Vosaroxin for Intermediate 2 or High-risk MDS After Failure With Hypomethylating Agent-based Therapy

Sponsor
Weill Medical College of Cornell University (Other)
Overall Status
Completed
CT.gov ID
NCT01980056
Collaborator
Sunesis Pharmaceuticals (Industry)
10
1
1
14.8
0.7

Study Details

Study Description

Brief Summary

Study WCMC IST/VOS/MDS evaluates the safety and tolerability of escalating doses of vosaroxin in adult patients with pathologically confirmed Myelodysplastic Syndrome, or MDS, (< 20% blasts in bone marrow, peripheral blood, or both) by World Health Organization (WHO) classification with an intermediate 2 (INT-2) or high-risk score (ie, ≥ 1.5) as assessed by the International Scoring System (IPSS) after failure of hypomethylating agent-based therapy. Based on 3 completed studies and xenograft models, Vosaroxin is hypothesized to be safe and will effective in this patient population.

Condition or Disease Intervention/Treatment Phase
Phase 1/Phase 2

Detailed Description

This is a phase 1-2, dose escalation study of the safety and clinical activity of vosaroxin in subjects with INT-2 or high risk MDS who have failed prior hypomethylating agent based therapy. The study will utilize a standard 3+3 design to estimate the MTD [maximum tolerated dose] for vosaroxin administered to subjects with MDS. MTD will be defined as the highest dose level at which no more than 33% of the subjects observed at a given dose level experience a DLT [dose limiting toxicity]. Subjects will be assessed for safety and DLT in the first cycle of vosaroxin. Subjects will be enrolled into the study in cohorts of 3. Three eligible subjects will be enrolled in sequential cohorts at increasing dose levels until at least 1 DLT is observed during the first cycle of vosaroxin therapy. Subjects who receive both doses of vosaroxin will be evaluated for the MTD, DLTs, and safety profile during the first cycle of therapy. Once the MTD has been determined, an expanded evaluation of safety and hematologic response or improvement rate at this dose level will be conducted in additional subjects so that the total number of subjects exposed to this dose level is up to 15 subjects, inclusive of those treated at this dose level in the dose-escalation phase. The exposure of additional subjects at the MTD will provide a better estimate of the toxicity rate. Subjects with a documented response of Complete Response, Partial Response, or hematologic improvement at the end of Cycle 2 may continue to receive vosaroxin for additional cycles at the discretion of the treating investigator and after discussion with the medical staff at Sunesis Pharmaceuticals. There will be a 30-day follow-up period following the termination of study drug treatment.

Study Design

Study Type:
Interventional
Actual Enrollment :
10 participants
Intervention Model:
Sequential Assignment
Intervention Model Description:
Dose level 1: Vosaroxin 50 mg/m^2 IV on Days 1 and 4 of 28 day cycle Dose level 2: Vosaroxin 72 mg/m^2 IV on Days 1 and 4 of 28 day cycle Dose level 3: Vosaroxin 50 mg/m^2 IV on Days 1, 4, 8 and 11 of 28 day cycleDose level 1: Vosaroxin 50 mg/m2 IV on Days 1 and 4 of 28 day cycle Dose level 2: Vosaroxin 72 mg/m2 IV on Days 1 and 4 of 28 day cycle Dose level 3: Vosaroxin 50 mg/m^2 IV on Days 1, 4, 8 and 11 of 28 day cycle
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase 1/2, Open-label, Dose Escalation Clinical Study of the Safety and Clinical Activity of Vosaroxin in Patients With Intermediate 2 or High-risk Myelodysplastic Syndrome (MDS) After Failure of Hypomethylating Agent-based Therapy
Actual Study Start Date :
Oct 25, 2013
Actual Primary Completion Date :
Jan 19, 2015
Actual Study Completion Date :
Jan 19, 2015

Arms and Interventions

Arm Intervention/Treatment
Experimental: Vosaroxin: All Patients

All patients will receive vosaroxin according to the dose cohort in which they are enrolled.

Drug: Vosaroxin
Dose level 1: Vosaroxin 50 mg^m2 IV on Days 1 and 4 of 28 day cycle Dose level 2: Vosaroxin 72 mg^m2 IV on Days 1 and 4 of 28 day cycle Dose level 3: Vosaroxin 50 mg^m2 IV on Days 1, 4, 8 and 11 of 28 day cycle
Other Names:
  • Qinprezo
  • Outcome Measures

    Primary Outcome Measures

    1. Dosage Determination for IV-infusion of Vosaroxin in Int-2 or High-risk Mds [1 year]

      Maximum tolerated dose of vosaroxin for short IV infusion in INT-2 or high-risk MDS

    Secondary Outcome Measures

    1. Number of Subjects Who Experience a Response [15 months]

      Evaluate the clinical activity of vosaroxin in MDS subjects by observing number of patients who achieve complete remission.

    2. Number of Transfusions Required During Treatment With Vosaroxin [15 months]

      Characterize the blood product transfusion requirements in this patient population when treated with vosaroxin

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Able to understand and to provide written informed consent

    • At least 18 years of age with pathologically confirmed MDS (< 20% blasts in bone marrow, peripheral blood, or both) by WHO classification with an intermediate 2 or high-risk score assessed by IPSS (score ≥ 1.5)

    • Must have received at least 4 cycles of decitabine-based or 6 cycles of azacitidine-based therapy and are either refractory to, relapsed after, or are intolerant of prior therapy with either agent.

    1. Primary failure/refractory: Stable or worsening disease after a minimum of 4 cycles of decitabine-based or 6 cycles of azacitidine-based therapy

    2. Secondary failure/relapse: Bone marrow blast count increase or loss of hematologic response after initial treatment response with hypomethylating agent-based therapy

    3. Intolerance: Intolerance of hypomethylating agent-based therapy regardless of number of cycles completed and clinical response

    • Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0-2

    • Must have a life expectancy of at least 2 months

    • Must demonstrate adequate clinical laboratory values (based on local laboratory results) as follows:

    1. Serum creatinine 1.5 ≤ x the upper limit of normal (ULN) or calculated creatinine clearance (CLCR) of ≥ 50 mL/min

    2. Total bilirubin ≤ 1.5 x ULN, higher levels are acceptable if these can be attributed to active hemolysis (as indicated by positive Coomb's test, decreased haptoglobin, Gilbert's disease, elevated indirect bilirubin, and/or lactate dehydrogenase) or ineffective erythropoiesis (as indicated by bone marrow findings).

    3. Aspartate aminotransferase (AST) ≤ 2.5 x ULN

    4. Alanine aminotransferase (ALT) ≤ 2.5 x ULN

    5. Must show adequate cardiac function defined as a left ventricular ejection fraction (LVEF)

    • 40% by echocardiogram (ECHO) or multigated acquisition (MUGA) scan

    • Must have acceptable recovery from clinically significant non-hematologic toxicity after prior therapy

    • Must be infertile or agree to use an effective contraceptive method for the duration of the study and for 30 days after the last dose (for men and women of child-producing potential).

    Exclusion Criteria:
    • Patients meeting any of the following criteria are excluded:

    • Presence of AML (≥ 20% blasts in bone marrow, peripheral blood, or both)

    • Presence of serious illness, medical condition, or other medical history, involving the heart, kidney, liver or other organ system, including abnormal laboratory parameters, which, in the opinion of the Investigator, would be likely to interfere with a subject's participation in the study or with the interpretation of the results.

    • Have known active central nervous system disease or active, uncontrolled, clinically significant infection(s).

    • Have other active malignancies (including other hematologic malignancies) or other malignancies within 12 months before enrollment, except nonmelanoma skin cancer or cervical intraepithelial neoplasia

    • Have experienced CTCAE Grade 2 or greater oral mucositis within the last 14 days

    • Are receiving any other investigational therapy or protocol-prohibited therapy

    • Have received previous treatment with vosaroxin

    • Pregnant or breastfeeding females

    • Known allergy to D-sorbitol or methanesulfonic acid (excipients used in vosaroxin)

    • Treatment with any anticancer therapy (including radiation) within the previous 14 days prior to the first dose of study drug or less than full recovery (CTCAE grade 1) from the clinically significant toxic effects of that treatment.

    • Treatment with any investigational drugs within the previous 14 days prior to Cycle 1, Day 1 or ongoing adverse events from previous cancer treatment with investigational drugs, regardless of the time period.

    • Have any other medical, psychological, or social condition that, in the opinion of the PI, would contraindicate the patient's participation in the clinical study due to safety or compliance with clinical study procedures

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Weill Cornell Medical College New York New York United States 10065

    Sponsors and Collaborators

    • Weill Medical College of Cornell University
    • Sunesis Pharmaceuticals

    Investigators

    • Principal Investigator: Gail Roboz, MD, Weill Medical College of Cornell University

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Weill Medical College of Cornell University
    ClinicalTrials.gov Identifier:
    NCT01980056
    Other Study ID Numbers:
    • 1305013919
    • IST/VOS/MDS
    First Posted:
    Nov 8, 2013
    Last Update Posted:
    Feb 19, 2019
    Last Verified:
    Jan 1, 2019
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Weill Medical College of Cornell University
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Vosaroxin: All Patients Receiving Dose Level 1: Vosaroxin 50 m Dose Level 2: Vosaroxin 72 mg/m^2 IV on Days 1 and 4 of 28 Day Dose Level 3: Vosaroxin 50 mg/m^2 IV on Days 1, 4, 8 and 11 of
    Arm/Group Description All patients will receive vosaroxin according to the dose cohort in which they are enrolled. Vosaroxin: Dose level 1: Vosaroxin 50 mg/m^2 IV on Days 1 and 4 of 28 day cycle All patient receiving Dose level 2: Vosaroxin 72 mg/m^2 IV on Days 1 and 4 of 28 day cycle All patient receiving Dose level 3: Vosaroxin 50 mg/m^2 IV on Days 1, 4, 8 and 11 of 28 day cycle
    Period Title: Overall Study
    STARTED 4 4 2
    COMPLETED 3 3 2
    NOT COMPLETED 1 1 0

    Baseline Characteristics

    Arm/Group Title Dose Level 1: Vosaroxin 50 mg/m^2 IV on Days 1 and 4 of 28 Day Dose Level 2: Vosaroxin 72 mg/m^2 IV on Days 1 and 4 of 28 Day Dose Level 3: Vosaroxin 50mg/m^2 IV on Days 1, 4, 8 and 11 of Total
    Arm/Group Description All patients will receive vosaroxin according to the dose cohort in which they are enrolled. Vosaroxin: Dose level 1: Vosaroxin 50 mg^m2 IV on Days 1 and 4 of 28 day cycle All patients will receive vosaroxin according to the dose cohort in which they are enrolled. Dose level 2: Vosaroxin 72 mg^m2 IV on Days 1 and 4 of 28 day cycle All patients will receive vosaroxin according to the dose cohort in which they are enrolled. Dose level 3: Vosaroxin 50 mg^m2 IV on Days 1, 4, 8 and 11 of 28 day cycle Total of all reporting groups
    Overall Participants 4 4 2 10
    Age (Count of Participants)
    <=18 years
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Between 18 and 65 years
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    >=65 years
    4
    100%
    4
    100%
    2
    100%
    10
    100%
    Sex: Female, Male (Count of Participants)
    Female
    1
    25%
    2
    50%
    1
    50%
    4
    40%
    Male
    3
    75%
    2
    50%
    1
    50%
    6
    60%
    Race/Ethnicity, Customized (Count of Participants)
    White
    2
    50%
    2
    50%
    1
    50%
    5
    50%
    Unknown or not reported
    2
    50%
    2
    50%
    1
    50%
    5
    50%
    Region of Enrollment (participants) [Number]
    United States
    4
    100%
    4
    100%
    2
    100%
    10
    100%

    Outcome Measures

    1. Primary Outcome
    Title Dosage Determination for IV-infusion of Vosaroxin in Int-2 or High-risk Mds
    Description Maximum tolerated dose of vosaroxin for short IV infusion in INT-2 or high-risk MDS
    Time Frame 1 year

    Outcome Measure Data

    Analysis Population Description
    All participants who received at least one dose of Vosaroxin were assessed for DLT in the first cycle of therapy. For this study. MTD is defined as the highest dose level at which no more than 33% of the patients observed at a given dose level experience a DLT.
    Arm/Group Title All Study Participants
    Arm/Group Description All patients will receive vosaroxin according to the dose cohort in which they are enrolled. Dose level 1: Vosaroxin 50 mg/m^2 IV on Days 1 and 4 of 28 day cycle Dose level 2: Vosaroxin 72 mg/m^2 IV on Days 1 and 4 of 28 day cycle Dose level 3: Vosaroxin 50 mg/m^2 IV on Days 1, 4, 8 and 11 of 28 day cycle
    Measure Participants 10
    Number [mg/m^2]
    200
    2. Secondary Outcome
    Title Number of Subjects Who Experience a Response
    Description Evaluate the clinical activity of vosaroxin in MDS subjects by observing number of patients who achieve complete remission.
    Time Frame 15 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Vosaroxin: Dose Level 1: Vosaroxin 50 mg/m^2 IV on Days 1 & 4 Dose Level 2: Vosaroxin 72 mg/m^2 IV on Days 1 and 4 of 28 Day Dose Level 3: Vosaroxin 50 mg/m^2 IV on Days 1, 4, 8 and 11 of
    Arm/Group Description All patients will receive vosaroxin according to the dose cohort in which they are enrolled. Vosaroxin: Dose level 1: Vosaroxin 50 mg/m^2 IV on Days 1 and 4 of 28 day cycle Dose level 2: Vosaroxin 72 mg/m^2 IV on Days 1 and 4 of 28 day cycle Dose level 3: Vosaroxin 50 mg/m^2 IV on Days 1, 4, 8 and 11 of 28 day cycle
    Measure Participants 4 4 2
    Count of Participants [Participants]
    0
    0%
    0
    0%
    0
    0%
    3. Secondary Outcome
    Title Number of Transfusions Required During Treatment With Vosaroxin
    Description Characterize the blood product transfusion requirements in this patient population when treated with vosaroxin
    Time Frame 15 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Vosaroxin: Dose Level 1: Vosaroxin 50 mg^m2 IV on Days 1 and 4 Dose Level 2: Vosaroxin 72 mg^m2 IV on Days 1 and 4 of 28 Day Dose Level 3: Vosaroxin 50 mg^m2 IV on Days 1, 4, 8 and 11 of
    Arm/Group Description All patients will receive vosaroxin according to the dose cohort in which they are enrolled. Vosaroxin: Dose level 1: Vosaroxin 50 mg^m2 IV on Days 1 and 4 of 28 day cycle Dose level 2: Vosaroxin 72 mg^m2 IV on Days 1 and 4 of 28 day cycle Dose level 3: Vosaroxin 50 mg^m2 IV on Days 1, 4, 8 and 11 of 28 day cycle
    Measure Participants 4 4 2
    Mean (Full Range) [Transfusions]
    19.8
    22.5
    22

    Adverse Events

    Time Frame Adverse events were collected over a period of 15 months.
    Adverse Event Reporting Description The adverse events and SAEs were assessed and graded by the principal investigator throughout the study.
    Arm/Group Title Dose Level 1: Vosaroxin 50 mg/m2 IV on Days 1 and 4 of 28 Day Dose Level 2: Vosaroxin 72 mg/m2 IV on Days 1 and 4 of 28 Day Dose Level 3: Vosaroxin 50 mg/m2 IV on Days 1, 4, 8 and 11 of
    Arm/Group Description Vosaroxin: Dose level 1: Vosaroxin 50 mg/m2 IV on Days 1 and 4 of 28 day cycle Dose level 2: Vosaroxin 72 mg/m2 IV on Days 1 and 4 of 28 day cycle Dose level 3: Vosaroxin 50 mg/m2 IV on Days 1, 4, 8 and 11 of 28 day cycle
    All Cause Mortality
    Dose Level 1: Vosaroxin 50 mg/m2 IV on Days 1 and 4 of 28 Day Dose Level 2: Vosaroxin 72 mg/m2 IV on Days 1 and 4 of 28 Day Dose Level 3: Vosaroxin 50 mg/m2 IV on Days 1, 4, 8 and 11 of
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 1/4 (25%) 1/4 (25%) 0/2 (0%)
    Serious Adverse Events
    Dose Level 1: Vosaroxin 50 mg/m2 IV on Days 1 and 4 of 28 Day Dose Level 2: Vosaroxin 72 mg/m2 IV on Days 1 and 4 of 28 Day Dose Level 3: Vosaroxin 50 mg/m2 IV on Days 1, 4, 8 and 11 of
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 3/4 (75%) 1/4 (25%) 2/2 (100%)
    Blood and lymphatic system disorders
    Febrile Neutropenia 3/4 (75%) 0/4 (0%) 1/2 (50%)
    Disease Progression 0/4 (0%) 0/4 (0%) 1/2 (50%)
    General disorders
    Non- Cardiogenic Shock 0/4 (0%) 1/4 (25%) 0/2 (0%)
    Sudden Death 1/4 (25%) 0/4 (0%) 0/2 (0%)
    Respiratory, thoracic and mediastinal disorders
    Respiratory Distress 1/4 (25%) 0/4 (0%) 0/2 (0%)
    Other (Not Including Serious) Adverse Events
    Dose Level 1: Vosaroxin 50 mg/m2 IV on Days 1 and 4 of 28 Day Dose Level 2: Vosaroxin 72 mg/m2 IV on Days 1 and 4 of 28 Day Dose Level 3: Vosaroxin 50 mg/m2 IV on Days 1, 4, 8 and 11 of
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 3/4 (75%) 3/4 (75%) 2/2 (100%)
    Blood and lymphatic system disorders
    Febrile Neutropenia 3/4 (75%) 1/4 (25%) 1/2 (50%)
    Gastrointestinal disorders
    Diarrhea 2/4 (50%) 2/4 (50%) 2/2 (100%)
    Constipation 3/4 (75%) 1/4 (25%) 0/2 (0%)
    Nausea 2/4 (50%) 3/4 (75%) 1/2 (50%)
    Vomiting 1/4 (25%) 2/4 (50%) 0/2 (0%)
    Mucositis 1/4 (25%) 1/4 (25%) 2/2 (100%)
    General disorders
    Fatigue 3/4 (75%) 1/4 (25%) 1/2 (50%)
    Epistaxis 2/4 (50%) 1/4 (25%) 1/2 (50%)
    Infections and infestations
    Oral Thrush 1/4 (25%) 1/4 (25%) 0/2 (0%)
    Bacterimia 0/4 (0%) 1/4 (25%) 2/2 (100%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Clinical Trials Administrator
    Organization Weill Cornell Medicine
    Phone 212-746-0284
    Email ray2013@med.cornell.edu
    Responsible Party:
    Weill Medical College of Cornell University
    ClinicalTrials.gov Identifier:
    NCT01980056
    Other Study ID Numbers:
    • 1305013919
    • IST/VOS/MDS
    First Posted:
    Nov 8, 2013
    Last Update Posted:
    Feb 19, 2019
    Last Verified:
    Jan 1, 2019