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Clofarabine and Low-Dose Total-Body Irradiation in Treating Patients With Acute Myeloid Leukemia Undergoing Donor Peripheral Blood Stem Cell Transplant

Information source: Fred Hutchinson Cancer Research Center
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: 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

Intervention: clofarabine (Drug); total-body irradiation (Radiation); cyclosporine (Drug); mycophenolate mofetil (Drug); peripheral blood stem cell transplantation (Procedure); allogeneic hematopoietic stem cell transplantation (Procedure); laboratory biomarker analysis (Other); pharmacological study (Other)

Phase: Phase 2

Status: Recruiting

Sponsored by: Fred Hutchinson Cancer Research Center

Official(s) and/or principal investigator(s):
Brenda Sandmaier, Principal Investigator, Affiliation: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Summary

This phase II trial studies the side effects and how well clofarabine works when given together with low-dose total-body irradiation (TBI) in treating patients with acute myeloid leukemia (AML) undergoing donor peripheral blood stem cell transplant (PBSCT). Giving chemotherapy and TBI before a donor PBSCT helps stop the growth of cancer cells. It may also 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.

Clinical Details

Official title: 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

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

Primary outcome:

Optimal dose of clofarabine in combination with 2, 3, or 4 Gy TBI in preparation for HCT from HLA-identical related and HLA-matched unrelated donors in patients with AML (Part 1)

Efficacy of the optimal dose of clofarabine combined with 2, 3, or 4 Gy TBI in reducing the relapse rate in patients with AML compared to our historical experience with fludarabine and 2, 3, or 4 Gy TBI (Part 2)

Secondary outcome:

Leukemia-free survival

Overall survival

NRM of less than 5%

Engraftment rate of greater than or equal to 95%

Prognostic cytogenetic and genetic markers (FLT3, RAS, nucleophosmin [NPM1], and C/EBP gene mutations)

Minimal residual/recurring disease

Pharmacokinetics of clofarabine

Detailed description: PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose of clofarabine in combination with 2, 3, or 4 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, 3, or 4 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 month relapse rate declines from 35% to 20% among high-risk (objective for low risk group terminated August 2014). (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]), retrovirus-associated deoxyribonucleic acid (DNA) sequences (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.

Eligibility

Minimum age: 2 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

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 (low risk group terminated August 2014)

- 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 > 3 mg/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

Locations and Contacts

University of Colorado Cancer Center - Anschutz Cancer Pavilion, Aurora, Colorado 80045, United States; Completed

Ochsner Medical Center Jefferson, New Orleans, Louisiana 70121, United States; Completed

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium, Seattle, Washington 98109, United States; Recruiting
Brenda M. Sandmaier, Phone: 206-667-4961
Brenda M. Sandmaier, Principal Investigator

VA Puget Sound Health Care System, Seattle, Washington 98101, United States; Recruiting
Thomas R. Chauncey, Phone: 206-762-1010
Thomas R. Chauncey, Principal Investigator

Additional Information

Starting date: January 2011
Last updated: May 11, 2015

Page last updated: August 23, 2015

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