Phase 2b, open-label, non-randomized, single arm study to evaluate the safety, and efficacy of HBI-8000 40 mg BIW in patients with relapsed or refractory ATL (R/R ATL)

This is a Phase 2b, open-label, non-randomized, single arm study to evaluate the safety, and efficacy of HBI-8000 40 mg BIW in patients with relapsed or refractory ATL (R/R ATL). HBI 8000 will be administered orally approximately 30 minutes after any regular meal twice a week. There will be 3 to 4 days between dosing. A treatment cycle is defined as 28 consecutive days. HBI-8000 administration will be continued until disease progression or unacceptable toxicities are observed despite appropriate dose reduction or treatment interruption.

Inclusion Criteria:

1. Histopathological, or cytological diagnosis of ATL confirmed as seropositive for anti-Human T-lymphotrophic Virus type-I (HTLV-I) antibody

2. Acute, lymphoma or unfavorable chronic types. The unfavorable chronic type is defined by the presence of at least 1 of the following: serum albumin <3.5 g/dL, lactic dehydrogenase (LDH) >300 U/L, or blood urea nitrogen (BUN) >25 mg/dL. The patient must have at least 1 of measurable lesion, or evaluable lesion in either of peripheral blood or skin

3. Relapsed or refractory disease after receiving prior systemic therapy with mogamulizumab, or ≥1 prior systemic therapy with cytotoxic chemotherapy in case of intolerance/contraindication for mogamulizumab. And there is no other standard treatment which can be considered appropriate for patients

4. Male or female, aged 20 years or older

5. ECOG Performance Status of 0-2

6. Life expectancy of greater than 3 months

7. Meeting the following baseline laboratory criteria for screening:

   • Absolute Neutrophil Count >1500/µL independent of growth factor support within 7 days
   • Platelets >75,000/µL independent of transfusion within 14 days
   • Hgb >8 g/dL independent of transfusion within 14 days
   • Serum creatinine < 1.5 X upper limit of normal (ULN)
   • Serum aspartate aminotransferase/glutamyl oxaloacetic transaminase (AST/SGOT) and alanine aminotransferase/glutamyl pyruvic transaminase (ALT/SGPT) less than or equal to 3 X ULN
   • Serum Bilirubin less than or equal to 1.5 X ULN

8. Negative serum pregnancy test for females of childbearing (reproductive) potential. Female patients of child bearing potential must use an effective method of birth control (e.g., hormonal contraceptive, intrauterine device, diaphragm with spermicide or condom with spermicide) during treatment period and 1 month thereafter; Males must use an effective method of birth control (2 barrier methods) during treatment period and 3 months thereafter.

   Note: Female patients will be considered to be women of childbearing potential unless having undergone permanent contraception or postmenopausal. Postmenopausal is defined as at least 12 months without menses with no other medical reasons (e.g., chemical menopause because of treatment with anti-malignant tumor agents).

9. Signed informed consent

Exclusion Criteria:

2.5.2 Exclusion Criteria:

1. Patients in whom central nervous system lymphoma is recognized during screening (if suspected clinically, imaging study should be performed to confirm)

2. Male patients with QTcF > 450 msec at screening, female patients with QTcF > 470 msec at screening, or patients with congenital long QT syndrome, clinically significant arrhythmia, history of congestive heart failure (New York Heart Association Class III or IV) or acute myocardial infarction within 6 months of starting the study drug at screening.

3. Patients with known hypersensitivity to benzamide class of compounds or any of the components of HBI-8000 tablets, and patients with prior exposure of HBI-8000;

4. Patients with a history of second malignancy other than disease under study. The exceptions are disease (excluding disease listed below) that has been treated with curative intent with no evidence of recurrence in past 5 years. Furthermore, if the second malignancy is one of the following diseases that were treated with curative intent, it is only required that there is no evidence of recurrence in past 2 years;

   • Basal cell carcinoma of the skin
   • Squamous cell carcinoma of the skin
   • Cervical carcinoma in situ
   • Carcinoma in situ of the breast
   • An incidental histological finding of prostate carcinoma (TNM stage T1a or T1b)
   • Early-stage gastric cancer treated with endoscopic mucosal resection or endoscopic submucosal dissection

5. Autologous stem cell transplantation within 12 weeks (84 days) of starting the study drug

6. History of allogeneic stem cell transplantation

7. Organ transplantation recipients except autologous hematopoietic stem cell transplantation

8. Uncontrolled inter-current infection

9. Hepatitis B surface antigen-positive, or hepatitis C virus antibody positive. In case hepatitis B core antibody and/or hepatitis B surface antibody is positive even if hepatitis B surface antigen negative, a hepatitis B virus DNA test (real-time PCR measurement) should be performed and if positive, the patient should be excluded from study

10. Any history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)

11. Uncontrolled diabetes mellitus, hypertension, endocrine disorder, bleeding disorder

12. Major surgery or radiation therapy within 28 days of starting the study drug

13. Receiving investigational agents or anti-cancer therapy within 28 days, nitrosourea or mitomycin C within 42 days, of starting the study drug

14. Receiving antibody therapy for ATL within 4 weeks of starting the study drug

15. Women who are breastfeeding or women who are not willing to stop breastfeeding during study treatment period and for 30 days after the last dose of study drug

16. Potential for non-compliance or at increased risk based on investigator's judgement