Clinical Trials /

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

NCT03074006

Description:

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).

Related Conditions:
  • Myelodysplastic Syndromes
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Dose Escalation and Proof-of-Concept Studies of Vactosertib (TEW-7197) Monotherapy in Patients With MDS
  • Official Title: Phase 1/2 Study of Vactosertib (TEW-7197) Monotherapy in Patients With Low or Intermediate Myelodysplastic Syndromes

Clinical Trial IDs

  • ORG STUDY ID: MP-MDS-01
  • NCT ID: NCT03074006

Conditions

  • Myelodysplastic Syndromes

Interventions

DrugSynonymsArms
TEW-7197low dose

Purpose

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).

Trial Arms

NameTypeDescriptionInterventions
low doseExperimental
  • TEW-7197
high doseExperimental
  • TEW-7197

Eligibility 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose (MTD) for dose escalation phase
Time Frame:4 weeks
Safety Issue:
Description:To define the MTD and determine RP2D

Secondary Outcome Measures

Measure:Hematologic Improvement (HI)
Time Frame:At 2, 4, 8, 12 and 16 weeks of treatment
Safety Issue:
Description:To evaluate the duration of HI
Measure:Red blood cell transfusion independency
Time Frame:At 2, 4, 8, 12 and 16 weeks of treatment
Safety Issue:
Description:To evaluate rate and duration of Red blood cell transfusion independency
Measure:Bone marrow response and cytogenetic response
Time Frame:At 2, 4, 8, 12 and 16 weeks of treatment
Safety Issue:
Description:To evaluate the frequency of bone marrow response (CP+PR) and cytogenetic response
Measure:Time to progression
Time Frame:At 2, 4, 8, 12 and 16 weeks of treatment
Safety Issue:
Description:Time to progression to higher risk or acute myeloid leukemia
Measure:Relationship between mutations and response
Time Frame:At 2, 4, 8, 12 and 16 weeks of treatment
Safety Issue:
Description:To evaluate the relationship between mutations and response
Measure:Relationship between various stem and progenitor alterations and response
Time Frame:At 2, 4, 8, 12 and 16 weeks of treatment
Safety Issue:
Description:To evaluate the relation ship between various stem and progenitor alterations and response
Measure:Quality of life with MDS
Time Frame:At 4, 8, 12 and 16 weeks of treatment
Safety Issue:
Description:To evaluate the quality of life parameters experienced by patients with MDS
Measure:Biomarker
Time Frame:At 4, 8, 12 and 16 weeks of treatment
Safety Issue:
Description:Determine pharmacodynamic markers in bone marrow

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:MedPacto, Inc.

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