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

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ClinicalTrials.gov Identifier: NCT02658487
Recruitment Status : Active, not recruiting
First Posted : January 18, 2016
Results First Posted : June 9, 2020
Last Update Posted : May 27, 2021
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Stephen Strickland, Vanderbilt-Ingram Cancer Center

Tracking Information
First Submitted Date  ICMJE January 14, 2016
First Posted Date  ICMJE January 18, 2016
Results First Submitted Date  ICMJE April 30, 2020
Results First Posted Date  ICMJE June 9, 2020
Last Update Posted Date May 27, 2021
Study Start Date  ICMJE March 2016
Actual Primary Completion Date April 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 27, 2020)
Complete Remission Rate (CR) [ Time Frame: Up to 3 months ]
CR is calculated as the percentage of patients with complete remission after the therapy. The response criteria is based on International Working Group Criteria. Complete Remission: Neutrophils(cells/μl)>1000, Platelets (plt/μl)≥ 100,000,Bone marrow blasts (%) <5; CR with incomplete count recovery (CRi): meets criteria for CR except for neutrophils ≤1000 or Meets criteria for CR except for platelets< 100,000; Partial Remission: CR except for Bone marrow blasts (%) Decrease of ≥ 50% to value between 5% and 25%; Treatment Failure:Persistent acute myeloid leukemia in blood or bone marrow, or therapy fails to achieve a remission of any category, or death prior to response assessment
Original Primary Outcome Measures  ICMJE
 (submitted: January 14, 2016)
Complete Remission Rate (CR) [ Time Frame: Up to 3 months ]
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%.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 27, 2020)
  • Event-free Survival [ Time Frame: From start of therapy up to 1 year ]
    Survival distribution will be estimated using the method of Kaplan and Meier. Event-free survival time is defined as the time from start of therapy to progression or death for any reason (which ever comes first), and those alive without progression are censored at the last day of follow up.
  • Frequency of Grade 3-5 Adverse Event Related to Cytarabine and Vosaroxin (7+V) [ Time Frame: Up to 3 months ]
    Events will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Counts of all events are summed up.
  • 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 ]
    Survival distribution will be estimated using the method of Kaplan and Meier. LFS time is defined as the time from complete remission to disease progression or death for any reason and those disease free and alive are censored at the last day of follow up.
  • Overall Survival [ Time Frame: The time from start of therapy to death, assessed up to 1 year ]
    Survival distribution will be estimated using the method of Kaplan and Meier. The overall survival time is defined as time from start of therapy to death of any reason. Those alive are censored at the last day of known alive.
  • Minimal Residual Disease [ Time Frame: Up to 3 months ]
    Frequency of minimal residual disease (MRD) remaining after "7+V" induction and/or re-induction
  • Rate of CR/CRi [ Time Frame: Up to 3 months ]
    Frequency of Complete Remission / Complete Remission with Incomplete Count Recovery (CR/CRi) after "7+V" induction and/or re-induction
Original Secondary Outcome Measures  ICMJE
 (submitted: January 14, 2016)
  • Event-free survival [ Time Frame: The time from start of therapy to progression or death for any reason, assessed up to 1 year ]
    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.
  • Frequency of Grade 3-5 Adverse Event Related to Cytarabine and Vosaroxin (7+V) [ Time Frame: Up to day 3 months ]
    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.
  • 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 ]
    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.
  • Overall Survival [ Time Frame: The time from start of therapy to death for any reason, assessed up to 1 year ]
    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.
  • Minimal Residual Disease [ Time Frame: Up to 3 months ]
    Frequency of minimal residual disease (MRD) remaining after "7+V" induction and/or re-induction
  • Rate of Complete Remission / Complete Remission with Incomplete Count Recovery (CR/CRi) [ Time Frame: Up to 3 months ]
    Frequency of CR/CRi after "7+V" induction and/or re-induction
Current Other Pre-specified Outcome Measures
 (submitted: January 14, 2016)
  • Correlate HSCT Comorbidity Index, Wheatley Index, and AML-Score Values With Disease Response [ Time Frame: Up to 3 months ]
  • Correlate HSCT Comorbidity Index, Wheatley Index, and AML-Score Values With DFS [ Time Frame: The time from complete remission to disease progression or death for any reason, assessed up to 1 year ]
  • Correlate HSCT Comorbidity Index, Wheatley Index, and AML-Score Values With OS [ Time Frame: The time from start of therapy to death for any reason, assessed up to 1 year ]
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Vosaroxin and Infusional Cytarabine in Treating Patients With Untreated Acute Myeloid Leukemia
Official Title  ICMJE Phase II Trial of Vosaroxin in Combination With Infusional Cytarabine in Patients With Untreated AML
Brief Summary 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • 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
Intervention  ICMJE
  • Drug: Cytarabine
    Given IV
    Other Names:
    • .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-28453
  • Drug: Vosaroxin
    Given IV
    Other Names:
    • AG-7352
    • SNS-595
    • SPC 595
    • Voreloxin
Study Arms  ICMJE Experimental: Treatment (vosaroxin, cytarabine)
Patients 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.
Interventions:
  • Drug: Cytarabine
  • Drug: Vosaroxin
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: May 27, 2020)
42
Original Estimated Enrollment  ICMJE
 (submitted: January 14, 2016)
61
Estimated Study Completion Date  ICMJE July 2021
Actual Primary Completion Date April 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02658487
Other Study ID Numbers  ICMJE VICC HEM 1553
NCI-2015-01735 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
P30CA068485 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Stephen Strickland, Vanderbilt-Ingram Cancer Center
Study Sponsor  ICMJE Vanderbilt-Ingram Cancer Center
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Stephen Strickland, MD Vanderbilt-Ingram Cancer Center
Principal Investigator: Michael Savona, MD Vanderbilt-Ingram Cancer Center
PRS Account Vanderbilt-Ingram Cancer Center
Verification Date May 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP