Chiauranib in Combination With Chidamide in Patients With Relapsed/Refractory Non-Hodgkin's Lymphoma

Phase Ib/IIa Study of Chiauranib in Combination With Chidamide in Patients With Relapsed/Refractory Non-Hodgkin's Lymphoma

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.

Study Overview

• Status: Completed
• Conditions: Non-hodgkin's Lymphoma
• Intervention / Treatment: Drug: Chiauranib; Drug: Chidamide

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.

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China
      • Beijing Cancer Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: treatment group; In this arm, patients would be given the regimen composed of Chiauranib and Chidamide orally. Intervention: Drug: Chiauranib and Chidamide

Drug: Chiauranib; 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.; Other Names: CS2164; Drug: Chidamide; 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; Other Names: CS055

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
dose-limiting toxicity (DLT)	Day 1 - 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
complete response rate		About 21 weeks
Objective response rate		About 21 weeks
Area under the concentration versus time curve (AUC)	pharmacokinetic profile of Chiauranib in combination with Chidamide	Day 1 of the lead-in period and Day 1 of the combination therapy
Peak plasma concentration (Cmax)	pharmacokinetic profile of Chiauranib in combination with Chidamide	Day 1 of the lead-in period and Day 1 of the combination therapy
Time of Cmax (Tmax)	pharmacokinetic profile of Chiauranib in combination with Chidamide	Day 1 of the lead-in period and Day 1 of the combination therapy
disease control rate		About 21 weeks
time to progression	duration from date of treatment until the date of first documented progression	About 21 weeks
Progression free survival	From date of treatment until the date of first documented progression or date of death from any cause, whichever came first	About 21 weeks
Duration of response	From the first date of response until the date of first documented progression	About 21 weeks
Adverse events	Number of participants with treatment-related adverse events according to CTCAE V4.03	About 21 weeks
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

Collaborators and Investigators

• Sponsor: Chipscreen Biosciences, Ltd.

Study record dates

Study Major Dates

• Study Start (ACTUAL): July 11, 2019
• Primary Completion (ACTUAL): December 31, 2021
• Study Completion (ACTUAL): December 31, 2021

Study Registration Dates

• First Submitted: May 30, 2019
• First Submitted That Met QC Criteria: June 3, 2019
• First Posted (ACTUAL): June 4, 2019

Study Record Updates

• Last Update Posted (ACTUAL): March 9, 2022
• Last Update Submitted That Met QC Criteria: March 7, 2022
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma; Lymphoma, Non-Hodgkin; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Chiauranib
• Other Study ID Numbers: CAR106

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No