAL: A total of 42 patients will be accrued for this study.

Inclusion Criteria


DISEASE CHARACTERISTICS:

- Histologically or cytologically confirmed diagnosis of 1 of the following:

- Acute myelogenous leukemia, meeting 1 of the following criteria:

- In first complete remission (CR), meeting 1 of the following criteria:

- Poor risk [no t(15,17), inv 16, or t(8,21)]

- Not a candidate for total body irradiation (TBI)

- Any infant in first CR

- In second CR, meeting the following criteria:

- All patients

- In more than second CR OR relapsed/refractory disease, meeting the
following criteria:

- All patients

- Blast percentage > 5% and < 25% in bone marrow (BM) at the time of
stem cell transplantation (SCT)

- Acute lymphoblastic leukemia, meeting 1 of the following criteria:

- In first CR, meeting 1 of the following criteria:

- Poor risk [t(9;22), t(4;11) AND no CR after 7-28 days of induction]

- Not a candidate for TBI

- Any infant in first CR

- In second CR, meeting the following criteria:

- All patients

- In more than second CR OR relapsed/refractory disease, meeting the
following criteria:

- All patients

- Blast percentage > 5% and < 25% in BM at the time of SCT

- Acute undifferentiated or biphenotypic leukemia, meeting the following
criteria:

- All patients

- Blast percentage > 5% and < 25% in BM at the time of SCT

- Chronic myelogenous leukemia, meeting the following criteria:

- All patients

- In first chronic phase

- Myelodysplastic syndrome, meeting 1 of the following criteria:

- Primary high risk disease

- Stage > RAEB1

- Secondary high risk disease

- All patients

- Any stage

- Juvenile myelomonocytic leukemia

- All patients

- No doubling of peripheral blast counts within a period of 2 weeks

- No active CNS disease

- HLA-compatible donor available meeting 1 of the following criteria:

- Related donor

- Genotypically or phenotypically matched at ≥ 7 or 8 of HLA-A, -B, -C and
-DRB1 alleles

- Unrelated donor meeting 1 of the following criteria:

- 8 of 8 alleles matched

- For patients < 18 years old only: 7 or 8 alleles matched with the mismatch
at only 1 HLA-A, -B, -C, or -DRB1 allele

- Two HLA-compatible unrelated cord blood (UCB) units available meeting the following
criteria:

- HLA-matched minimally at 4 of 6 HLA-A, HLA-B, and DRB1 allele

- HLA-A and HLA-B matched at intermediate resolution by molecular technique

- DRB1 allele matched at high resolution by molecular technique

- Both matched UCB units with cryopreserved nucleated cell dose ≥ 1.5 x 10^7/kg

PATIENT CHARACTERISTICS:

- Karnofsky OR Lansky performance status 70-100%

- SGOT < 2 times upper limit of normal

- Bilirubin < 1.5 mg/dL (unless there is liver disease involvement)

- Creatinine normal OR creatinine clearance > 60 mL/min

- LVEF > 50% at rest OR shortening fraction ≥ 29%

- Patients with asymptomatic pulmonary disease with no prior risk factors OR
symptomatic pulmonary disease with diffusion capacity > 50% of predicted (corrected
for hemoglobin) are eligible

- No active uncontrolled viral, bacterial, or fungal infection

- No known HIV I or II positivity

- No known human T-cell lymphotrophic virus I or II positivity

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

- No hydroxyurea within the past 2 weeks

- No allogeneic or autologous stem cell transplantation within the past 6 months

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Relapse of leukemia

Outcome Time Frame:

1 year

Safety Issue:

No

Principal Investigator

Farid Boulad, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Memorial Sloan-Kettering Cancer Center

Authority:

United States: Institutional Review Board

Study ID:

06-125

NCT ID:

NCT00423514

Start Date:

November 2006

Completion Date:

November 2014

Related Keywords:

  • Graft Versus Host Disease
  • Leukemia
  • Myelodysplastic Syndromes
  • graft versus host disease
  • adult acute lymphoblastic leukemia in remission
  • adult acute myeloid leukemia in remission
  • childhood acute lymphoblastic leukemia in remission
  • childhood chronic myelogenous leukemia
  • recurrent childhood acute myeloid leukemia
  • accelerated phase chronic myelogenous leukemia
  • acute undifferentiated leukemia
  • adult acute myeloid leukemia with 11q23 (MLL) abnormalities
  • blastic phase chronic myelogenous leukemia
  • juvenile myelomonocytic leukemia
  • previously treated myelodysplastic syndromes
  • recurrent adult acute lymphoblastic leukemia
  • recurrent adult acute myeloid leukemia
  • relapsing chronic myelogenous leukemia
  • secondary acute myeloid leukemia
  • secondary myelodysplastic syndromes
  • childhood acute myeloid leukemia in remission
  • de novo myelodysplastic syndromes
  • recurrent childhood acute lymphoblastic leukemia
  • chronic phase chronic myelogenous leukemia
  • 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)
  • childhood myelodysplastic syndromes
  • Graft vs Host Disease
  • Leukemia
  • Myelodysplastic Syndromes
  • Preleukemia

Name

Location

Memorial Sloan-Kettering Cancer CenterNew York, New York  10021