Clinical Trials /

Vosaroxin and Infusional Cytarabine in Treating Patients With Untreated Acute Myeloid Leukemia

NCT02658487

Description:

This phase II trial studies how well vosaroxin and cytarabine work in treating patients with untreated acute myeloid leukemia. Drugs used in chemotherapy, such as vosaroxin and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Vosaroxin and Infusional Cytarabine in Treating Patients With Untreated Acute Myeloid Leukemia
  • Official Title: Phase II Trial of Vosaroxin in Combination With Infusional Cytarabine in Patients With Untreated AML

Clinical Trial IDs

  • ORG STUDY ID: VICC HEM 1553
  • SECONDARY ID: NCI-2015-01735
  • SECONDARY ID: P30CA068485
  • NCT ID: NCT02658487

Conditions

  • Acute Myeloid Leukemia
  • Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome
  • Acute Myeloid Leukemia With Multilineage Dysplasia
  • Myeloid Sarcoma
  • Secondary Acute Myeloid Leukemia
  • Therapy-Related Acute Myeloid Leukemia
  • Therapy-Related Myelodysplastic Syndrome

Interventions

DrugSynonymsArms
Cytarabine.beta.-Cytosine arabinoside, 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-.beta.-D-Arabinofuranosylcytosine, 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-Beta-D-arabinofuranosylcytosine, 1.beta.-D-Arabinofuranosylcytosine, 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-, 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-, Alexan, Ara-C, ARA-cell, Arabine, Arabinofuranosylcytosine, Arabinosylcytosine, Aracytidine, Aracytin, Aracytine, Beta-Cytosine Arabinoside, CHX-3311, Cytarabinum, Cytarbel, Cytosar, Cytosar-U, Cytosine Arabinoside, Cytosine-.beta.-arabinoside, Cytosine-beta-arabinoside, Erpalfa, Starasid, Tarabine PFS, U 19920, U-19920, Udicil, WR-28453Treatment (vosaroxin, cytarabine)
VosaroxinAG-7352, SNS-595, SPC 595, VoreloxinTreatment (vosaroxin, cytarabine)

Purpose

This phase II trial studies how well vosaroxin and cytarabine work in treating patients with untreated acute myeloid leukemia. Drugs used in chemotherapy, such as vosaroxin and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To assess the rate of complete remission (CR) after induction therapy with the combination
      of "7+V" (vosaroxin and standard dose infusional cytosine arabinoside [ara-C]) for patients
      with newly diagnosed, previously untreated acute myelogenous leukemia (AML).

      SECONDARY OBJECTIVES:

      I. Frequency of grade 3-5 adverse events related to administration of "7+V".

      II. To evaluate for the presence of minimal residual disease (MRD) remaining after "7+V"
      induction and/or re-induction.

      III. To determine the CR/CR with incomplete blood count recovery (CRi) rate after one and/or
      2 cycles of "7+V" induction.

      IV. To determine the time to neutrophil and platelet recovery following "7+V" induction.

      V. To assess disease-free survival (DFS) at 1 year (yr) of patients achieving CR/CRi after
      "7+V" induction.

      VI. To assess overall survival (OS) at 1 yr of all patients receiving protocol-defined
      therapy.

      VII. To determine the correlation of hematopoietic stem cell transplant (HSCT) comorbidity
      index and Wheatley Index scores with disease response, DFS and OS.

      TERTIARY OBJECTIVES:

        -  I. To describe the mutational burden of this cohort of AML patients.

        -  II. To correlate genomic aberration with response rate, DFS, and OS.

        -  III. To determine the number of patients treated with vosaroxin who eventually go to
           allogeneic HSCT.

      OUTLINE:

      Patients receive vosaroxin intravenously (IV) on days 1 and 4 and cytarabine IV continuously
      on days 1-7 (Induction-I). Patients with residual leukemia and for whom a second course is
      indicated in the judgment of the investigator may undergo a second course of treatment
      (Induction-II) 14-57 days after day 1 of Induction-1

      After completion of study treatment, patients are followed every 3 months for 1 year.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (vosaroxin, cytarabine)ExperimentalPatients receive vosaroxin IV on days 1 and 4 and cytarabine IV continuously on days 1-7 (Induction I). Patients with residual leukemia and for whom a second course is indicated in the judgment of the investigator may undergo a second course of treatment (Induction II) 14-57 days after day 1 of Induction I.
  • Cytarabine
  • Vosaroxin

Eligibility Criteria

        Inclusion Criteria:

          -  Ability to provide informed consent

          -  Ability to tolerate intensive therapy with vosaroxin 90 mg/m^2 and cytarabine

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-2 at time of study
             entry

          -  Morphologically confirmed new diagnosis of AML in accordance with World Health
             Organization (WHO) diagnostic criteria

          -  Patients who have received hydroxyurea alone or have previously received
             "non-cytotoxic" therapies for myelodysplastic syndromes (MDS) or myeloproliferative
             neoplasms (MPN) (e.g., thalidomide or lenalidomide, 5-azacytidine or decitabine,
             histone deacetylase inhibitors, low-dose Cytoxan, tyrosine kinase or dual tyrosine
             kinase [TK]/SRC proto-oncogene, non-receptor tyrosine kinase [src] inhibitors) will be
             allowed

          -  Serum creatinine =< 2.0 mg/dL

          -  Hepatic enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST]) =<
             2.5 x upper limit of normal

          -  Total bilirubin =< 1.5 x upper limit of normal unless clearly related to Gilbert's
             disease, hemolysis or leukemic infiltrate

          -  FOR PATIENTS IN STAGE 1 (PATIENTS #1-#17)

          -  >= 55 years of age with AML of any risk classification, or 18-54 years of age with
             high-risk AML disease based on one of the following:

               -  Antecedent hematologic disorder including myelodysplasia (MDS)-related AML
                  (MDS/AML) and prior myeloproliferative disorder (MPD)

               -  Treatment-related myeloid neoplasms (t-AML/t-MDS)

               -  AML with FLT3-ITD

               -  Myeloid sarcoma

               -  AML with multilineage dysplasia (AML-MLD)

               -  Adverse cytogenetics (defined as -5/-5q; -7/-7q; abnormal 3q, 9q, 11q, 20q, 21q
                  or 17p; t(6;9); t(9;22); trisomy 8; trisomy 13; trisomy 21; complex karyotypes
                  (>= 3 clonal abnormalities); monosomal karyotypes

          -  FOR PATIENTS IN STAGE 2 (ENROLLED PATIENT #18 AND BEYOND)

          -  >= 55 years of age with AML of any risk classification, or 18-54 years of age with
             intermediate or high risk AML as defined by National Comprehensive Cancer Network
             (NCCN) risk assignment

        Exclusion Criteria:

          -  STAGES 1 AND 2

          -  Patients with acute promyelocytic leukemia (APL) as diagnosed by morphologic criteria,
             flow cytometric characteristics, and rapid cytogenetics or fluorescence in situ
             hybridization (FISH) or molecular testing

          -  Any previous treatment with vosaroxin

          -  Concomitant chemotherapy, radiation therapy

               -  For patients with hyperleukocytosis with > 50,000 blasts/μL; leukapheresis or
                  hydroxyurea may be used prior to study drug administration for cytoreduction at
                  the discretion of the treating physician

          -  Active, uncontrolled infection

               -  Patients with infection under active treatment and controlled with antibiotics,
                  antivirals, or antifungals are eligible

               -  Chronic hepatitis is acceptable

          -  Active, uncontrolled graft vs. host disease (GVHD) following allogeneic transplant for
             non-AML condition (e.g. MDS, lymphoid malignancy, aplastic anemia); patients with GVHD
             controlled on stable doses of immunosuppressants are eligible

          -  Presence of other life-threatening illness

          -  Left ventricular ejection fraction (LVEF) < 40% as measured by echocardiogram or multi
             gated acquisition scan (MUGA)

          -  Known or suspected central nervous system (CNS) involvement of active AML

          -  Other active malignancies including other hematologic malignancies or other
             malignancies within 12 months before randomization, except nonmelanoma skin cancer or
             cervical intraepithelial neoplasia

          -  History of myocardial infarction (MI), unstable angina, cerebrovascular accident, or
             transient ischemic attack (CVA/TIA) within 3 months before randomization

          -  Prior or current therapy:

               -  Hydroxyurea or medications to reduce blast count within 24 hours before
                  randomization

               -  Treatment with an investigational product within 14 days before randomization, or
                  not recovered from all acute effects of previously administered investigational
                  products

          -  Renal insufficiency requiring hemodialysis or peritoneal dialysis

          -  Pregnant or breastfeeding

          -  Known human immunodeficiency virus (HIV) seropositivity

          -  Any other medical, psychological, or social condition that may interfere with study
             participation or compliance, or compromise patient safety in the opinion of the
             investigator or medical monitor

          -  ADDITIONAL EXCLUSION CRITERIA APPLIED TO STAGE 1

          -  Patients 18-54 years of age with "good risk" AML defined as the presence of t(8;21),
             inv(16), or t(16;16) as diagnosed by morphologic criteria, flow cytometric
             characteristics, and rapid cytogenetics or FISH

          -  Patients with t(8;21), inv(16), t(16;16) who are unable to receive anthracycline based
             induction will be allowed to enroll provided the medical reason they are unable to
             receive anthracyclines is clearly documented and provided they fulfill all other
             eligibility and criteria
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Complete remission rate (CR)
Time Frame:Up to 3 months
Safety Issue:
Description:A likelihood ratio, not a tail area probability (p-value), will be used to represent the strength of statistical evidence with respect to either a 40% or 60% true CR rate. It is assumed the complete remission rate of standard induction chemotherapy is 40% in the targeted population of this trial and that the use of vosaroxin in combination with cytarabine may increase this rate to 60%.

Secondary Outcome Measures

Measure:Event-free survival
Time Frame:The time from start of therapy to progression or death for any reason, assessed up to 1 year
Safety Issue:
Description:Survival distribution will be estimated using the method of Kaplan and Meier and comparison of the distribution among patient subgroups will be made using the logrank test. Multivariable models of response and survival estimates will be constructed using logistic and Cox (proportional hazards) regression.
Measure:Frequency of grade 3-5 adverse event related to Cytarabine and Vosaroxin (7+V)
Time Frame:Up to day 3 months
Safety Issue:
Description:Events will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Frequency and percentage of patients will be summarized for any adverse event by grade, attribution, organ class, and preferred term overall and by patient. Change in continuous laboratory data from just prior to therapy and by visit will be summarized by frequency of abnormal values. Linear and non-linear regression will be used to model changes over time, accounting for intra-patient correlation using mixed models or generalized estimating equation, as appropriate.
Measure:Leukemia-free survival (LFS or DFS)
Time Frame:The time from complete remission to disease progression or death for any reason, assessed up to 1 year
Safety Issue:
Description:Survival distribution will be estimated using the method of Kaplan and Meier and comparison of the distribution among patient subgroups will be made using the logrank test. Multivariable models of response and survival estimates will be constructed using logistic and Cox (proportional hazards) regression. Time to response will be implemented as a time-dependent covariate in models assessing LFS.
Measure:Overall Survival
Time Frame:The time from start of therapy to death for any reason, assessed up to 1 year
Safety Issue:
Description:Survival distribution will be estimated using the method of Kaplan and Meier and comparison of the distribution among patient subgroups will be made using the logrank test. Multivariable models of response and survival estimates will be constructed using logistic and Cox (proportional hazards) regression.
Measure:Minimal Residual Disease
Time Frame:Up to 3 months
Safety Issue:
Description:Frequency of minimal residual disease (MRD) remaining after "7+V" induction and/or re-induction
Measure:Rate of Complete Remission / Complete Remission with Incomplete Count Recovery (CR/CRi)
Time Frame:Up to 3 months
Safety Issue:
Description:Frequency of CR/CRi after "7+V" induction and/or re-induction

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Suspended
Lead Sponsor:Vanderbilt-Ingram Cancer Center

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