Study of Clinical Efficacy and Safety of Tosedostat in MDS (IST-CTI-MDS)
Primary Purpose
Myelodysplastic Syndrome
Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Tosedostat
Sponsored by
About this trial
This is an interventional treatment trial for Myelodysplastic Syndrome focused on measuring MDS
Eligibility Criteria
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
Sites / Locations
- Weill Cornell Medical College
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
All Patients
Arm Description
Tosedostat 120 mg PO once daily will be administered.
Outcomes
Primary Outcome Measures
Over All Survival
Survival following treatment to the date of death, assessed up to a period of 3-4 years.
Secondary Outcome Measures
Overall Response
Overall response according to IWG 2006 criteira
One Year and Two Year Survival
Full Information
NCT ID
NCT02452346
First Posted
January 28, 2015
Last Updated
June 7, 2018
Sponsor
Weill Medical College of Cornell University
Collaborators
CTI BioPharma
1. Study Identification
Unique Protocol Identification Number
NCT02452346
Brief Title
Study of Clinical Efficacy and Safety of Tosedostat in MDS
Acronym
IST-CTI-MDS
Official Title
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 Type
Interventional
2. Study Status
Record Verification Date
June 2018
Overall Recruitment Status
Completed
Study Start Date
March 20, 2015 (Actual)
Primary Completion Date
October 25, 2017 (Actual)
Study Completion Date
October 25, 2017 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Weill Medical College of Cornell University
Collaborators
CTI BioPharma
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
Study WCMC IST-CTI-MDS evaluates the safety and tolerability of tosedostat in adult patients with pathologically confirmed MDS (< 20% blasts in bone marrow, peripheral blood, or both) by World Health Organization (WHO) classification after failure of hypomethylating agent-based therapy.
Detailed Description
This is a single-center, open label, two-arm phase II study of clinical activity of tosedostat in adult patients with MDS who have failed prior hypomethylating agent-based therapy. Arm A is defined as Revised International Prognostic Scoring Systems (IPSS-R) very low, low, and intermediate disease. Arm B is defined as IPSS-R high or very high risk disease. The two arms are separate and will enroll simultaneously. The dose of tosedostat will be 120 mg once a day continuously for each 28 day treatment cycle. Patients will be assessed for disease response, on average, every two cycles as defined in the protocol. If patient has no response as defined by the protocol after two cycles, azacitidine 75 mg/m2 SC or IV for 5 days may be combined with tosedostat, at the investigator's discretion.The primary endpoint the study is to evaluate the safety and efficacy of tosedostat in two groups of patients with myelodysplastic syndrome who have relapsed after or are refractory or intolerant to azacitidine or decitabine. The primary endpoint for patients with IPSS-R very low, low and intermediate disease is transfusion independence and the primary endpoint for patients with high or very high risk disease is overall survival.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Myelodysplastic Syndrome
Keywords
MDS
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
12 (Actual)
8. Arms, Groups, and Interventions
Arm Title
All Patients
Arm Type
Experimental
Arm Description
Tosedostat 120 mg PO once daily will be administered.
Intervention Type
Drug
Intervention Name(s)
Tosedostat
Other Intervention Name(s)
CHR-2797
Intervention Description
120 mg PO once daily continuously for each 28 day treatment cycle
Primary Outcome Measure Information:
Title
Over All Survival
Description
Survival following treatment to the date of death, assessed up to a period of 3-4 years.
Time Frame
from start of treatment until death, assessed up to a period of 3-4 years.
Secondary Outcome Measure Information:
Title
Overall Response
Description
Overall response according to IWG 2006 criteira
Time Frame
Approximately 3 years
Title
One Year and Two Year Survival
Time Frame
from start of treatment to 1 year and 2 years post treatment initiation
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Gail Roboz, MD
Organizational Affiliation
Weill Medical College of Cornell University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Weill Cornell Medical College
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
33043735
Citation
Lee S, Desai P, Edirisinghe B, Pianello S, Curcio T, Samuel M, Ritchie EK, Roboz GJ. Phase II study of the clinical efficacy and safety of tosedostat in patients with myelodysplastic syndromes (MDS) after failure of hypomethylating agent-based therapy. Leuk Lymphoma. 2021 Feb;62(2):498-500. doi: 10.1080/10428194.2020.1832674. Epub 2020 Oct 10. No abstract available.
Results Reference
derived
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Study of Clinical Efficacy and Safety of Tosedostat in MDS
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