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Omacetaxine + Azacitidine in Untreated Patients With High Grade MDS

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ClinicalTrials.gov Identifier: NCT03564873
Recruitment Status : Recruiting
First Posted : June 21, 2018
Last Update Posted : January 11, 2021
Sponsor:
Information provided by (Responsible Party):
University of Colorado, Denver

Brief Summary:
This study will treat patients with previously untreated high grade myleodysplastic syndromes (MDS) with both omacetaxine mepesuccinate and azacitidine.

Condition or disease Intervention/treatment Phase
High Grade Myelodysplastic Syndromes Drug: Omacetaxine Drug: Azacitidine Phase 1 Phase 2

Detailed Description:
This is an open-label, phase I/II study for previously untreated patients with high grade MDS using omacetaxine and azacitidine. Phase I features dose escalation, where patients will be assigned to one of three cohorts to receive different doses of omacetaxine with the standard dose and schedule of azacitidine, over a 28 day cycle. Phase II features the maximum tolerated dose from the Phase 1 study.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 51 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Concomitant Omacetaxine Mepesuccinate and Azacitidine for Patients With Previously Untreated High Grade Myelodysplastic Syndromes
Actual Study Start Date : September 17, 2018
Estimated Primary Completion Date : June 2025
Estimated Study Completion Date : June 2026

Resource links provided by the National Library of Medicine

Drug Information available for: Azacitidine

Arm Intervention/treatment
Experimental: Phase I
Up to 18 patients will be enrolled to one of three cohorts to receive various doses of omacetaxine over a 28 day cycle. Azacitidine will be given at the standard dose over a 28 day cycle.
Drug: Omacetaxine
Phase I is a dose escalation phase. Patients will be enrolled into one of three cohorts to receive omacetaxine subcutaneously (0.5, 0.75, 1.0, or 1.25 mg/m2) twice daily on days 1 to 7.

Drug: Azacitidine
Azacitidine will be given at the standard dose and schedule, 75 mg/m2 once daily, on days 1 to 7. The patients will then be monitored for 21 more days ( to complete one 28 day cycle) but no more medication will be administered during those 21 days.

Experimental: Phase II
Up to 33 patients will be enrolled to receive the maximum tolerated dose (determined in phase I) over a 28 day cycle. Azacitidine will be given at the standard dose over a 28 day cycle.
Drug: Omacetaxine
Phase II is a maximum tolerated dose phase. Phase I will determine the maximum tolerated dose (highest amount that can be safely administered). Patients will receive omacetaxine subcutaneously at the maximum tolerated dose (0.5, 0.75, 1.0, or 1.25 mg/m2) twice daily on days 1 to 7.

Drug: Azacitidine
Azacitidine will be given at the standard dose and schedule, 75 mg/m2 once daily, on days 1 to 7. The patients will then be monitored for 21 more days ( to complete one 28 day cycle) but no more medication will be administered during those 21 days.




Primary Outcome Measures :
  1. Recommended Dose [ Time Frame: Start of study to end of study, for up to four years ]
    Determine the recommended dose of omacetaxine based on the maximum tolerated dose.

  2. Overall Response Rate [ Time Frame: Study start date to study end date, or death, whichever comes first, up to 4 years. ]
    Defined by the proportion of patients who achieve any category of complete remission (CR, includes CR and marrow CR) or partial remission (PR) based on the 2006 International Working Group (IWG) criteria for MDS1.


Secondary Outcome Measures :
  1. Overall Survival [ Time Frame: Study start date to study end date, or death, whichever comes first, up to 4 years. ]
    Overall Survival will be defined as the time from administration of the initial dose of omacetaxine and azacitidine until death from any cause. This will be measured using Kaplan-Meier survival analysis curves.

  2. Progression Free Survival [ Time Frame: Study start date to study end date, or death, whichever comes first, up to 4 years. ]
    Progression Free Survival will be defined as the amount of time from administration of the initial dose of omacetaxine and azacitidine that a patient lives with the disease but does not get worse. This will be measured using Kaplan-Meier survival analysis curves.

  3. Duration of Response [ Time Frame: Study start date to study end date, or death, whichever comes first, up to 4 years. ]
    Duration of Response will be defined as Time from documentation of tumor response to disease progression.This will be measured using Kaplan-Meier survival analysis curves.

  4. Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]). [ Time Frame: Start of study to end of study, up to four years ]
    Safety and tolerability analysis of omacetaxine and azacitidine will be summarized by dose and severity as assessed by the Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0 and relationship to study drug.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

A subject will be eligible for study participation if he/she meets the following criteria within 14 days prior to the first day of therapy (bone marrow biopsy can be performed 28 days prior to the first day of therapy).

  1. Subject must have confirmation of high grade MDS (MDS with excess blasts by WHO criteria) or chronic myelomonocytic leukemia (CMML)-1 with greater than 5% bone marrow blasts or CMML-2, also by WHO criteria
  2. Subject must have received no prior treatment with a hypomethylating agent for MDS
  3. Subject must be ≥ 18 years of age
  4. Subject must have a projected life expectancy of at least 12 weeks
  5. Subject must have an Eastern Cooperative Oncology Group (ECOG) Performance status of ≤2
  6. Subject must have adequate renal function as demonstrated by a calculated creatinine clearance ≥ 30 mL/min; determined via urine collection for 24-hour creatinine clearance or by the Cockcroft Gault formula
  7. Subject must have adequate liver function as demonstrated by:

    • aspartate aminotransferase (AST) ≤ 3.0 × ULN
    • alanine aminotransferase (ALT) ≤ 3.0 × ULN
    • bilirubin ≤ 3.0 × ULN, unless due to Gilbert's syndrome
  8. Non-sterile male subjects must use contraceptive methods with partner(s) from time of enrollment and continuing up to 90 days after the last dose of study drug. Male subjects must agree to refrain from sperm donation from initial study drug administration until 90 days after the last dose of study drug.
  9. Female subjects must agree to use two reliable forms of contraception simultaneously or to practice complete abstinence from heterosexual intercourse during the following time periods related to this study:

1) for at least 28 days before starting omacetaxine; 2) throughout the entire duration of omacetaxine treatment; 3) during dose interruptions; and 4) for at least 90 days after omacetaxine discontinuation.

10. Subject must voluntarily sign and date an informed consent, approved by an Institutional Review Board (IRB), prior to the initiation of any screening or study-specific procedures.

Exclusion Criteria:

A subject will not be eligible for study participation if he/she meets any of the following criteria:

  1. Subject is known to be positive for HIV. HIV testing is not required.
  2. Subject is known to be positive for hepatitis B or C infection with the exception of those with an undetectable viral load. Hepatitis B or C testing is not required and subjects with serologic evidence of prior vaccination to HBV (i.e., HBs Ag-, anti-HBs+ and anti-HBc-) may participate.
  3. Subject has any history of clinically significant condition(s) that in the opinion of the investigator would adversely affect his/her participating in this study including, but not limited to:

    • New York Heart Association heart failure > class 2
    • Renal, neurologic, psychiatric, endocrine, metabolic, immunologic, hepatic, cardiovascular disease, or bleeding disorder independent of leukemia
  4. Subject exhibits evidence of uncontrolled systemic infection requiring therapy (viral, bacterial or fungal). Patients on antibiotics with controlled systemic symptoms will not be excluded.
  5. Subject has uncontrolled diabetes
  6. Subject has had a recent major hemorrhage or has a bleeding diathesis associated with a high risk of bleeding
  7. Pregnant and breastfeeding females.
  8. Subject has a history of other malignancies prior to study entry, except for:

    • Adequately treated in situ carcinoma of the breast or cervix uteri
    • Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin
    • Prostate cancer with no plans for therapy of any kind
    • Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent.

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): NCT03564873


Contacts
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Contact: Emily Berens 720-848-8031 emily.berens@cuanschutz.edu

Locations
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United States, Colorado
Universtiy of Colorado Denver Recruiting
Aurora, Colorado, United States, 80045
Contact: Emily Berens    720-848-8031    emily.berens@cuanschutz.edu   
Principal Investigator: Daniel Pollyea, MD         
Sponsors and Collaborators
University of Colorado, Denver
Investigators
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Principal Investigator: Daniel Pollyea, MD University of Colorado, Denver
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Responsible Party: University of Colorado, Denver
ClinicalTrials.gov Identifier: NCT03564873    
Other Study ID Numbers: 17-2215.cc
First Posted: June 21, 2018    Key Record Dates
Last Update Posted: January 11, 2021
Last Verified: January 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University of Colorado, Denver:
Omacetaxine
Azacitidine
Previously Untreated
Phase I/II
Dose Escalation
Maximum Tolerated Dose
Additional relevant MeSH terms:
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Preleukemia
Myelodysplastic Syndromes
Syndrome
Disease
Pathologic Processes
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Neoplasms
Azacitidine
Homoharringtonine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors
Antineoplastic Agents, Phytogenic
Protein Synthesis Inhibitors