Non-hodgkin's Lymphoma
Conditions
Brief summary
The purpose of this dose-escalation study is to assess the safety and tolerability of treatment with Chiauranib and Chidamide administered orally over a range of doses in patients with relapsed or refractory non-Hodgkin's lymphoma, in the meantime, exploring the pharmacodynamic profile and latent biomarkers accompany with Chiauranib and Chidamide , as well as the relevancy of which and clinical benefit.
Detailed description
The purpose of this study is to assess the tolerability and safety include adverse events, vital signs, laboratory tests ,etc., of a range of doses of Chiauranib and Chidamide in patients with relapsed or refractory non-Hodgkin's lymphoma, and to determine the dose limit toxicity and the maximum tolerable dose. In the meantime, exploring the pharmacodynamic profile and latent biomarkers accompany with Chiauranib and Chidamide , as well as the relevancy of which and clinical benefit.
Interventions
DRUGChiauranib
In the lead-in period, patients take 50mg Chiauranib capsules on the forth day . In the subsequent treatment cycles, Chiauranib capsules are given orally once daily, 28 days as a cycle.
DRUGChidamide
In the lead-in period, patients take a single dose of Chidamide tablet on the first day and then off for 3 days before the first cycle begins. In the subsequent treatment cycles, Chidamide tablets are given orally on Day 1,4,8,11,15,18,22 and 25 of each cycle. 28 days as a cycle
Sponsors
Chipscreen Biosciences, Ltd.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Male or Female, aged ≥ 18 yrs and ≤70 yrs; 2. Patients with NHL refractory to at least 2 different chemotherapies , for which no standard therapy exists; 3. At least 1 lesion can be accurately measured, as defined by Lugano 2014 criteria. 4. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1; 5. Subjects received anti-cancer therapy (including chemotherapy, radiotherapy, immunotherapy and surgical therapy, et al) should beyond 4 weeks prior to study entry; Subjects received mitomycin chemotherapy should beyond 6 weeks prior to study entry; Subjects received autologous stem cell transplantation should beyond 3 months prior to study entry; 6. Laboratory criteria are as follows: Complete blood count: hemoglobin (Hb) ≥90g/L ; absolute neutrophil count (ANC) ≥1.5×109/L ; platelets \>=90×109/L Biochemistry test: total bilirubin≦1.5×ULN; alanine aminotransferase(ALT) ,aspartate aminotransferase(AST)≦1.5×ULN; (ALT,AST≦5×ULN if liver involved) ;serum creatinine(cr)≦1.5×ULN; Coagulation test: International Normalized Ratio (INR) \< 1.5 7. Life expectancy of at least 3 months. 8. Willingness to sign a written informed consent document.
Exclusion criteria
1. Clinical evidence of central nervous system involvement 2. Patients with prior invasive malignancies with the exception of curatively-treated basal cell or squamous cell carcinoma of the skin or cervical carcinoma in situ, unless received curative treatment and with documented evidence of no recurrence in the past five years; 3. Previous treatment with HDAC inhibitors(include Chidamide) or aurora kinase(include Chiauranib) inhibitors; 4. Have uncontrolled or significant cardiovascular disease, including: 1. Congestive heart failure, unstable angina pectoris, myocardial infarction within 6 months prior to study entry; arrhythmia, or Left Ventricular Ejection Fraction (LVEF) \< 50% requiring treatment with agents during screening stage. 2. primary cardiomyopathy(dilated cardiomyopathy, hypertrophic cardiomyocyte, arrhythmogenic right ventricular cardiomyopathy, restrictive cardiomyopathy, et,al) 3. History of significant QT interval prolongation, or Corrected QT Interval (QTc) \> 450 ms prior to study entry 4. Symptomatic coronary heart disease requiring treatment with agents 5. Uncontrolled hypertension (\> 140/90 mmHg) by single agent; 5. Have active bleeding current thrombotic disease, patients with bleeding potential ,or receiving anticoagulation therapy; within 2 months prior to screening; 6. Proteinuria positive(≥1g/24h); 7. History of deep vein thrombosis or pulmonary embolism; 8. Have unsolved toxicities (\> grade 1) from prior anti-cancer therapy; 9. Have clinical significant gastrointestinal abnormality, e.g., unable to swallow, chronic diarrhea, ileus, that would impair the ingestion,transportation or absorption of oral agents, or patients undergone gastrectomy; 10. History of organ transplantation ，Allogeneic bone marrow transplantation or autologous stem cell transplantation; 11. High-risk surgery for vital organs within 6 weeks prior to screening or the investigators determined that other surgical wounds did not heal well; 12. Serologically positive for HIV, hepatitis B or C, or other serious infectious diseases; 13. History of interstitial lung disease(ILD); 14. Any mental or cognitive disorder, that would impair the ability to understand the informed consent document or the operation and compliance of study; 15. Candidate with drug and alcohol abuse; 16. Participants of reproductive potential not willing to use adequate contraceptive measures for the duration of the study (both male and female participants).Pregnant or breastfeeding women. Female participants must have a negative urinary or serum pregnancy test when done or have evidence of post-menopausal status (Defined as absence of menstruation for greater than 12 months, bilateral oophorectomy or hysterectomy); 17. Any other condition which is inappropriate for the study in the opinion of the investigators.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| dose-limiting toxicity (DLT) | Day 1 - 28 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Peak plasma concentration (Cmax) | Day 1 of the lead-in period and Day 1 of the combination therapy | pharmacokinetic profile of Chiauranib in combination with Chidamide |
| Time of Cmax (Tmax) | Day 1 of the lead-in period and Day 1 of the combination therapy | pharmacokinetic profile of Chiauranib in combination with Chidamide |
| Objective response rate | About 21 weeks | — |
| complete response rate | About 21 weeks | — |
| disease control rate | About 21 weeks | — |
| Area under the concentration versus time curve (AUC) | Day 1 of the lead-in period and Day 1 of the combination therapy | pharmacokinetic profile of Chiauranib in combination with Chidamide |
| Progression free survival | About 21 weeks | From date of treatment until the date of first documented progression or date of death from any cause, whichever came first |
| Duration of response | About 21 weeks | From the first date of response until the date of first documented progression |
| Adverse events | About 21 weeks | Number of participants with treatment-related adverse events according to CTCAE V4.03 |
| Any single mutation of oncogene and copy number variation in ctDNA(single gene analysis) | day -1 of therapy | — |
| Mutation of polygene and copy number variation in signal pathway(multi-gene analysis) | day -1 of therapy | — |
| time to progression | About 21 weeks | duration from date of treatment until the date of first documented progression |
Countries
China
Outcome results
None listed