Safety and Pharmacokinetics Study of SyB C-1101 in Patients With Recurrent/Relapsed or Refractory Myelodysplastic Syndrome (MDS)
Condition: Myelodysplastic Syndrome
MeSH terms: Preleukemia; Myelodysplastic Syndromes; Syndrome
Intervention: SyB C-1101
Intervention description: SyB C-1101（rigosertib sodium） will be administered to two cohorts at either 280 mg/day or 560 mg/day.
The dose will be administered orally twice daily for 14 consecutive days, followed by 7-day observation period. The treatment period of 21 days (14 days of administration + 7 days of observation) constitutes 1 cycle.
The study will involve treatment through the second cycle, but treatment can be continued for 3 or more cycles if conditions for continued administration are satisfied. However, treatment will be limited to a maximum of 6 cycles including the first cycle.
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 10.0
Sex: All
Minimum age: 20 Years
Healthy volunteers: No

Summary:

      The purpose of this study is to investigate tolerability when SyB C-1101 is orally
      administered twice daily for 14 consecutive days to the patients with recurrent/relapsed or
      refractory myelodysplastic syndrome, to determine the dose-limiting toxicity and maximum
      tolerated dose, and to estimate the recommended dose for phase II studies. Pharmacokinetics
      and antitumor effects will also be investigated.
    

Eligibility criteria:

        Inclusion Criteria:

        Patients must satisfy the following conditions listed below:

          1. Patients who have been histologically documented or cytologically confirmed with
             myelodysplastic syndrome (MDS), and who have been found to meet any of the following
             criteria on the basis of the World Health Organization (WHO) classification or the
             French-American-British (FAB) classification.

               -  Refractory Anemia (RA)* (< 5% myeloblasts, < 15% ringed sideroblasts)

               -  RA with Ring Sideroblasts (RARS)* (< 5% myeloblasts, >= 15% ringed sideroblasts)

               -  RA with Excess of Blasts-1(RAEB-1)(5% to 9% myeloblasts)

               -  RAEB-2 (10% to 19% myeloblasts)

               -  RAEB-t (20% to 29% myeloblasts or < 25,000/mm^3 peripheral leukocytes)

               -  Chronic myelomonocytic leukemia (CMML) (10% to 19% myeloblasts, >= 1,000/mm^3
                  peripheral monocytes, < 13,000/mm^3 leukocytes) * RA and RARS patients should
                  have 2 or more units of erythrocyte transfusion within 8 weeks.

          2. Patients with a low value in at least one blood cell lineage (having at least one of
             the following cytopenias).

               -  Neutrophils : < 1,800/mm^3

               -  Platelets : < 100,000/mm^3

               -  Hemoglobin : < 10 g/dL

          3. Patients with a previous history of chemotherapy (including immunosuppressive therapy,
             anabolic steroid and lenalidomide) for the target disease who meet any of the
             following criteria.

               -  Patients who have not achieved complete remission, partial remission, or
                  hematologic improvement.*

               -  Patients with recurrence/relapse after complete remission, partial remission, or
                  hematologic improvement.*

               -  Patients with intolerability that has led to discontinuation of treatment because
                  of the development of liver dysfunction, kidney dysfunction, etc., after the
                  start of treatment. *Proximate therapeutic efficacy judged under International
                  Working Group (IWG) 2006 criteria.

          4. For the patients who have received chemotherapy such as immunosuppressive therapy,
             anabolic steroid and lenalidomide, the patients should have not been treated for four
             weeks or longer after the end of the previous therapy and be judged to have no
             residual effects (antitumor effects) from the previous therapy.

          5. Patients who can be expected to survive at least three months or longer.

          6. Patients at least 20 years old (when informed consent is obtained).

          7. Patients who have score of 0 to 2 in The Eastern Cooperative Oncology Group (ECOG)
             Performance Status (PS).

          8. Patients with adequate function in major organs (heart, lungs, liver, kidneys, etc.).

               -  Aspartate aminotransferase (AST) : no greater than 3.0 times the upper boundary
                  of the reference range at each institution

               -  Alanine aminotransferase (ALT) : no greater than 3.0 times the upper boundary of
                  the reference range at each institution

               -  Total bilirubin: no more than 1.5 times the upper boundary of the reference range
                  at each institution

               -  Serum creatinine: no more than 1.5 times the upper boundary of the reference
                  range at each institution

               -  ECG: no abnormal findings requiring treatment

               -  Echocardiography: no abnormal findings requiring treatment

          9. Patients who personally signed an informed consent document for participation in this
             study.

        Exclusion Criteria:

        Patients who satisfy any of the following conditions will not be enrolled in the study.

          1. Patients with anemia caused by factors other than MDS (hemolytic anemia,
             gastrointestinal (GI) bleeding, etc.)

          2. Patients with hypoplasia MDS (< 10% osteocyte density)

          3. Patients who have undergone treatment for an active malignant tumor within the past
             year (except basal cell or squamous cell skin cancer, or primary squamous cell
             carcinoma of the cervix or noninvasive breast cancer).

          4. Patients who have been administered a cytokine preparation such as G-CSF
             (granulocyte-colony stimulating factor), erythropoietin, etc. within 14 days of tests
             for enrollment of the study.

          5. Patients with obvious infectious diseases (including viral infections).

          6. Patients with serious complications (liver failure, renal failure, etc.).

          7. Patients with a complication or previous history of serious heart disease (myocardial
             infarction, ischemic heart disease, etc.) within the past two years before enrollment,
             and with cardiac arrhythmia requiring treatment.

          8. Patients with a serious gastrointestinal condition (severe or significant
             nausea/vomiting, diarrhea, etc.)

          9. Patients who are positive for the Hepatitis B surface (HBs) antigen or HIV antibodies.

         10. Patients with serious bleeding tendencies (disseminated intravascular coagulation
             (DIC), internal hemorrhage, etc.).

         11. Ascites or pleural fluid requiring active medical management including paracentesis,
             or hyponatremia (defined as serum sodium value of < 130 mEq/L).

         12. Patients who have been administered a drug in a clinical trial or an unapproved drug
             within three months before enrollment.

         13. Patients who have previously treated with the test drug (rigosertib sodium).

         14. Patients with known allergy to polyethylene glycol or gelatin capsules.

         15. Patients with an addiction to a legal or illegal drug, or with alcohol dependency.

         16. Patients who are pregnant or may become pregnant, or lactating mothers.

         17. Patients who have not consented to the following contraceptive measures. Patients will
             avoid sexual intercourse with sexual partners or should use the following
             contraceptive methods in these time periods: for male patients during the
             administration period of the trial and for six months after the end of administration;
             female patients during the administration period of the trial, and until a second
             menstrual period is confirmed after the end of administration (or in the case of
             female patients with no menstrual period, for two months after the end of
             administration).

               -  Male patients: Patients will always use a condom. For effective contraception, it
                  is recommended that the female partner also use the contraceptive methods for
                  female patients.

               -  Female patients: Female patients who may become pregnant should use one or more
                  types of the following contraceptive methods. In addition, the male partner will
                  always use a condom. Oral contraceptive (birth control pills) , Intrauterine
                  device (IUD) , Tubal ligation

         18. Other patients judged to be unsuitable by an investigator or sub-investigators.