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

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by Fred Hutchinson Cancer Research Center
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier:
NCT01252667
First received: November 29, 2010
Last updated: May 16, 2014
Last verified: May 2014
  Purpose

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.


Condition Intervention Phase
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
Drug: clofarabine
Radiation: total-body irradiation
Drug: cyclosporine
Drug: mycophenolate mofetil
Procedure: peripheral blood stem cell transplantation
Procedure: allogeneic hematopoietic stem cell transplantation
Other: laboratory biomarker analysis
Other: pharmacological study
Phase 2

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

Resource links provided by NLM:


Further study details as provided by Fred Hutchinson Cancer Research Center:

Primary Outcome Measures:
  • 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) [ Time Frame: Day 14 after HCT (21 days after initiation of clofarabine) ] [ Designated as safety issue: Yes ]
  • 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) [ Time Frame: At 6 months ] [ Designated as safety issue: No ]
    Rate of disease relapse or progression, defined as the presence of > 5% blasts by morphology on a marrow aspirate or the presence of circulating blasts in the peripheral blood. A satisfactory improvement will be considered declines from 35% to 20% among high-risk and from 15% to 5% among low risk patients.


Secondary Outcome Measures:
  • Leukemia-free survival [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
  • NRM of less than 5% [ Time Frame: At day 100 ] [ Designated as safety issue: No ]
  • Engraftment rate of greater than or equal to 95% [ Time Frame: At day 100 ] [ Designated as safety issue: No ]
  • Minimal residual/recurring disease [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Intensified monitoring by more frequent leukemia assessments and by adding molecular methods to improve leukemia-free and overall survival.

  • Pharmacokinetics of clofarabine [ Time Frame: After the first clofarabine infusion at 2, 3, 4, 5, and 6 hours; prior to the 2nd, 3rd, 4th, and 5th doses of clofarabine; within 2 hours before the infusion of PBSC ] [ Designated as safety issue: No ]
  • Overall survival [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
  • Prognostic cytogenetic and genetic markers (FLT3, RAS, nucleophosmin [NPM1], and C/EBP gene mutations) [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Assessed by polymerase chain reaction (PCR) to determine their prognostic value.


Estimated Enrollment: 78
Study Start Date: January 2011
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (chemotherapy and low-dose TBI before PBSCT)

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

IMMUNOSUPPRESSION: Patients with related donors receive cyclosporine 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.

Drug: clofarabine
Given IV
Other Names:
  • CAFdA
  • Clofarex
  • Clolar
Radiation: total-body irradiation
Undergo TBI
Other Name: TBI
Drug: cyclosporine
Given PO
Other Names:
  • ciclosporin
  • cyclosporin
  • cyclosporin A
  • CYSP
  • Sandimmune
Drug: mycophenolate mofetil
Given PO
Other Names:
  • Cellcept
  • MMF
Procedure: peripheral blood stem cell transplantation
Undergo allogeneic hematopoietic PBSCT
Other Names:
  • PBPC transplantation
  • PBSC transplantation
  • peripheral blood progenitor cell transplantation
  • transplantation, peripheral blood stem cell
Procedure: allogeneic hematopoietic stem cell transplantation
Undergo allogeneic hematopoietic PBSCT
Other: laboratory biomarker analysis
Correlative studies
Other: pharmacological study
Optional correlative studies
Other Name: pharmacological studies

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 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]), 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

Ages Eligible for Study:   2 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  • 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01252667

Locations
United States, Colorado
University of Colorado Cancer Center - Anschutz Cancer Pavilion Completed
Aurora, Colorado, United States, 80045
United States, Louisiana
Ochsner Medical Center Jefferson Completed
New Orleans, Louisiana, United States, 70121
United States, Washington
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium Recruiting
Seattle, Washington, United States, 98109
Contact: Brenda M. Sandmaier    206-667-4961      
Principal Investigator: Brenda M. Sandmaier         
VA Puget Sound Health Care System Recruiting
Seattle, Washington, United States, 98101
Contact: Thomas R. Chauncey    206-762-1010      
Principal Investigator: Thomas R. Chauncey         
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center
Investigators
Principal Investigator: Brenda Sandmaier Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
  More Information

No publications provided

Responsible Party: Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier: NCT01252667     History of Changes
Other Study ID Numbers: 2430.00, NCI-2010-02247, 2430.00, P01CA018029, P01CA078902, P30CA015704
Study First Received: November 29, 2010
Last Updated: May 16, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Leukemia
Leukemia, Myelomonocytic, Acute
Leukemia, Myelomonocytic, Chronic
Leukemia, Monocytic, Acute
Leukemia, Megakaryoblastic, Acute
Leukemia, Erythroblastic, Acute
Neoplasms by Histologic Type
Neoplasms
Myelodysplastic-Myeloproliferative Diseases
Bone Marrow Diseases
Hematologic Diseases
Myeloproliferative Disorders
Cyclosporins
Cyclosporine
Mycophenolic Acid
Mycophenolate mofetil
Clofarabine
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antifungal Agents
Anti-Infective Agents
Therapeutic Uses
Dermatologic Agents
Antirheumatic Agents

ClinicalTrials.gov processed this record on October 02, 2014