| Eligibility |
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
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