Metastatic Colorectal Cancer
Conditions
Keywords
Metastatic Colorectal Cancer
Brief summary
This study is designed as an open-label, dose-escalation manner to determine the MFD of chidamide in combination with celecoxib in patients with advanced mCRC.
Detailed description
This is a monocentric, open-label, non-randomized dose feasibility study trial to characterize the safety, tolerability, pharmacokinetics, and preliminary efficacy of chidamide in combination with celecoxib in patients with advanced mCRC. Each cohort will have up to 6 subjects. Eligible patients will be assigned to 1 of up to 2 sequential cohorts. The planned dose levels of the two cohorts include (1) 20 mg chidamide plus 200 mg celecoxib; and (2) 30 mg chidamide plus 200 mg celecoxib. For each subject, the treatment period is divided into two periods, a run-in period and a combination therapy period.
Interventions
DRUGchidamide
During the run-in period, the patients will take a single dose of chidamide on Day 3. In a 28-day treatment cycle, the dosing schedule is four/six table (20/30mg) BIW .
DRUGcelecoxib
During the run-in period, the patients will take a single dose of celecoxib on Day 1. In a treatment cycle, the dosing schedule is one capsule(200 mg) daily.
Sponsors
Taipei Medical University Shuang Ho Hospital
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Cohort1: Chidamide(20mg)+Celecoxib(200mg); Cohort2: Chidamide(30mg)+Celecoxib(200mg)
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. The patient is 20-year-old or older on the day that consent is provided. 2. With histologically or cytologically proven metastatic colorectal adenocarcinoma. 3. Have measurable lesions according to RECIST v1.1. 4. Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 to 2. 5. Adequate organ function as defined below: i. White blood cells (WBC) ≥3,000/μL ii. Absolute neutrophil count ≥1,500/μL iii. Platelets ≥1 x 105/μL iv. Hemoglobin ≥9.0 g/dL v. Total bilirubin ≤1.5 x the upper limit of normal (ULN) vi. AST(SGOT)/ALT(SGPT) ≤3 x ULN (or ≤5 x ULN if liver metastases are present) vii. Serum creatinine ≤1.5 x ULN 6. Patients who had received or were intolerant of at least 2 front-line systemic treatments. In addition, patients have failed or refused all available standard treatment, or were intolerant of such treatments. For K-ras wild type tumor, anti-EGFR therapy must have been done. For K-ras mutant tumor, antiangiogenic therapy must have been done. 7. Able to take oral medication. 8. With a life expectancy of at least 3 months. 9. Female patients of childbearing potential must have a negative urine or serum pregnancy test. 10. Patients in reproductive age must be willing to use adequate contraception (refer to Section 8.4.2 of the protocol for adequate contraception methods) during the study and 3 months after the end of the study. 11. Ability to understand and the willingness to provide a written informed consent document.
Exclusion criteria
(I) Inclusion criteria: 1. The patient is 20-year-old or older on the day that consent is provided. 2. With histologically or cytologically proven metastatic colorectal adenocarcinoma. 3. Have measurable lesions according to RECIST v1.1. 4. Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 to 2. 5. Adequate organ function as defined below: i. White blood cells (WBC) ≥3,000/μL ii. Absolute neutrophil count ≥1,500/μL iii. Platelets ≥1 x 105/μL iv. Hemoglobin ≥9.0 g/dL v. Total bilirubin ≤1.5 x the upper limit of normal (ULN) vi. AST(SGOT)/ALT(SGPT) ≤3 x ULN (or ≤5 x ULN if liver metastases are present) vii. Serum creatinine ≤1.5 x ULN 6. Patients who had received or were intolerant of at least 2 front-line systemic treatments. In addition, patients have failed or refused all available standard treatment, or were intolerant of such treatments. For K-ras wild type tumor, anti-EGFR therapy must have been done. For K-ras mutant tumor, antiangiogenic therapy must have been done. 7. Able to take oral medication. 8. With a life expectancy of at least 3 months. 9. Female patients of childbearing potential must have a negative urine or serum pregnancy test. 10. Patients in reproductive age must be willing to use adequate contraception (refer to Section 8.4.2 of the protocol for adequate contraception methods) during the study and 3 months after the end of the study. 11. Ability to understand and the willingness to provide a written informed consent document. (II)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics profiles-(DF) | Run-in period, on day1, blood sample will be 0, 1, 2, 6, 12, and 24 hours; on day3, blood sample will be 0, 1, 2, 6, 12, 24, 48, and 72 hours.Combination therapy period, on day1 & day25, blood sample will be 0, 1, 2, 6, 12, 24, 48 and 72 hours. | Degree of fluctuation(DF) |
| Pharmacokinetics profiles-(Cmax,ss) | Run-in period, on day1, blood sample will be 0, 1, 2, 6, 12, and 24 hours; on day3, blood sample will be 0, 1, 2, 6, 12, 24, 48, and 72 hours.Combination therapy period, on day1 & day25, blood sample will be 0, 1, 2, 6, 12, 24, 48 and 72 hours. | Maximum (peak) plasma concentration at steady state(Cmax,ss) |
| Pharmacokinetics profiles-(Tmax,ss) | Run-in period, on day1, blood sample will be 0, 1, 2, 6, 12, and 24 hours; on day3, blood sample will be 0, 1, 2, 6, 12, 24, 48, and 72 hours.Combination therapy period, on day1 & day25, blood sample will be 0, 1, 2, 6, 12, 24, 48 and 72 hours. | Time to maximum plasma concentration at steady state(Tmax,ss) |
| Maximum Feasible Dose (MFD) | defined as the highest dose for which ≤1 of 6 evaluable subjects experiencing DLT during the first treatment cycle (28 days) of the combination therapy, assessed up to 24 months | Maximum Feasible Dose (MFD): is defined as the highest dose for which ≤1 of 6 evaluable subjects experiencing DLT during the first treatment cycle (28 days) of the combination therapy. If the dose of Cohort 1 is not tolerable by ≥2 evaluable subjects, the MFD will be considered as not determined. |
| Pharmacokinetics profiles-(AUC0-t) | Run-in period, on day1, blood sample will be 0, 1, 2, 6, 12, and 24 hours; on day3, blood sample will be 0, 1, 2, 6, 12, 24, 48, and 72 hours.Combination therapy period, on day1 & day25, blood sample will be 0, 1, 2, 6, 12, 24, 48 and 72 hours. | Area under the plasma concentration-time curve from time zero to time t(AUC0-t) |
| Pharmacokinetics profiles-(AUC0-∞) | Run-in period, on day1, blood sample will be 0, 1, 2, 6, 12, and 24 hours; on day3, blood sample will be 0, 1, 2, 6, 12, 24, 48, and 72 hours.Combination therapy period, on day1 & day25, blood sample will be 0, 1, 2, 6, 12, 24, 48 and 72 hours. | Area under the plasma concentration-time curve from time zero to infinity(AUC0-∞) |
| Pharmacokinetics profiles-(Cmax) | Run-in period, on day1, blood sample will be 0, 1, 2, 6, 12, and 24 hours; on day3, blood sample will be 0, 1, 2, 6, 12, 24, 48, and 72 hours.Combination therapy period, on day1 & day25, blood sample will be 0, 1, 2, 6, 12, 24, 48 and 72 hours. | Maximum plasma concentration(Cmax) |
| Pharmacokinetics profiles-(Tmax) | Run-in period, on day1, blood sample will be 0, 1, 2, 6, 12, and 24 hours; on day3, blood sample will be 0, 1, 2, 6, 12, 24, 48, and 72 hours.Combination therapy period, on day1 & day25, blood sample will be 0, 1, 2, 6, 12, 24, 48 and 72 hours. | Time to maximum plasma concentration(Tmax) |
| Pharmacokinetics profiles-(T1/2) | Run-in period, on day1, blood sample will be 0, 1, 2, 6, 12, and 24 hours; on day3, blood sample will be 0, 1, 2, 6, 12, 24, 48, and 72 hours.Combination therapy period, on day1 & day25, blood sample will be 0, 1, 2, 6, 12, 24, 48 and 72 hours. | Half-life(T1/2) |
| Pharmacokinetics profiles-(Kel) | Run-in period, on day1, blood sample will be 0, 1, 2, 6, 12, and 24 hours; on day3, blood sample will be 0, 1, 2, 6, 12, 24, 48, and 72 hours.Combination therapy period, on day1 & day25, blood sample will be 0, 1, 2, 6, 12, 24, 48 and 72 hours. | Elimination rate constant(Kel) |
| Pharmacokinetics profiles-(AUC0-τ,ss) | Run-in period, on day1, blood sample will be 0, 1, 2, 6, 12, and 24 hours; on day3, blood sample will be 0, 1, 2, 6, 12, 24, 48, and 72 hours.Combination therapy period, on day1 & day25, blood sample will be 0, 1, 2, 6, 12, 24, 48 and 72 hours. | Area under the plasma concentration-time curve from time zero to time τ (dosing interval) at steady state(AUC0-τ,ss) |
| Pharmacokinetics profiles-(Cave,ss) | Run-in period, on day1, blood sample will be 0, 1, 2, 6, 12, and 24 hours; on day3, blood sample will be 0, 1, 2, 6, 12, 24, 48, and 72 hours.Combination therapy period, on day1 & day25, blood sample will be 0, 1, 2, 6, 12, 24, 48 and 72 hours. | Average plasma concentration at steady state(Cave,ss) |
| Pharmacokinetics profiles-(Cmin,ss) | Run-in period, on day1, blood sample will be 0, 1, 2, 6, 12, and 24 hours; on day3, blood sample will be 0, 1, 2, 6, 12, 24, 48, and 72 hours.Combination therapy period, on day1 & day25, blood sample will be 0, 1, 2, 6, 12, 24, 48 and 72 hours. | Minimum (trough) plasma concentration at steady state(Cmin,ss) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective response | From enrollment until disease progression or unacceptable toxicity, assessed up to 24 months | ORR, defined as the percentage of patients with CR and PR of total number of analysis set |
| Progression-free survival | from the time of first day of dosing (Run-in period Day1) until the date of first objective disease progression or death, assessed up to 24 months | defined as the time from first day of dosing until the date of first objective disease progression or death. Patients who have not progressed or died at the time of analysis will be censored at the time of the latest date of tumor assessment |
Countries
Taiwan
Outcome results
None listed