Safety and Pharmacokinetics Study of SyB C-1101 in Patients With Recurrent/Relapsed or Refractory Myelodysplastic Syndrome (MDS)

Phase I Clinical Trial of SyB C-1101 in Patients With Myelodysplastic Syndrome

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.

In Cohort 1, SyB C-1101 280 mg/dose group, Participants will be administered 280 mg/dose of SyB C-1101 twice daily orally for 14 consecutive days, followed by 7-day observation period.

In Cohort 2, SyB C-1101 560 mg/dose group, Participants will be administered 560 mg/dose of SyB C-1101 twice daily orally for 14 consecutive days, followed by 7-day observation period.

In both Cohorts, the treatment period of 21 days constitutes 1 cycle, and the treatment was allowed for up to cycles. The participants received SyB C-1101 only once daily on Day 1 and Day 14 of Cycle 1 for the investigation of the pharmacokinetics.

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.