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Dose Escalation and Proof-of-Concept Studies of Vactosertib (TEW-7197) Monotherapy in Patients With MDS

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ClinicalTrials.gov Identifier: NCT03074006
Recruitment Status : Recruiting
First Posted : March 8, 2017
Last Update Posted : March 6, 2019
Sponsor:
Information provided by (Responsible Party):
MedPacto, Inc.

Brief Summary:
This is a prospective, open-label, multicenter, phase 1/2 study of TEW-7197 in patients with low and intermediate risk of myelodysplastic syndrome (MDS).

Condition or disease Intervention/treatment Phase
Myelodysplastic Syndromes Drug: TEW-7197 Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Phase 1/2 Study of Vactosertib (TEW-7197) Monotherapy in Patients With Low or Intermediate Myelodysplastic Syndromes
Actual Study Start Date : January 4, 2018
Estimated Primary Completion Date : July 2019
Estimated Study Completion Date : August 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: low dose Drug: TEW-7197
20mg tablets (doses will be determined through dose-escalation part)

Experimental: high dose Drug: TEW-7197
20mg tablets (doses will be determined through dose-escalation part)




Primary Outcome Measures :
  1. Maximum Tolerated Dose (MTD) for dose escalation phase [ Time Frame: 4 weeks ]
    To define the MTD and determine RP2D

  2. Hematologic improvement (HI) [ Time Frame: At 2, 4, 8, 12 and 16 weeks of treatment ]
    To evaluate the best hematologic improvement (HI) based on IWG 2006 criteria


Secondary Outcome Measures :
  1. Hematologic Improvement (HI) [ Time Frame: At 2, 4, 8, 12 and 16 weeks of treatment ]
    To evaluate the duration of HI

  2. Red blood cell transfusion independency [ Time Frame: At 2, 4, 8, 12 and 16 weeks of treatment ]
    To evaluate rate and duration of Red blood cell transfusion independency

  3. Bone marrow response and cytogenetic response [ Time Frame: At 2, 4, 8, 12 and 16 weeks of treatment ]
    To evaluate the frequency of bone marrow response (CP+PR) and cytogenetic response

  4. Time to progression [ Time Frame: At 2, 4, 8, 12 and 16 weeks of treatment ]
    Time to progression to higher risk or acute myeloid leukemia

  5. Relationship between mutations and response [ Time Frame: At 2, 4, 8, 12 and 16 weeks of treatment ]
    To evaluate the relationship between mutations and response

  6. Relationship between various stem and progenitor alterations and response [ Time Frame: At 2, 4, 8, 12 and 16 weeks of treatment ]
    To evaluate the relation ship between various stem and progenitor alterations and response

  7. Quality of life with MDS [ Time Frame: At 4, 8, 12 and 16 weeks of treatment ]
    To evaluate the quality of life parameters experienced by patients with MDS

  8. Biomarker [ Time Frame: At 4, 8, 12 and 16 weeks of treatment ]
    Determine pharmacodynamic markers in bone marrow



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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:

Subjects are eligible to be included in the study only if they meet all of the following criteria:

  1. Subjects who are males or females ≥ 18 years of age.
  2. Subjects who are able to give written informed consent.
  3. Subjects who have a documented diagnosis of MDS according to WHO criteria.
  4. Subjects who have Revised International Prognostic Scoring System (IPSS-R) categories of Very Low, Low- or Intermediate-risk disease. Subjects with cytogenetic failure and ≤ 10% marrow blasts will be eligible.
  5. Subjects who meet one of the following hematologic criteria within 8 weeks of registration (according to the IWG criteria) and as documented in prior transfusion logs or weekly hematology evaluations:

    • Symptomatic anemia untransfused with hemoglobin ≤ 9.0 g/dL or with RBC transfusion-dependence (i.e., ≥ 2 units/month) confirmed for a minimum of 8 weeks before randomization.
    • Platelet counts of < 100 x109/L
    • Absolute neutrophil count < 1500
  6. Subjects with del(5q) who should have failed or not be a candidate for approved therapy (Lenalidomide) prior to enrolling on this study.
  7. Subjects must meet accepted standard criteria for treatment and have failed or not be candidates for standard, accepted treatments.
  8. Subjects who have sufficient hepatic function, defined as bilirubin 2 times the upper limit of normal (ULN) and alanine transaminase (ALT) and aspartate transaminase (AST) levels 2.5 times ULN.
  9. Subjects who have sufficient renal function, defined as serum creatinine levels 1.5 ULN.
  10. Subjects who have a performance status of 2 on the Eastern Cooperative Oncology Group (ECOG) scale (refer to Appendix 2).
  11. Subjects who have discontinued all previous therapies for MDS or other investigational therapy for at least 28 days prior to study enrollment and recovered to less than grade 2 toxicity from prior therapy.
  12. Subjects who are able to swallow tablets.
  13. Subject who are willing and able to comply with scheduled visits, treatment plans, laboratory tests and procedures.
  14. Female subjects of childbearing potential must have a negative serum pregnancy test within 7 days of the first administration of study drug. For the purpose of this study, female subjects of childbearing potential are defined as all female subjects after puberty unless they are postmenopausal for at least 1 year, or are surgically sterile (hysterectomy or bilateral oophorectomy or tubal ligation).
  15. Female subjects of child bearing potential who are willing to avoid the pregnancy during the duration of the study and for 30 days following the last dose of study drug. The effects of TEW-7197 on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
  16. Subjects with QTc interval calculated according to Fridericia's formula (QTcF = QT/RR0.33; RR = RR interval) of ≤ 470 ms for males and 450 ms for females on screening electrocardiogram (ECG).
  17. Subjects must have ejection fraction more than 50% and no clinically significant valvular dysfunction.
  18. Subjects must have discontinued radiotherapy at least 14 days with resolution of any toxicity to Grade 1 or better prior to the start of treatment.

Exclusion Criteria:

Subjects will be excluded from the study if they meet any of the following criteria:

  1. Subjects who have received treatment within the last 28 days with a drug that has not received regulatory approval for any indication at the time of study entry.
  2. Subjects who have moderate or severe cardiac disease:
  3. Subjects who have the presence of cardiac disease, including a myocardial infarction within 6 months prior to study entry, unstable angina pectoris, New York Heart Association (NYHA) Class III/IV congestive heart failure, or uncontrolled hypertension.
  4. Subjects who have documented major electrocardiogram (ECG) abnormalities at the investigator's discretion (for example, symptomatic or sustained atrial or ventricular arrhythmias, second- or third-degree atrioventricular block, bundle branch blocks, ventricular hypertrophy, or recent myocardial infarction).
  5. Subjects who have major abnormalities documented by echocardiography with Doppler (for example, moderate or severe heart valve function defect and/or left ventricular ejection fraction (LVEF) <50%, evaluation based on the institutional lower limit of normal).
  6. Subjects who have predisposing conditions that are consistent with development of aneurysms of the ascending aorta or aortic stress (for example, family history of aneurysms, Marfan-Syndrome, bicuspid aortic valve, evidence of damage to the large vessels of the heart documented by CT scan with contrast).
  7. Subjects who have documented iron, B12, folate deficiency as determined by the investigator.
  8. Female subjects who are breastfeeding, or intend to breastfeed during the duration of the study and for 30 days following the last dose of study drug.
  9. Subjects with any other serious medical condition which in the Investigator's opinion would preclude safe participation in the study.
  10. Subjects, in the opinion of the Investigator, who are unsuitable to participate in the study.
  11. Subjects with elevated Troponin 1 levels at screening or known to have persistently elevated brain natriuretic peptide (BNP).
  12. Subjects with serious pre-existing medical conditions as follows:

    • History of cardiac or aortic surgery,
    • Hypertension that is not controlled by standard medication (to 150/90 mmHg or below),
    • Cirrhosis of the liver, Child-Pugh Stage B or C, or history of liver transplant,
    • Severe diabetes that is not currently controlled,
    • Current or history of interstitial pneumonitis,
    • Presence of aneurisms of the ascending aorta or aortic stress.
  13. Subjects with known history of difficulty swallowing, malabsorption or other conditions that may reduce absorption of the product.
  14. Subjects with major abnormalities identified by ECG or echocardiogram (ECHO), at the Investigator's discretion.
  15. Subjects with active infection with human immunodeficiency virus, hepatitis B virus or hepatitis C virus.
  16. Subjects with active infection requiring systemic antibiotic therapy.
  17. Subjects who are currently using or planning to use:

Drugs which are exclusively or primarily eliminated by cytochrome P-450 isozyme 3A4


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): NCT03074006


Contacts
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Contact: Hugh Lee 3015402600 hughlee@kcrnresearch.com
Contact: Christine Lee 3015402600 christinelee@kcrnresearch.com

Locations
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United States, Florida
Site 03 Not yet recruiting
Tampa, Florida, United States, 33612
United States, Maryland
Site 02 Recruiting
Baltimore, Maryland, United States, 21201
United States, New York
Site 01 Recruiting
Bronx, New York, United States, 10461
Sponsors and Collaborators
MedPacto, Inc.

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Responsible Party: MedPacto, Inc.
ClinicalTrials.gov Identifier: NCT03074006     History of Changes
Other Study ID Numbers: MP-MDS-01
First Posted: March 8, 2017    Key Record Dates
Last Update Posted: March 6, 2019
Last Verified: March 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Syndrome
Myelodysplastic Syndromes
Preleukemia
Disease
Pathologic Processes
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Neoplasms