Study of Clinical Efficacy and Safety of Tosedostat in MDS
Condition: Myelodysplastic Syndrome
MeSH terms: Preleukemia; Myelodysplastic Syndromes; Syndrome
Intervention: Tosedostat
Intervention description: 120 mg PO once daily continuously for each 28 day treatment cycle
Intervention MeSH terms: Tosedostat
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 12.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: MDS

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.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Able to understand and to provide written informed consent

          2. 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

          3. 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

          4. 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.

          5. Has failed to respond to, relapsed following, not eligible, or opted not to
             participate in BM transplantation

          6. 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

          7. 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

          8. Eastern Cooperative Oncology Group (ECOG) performance status of 0-3

          9. 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

         10. Must have acceptable recovery from clinically significant non-hematologic toxicity
             after prior therapy.

         11. Must have a life expectancy of at least 2 months

         12. Screening left ventricular ejection fraction (LVEF) greater than 50% as documented by
             transthoracic echocardiogram (TTE)

         13. 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.

         14. Able to comply with all study procedures during the study including all visits and
             tests

         15. Willing to adhere to the prohibitions and restrictions specified in this protocol

         16. 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:

          1. Presence of AML (≥20% blasts in bone marrow, peripheral blood, or both)

          2. 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.

          3. Have known active central nervous system disease or active, uncontrolled, clinically
             significant infection(s)

          4. 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

          5. Are receiving any other investigational therapy or protocol-prohibited therapy

          6. Have received previous treatment with tosedostat

          7. Pregnant or breastfeeding females

          8. 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

          9. Psychiatric disorders or altered mental status precluding understanding of the
             informed consent process and/or completion of the necessary study procedures

         10. 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.

         11. LVEF ≤ 50%

         12. Baseline troponin I and b-type natriuretic peptide > Grade I

         13. Prior exposure cardiotoxic agent, such as anthracycline, within 3 months of enrollment

         14. 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.

         15. Gastrointestinal disorders that may interfere with absorption of drug

         16. Active serious infection or sepsis

         17. Clinically significant interstitial lung disease