Acute Myeloid Leukemia
Conditions
Keywords
Leukemia, Acute Myeloid, Relapsed, Refractory, Cancer, AML, Cytarabine, SNS-595, Phase 1, Voreloxin
Brief summary
This study will evaluate the safety and tolerability of voreloxin (vosaroxin) injection in combination with cytarabine in patients with relapsed or refractory acute myeloid leukemia.
Detailed description
An open-label, Phase 1b/2 study using a dose-escalation design with expansion at the maximum tolerated dose (MTD) using 2 dosing schedules: During the Schedule A dose-escalation phase, patients with relapsed or refractory acute myeloid leukemia (AML) enrolled in cohorts of at least 3 patients to identify the MTD. Begin with a starting dosing regimen of vosaroxin of 10 mg/m2 on Days 1 and 4 of each cycle in combination with a 24-hour continuous intravenous (CIV) infusion of cytarabine 400 mg/m2/day × 5 days. If none of the 3 patients or 1 of 6 patients experience a dose-limiting toxicity (DLT) at the vosaroxin starting dose, dose-escalate vosaroxin. If 2 of 6 patients experienced a DLT at the vosaroxin starting dose, reduce the dose of cytarabine to reduced to 200 mg/m2 (only case in which the cytarabine could have been reduced). The vosaroxin dose escalated following a modified Fibonacci schema. For Schedule B dose-escalation phase, patients with relapsed or refractory AML enrolled in cohorts of at least 3 patients to identify the MTD. Begin with a starting dose regimen of vosaroxin of 70 mg/m2 on Days 1 and 4 in combination with cytarabine as a 2-hour infusion of 1 g/m2/day × 5 days. No reductions of cytarabine allowed in Schedule B. If none of the 3 patients or 1 of 6 patients experienced a DLT in the first cohort of Schedule B, escalate the dose of vosaroxin. If DLTs occurred in 2 of 6 patients during the starting dose, reduce the vosaroxin dose to 50 mg/m2. For both Schedules, the highest dose at which fewer than 2 of 6 patients experienced a DLT during induction became the MTD and the recommended future dose. Once the MTD of vosaroxin was determined for Schedule A, first relapse patients were enrolled in the expansion phase at that dose level to obtain additional safety and efficacy information. When the MTD of vosaroxin was determined for Schedule B, first relapse patients and patients with primary refractory disease were enrolled in the expansion phase at that dose level to characterize the safety and efficacy profile in this population.
Interventions
DRUGVoreloxin injection and cytarabine
Dose-escalation Phase * Schedule A: vosaroxin injection (dose-escalation from 10 to 90 mg/m2) on Days 1 and 4 in combination with cytarabine (24-hour CIV infusion of 400 mg/m2/day × 5 days) * Schedule B: vosaroxin injection (dose-escalation from 70 to 90 mg/m2) on Days 1 and 4 in combination with cytarabine (2-hour intravenous \[IV\] infusion of 1 g/m2/day × 5 days) Expansion Phase The MTD determined in the dose-escalation phase was used in the expansion phase. * Schedule A: 80 mg/m2 vosaroxin on Days 1 and 4 in combination with cytarabine (24-hour CIV infusion at 400 mg/m2/day × 5 days) * Schedule B: 90 mg/m2 vosaroxin (dose-escalation) on Days 1 and 4 in combination with cytarabine (2 hour IV infusion at 1 g/m2/day × 5 days)
Sponsors
Sunesis Pharmaceuticals
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
KEY INCLUSION CRITERIA 1. Relapsed or refractory AML subtypes defined by WHO, except acute promyelocytic leukemia. Relapsed/refractory disease may be de novo AML or secondary AML 2. Treated with one to threee induction/reinduction AML regimens, prior induction or consolidation therapy with cytarabine allowed 3. At least 10% blasts by BM biopsy or aspirate 4. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1 5. Clinical laboratory values of a) Serum creatinine ≤1.5 mg/dL and calculated or measured creatinine clearance (CRcl) of ≥50 mL/min, b) Total bilirubin ≤1.5 X upper limit of normal and c) Aspartate aminotransferase (AST) or alkaline phosphatase ≤2.5 X ULN. KEY
Exclusion criteria
Patients with: 1. Allogenic bone marrow transplant/stem cell transplant 2. Persistent, clinically significant, chronic toxicities from prior AML therapy that would contraindicate the patient's participation in the clinical study due to safety concerns or compliance with study procedures 3. Acute promyelocytic leukemia 4. Disseminated intravascular coagulation 5. Active infections, unless adequately treated with antibiotic, antiviral, or antifungal agents within in 7 days before Induction Day 1 6. Active central nervous system involvement by AML 7. Other active malignancies or other malignancies within the last 12 months except nonmelanoma skin cancer or cervical intraepithelial neoplasia 8. A requirement for hemodialysis or peritoneal dialysis 9. A history of myocardial infarction within the 3 months before treatment with vosaroxin 10. A history of cerebrovascular accident/transient ischemic attack within the 3 months before treatment with vosaroxin 11. A thromboembolic event (deep vein thrombosis or pulmonary embolus) within 28 days before treatment with vosaroxin 12. Investigational products taken within 28 days before treatment with vosaroxin, and non-investigational cancer therapies or radiation therapy within 14 days before treatment with vosaroxin, with the exception of hydroxyurea. 13. A known intolerance to cytarabine or known allergy to D-sorbitol or methanesulfonic acid (excipients used in vosaroxin) 14. Prior exposure to vosaroxin 15. Any other medical, psychological, or social condition that contraindicates their participation in the clinical study due to safety concerns or compliance with study procedures in the opinion of the Investigator,or Sunesis Medical Monitor In addition: 16. Women who are pregnant or breastfeeding 17. Women who are of childbearing potential or male patients who had partners of childbearing potential who were unwilling to use an approved, effective means of contraception according to the study site's standards
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Dose-Limiting Toxicity (DLT) to Determine Maximum Tolerated Dose in Schedule A and Schedule B of Dose Escalation Phase (Group 1 and Group 2) | From start of treatment (Day 1) through Induction Day 29 or the start of reinduction, whichever occurred first. | Patients were treated in cohorts with escalating doses of vosaroxin administered in combination with cytarabine in Schedule A, and with vosaroxin in escalating doses in Schedule B. For both Schedules, the highest dose at which fewer than 2 of 6 (\<0.33) patients experienced a dose-limiting toxicity (DLT) during induction became the MTD and the recommended future dose. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Remission Rates (CR+CRp) | Monthly after the end of treatment for the first year, then every 2 months thereafter for upto 2 years | Complete remission (CR) plus CR with incomplete platelet recovery (CRp) per The IWG criteria for remission modified by Sunesis, assessed by investigator. CR is defined as \>1000 Neutrophils (ul), \>100,000 Platelets (uL) and \<5 BM Blasts (%); CRp is defined as \>1000 Neutrophils (ul), \<=100,000 Platelets (uL) and \<5 BM Blasts (%); CRi is defined as \>1000 Neutrophils (ul), \<100,000 Platelets (uL) and \<5 BM Blasts (%); Investigators were to determine a response category for each patient by examination of bone marrow and blood counts at the time of hematologic recovery after induction or reinduction. Investigator assessment categories included CR, CRp, CRi (CR with morphologic CR with incomplete blood count recovery), PR (partial remission), treatment failure, and relapse. |
| Leukemia-free Survival (LFS) | From time of the start of CR or CRp to the earliest date of relapse, commencement of reinduction therapy, or death, assessed monthly up to 2 years after the end of study visit. | Leukemia-free survival is censored at the last known alive date without report of relapse. |
| Overall Survival | Time between the date of first study treatment and the date of death due to any cause for upto 2 years after the end of study visit | Overall survival is censored at the earlier of the cutoff date for analysis and the last date known to be alive for patients not known to have died. |
| All Cause Mortality | 30 and 60 days | Mortality of those patients enrolled in the study and receiving intervention |
Countries
United States
Participant flow
Recruitment details
Conducted in 7 centers in the USA between 2007 and 2010
Pre-assignment details
Dose-escalation phase Group 1 (Sch A, 10 to 90 mg/m2): 41 patients (39 treated) Group 2 (Sch B, 70 to 90 mg/m2): 18 patients Dose-expansion phase Group 3 (Sch A first relapse, 80 mg/m2): 17 patients Group 4 (Sch B first relapse, 90 mg/m2): 16 patients Group 5 (Sch B primary refractory, 90 mg/m2): 18 patients Total: 110. Treated: 108
Participants by arm
| Arm | Count |
|---|---|
| Group 1 (Sch A, 10 to 90 mg/m2) Schedule A: vosaroxin injection (dose-escalation from 10 to 90 mg/m2) on Days 1 and 4 in combination with cytarabine (24-hour continuous IV \[CIV\] infusion of 400 mg/m2/day × 5 days) | 39 |
| Group 2 (Sch B, 70 to 90 mg/m2): Schedule B: vosaroxin injection (dose-escalation from 70 to 90 mg/m2) on Days 1 and 4 in combination with cytarabine (2-hour intravenous \[IV\] infusion of 1 g/m2/day × 5 days) | 18 |
| Group 3 (Sch A, First Relapse, 80 mg/m2): Schedule A: vosaroxin injection (dose-escalation from 10 to 90 mg/m2) on Days 1 and 4 in combination with cytarabine (24-hour continuous IV \[CIV\] infusion of 400 mg/m2/day × 5 days) | 17 |
| Group 4 (Sch B, First Relapse, 90 mg/m2) Schedule B: vosaroxin injection (dose-escalation from 70 to 90 mg/m2) on Days 1 and 4 in combination with cytarabine (2-hour intravenous \[IV\] infusion of 1 g/m2/day × 5 days) | 16 |
| Group 5 (Sch B, Primary Refractory, 90 mg/m2): Schedule B: vosaroxin injection (dose-escalation from 70 to 90 mg/m2) on Days 1 and 4 in combination with cytarabine (2-hour intravenous \[IV\] infusion of 1 g/m2/day × 5 days) | 18 |
| Total | 108 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 3 | 0 | 0 | 0 | 0 |
| Overall Study | Death | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Lack of Efficacy | 19 | 15 | 10 | 12 | 14 |
| Overall Study | Not Reported or Other | 11 | 3 | 3 | 3 | 1 |
| Overall Study | Physician Decision | 0 | 0 | 2 | 1 | 0 |
Baseline characteristics
| Characteristic | Group 1 (Sch A, 10 to 90 mg/m2) | Group 2 (Sch B, 70 to 90 mg/m2): | Group 3 (Sch A, First Relapse, 80 mg/m2): | Group 4 (Sch B, First Relapse, 90 mg/m2) | Group 5 (Sch B, Primary Refractory, 90 mg/m2): | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 58.0 Years STANDARD_DEVIATION 10.9 | 47.4 Years STANDARD_DEVIATION 13.83 | 59.7 Years STANDARD_DEVIATION 9.29 | 58.4 Years STANDARD_DEVIATION 11.03 | 56.3 Years STANDARD_DEVIATION 12.09 | 56.3 Years STANDARD_DEVIATION 11.95 |
| Region of Enrollment United States | 39 participants | 18 participants | 17 participants | 16 participants | 18 participants | 108 participants |
| Sex: Female, Male Female | 11 Participants | 5 Participants | 6 Participants | 6 Participants | 8 Participants | 36 Participants |
| Sex: Female, Male Male | 28 Participants | 13 Participants | 11 Participants | 10 Participants | 10 Participants | 72 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 36 / 39 | 16 / 18 | 15 / 17 | 14 / 16 | 13 / 18 |
| other Total, other adverse events | 39 / 39 | 18 / 18 | 17 / 17 | 16 / 16 | 18 / 18 |
| serious Total, serious adverse events | 20 / 39 | 7 / 18 | 9 / 17 | 3 / 16 | 11 / 18 |
Outcome results
Primary
Incidence of Dose-Limiting Toxicity (DLT) to Determine Maximum Tolerated Dose in Schedule A and Schedule B of Dose Escalation Phase (Group 1 and Group 2)
Patients were treated in cohorts with escalating doses of vosaroxin administered in combination with cytarabine in Schedule A, and with vosaroxin in escalating doses in Schedule B. For both Schedules, the highest dose at which fewer than 2 of 6 (\<0.33) patients experienced a dose-limiting toxicity (DLT) during induction became the MTD and the recommended future dose.
Time frame: From start of treatment (Day 1) through Induction Day 29 or the start of reinduction, whichever occurred first.
Population: Patients experiencing a dose-limiting toxicity (DLT) during induction when treated with escalating doses of vosaroxin administered in combination with cytarabine on Days 1 and 4 in Schedule A, and with vosaroxin in escalating doses administered on Days 1 and 4 in Schedule B.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sch A, Cohort 10mg/m2 | Incidence of Dose-Limiting Toxicity (DLT) to Determine Maximum Tolerated Dose in Schedule A and Schedule B of Dose Escalation Phase (Group 1 and Group 2) | 0 Participants |
| Sch A, Cohort 20mg/m2 | Incidence of Dose-Limiting Toxicity (DLT) to Determine Maximum Tolerated Dose in Schedule A and Schedule B of Dose Escalation Phase (Group 1 and Group 2) | 0 Participants |
| SchA, Cohort 34mg/m2 | Incidence of Dose-Limiting Toxicity (DLT) to Determine Maximum Tolerated Dose in Schedule A and Schedule B of Dose Escalation Phase (Group 1 and Group 2) | 0 Participants |
| Sch A, Cohort 50mg/m2 | Incidence of Dose-Limiting Toxicity (DLT) to Determine Maximum Tolerated Dose in Schedule A and Schedule B of Dose Escalation Phase (Group 1 and Group 2) | 0 Participants |
| Sch A, Cohort 70mg/m2 | Incidence of Dose-Limiting Toxicity (DLT) to Determine Maximum Tolerated Dose in Schedule A and Schedule B of Dose Escalation Phase (Group 1 and Group 2) | 1 Participants |
| Sch A, Cohort 80mg/m2 | Incidence of Dose-Limiting Toxicity (DLT) to Determine Maximum Tolerated Dose in Schedule A and Schedule B of Dose Escalation Phase (Group 1 and Group 2) | 1 Participants |
| Sch A, Cohort 90mg/m2 | Incidence of Dose-Limiting Toxicity (DLT) to Determine Maximum Tolerated Dose in Schedule A and Schedule B of Dose Escalation Phase (Group 1 and Group 2) | 2 Participants |
| Sch B, Cohort 70 mg/m2 | Incidence of Dose-Limiting Toxicity (DLT) to Determine Maximum Tolerated Dose in Schedule A and Schedule B of Dose Escalation Phase (Group 1 and Group 2) | 0 Participants |
| Sch B, Cohort 80mg/m2 | Incidence of Dose-Limiting Toxicity (DLT) to Determine Maximum Tolerated Dose in Schedule A and Schedule B of Dose Escalation Phase (Group 1 and Group 2) | 1 Participants |
| Sch B, Cohort 90mg/m2 | Incidence of Dose-Limiting Toxicity (DLT) to Determine Maximum Tolerated Dose in Schedule A and Schedule B of Dose Escalation Phase (Group 1 and Group 2) | 1 Participants |
Secondary
All Cause Mortality
Mortality of those patients enrolled in the study and receiving intervention
Time frame: 30 and 60 days
Population: All treated analysis set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sch A, Cohort 10mg/m2 | All Cause Mortality | 30 Days | 8 Participants |
| Sch A, Cohort 10mg/m2 | All Cause Mortality | 60 Days | 10 Participants |
| Sch A, Cohort 20mg/m2 | All Cause Mortality | 60 Days | 2 Participants |
| Sch A, Cohort 20mg/m2 | All Cause Mortality | 30 Days | 0 Participants |
| SchA, Cohort 34mg/m2 | All Cause Mortality | 60 Days | 2 Participants |
| SchA, Cohort 34mg/m2 | All Cause Mortality | 30 Days | 1 Participants |
| Sch A, Cohort 50mg/m2 | All Cause Mortality | 30 Days | 0 Participants |
| Sch A, Cohort 50mg/m2 | All Cause Mortality | 60 Days | 1 Participants |
| Sch A, Cohort 70mg/m2 | All Cause Mortality | 60 Days | 1 Participants |
| Sch A, Cohort 70mg/m2 | All Cause Mortality | 30 Days | 1 Participants |
Secondary
Leukemia-free Survival (LFS)
Leukemia-free survival is censored at the last known alive date without report of relapse.
Time frame: From time of the start of CR or CRp to the earliest date of relapse, commencement of reinduction therapy, or death, assessed monthly up to 2 years after the end of study visit.
Population: All treated analysis set.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sch A, Cohort 10mg/m2 | Leukemia-free Survival (LFS) | 12.0 months |
| Sch A, Cohort 20mg/m2 | Leukemia-free Survival (LFS) | 4.7 months |
| SchA, Cohort 34mg/m2 | Leukemia-free Survival (LFS) | 7.4 months |
| Sch A, Cohort 50mg/m2 | Leukemia-free Survival (LFS) | 25.2 months |
| Sch A, Cohort 70mg/m2 | Leukemia-free Survival (LFS) | NA months |
Secondary
Overall Survival
Overall survival is censored at the earlier of the cutoff date for analysis and the last date known to be alive for patients not known to have died.
Time frame: Time between the date of first study treatment and the date of death due to any cause for upto 2 years after the end of study visit
Population: All treated analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sch A, Cohort 10mg/m2 | Overall Survival | 4.1 months |
| Sch A, Cohort 20mg/m2 | Overall Survival | 8.0 months |
| SchA, Cohort 34mg/m2 | Overall Survival | 4.1 months |
| Sch A, Cohort 50mg/m2 | Overall Survival | 7.1 months |
| Sch A, Cohort 70mg/m2 | Overall Survival | 5.9 months |
Secondary
Remission Rates (CR+CRp)
Complete remission (CR) plus CR with incomplete platelet recovery (CRp) per The IWG criteria for remission modified by Sunesis, assessed by investigator. CR is defined as \>1000 Neutrophils (ul), \>100,000 Platelets (uL) and \<5 BM Blasts (%); CRp is defined as \>1000 Neutrophils (ul), \<=100,000 Platelets (uL) and \<5 BM Blasts (%); CRi is defined as \>1000 Neutrophils (ul), \<100,000 Platelets (uL) and \<5 BM Blasts (%); Investigators were to determine a response category for each patient by examination of bone marrow and blood counts at the time of hematologic recovery after induction or reinduction. Investigator assessment categories included CR, CRp, CRi (CR with morphologic CR with incomplete blood count recovery), PR (partial remission), treatment failure, and relapse.
Time frame: Monthly after the end of treatment for the first year, then every 2 months thereafter for upto 2 years
Population: All treated set which includes all enrolled patients who received any IMP.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sch A, Cohort 10mg/m2 | Remission Rates (CR+CRp) | 9 Participants |
| Sch A, Cohort 20mg/m2 | Remission Rates (CR+CRp) | 4 Participants |
| SchA, Cohort 34mg/m2 | Remission Rates (CR+CRp) | 7 Participants |
| Sch A, Cohort 50mg/m2 | Remission Rates (CR+CRp) | 3 Participants |
| Sch A, Cohort 70mg/m2 | Remission Rates (CR+CRp) | 4 Participants |
| Sch A, Cohort 80mg/m2 | Remission Rates (CR+CRp) | 27 Participants |