Acute Myeloid Leukemia (AML), 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
Conditions
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.
Interventions
DRUGCytarabine
Given IV
DRUGVosaroxin
Given IV
Sponsors
National Cancer Institute (NCI)
Vanderbilt-Ingram Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 FMS-like tyrosine kinase 3 (FLT3) - internal tandem duplication (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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Complete Remission Rate (CR) | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Leukemia-free Survival (LFS or DFS) | 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 | 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 | Up to 3 months | Frequency of minimal residual disease (MRD) remaining after 7+V induction and/or re-induction |
| Rate of CR/CRi | Up to 3 months | Frequency of Complete Remission / Complete Remission with Incomplete Count Recovery (CR/CRi) after 7+V induction and/or re-induction |
| Event-free Survival | 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) | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Correlation of Standard Prognostic Scores of AML Risk With Survival | The time from start of therapy to death for any reason, assessed up to 1 year | Correlate HSCT comorbidity index, Wheatley Index, and AML-Score values with overall survival |
| Correlation of Three Standard Prognostic Scores of AML Risk With Disease Response | Up to 3 months | Correlate hematopoietic stem cell transplant (HSCT) comorbidity index, Wheatley Index, and AML-Score values with disease response |
| Correlate HSCT Comorbidity Index, Wheatley Index, and AML-Score Values With DFS | The time from complete remission to disease progression or death for any reason, assessed up to 1 year | Correlation of three standard prognostic scores of AML risk with disease free survival |
Countries
United States
Participant flow
Recruitment details
The recruitment period for this trial was March 2016 to April 2019. Participants were recruited at Vanderbilt University Medical Center, Yale University, and University Medical School, South Carolina.
Pre-assignment details
42 participants met all eligibility criteria and were enrolled on this study. Nine of the participants received a second induction.
Participants by arm
| Arm | Count |
|---|---|
| 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.
Cytarabine: Given IV
Vosaroxin: Given IV | 42 |
| Total | 42 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Alternative therapy | 1 |
| Overall Study | Death | 2 |
| Overall Study | Disease progression | 10 |
| Overall Study | Refractory acute myeloid leukemia (AML) | 1 |
| Overall Study | Treatment Failure, circulating blasts | 1 |
Baseline characteristics
| Characteristic | Treatment (Vosaroxin, Cytarabine) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 17 Participants |
| Age, Categorical Between 18 and 65 years | 25 Participants |
| Age, Continuous | 64.4 Years |
| Race/Ethnicity, Customized Black or African American | 5 Participants |
| Race/Ethnicity, Customized Unknown/unreported | 2 Participants |
| Race/Ethnicity, Customized White | 35 Participants |
| Region of Enrollment United States | 42 participants |
| Sex: Female, Male Female | 13 Participants |
| Sex: Female, Male Male | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 18 / 33 | 4 / 9 |
| other Total, other adverse events | 33 / 33 | 9 / 9 |
| serious Total, serious adverse events | 10 / 33 | 5 / 9 |
Outcome results
Primary
Complete Remission Rate (CR)
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
Time frame: Up to 3 months
Population: Evaluable patients
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Vosaroxin, Cytarabine) | Complete Remission Rate (CR) | 20 Participants |
Secondary
Event-free Survival
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.
Time frame: From start of therapy up to 1 year
Population: All patients participated
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Vosaroxin, Cytarabine) | Event-free Survival | 7.6 months |
Secondary
Frequency of Grade 3-5 Adverse Event Related to Cytarabine and Vosaroxin (7+V)
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.
Time frame: Up to 3 months
Population: All participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Vosaroxin, Cytarabine) | Frequency of Grade 3-5 Adverse Event Related to Cytarabine and Vosaroxin (7+V) | 133 adverse events |
Secondary
Leukemia-free Survival (LFS or DFS)
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.
Time frame: The time from complete remission to disease progression or death for any reason, assessed up to 1 year
Population: Patients who had complete remission after the therapy
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Vosaroxin, Cytarabine) | Leukemia-free Survival (LFS or DFS) | NA months |
Secondary
Minimal Residual Disease
Frequency of minimal residual disease (MRD) remaining after 7+V induction and/or re-induction
Time frame: Up to 3 months
Population: When this study was designed, it was anticipated that the data needed to calculate MRD was going to be available from standard of care. However, this ended up not being the case. MRD requires NGS testing and the study did not have budget to cover this testing. Since the NGS was not part of the standard of care for these patients, these data were not available to collect as part of the study. There is no intention to go back and report data for this Outcome Measure if funding became available.
Secondary
Overall Survival
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.
Time frame: The time from start of therapy to death, assessed up to 1 year
Population: All participated patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Vosaroxin, Cytarabine) | Overall Survival | 10.7 months |
Secondary
Rate of CR/CRi
Frequency of Complete Remission / Complete Remission with Incomplete Count Recovery (CR/CRi) after 7+V induction and/or re-induction
Time frame: Up to 3 months
Population: Evaluable patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Vosaroxin, Cytarabine) | Rate of CR/CRi | 0.55 Proportion of participants |
Other Pre-specified
Correlate HSCT Comorbidity Index, Wheatley Index, and AML-Score Values With DFS
Correlation of three standard prognostic scores of AML risk with disease free survival
Time frame: The time from complete remission to disease progression or death for any reason, assessed up to 1 year
Population: Data for this outcome measure were not collected.
Other Pre-specified
Correlation of Standard Prognostic Scores of AML Risk With Survival
Correlate HSCT comorbidity index, Wheatley Index, and AML-Score values with overall survival
Time frame: The time from start of therapy to death for any reason, assessed up to 1 year
Population: Data for this outcome measure were not collected.
Other Pre-specified
Correlation of Three Standard Prognostic Scores of AML Risk With Disease Response
Correlate hematopoietic stem cell transplant (HSCT) comorbidity index, Wheatley Index, and AML-Score values with disease response
Time frame: Up to 3 months
Population: Data for this outcome measure were not collected.