Clinical trial NCT01168219: Busulfan, Fludarabine Phosphate, and Anti-Thymocyte Globulin Followed By Donor Stem Cell Transplant and Azacitidine in Treating Patients With High-Risk Myelodysplastic Syndrome and Older Patients With Acute Myeloid Leukemia
Official title: Phase II Study of the Addition of Azacitidine (NSC#102816) to Reduced-Intensity Conditioning Allogeneic Transplantation for Myelodysplasia (MDS) and Older Patients With AML
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Acute Myeloid Leukemia
Adult Acute Megakaryoblastic Leukemia
Adult Acute Monoblastic Leukemia
Adult Acute Monocytic Leukemia
Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11
Adult Acute Myeloid Leukemia With Maturation
Adult Acute Myeloid Leukemia With Minimal Differentiation
Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11
Adult Acute Myeloid Leukemia With t(8;21); (q22; q22.1); RUNX1-RUNX1T1
Adult Acute Myeloid Leukemia With t(9;11)(p21.3;q23.3); MLLT3-MLL
Adult Acute Myeloid Leukemia Without Maturation
Adult Acute Myelomonocytic Leukemia
Adult Erythroleukemia
Adult Pure Erythroid Leukemia
Alkylating Agent-Related Acute Myeloid Leukemia
de Novo Myelodysplastic Syndrome
Myelodysplastic Syndrome
Myelodysplastic Syndrome With Excess Blasts
Recurrent Adult Acute Myeloid Leukemia
Secondary Myelodysplastic Syndrome
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2010-07-23
Enrollment: 68
Sex: ALL
Minimum age (years): 18
Maximum age (years): 74
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This phase II clinical trial is studying how well giving busulfan, fludarabine phosphate, and anti-thymocyte globulin followed by donor stem cell transplant and azacitidine works in treating patients with high-risk myelodysplastic syndrome and older patients with acute myeloid leukemia. Giving low doses of chemotherapy, such as busulfan and fludarabine phosphate, before a donor stem cell transplant helps stop the growth of cancer cells. It also stops the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-vs-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving anti-thymocyte globulin before transplant and giving azacitidine, tacrolimus, and methotrexate after the transplant may stop this from happening.

Detailed description: PRIMARY OBJECTIVE:

I. To determine if this treatment can improve 2-year progression-free survival (PFS) in patients with high risk myelodysplastic syndrome (MDS) and in patients with acute myeloid leukemia (AML) \>= 60 yrs age

SECONDARY OBJECTIVES:

I. To determine the safety and feasibility of using post-transplantation azacitidine.

II. To determine the ability to use pharmacokinetic-directed busulfan to achieve area under the curve (AUC) within 20% of target AUC in \> 80% of patients.

III. To determine the rate of grade II-IV and III-IV acute graft-vs-host disease (GVHD).

IV. To determine the incidence of extensive chronic GVHD. V. To determine treatment-related mortality at 100 days and at 1 year. VI. To determine 5-year overall survival.

OUTLINE:

REDUCED-INTENSITY CONDITIONING: Patients receive fludarabine phosphate intravenously (IV) over 30 minutes on days -7 to -3, busulfan IV over 45 minutes on days -6 to -3, and anti-thymocyte globulin IV over 4-10 hours on days -6 to -5 (matched sibling donor \[MSD\]) or -6 to -4 (matched unrelated donor \[MUD\]).

TRANSPLANTATION: Patients undergo allogeneic hematopoietic stem cell transplantation on day 0 or on days 0-1.

GRAFT-VS-HOST DISEASE PROPHYLAXIS: Patients receive tacrolimus orally (PO) or IV on days -2 to 90 with taper on days 150-180. Patients also receive methotrexate IV on days 1, 3, 6 (MSD), and 11 (MUD).

CONSOLIDATION: Beginning on day 42, patients receive azacitidine subcutaneously (SC) or IV on days 1-5.

Treatment repeats every 4 weeks for 6 courses. Blood and bone marrow samples may be collected periodically for correlative and pharmacokinetic studies.

After completion of study treatment, patients are followed up every 6 months for 5 years.

Eligibility criteria: Inclusion Criteria:

* Meets one of the following sets of criteria:

  * Myelodysplastic syndromes (MDS):

    * Disease with high-risk features (found either at diagnosis or before initiation of cytotoxic therapy), defined as one of the following:

      * International prognostic scoring system (IPSS) risk \>= intermediate-2
      * Refractory anemia with excess blasts by French-American-British (FAB) classification
      * High-risk cytogenetics (either complex or -7)
    * Less than 10% bone marrow blasts as determined by bone marrow biopsy within the past 4 weeks (reduction in marrow blast percentage may be achieved with chemotherapy or other therapy)
    * Less than 75 years old
  * Acute myeloid leukemia (AML):

    * No FAB M3
    * No acute leukemia following blast transformation of prior chronic myelogenous leukemia or other myeloproliferative disease
    * Patients with preceding MDS or treatment-related AML are eligible
    * Prior central nervous system (CNS) involvement is allowed provided the disease is in remission at transplantation
    * Morphologic complete remission (leukemia-free state) is defined as meeting all of the following criteria:

      * Bone marrow blasts \< 5% (as determined by bone marrow within the past 4 weeks), but without requirement for normal peripheral blood counts
      * No extramedullary leukemia
      * No blasts in peripheral blood
    * Achieved complete remission (CR) after no more than 2 courses of induction chemotherapy

      * Patients treated with azacitidine or decitabine who achieve a leukemia-free state are eligible (may have required up to 4 courses of therapy to reach this status)
    * Age 60 to 74 years
* Donors must meet the following criteria:

  * One of the following:

    * HLA-identical sibling (6/6) by serologic typing for class (A, B) and low-resolution molecular typing for class II (DRB1)
    * Matched unrelated donor (8/8) by high-resolution molecular typing at HLA-A, -B, -C, and DRB1
  * No syngeneic donors
* Eastern Cooperative Oncology Group (ECOG) performance status 0-2
* Calculated creatinine clearance ≥ 40 mL/min
* Bilirubin \< 2 mg/dL OR bilirubin 2-3 mg/dL provided direct bilirubin is normal
* Aspartate aminotransferase (AST) \< 3 times upper limit of normal
* Diffusing capacity of the lung for carbon monoxide (DLCO) \> 40% with no symptomatic pulmonary disease
* Left ventricle ejection fraction (LVEF) \>= 30% by echocardiogram (ECHO) or multigated acquisition (MUGA)
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception
* No uncontrolled diabetes mellitus or active serious infections
* No known hypersensitivity to E. coli-derived products, azacitidine, or mannitol
* No human immunodeficiency virus (HIV) infection or active hepatitis B or C
* Prior azacitidine or decitabine allowed

  * No patients who progressed from MDS to AML during treatment with azacitidine or decitabine
* At least 4 weeks since prior deoxyribonucleic acid (DNA)-hypomethylating chemotherapy, radiotherapy, and/or surgery
* No more than 2 courses of consolidation therapy before transplantation (for patients with AML)

  * Any consolidation regimen that does not require transplantation can be used
  * No more than 6 months from documentation of morphologic CR to transplantation

Primary outcomes:
measure: Progression-free Survival
timeFrame: Up to 5 years
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: Up to 5 years
measure: 100-day Mortality
timeFrame: Up to 100 days post-treatment
Other outcomes:
Locations:
city: Lewes
country: United States
facility: Beebe Medical Center
state: Delaware
city: Newark
country: United States
facility: Christiana Care Health System-Christiana Hospital
state: Delaware
city: Orlando
country: United States
facility: AdventHealth Orlando
state: Florida
city: Iowa City
country: United States
facility: University of Iowa/Holden Comprehensive Cancer Center
state: Iowa
city: Baltimore
country: United States
facility: University of Maryland/Greenebaum Cancer Center
state: Maryland
city: Elkton
country: United States
facility: Christiana Care - Union Hospital
state: Maryland
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Lebanon
country: United States
facility: Dartmouth Hitchcock Medical Center
state: New Hampshire
city: Camden
country: United States
facility: Cooper Hospital University Medical Center
state: New Jersey
city: Lake Success
country: United States
facility: Northwell Health NCORP
state: New York
city: Lake Success
country: United States
facility: Northwell Health/Center for Advanced Medicine
state: New York
city: Manhasset
country: United States
facility: North Shore University Hospital
state: New York
city: New York
country: United States
facility: Mount Sinai Hospital
state: New York
city: New York
country: United States
facility: NYP/Weill Cornell Medical Center
state: New York
city: Chapel Hill
country: United States
facility: UNC Lineberger Comprehensive Cancer Center
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Health Sciences
state: North Carolina
city: Columbus
country: United States
facility: Ohio State University Comprehensive Cancer Center
state: Ohio
Study officials:
affiliation: Alliance for Clinical Trials in Oncology
name: Ravi Vij
role: PRINCIPAL_INVESTIGATOR
References:
citation: Vij R, Le-Rademacher J, Laumann K, Hars V, Owzar K, Shore T, Vasu S, Cashen A, Isola L, Shea T, DeMagalhaes-Silverman M, Hurd D, Meehan K, Beardell F, Devine S. A Phase II Multicenter Study of the Addition of Azacitidine to Reduced-Intensity Conditioning Allogeneic Transplant for High-Risk Myelodysplasia (and Older Patients with Acute Myeloid Leukemia): Results of CALGB 100801 (Alliance). Biol Blood Marrow Transplant. 2019 Oct;25(10):1984-1992. doi: 10.1016/j.bbmt.2019.06.007. Epub 2019 Jun 15.