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A Phase II Study of Optimally Dosed Clofarabine in Combination With Low-Dose TBI to Decrease Relapse Rates After Related or Unrelated Donor Hematopoietic Cell Transplantation in Patients With AML


Phase 2
1 Year
N/A
Open (Enrolling)
Both
Adult Acute Megakaryoblastic Leukemia (M7), Adult Acute Minimally Differentiated Myeloid Leukemia (M0), Adult Acute Monoblastic Leukemia (M5a), Adult Acute Monocytic Leukemia (M5b), Adult Acute Myeloblastic Leukemia With Maturation (M2), Adult Acute Myeloblastic Leukemia Without Maturation (M1), Adult Acute Myeloid Leukemia in Remission, Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Del(5q), Adult Acute Myeloid Leukemia With Inv(16)(p13;q22), Adult Acute Myeloid Leukemia With t(16;16)(p13;q22), Adult Acute Myeloid Leukemia With t(8;21)(q22;q22), Adult Acute Myelomonocytic Leukemia (M4), Adult Erythroleukemia (M6a), Adult Pure Erythroid Leukemia (M6b), Childhood Acute Erythroleukemia (M6), Childhood Acute Megakaryocytic Leukemia (M7), Childhood Acute Minimally Differentiated Myeloid Leukemia (M0), Childhood Acute Monoblastic Leukemia (M5a), Childhood Acute Monocytic Leukemia (M5b), Childhood Acute Myeloblastic Leukemia With Maturation (M2), Childhood Acute Myeloblastic Leukemia Without Maturation (M1), Childhood Acute Myeloid Leukemia in Remission, Childhood Acute Myelomonocytic Leukemia (M4), Recurrent Adult Acute Myeloid Leukemia, Recurrent Childhood Acute Myeloid Leukemia

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Trial Information

A Phase II Study of Optimally Dosed Clofarabine in Combination With Low-Dose TBI to Decrease Relapse Rates After Related or Unrelated Donor Hematopoietic Cell Transplantation in Patients With AML


PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose of clofarabine in combination with 2 Gy TBI in
preparation for hematopoietic cell transplantation (HCT) from human leukocyte antigen
(HLA)-identical related and HLA-matched unrelated donors in patients with AML. (Part 1)

II. To determine the efficacy of the maximum tolerated dose of clofarabine combined with 2
Gy TBI in reducing the 6 month relapse rate in patients with AML compared to our historical
experience with fludarabine and 2 Gy TBI. A satisfactory improvement will be considered 6
months relapse rate declines from 35% to 20% among high-risk and from 15% to 5% among
low-risk patients. (Part 2)

SECONDARY OBJECTIVES:

I. Leukemia-free and overall survivals.

II. Non-relapse mortality (NRM) of < 5% at 100 days.

III. Engraftment rate of >= 95%.

IV. Prognostic significance of cytogenetics and genetic markers not detected by traditional
karyotype analysis, with special respect to tyrosine kinase receptor mutations (such as
fms-like tyrosine kinase 3 [FLT3]), RAS- and nucleophosmin gene mutations along with
CCAAT/enhancer binding protein, alpha (C/EBP) mutations.

V. Rigorous monitoring for minimal residual/recurring disease by standard morphologic, flow
cytometric, and molecular techniques in order to facilitate early intervention.

VI. To evaluate the pharmacokinetics of clofarabine.

OUTLINE: This is a dose-escalation study of clofarabine.

CONDITIONING REGIMEN: Patients receive clofarabine intravenously (IV) over 2 hours on days
-6 to -2. Patients also undergo TBI on day 0.

IMMUNOSUPPRESSION: Patients with related donors receive cyclosporine orally (PO) every 12
hours on days -3 to 56 with taper to day 180 and mycophenolate mofetil PO every 12 hours on
days 0 to 28. Patients with unrelated donors receive cyclosporine PO every 12 hours on days
-3 to 100 with taper to day 180 and mycophenolate mofetil PO every 8 hours on days 0 to 40
with taper to day 96.

TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0.

After completion of study treatment, patients are followed up at 4 months and every year
thereafter.


Inclusion Criteria:



- Patients age >= 55 years with AML OR patients age < 55 years with AML, who also
through pre-existing medical conditions or prior therapy are considered to be at high
risk for serious toxicities associated with a conventional, high-dose preparative
regimen

- Patients must be in morphologic leukemia-free state (marrow blasts < 5%) without
evidence of extramedullary disease within 21 days of HCT

- Only patients with Relapse Risk Score > 0 ("high risk") will be enrolled during Part
1; patients with all Relapse Risk Scores will be enrolled during Part 2

- HLA-identical related or HLA-matched unrelated donor available

- A signed informed consent form or minor assent form

- Patients treated at the Fred Hutchinson Cancer Research Center (FHCRC), with actual
body weight > 15 kg will be eligible for clofarabine pharmacokinetic studies;
participation in pharmacokinetic studies will be optional and will be offered to
patients at the time of enrollment

- DONOR: FHCRC matching allowed will be Grade 1.0 to 2.1: unrelated donors who are
prospectively: matched for HLA-A, B, C, DRB1 and DQB1 by high resolution typing; only
a single allele disparity will be allowed for HLA-A, B, or C as defined by high
resolution typing

- DONOR: A positive anti-donor cytotoxic crossmatch is an absolute donor exclusion;
donors are excluded when preexisting immunoreactivity is identified that would
jeopardize donor hematopoietic cell engraftment; this determination is based on the
standard practice of the individual institution; the recommended procedure for
patients with 10 of 10 HLA allele level (phenotypic) match is to obtain a panel
reactive antibody (PRA) screens to class I and class II antigens for all patients
before HCT; if the PRA shows > 10% activity, then flow cytometric or B and T cell
cytotoxic cross matches should be obtained; the donor should be excluded if any of
the cytotoxic cross match assays are positive; for those patients with an HLA Class I
allele mismatch, flow cytometric or B and T cell cytotoxic cross matches should be
obtained regardless of the PRA results

- DONOR: Patient and donor pairs homozygous at a mismatched allele are considered a
two-allele mismatch, i.e., the patient is A*0101 and the donor is A*0102, and this
type of mismatch is not allowed

- DONOR: Peripheral blood stem cells (PBSC) only will be permitted as a HSC source on
this protocol

Exclusion Criteria:

- AML French-American-British (FAB) M3 in first complete remission (CR1)

- Active AML involvement of the central nervous system (CNS) with disease refractory to
intrathecal chemotherapy

- Presence of circulating leukemic blasts in the peripheral blood detected by standard
morphology

- Patients who are human immunodeficiency virus (HIV)+ (HIV+ patients registered at
Fred Hutchinson Cancer Research Center [FHCRC] should be offered treatment on
Protocol 1410)

- Fertile men and women unwilling to use contraceptive techniques during and for 12
months following treatment

- Left ventricular ejection fraction < 35% (or, if unable to obtain ejection fraction,
shortening fraction of < 26%); ejection fraction is required if age > 50 years or
there is a history of anthracycline exposure or history of cardiac disease; patients
with a shortening fraction < 26% may be enrolled if approved by a cardiologist

- Diffusion capacity of the lung for carbon monoxide (DLCO) < 40% (corrected), total
lung capacity (TLC) < 40%, forced expiratory volume in one second (FEV1) < 40% and/or
receiving supplementary continuous oxygen

- The FHCRC Principal Investigator (PI) of the study must approve enrollment of all
patients with pulmonary nodules

- Patients with clinical or laboratory evidence of liver disease will be evaluated for
the cause of liver disease, its clinical severity in terms of liver function, and the
degree of portal hypertension; patients will be excluded if they are found to have
fulminant liver failure, cirrhosis of the liver with evidence of portal hypertension,
alcoholic hepatitis, esophageal varices, a history of bleeding esophageal varices,
hepatic encephalopathy, uncorrectable hepatic synthetic dysfunction evinced by
prolongation of the prothrombin time, ascites related to portal hypertension,
bridging fibrosis, bacterial or fungal liver abscess, biliary obstruction, chronic
viral hepatitis with total serum bilirubin > 3mg/dL, or symptomatic biliary disease

- Serum creatinine should be within normal limits as specified by institutional
guidelines; for patients with serum creatinine > upper limit of normal, a 24-hour
creatinine clearance will be performed and should be equal to or more than the lower
limit of normal

- Karnofsky score < 60 or Lansky Score < 50

- Patients with poorly controlled hypertension and on multiple antihypertensives

- Females who are pregnant or breastfeeding

- Patients with active non-hematologic malignancies (except non-melanoma skin cancers)
or those with non-hematologic malignancies (except non-melanoma skin cancers) who
have been rendered with no evidence of disease, but have a greater than 20% chance of
having disease recurrence within five years; this exclusion does not apply to
patients with non-hematologic malignancies that do not require therapy

- The addition of cytotoxic agents for "cytoreduction" with the exception of tyrosine
kinase inhibitors (such as imatinib mesylate), cytokine therapy, hydroxyurea, low
dose cytarabine, chlorambucil, or Rituxan will not be allowed within three weeks of
the initiation of conditioning

- Fungal infections with radiological progression after receipt of amphotericin B or
active triazole for greater than 1 month

- Patients with active bacterial or fungal infections unresponsive to medical therapy

- DONOR: Marrow donors

- DONOR: Donors who are HIV-positive and/or medical conditions that would result in
increased risk to the donor filgrastim (G-CSF) mobilization and PBSC collections

- DONOR: Identical twin

- DONOR: Any contraindication to the administration of subcutaneous G-CSF at a dose of
16 mg/kg/day for 5 consecutive days

- DONOR: Serious medical or psychological illness

- DONOR: Pregnant or lactating females

- DONOR: Prior malignancy within the preceding 5 years, with the exception of
non-melanoma skin cancers

- DONOR: Children < 12 years old

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Optimal dose of clofarabine in combination with 2 Gy TBI in preparation for HCT from HLA-identical related and HLA-matched unrelated donors in patients with AML

Outcome Time Frame:

Day 14 after HCT (21 days after initiation of clofarabine)

Safety Issue:

Yes

Principal Investigator

Boglarka Gyurkocza

Investigator Role:

Principal Investigator

Investigator Affiliation:

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Authority:

United States: Food and Drug Administration

Study ID:

2430.00

NCT ID:

NCT01252667

Start Date:

January 2011

Completion Date:

Related Keywords:

  • Adult Acute Megakaryoblastic Leukemia (M7)
  • Adult Acute Minimally Differentiated Myeloid Leukemia (M0)
  • Adult Acute Monoblastic Leukemia (M5a)
  • Adult Acute Monocytic Leukemia (M5b)
  • Adult Acute Myeloblastic Leukemia With Maturation (M2)
  • Adult Acute Myeloblastic Leukemia Without Maturation (M1)
  • Adult Acute Myeloid Leukemia in Remission
  • Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
  • Adult Acute Myeloid Leukemia With Del(5q)
  • Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
  • Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
  • Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)
  • Adult Acute Myelomonocytic Leukemia (M4)
  • Adult Erythroleukemia (M6a)
  • Adult Pure Erythroid Leukemia (M6b)
  • Childhood Acute Erythroleukemia (M6)
  • Childhood Acute Megakaryocytic Leukemia (M7)
  • Childhood Acute Minimally Differentiated Myeloid Leukemia (M0)
  • Childhood Acute Monoblastic Leukemia (M5a)
  • Childhood Acute Monocytic Leukemia (M5b)
  • Childhood Acute Myeloblastic Leukemia With Maturation (M2)
  • Childhood Acute Myeloblastic Leukemia Without Maturation (M1)
  • Childhood Acute Myeloid Leukemia in Remission
  • Childhood Acute Myelomonocytic Leukemia (M4)
  • Recurrent Adult Acute Myeloid Leukemia
  • Recurrent Childhood Acute Myeloid Leukemia
  • Congenital Abnormalities
  • Leukemia
  • Leukemia, Erythroblastic, Acute
  • Leukemia, Megakaryoblastic, Acute
  • Leukemia, Monocytic, Acute
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Leukemia, Myelomonocytic, Acute
  • Leukemia, Myelomonocytic, Chronic

Name

Location

Ochsner Clinic FoundationNew Orleans, Louisiana  70121
Fred Hutchinson Cancer Research Center/University of Washington Cancer ConsortiumSeattle, Washington  98109
University of ColoradoDenver, Colorado  80217
VA Puget Sound Health CareSeattle, Washington  98108