Differences Between Chidamide Taken Daily and Twice a Week in Therapeutic Effect，Pharmacokinetics, Pharmacodynamics and EB Virus Activation

Phase 2

• Conditions: Lymphoma, Extranodal NK-T-Cell; EBV
• Interventions: Drug: Chidamide BIW; Drug: Chidamide QD

• Registration Number: NCT02878278
• Lead Sponsor: Huiqiang Huang

Brief Summary

1. To compare the therapeutic effects, safety and the corresponding pharmacokinetics and pharmacodynamics between two different method of drug administration: 10mg, daily and 30mg/d, twice every week, and find out the more effect way of Chidamide administration.

2. To examine whether Chidamide could activate EB virus, and whether the above two different ways of administration are different in EB virus activation.

Detailed Description

Currently, Chidamide is taken twice a week, this comes from cell experiment and phase I clinical trial, which showed that the de-acetylation effect of Chidamide could last for 72 hours after administration. However, daily administration of Chidamide may create a more steady Chidamide concentration, thus improve the de-acetylation effect of Chidamide, so it's necessary to compare the two different ways of administration.

Current study showed that Romidepsin, a HDACI, could activate EBV during the treatment of NKTCL, whether Chidamide, as a novel HDACI, could activate EBV is still not clear, so this problem is worth to be accessed.

Study Timeline

• Status Verified: 2016-08
• Study First Submitted: 2016-08-20
• Study First Submitted QC: 2016-08-22
• Last Update Submitted: 2016-08-22
• Study First Posted: 2016-08-25
• Last Update Posted: 2016-08-25
• Study Start: 2016-09
• Primary Completion: 2019-03
• Study Completion: 2019-09

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 24

Inclusion Criteria

1. NKTCL patients confirmed by histopathology examination.
2. Age 18-75 years old, male or female, fertile women should have effective contraceptive measures.
3. NT/T cell lymphoma patients with disease progression or non-remission after L-asparaginase treatment or L-asparaginase-contained regimen treatment. Non-remission is defined as: patients do not have partial remission (PR) or better responses after treated by L-asparaginase contained regimen.
4. Patients who had 1-3 regimens (including chemotherapy, stem cell transplantation), but did not achieve remission or relapsed after remission.
5. With at least 1 measurable focus, whose long diameter ˃ 1.5cm, short diameter ˃1.0cm, or at least one evaluable focus.
6. Body weight: male 67±20 kilograms (47-87 kg), female 55±20 kilograms (35-75 kg);
7. Blood-routine test within 14 days of enrollment should satisfy (except lymphoma-related abnormalities): Hb≥80g/L，ANC≥1.0×109/L，PLT≥75×109/L；
8. ECOG: 0-2;
9. Estimated survival ≥ 3 months;
10. Willing to sign the written consent before the trial.

Exclusion Criteria

1. Women during pregnancy or lactation, or fertile women unwilling to take contraceptive measures.
2. QTc elongation with clinical significance ( male˃ 450ms, female˃ 470ms), ventricular tachycardia, atrial fibrillation, cardiac conducting blockage, myocardial infarction within 1 year, congestive heart failure, symptomatic coronary heart disease that requires treatment.
3. Cardiac B ultrasound show end-diastolic pericardial dark zone≥ 10cm
4. Patients who have received organ transplantation.
5. Patients received symptomatic treatment for bone marrow toxicity within 7 days prior to enrollment.
6. Patients with active hemorrhage.
7. Patients with or with history of thrombosis, embolism, cerebral hemorrhage, or cerebral infarction.
8. Patients with active infection, or with continuous fever within 14 days prior to enrollment.
9. Had major organ surgery within 6 weeks prior to enrollment.
10. Abnormal blood routine test results within 14 days prior to enrollment (Hb˂80g/L，ANC˂1.0×109/L，PLT˂75×109/L； Impaired liver function ( Total bilirubin ˃ 1.5 times of normal maximum, ALT/AST˃ 2.5 times of normal maximum, for patients with infiltrative liver disease ALT/AST ˃ 5 times of normal maximum), impaired renal function (serum creatinin˃ 1.5 times of normal maximum).
11. Patients with history of Chidamide treatment and had disease progression within 6 months afterward;
12. Patients that received large dose of steroids (˃10mg/d dexamethasone or other steroids of the equivalent dosage) within 4 weeks prior to enrollment;
13. Patients with hemophagocytic syndrome;
14. Patients with central nerve system diseases or history of central nerve system diseases;
15. Patients with mental disorders or those do not have the ability to consent;
16. Patients that had been enrolled in other clinical trials within 3 months prior to enrollment;
17. Patients with drug abuse, long term alcoholism that may impact the results of the trial.
18. Non-appropriate patients for the trial according to the judgment of the investigators.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Chidamide BIW	Chidamide BIW	Chidamide is given 30mg,5mg/pill,twice a week, for at least 6 weeks
Chidamide QD	Chidamide QD	Chidamide is given 10mg,5mg/pill, everyday,for at least 6 weeks.

Primary Outcome Measures

Name	Time	Method
Overall Response Rate (ORR)	through study completion, an average of 30 months
Duration of Response (DOR)	through study completion, an average of 30 months

Secondary Outcome Measures

Name	Time	Method
EBV-DNA	through study completion, an average of 30 months
fasting blood glucose level	every 3 weeks though study completion，from date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 30 months
blood electrolytes level（K+, Na+，Cl-，Ca2+，Mg2+）	every 3 weeks though study completion，from date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 30 months
blood LDH level	every 6 weeks though study completion，from date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 30 months
QTc from ECG	every 6 weeks though study completion，from date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 30 months
EBV-antibodies	through study completion, an average of 30 months
Progression Free Survival (PFS)	through study completion, an average of 30 months
Overall Survival (OS)	through study completion, an average of 30 months
white blood cell count	every week though study completion，from date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 30 months
red blood cell count	every week though study completion，from date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 30 months
blood platelet count	every week though study completion，from date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 30 months
vital signs	every week though study completion，from date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 30 months
Serum alanine aminotransferase level	every 3 weeks though study completion，from date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 30 months
Serum aspartate transaminase level	every 3 weeks though study completion，from date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 30 months
Serum total bilirubin level	every 3 weeks though study completion，from date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 30 months
Serum direct bilirubin level	every 3 weeks though study completion，from date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 30 months
Serum indirect bilirubin level	every 3 weeks though study completion，from date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 30 months
Serum glutamyltranspeptidase level	every 3 weeks though study completion，from date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 30 months
Serum albumin level	every 3 weeks though study completion，from date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 30 months
Serum ureal nitrogen level	every 3 weeks though study completion，from date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 30 months
blood Hb level	every week though study completion，from date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 30 months
Serum creatinin level	every 3 weeks though study completion，from date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 30 months