- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02452346
Study of Clinical Efficacy and Safety of Tosedostat in MDS (IST-CTI-MDS)
Phase II Clinical Study of the Clinical Efficacy and Safety of Tosedostat in Atients With Myelodysplastic Syndromes (MDS) After Failure of Hypomethylating Agent-Based Therapy
Study Overview
Detailed Description
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
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New York
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New York, New York, United States, 10065
- Weill Cornell Medical College
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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) within 6 weeks prior to screening by WHO classification
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 intolerant to prior therapy with either agent.
- Primary failure/refractory: Stable or worsening disease after a minimum of 4 cycles of decitabine-based or 6 cycles of azacitidine-based therapy
- Secondary failure/relapse: Bone marrow blast count increase or loss of hematologic response after initial treatment response with hypomethylating agent-based therapy
- Intolerance: Intolerance of hypomethylating agent-based therapy regardless of number of cycles completed and clinical response
Progression (according to 2006 IWG criteria) at any time after initiation of subcutaneous or intravenous azacitidine or decitabine treatment per labeling during the past 2 years, defined as follows:
- For patients with <5% BMBL, ≥ 50% increase in BMBL to >5% BMBL
- For patients with 5-10% BMBL, ≥ 50% increase in BMBL to >10% BMBL
- For patients with 10-20% BMBL, ≥ 50% increase in BMBL to >20% BMBL
- For patients with 20-30% BMBL, ≥ 50% increase in BMBL to >30% BMBL
- Any of the following:
- ≥ 50% decrease from maximum remission/response levels in granulocytes or PLT
- Decrease in Hgb concentration by ≥2 g/dL
- Transfusion dependence, defined as administration of at least 4 RBC units in the past 8 weeks before Screening (patients must have Hgb values < 9 g/dL prior to transfusion to be considered), in the absence of another explanation.
- Has failed to respond to, relapsed following, not eligible, or opted not to participate in BM transplantation
- Patients with very low, low or intermediate risk MDS by the IPSS-R must be transfusion-dependent, with a packed red blood cell requirement of ≥ 2 units/month
- Off azacitidine or decitabine for at least 2 weeks, off all other treatments for MDS for at least 4 weeks. Filgrastim (G-CSF) and EPO are allowed before and during the study as clinically indicated
- Eastern Cooperative Oncology Group (ECOG) performance status of 0-3
Subjects must have adequate hepatic and renal function including the following:
- Total bilirubin ≤ 1.5 x upper limit of normal (in the absence of Gilbert's syndrome)
- AST and ALT ≤ 2.5 x upper limit of normal
- Serum creatinine ≤ 1.5 x upper limit of normal
- Must have acceptable recovery from clinically significant non-hematologic toxicity after prior therapy.
- Must have a life expectancy of at least 2 months
- Screening left ventricular ejection fraction (LVEF) greater than 50% as documented by transthoracic echocardiogram (TTE)
- Female subject of child-bearing potential and male subjects with female partners of reproductive potential must use acceptable contraceptive methods (hormonal or barrier method of birth control; abstinence) for the duration of time on study and continue to do so for a further 3 months after the end of tosedostat treatment. Should a female subject become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
- Able to comply with all study procedures during the study including all visits and tests
- Willing to adhere to the prohibitions and restrictions specified in this protocol
- Patient must sign an informed consent form (ICF) indicating that s/he understands the purpose of and procedures required for the study and is willing to participate.
Exclusion Criteria:
- 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 non-melanoma skin cancer or cervical intraepithelial neoplasia
- Are receiving any other investigational therapy or protocol-prohibited therapy
- Have received previous treatment with tosedostat
- Pregnant or breastfeeding females
- Any prior or co-existing medical condition that in the Investigator's judgment will substantially increase the risk associated with the subject's participation in the study
- Psychiatric disorders or altered mental status precluding understanding of the informed consent process and/or completion of the necessary study procedures
Significant* cardiovascular disease defined as:
- Active heart disease including myocardial infarction within 6 months prior to study entry
- Symptomatic coronary artery disease
- Uncontrolled or clinically significant arrhythmia, angina, congestive heart failure
- Presence of clinically significant valvular heart disease
- Presence of clinically significant conduction defect on screening ECG
- Uncontrolled hypertension (i.e., systolic BP >160mmHg, diastolic >90 mmHg in repeated measurements) despite adequate therapy
- Clinically significant atrial fibrillation * Grade 3/4 in the CTCAE v4.0 grading would generally be considered clinically significant, although this remains a judgment for the Investigator to make.
- LVEF ≤ 50%
- Baseline troponin I and b-type natriuretic peptide > Grade I
- Prior exposure cardiotoxic agent, such as anthracycline, within 3 months of enrollment
- Concomitant use of drugs that prolong QT/QTc interval except antibiotics, antifungals, and other antimicrobials used as standard of care for the treatment and prevention of infection and/or other such drugs clinically indicated for patient care. When use of concomitant medications with QT-prolonging potential is necessary, ECG must be repeated 4 hours post-dose on Day 1, on Day 3, and on Day 7, and as clinically indicated, relative to start of agent with QT-prolonging potential.
- Gastrointestinal disorders that may interfere with absorption of drug
- Active serious infection or sepsis
- Clinically significant interstitial lung disease
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Experimental: All Patients
Tosedostat 120 mg PO once daily will be administered.
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120 mg PO once daily continuously for each 28 day treatment cycle
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Over All Survival
Time Frame: from start of treatment until death, assessed up to a period of 3-4 years.
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Survival following treatment to the date of death, assessed up to a period of 3-4 years.
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from start of treatment until death, assessed up to a period of 3-4 years.
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Overall Response
Time Frame: Approximately 3 years
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Overall response according to IWG 2006 criteira
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Approximately 3 years
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One Year and Two Year Survival
Time Frame: from start of treatment to 1 year and 2 years post treatment initiation
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from start of treatment to 1 year and 2 years post treatment initiation
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Collaborators and Investigators
Collaborators
Investigators
- Principal Investigator: Gail Roboz, MD, Weill Medical College of Cornell University
Publications and helpful links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- 1409015482
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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