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

NCT01707004 | Completed Phase 2 Results DMC

• 7 other identifiers: HO11421NCI-2012-013252012-02172017-0116P30CA014520A534260SMPH/MEDICINE/MEDICINE*H
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

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.

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

Outcome Measures

Primary Outcomes (1)

• Overall Survival (OS)

  Will be analyzed using Kaplan-Meier (KM) method, and OS will be obtained from the KM estimates along with 95% confidence intervals.

  Day 100

Secondary Outcomes (7)

• Time to Neutrophil Recovery

  Up to 1 year

• Percentage of Participants With Platelet Recovery by Day 30

  Up to day 30

• Number of Participants With Primary Graft Failure

  Day 30

• Cumulative Incidence of Grade III-IV Acute GVHD

  Day 100

• Cumulative Incidence of Chronic GVHD According to BMTCTN

  Up to 1 year

Study Arms (1)

Treatment (donor bone marrow transplant)

EXPERIMENTAL

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.

Drug: decitabine; Drug: fludarabine phosphate; Drug: busulfan; Drug: cyclophosphamide; Drug: tacrolimus; Drug: mycophenolate mofetil; Biological: filgrastim; Radiation: total-body irradiation; Procedure: allogeneic bone marrow transplantation; Other: laboratory biomarker analysis

Interventions

decitabine DRUG

Given IV

Also known as: 5-aza-2'-deoxycytidine (5-aza-dCyd), 5-azacytidine (5AZA), decitabine (DAC)

Treatment (donor bone marrow transplant)

fludarabine phosphate DRUG

Given IV

Also known as: Fludarabine phosphate (2-F-ara-AMP), Beneflur, Fludara

Treatment (donor bone marrow transplant)

busulfan DRUG

Given IV

Also known as: busulfan (BSF), busulfan (BU), Misulfan, Mitosan, Myeloleukon

Treatment (donor bone marrow transplant)

cyclophosphamide DRUG

Given IV

Also known as: cyclophosphamide (CPM), cyclophosphamide (CTX), Cytoxan, Endoxan, Endoxana

Treatment (donor bone marrow transplant)

tacrolimus DRUG

Given PO or IV

Also known as: tacrolimus (FK 506), Prograf

Treatment (donor bone marrow transplant)

mycophenolate mofetil DRUG

Given PO

Also known as: Cellcept, mycophenolate mofetil (MMF)

Treatment (donor bone marrow transplant)

filgrastim BIOLOGICAL

Given SC

Also known as: granulocyte-colony stimulating factor (G-CSF), Neupogen

Treatment (donor bone marrow transplant)

total-body irradiation RADIATION

Undergo total-body irradiation

Also known as: total body irradiation (TBI)

Treatment (donor bone marrow transplant)

allogeneic bone marrow transplantation PROCEDURE

Undergo allogeneic bone marrow transplantation

Also known as: bone marrow therapy, allogeneic, bone marrow therapy, allogenic, transplantation, allogeneic bone marrow, transplantation, allogenic bone marrow

Treatment (donor bone marrow transplant)

laboratory biomarker analysis OTHER

Correlative studies

Treatment (donor bone marrow transplant)

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Wisconsin, Madison: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

University of Wisconsin Hospital and Clinics

Madison, Wisconsin, 53792, United States

Location

Related Publications (1)

• 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.

  PMID: 32683127 DERIVED

Related Links

• University of Wisconsin Carbone Cancer Center

MeSH Terms

Conditions

Congenital Abnormalities; Leukemia, Myeloid, Acute

Interventions

Decitabine; Azacitidine; fludarabine phosphate; Busulfan; Cyclophosphamide; Tacrolimus; Mycophenolic Acid; Filgrastim; Granulocyte Colony-Stimulating Factor; Whole-Body Irradiation; Transplantation

Condition Hierarchy (Ancestors)

Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Butylene Glycols; Glycols; Alcohols; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Hydrocarbons; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Macrolides; Lactones; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Radiotherapy; Therapeutics; Investigative Techniques; Surgical Procedures, Operative

Results Point of Contact

• Title: Aric Hall
• Organization: UW Carbone Cancer Center

achall@medicine.wisc.edu

608-262-1604

Study Officials

• Mark Juckett

  University of Wisconsin, Madison

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 8, 2012
• First Posted: October 15, 2012
• Study Start: May 16, 2013
• Primary Completion: July 22, 2017
• Study Completion: October 7, 2017
• Last Updated: November 21, 2019
• Results First Posted: May 22, 2019

Record last verified: 2019-05

Locations

US (1)