Decitabine and Total-Body Irradiation Followed By Donor Bone Marrow Transplant and Cyclophosphamide in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

NCT ID: NCT01707004

Last Updated: 2019-11-21

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 20 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-05-16
• Study Completion Date: 2017-10-07

Brief Summary

This phase II trial studies how well decitabine and total-body irradiation followed by donor bone marrow transplant and cyclophosphamide works in treating patients with relapsed or refractory acute myeloid leukemia. Giving decitabine and total-body irradiation before a donor bone marrow transplant 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. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving decitabine and total-body irradiation before the transplant together with high-dose cyclophosphamide, tacrolimus, and mycophenolate mofetil after the transplant may stop this from happening.

Detailed Description

PRIMARY OBJECTIVES:

I. To determine overall survival at 100 days after transplantation following decitabine and a bone marrow transplant using a donor that is at least partially-matched and a myeloablative preparative regimen with post-transplantation cyclophosphamide for graft-versus-host disease (GVHD) prophylaxis.

SECONDARY OBJECTIVES:

I. Patients enrolled in this study will also be followed for the following endpoints: neutrophil and platelet recovery, graft failure, acute graft-versus-host disease (GVHD), chronic GVHD, incidence of infection, treatment-related mortality, time to relapse/progression, overall survival, and progression-free survival.

OUTLINE:

Beginning between days -29 and -22, patients receive decitabine intravenously (IV) over 1 hour daily for 10 days, fludarabine phosphate IV over 30 minutes on days -5 to -2, and busulfan IV over 3 hours on days -5 to -2.

PREPARATIVE REGIMEN: Patients undergo total-body irradiation twice daily (BID) on day -1.

TRANSPLANT: Patients undergo allogeneic bone marrow transplant on day 0.

GVHD PROPHYLAXIS: Patients receive cyclophosphamide IV over 2 hours on days 3 and 4, tacrolimus orally (PO) BID or IV continuously on days 5-180, mycophenolate mofetil PO three times daily (TID) on days 5-35 and filgrastim subcutaneously (SC) beginning day 5 until absolute neutrophil count (ANC) >= 1,000/mm^3 for 3 consecutive days.

After completion of study treatment, patients are followed up at 6 months and 1 year.

Conditions

Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome; 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(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); de Novo Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Treatment (donor bone marrow transplant)

Beginning between days -29 and -22, patients receive decitabine IV over 1 hour daily for 10 days, fludarabine phosphate IV over 30 minutes on days -5 to -2, and busulfan IV over 3 hours on days -5 to -2.

PREPARATIVE REGIMEN: Patients undergo total-body irradiation BID on day -1.

TRANSPLANT: Patients undergo allogeneic bone marrow transplant on day 0.

GVHD PROPHYLAXIS: Patients receive cyclophosphamide IV over 2 hours on days 3 and 4, tacrolimus PO BID or IV continuously on days 5-180, mycophenolate mofetil PO TID on days 5-35, and filgrastim SC beginning day 5 until ANC >= 1,000/mm^3 for 3 consecutive days.

Group Type: EXPERIMENTAL

decitabine

Intervention Type: DRUG

Given IV

fludarabine phosphate

Intervention Type: DRUG

Given IV

busulfan

Intervention Type: DRUG

Given IV

cyclophosphamide

Intervention Type: DRUG

Given IV

tacrolimus

Intervention Type: DRUG

Given PO or IV

mycophenolate mofetil

Intervention Type: DRUG

Given PO

filgrastim

Intervention Type: BIOLOGICAL

Given SC

total-body irradiation

Intervention Type: RADIATION

Undergo total-body irradiation

allogeneic bone marrow transplantation

Intervention Type: PROCEDURE

Undergo allogeneic bone marrow transplantation

laboratory biomarker analysis

Intervention Type: OTHER

Correlative studies

Interventions

decitabine

Given IV

Intervention Type: DRUG

fludarabine phosphate

Given IV

Intervention Type: DRUG

busulfan

Given IV

Intervention Type: DRUG

cyclophosphamide

Given IV

Intervention Type: DRUG

tacrolimus

Given PO or IV

Intervention Type: DRUG

mycophenolate mofetil

Given PO

Intervention Type: DRUG

filgrastim

Given SC

Intervention Type: BIOLOGICAL

total-body irradiation

Undergo total-body irradiation

Intervention Type: RADIATION

allogeneic bone marrow transplantation

Undergo allogeneic bone marrow transplantation

Intervention Type: PROCEDURE

laboratory biomarker analysis

Correlative studies

Intervention Type: OTHER

Other Intervention Names

5-aza-2'-deoxycytidine (5-aza-dCyd); 5-azacytidine (5AZA); decitabine (DAC); Fludarabine phosphate (2-F-ara-AMP); Beneflur; Fludara; busulfan (BSF); busulfan (BU); Misulfan; Mitosan; Myeloleukon; cyclophosphamide (CPM); cyclophosphamide (CTX); Cytoxan; Endoxan; Endoxana; tacrolimus (FK 506); Prograf; Cellcept; mycophenolate mofetil (MMF); granulocyte-colony stimulating factor (G-CSF); Neupogen; total body irradiation (TBI); bone marrow therapy, allogeneic; bone marrow therapy, allogenic; transplantation, allogeneic bone marrow; transplantation, allogenic bone marrow

Eligibility Criteria

Inclusion Criteria

• Patients must meet one of two disease criteria:

• Acute myelogenous leukemia (AML) within one of the following categories:

• Primary induction failure (PIF): patients who have not achieved a complete remission following initial diagnosis and after at least two induction cycles of chemotherapy consisting of cytarabine and an anthracycline or high-dose cytarabine
• Relapsed AML: Patients are defined as having relapsed disease if they entered a complete remission confirmed with a bone marrow biopsy following initial treatment, and then were found to have morphological or cytogenetic evidence of recurrent disease on a subsequent bone marrow exam
• Any complete remission (CR) 2 or greater: CR must be defined using a bone marrow exam taken at least 21 days since the last chemotherapy (including a methyltransferase inhibitor), and may include CRp (morphologic CR without peripheral platelet recovery)
• CR1 with high-risk features: includes patients with treatment-related AML, secondary AML (following myelodysplastic syndrome (MDS) or myeloproliferative neoplasms (MPN)), high-risk cytogenetic or molecular phenotype (by National Comprehensive Cancer Network (NCCN) criteria)
• Untreated AML (> 20% blasts on a bone marrow) arising from a previous confirmed diagnosis of MDS or MPN (excluding BCR-ABL (a genetic mutation) positive diseases).
• Myelodysplastic syndromes within one of the following categories:

• High-risk myelodysplastic syndrome (MDS) at diagnosis as defined by the International Prognostic Scoring System (IPSS) or World Health Organization (WHO) classification based Prognostic Scoring System (WPSS)
• Transfusion dependent MDS (either red blood cells (RBC) or platelet dependent) without a hematologic response to at least 4 months of methyltransferase inhibitor (MTI) therapy; hematological response is defined as transfusion independence for two or more months
• Progressive MDS following at least 4 months of MTI therapy; progression is defined as resumption of transfusion dependence after at least two months of transfusion independence OR increase of marrow blasts by 50% from pretreatment OR overall blasts over 10% of marrow cells at any time after treatment
• Available related donor that is at least an allele level haplotype-match at human leukocyte antigen (HLA)- A, B, C, DP Beta 1 (DRB1) and DPB1 loci (DPB1 matching according to the "permissive - non-permissive" dichotomy as stated by University of Wisconsin (UW) Histocompatibility Laboratory); a minimum match of 5/10 loci is required; an unrelated donor search is not required for a patient to be eligible for this protocol
• Karnofsky score of 60% or better (requires occasional assistance, but is able to care for most of his/her needs)
• Diffusing capacity of the lungs for carbon monoxide (DLCO) (corrected for hemoglobin > 40%; and forced expiratory volume in one second (FEV1) > 50%
• Ejection fraction (EF) >= 50% and no uncontrolled angina, symptomatic ventricular arrhythmias, or electrocardiogram (ECG) evidence of active ischemia
• Serum creatinine within normal range for age, or if serum creatinine outside normal range, then renal function (estimated glomerular filtration rate (GFR) by modification of diet in renal disease (MDRD) formula) > 40 mL/min/1.73 m^2
• Women of child bearing potential must have a negative pregnancy test within 14 days prior to study registration and agree to use adequate birth control during study treatment
• Voluntary written consent
• Patients must be 28 days from the end of the last induction course or at least 14 days from completion of previous methyltransferase inhibitor therapy (azacitidine or decitabine) at the time of registration
• DONOR: Donors must be at least HLA-haploidentical first degree relatives of the patients; eligible donors include biological parents, siblings, half-siblings or children
• DONOR: Age >= 18 years and =< 60 years
• DONOR: Donors must meet the selection criteria prior to the start of the recipient's pre-transplant conditioning regimen as defined by the Foundation for the Accreditation of Cell Therapy (FACT) and will be screened according to the American Association of Blood Banks (AABB) guidelines and UW Bone Marrow Transplant (BMT) program standard operating procedure (SOP)

Exclusion Criteria

• Active central nervous system (CNS) leukemia within two weeks of registration; patients with a history of CNS leukemia must have adequate treatment as defined by at least two negative spinal fluid assessments separated by at least one week; patients who have received cranial radiation therapy (XRT) must still be eligible to receive total body irradiation to 4 Gy
• New or active infection as determined by fever, unexplained pulmonary infiltrate or sinusitis on radiographic assessment; infections diagnosed within 4 weeks of registration must be determined to be controlled or resolving prior to treatment
• Active human immunodeficiency virus (HIV), hepatitis A, B or C infection
• Allergy or hypersensitivity to agents used within the treatment protocol
• DONOR: Recipient derived anti-donor high-titer (> 3000 MFI) HLA antibody as determined by Luminex assay
• DONOR: Not suitable for donation according to UW BMT program donor selection SOP

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

University of Wisconsin, Madison

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Mark Juckett

Role: PRINCIPAL_INVESTIGATOR

University of Wisconsin, Madison

Locations

University of Wisconsin Hospital and Clinics

Madison, Wisconsin, United States

Countries

United States

References

D'Angelo CR, Hall A, Woo KM, Kim K, Longo W, Hematti P, Callander N, Kenkre VP, Mattison R, Juckett M. Decitabine induction with myeloablative conditioning and allogeneic hematopoietic stem cell transplantation in high-risk patients with myeloid malignancies is associated with a high rate of infectious complications. Leuk Res. 2020 Sep;96:106419. doi: 10.1016/j.leukres.2020.106419. Epub 2020 Jul 8.

Reference Type: DERIVED

PMID: 32683127 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Related Links

https://cancer.wisc.edu/

University of Wisconsin Carbone Cancer Center

Other Identifiers

NCI-2012-01325

Identifier Type: REGISTRY

Identifier Source: secondary_id

2012-0217

Identifier Type: -

Identifier Source: secondary_id

2017-0116

Identifier Type: -

Identifier Source: secondary_id

P30CA014520

Identifier Type: NIH

Identifier Source: secondary_id

View Link

A534260

Identifier Type: OTHER

Identifier Source: secondary_id

SMPH/MEDICINE/MEDICINE*H

Identifier Type: OTHER

Identifier Source: secondary_id

HO11421

Identifier Type: -

Identifier Source: org_study_id