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Safety and Tolerability Study of Voreloxin and Cytarabine Combination in Acute Myeloid Leukemia in Humans

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ClinicalTrials.gov Identifier: NCT00541866
Recruitment Status : Completed
First Posted : October 10, 2007
Results First Posted : January 9, 2018
Last Update Posted : January 9, 2018
Sponsor:
Information provided by (Responsible Party):

Study Description
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.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Drug: Voreloxin injection and cytarabine Phase 1 Phase 2

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.


Study Design

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 110 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 1b/2, Open-Label, Multicenter, Dose-Escalating, Clinical Study of the Safety, Tolerability, and PK and PD Profiles of Voreloxin Injection in Combination With Cytarabine in Patients With Relapsed or Refractory AML
Actual Study Start Date : October 6, 2007
Primary Completion Date : February 15, 2012
Study Completion Date : February 15, 2012


Arms and Interventions

Arm Intervention/treatment
Experimental: Voreloxin injection and cytarabine

Dose-escalation Phase

  • Schedule A:
  • Schedule B:

Expansion Phase

  • Schedule A:
  • Schedule B:
Drug: Voreloxin 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)
Other Name: ARA-C, Cytosar-U


Outcome Measures

Primary Outcome Measures :
  1. 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) [ Time Frame: 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 Outcome Measures :
  1. Remission Rates (CR+CRp) [ Time Frame: 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.


  2. Leukemia-free Survival (LFS) [ 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. ]
    Leukemia-free survival is censored at the last known alive date without report of relapse.

  3. Overall Survival [ 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 ]
    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.

  4. All Cause Mortality [ Time Frame: 30 and 60 days ]
    Mortality of those patients enrolled in the study and receiving intervention


Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00541866


Locations
United States, Colorado
HealthOne Presbyterian/St. Luke's Medical Center
Denver, Colorado, United States, 80218
Rocky Mountain Cancer Centers
Denver, Colorado, United States, 80218
United States, Florida
H. Lee Moffitt Cancer Center
Tampa, Florida, United States, 33612
United States, Illinois
Northwestern Medical Faculty Foundation
Chicago, Illinois, United States, 60611
Northwestern Memorial Hospital
Chicago, Illinois, United States, 60611
United States, Indiana
Indiana University Cancer Center
Indianapolis, Indiana, United States, 46206
United States, Maryland
Johns Hopkins University - Sidney Kimmel Cancer Center
Baltimore, Maryland, United States, 21205
United States, New York
New York Presbyterian Hospital-Weill Cornell Medical College
New York, New York, United States, 10065
United States, Texas
MD Anderson Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
Sunesis Pharmaceuticals
Investigators
Study Director: Sunesis Medical Monitor, MD Sunesis Pharmaceuticals
More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Sunesis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT00541866     History of Changes
Other Study ID Numbers: SPO-0012
First Posted: October 10, 2007    Key Record Dates
Results First Posted: January 9, 2018
Last Update Posted: January 9, 2018
Last Verified: December 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Aggregate data of Adverse Events

Keywords provided by Sunesis Pharmaceuticals:
Leukemia
Acute Myeloid
Relapsed
Refractory
Cancer
AML
Cytarabine
SNS-595
Phase 1
Voreloxin

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Cytarabine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs