Colorectal Neoplasms, Raltitrexed, Regorafenib, Third-line Treatment
Conditions
Brief summary
This is a multicenter, open, single-arm, phase I/II study to evaluate the efficacy and safety of regorafenib plus raltitrexed as third-line treatment in patients with advanced colorectal cancer.
Detailed description
This is a multicenter, open, single-arm, phase I/II study to evaluate the efficacy and safety of regorafenib plus raltitrexed as third-line treatment in patients with advanced colorectal cancer.This Phase Ib/II study consists of two parts, Phase Ib, an open-ended, single-arm, multi-centre, dose-escalation study evaluating regorafenib, and Phase II, an open-label, multi-centre study evaluating the efficacy and safety of regorafenib in combination with raltitrexed.The primary study endpoint: progression-free survival (PFS).The secondary end endpoints include ORR (overall effectiveness of tumour treatment)，DCR (disease control rate)，3 month/6 month/9 month/12 month survival OS%，OS (overall survival)，incidence and severity of adverse events (AEs), serious adverse events (SAEs).
Interventions
DRUGRegorafenib
Regorafenib:120mg/d，Po，qd,d1-d21，Every 4 weeks
DRUGRaltitrexed
Raltitrexed:3mg/㎡，ivgtt，d1，Every 3 weeks
Sponsors
The People's Hospital of Liaoning Province
Anshan Tumor Hospital
The First Affiliated Hospital of Dalian Medical University
The Second Affiliated Hospital of Dalian Medical University
Benxi Cental Hospital
China Medical University, China
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Single Group Assignment
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Sign a consent form 2. Age\> 18 years 3. Pathological diagnosis as metastatic colorectal adenocarcinoma 4. Metastatic colorectal cancer with disease progression after 1st and 2nd line treatment；Received standard chemotherapy based on fluorouracil, oxaliplatin, irinotecan, patients are allowed to receive EGFR and/or VEGF inhibitors, patients are allowed to receive immunotherapy. 5. Measurable disease according to RECIST 6. ECOG score 0-1 points 7. Life expectancy ≥3 months 8. ALT and AST\< 2.5 times the upper limit of normal (ULN), patients with liver metastases \< 5 times ULN 9. Serum albumin ≥ 3.0g/ dL 10. Serum ALP \<2.5 times ULN 11. Total bilirubin \<l.5mg / dL 12. Estimated creatinine clearance (CLcr) ≥30mL/min as calculated using the Cockcroft-Gault equation 13. Lipase≤1.5x the ULN 14. Neutrophil absolute count (ANC) ≥1500/mm³, hemoglobin (Hb)\>9g/dl, platelets\> 10000/mm³ 15. Pregnant or breastfeeding patients. (1) Women and men of childbearing potential must agree to use appropriate contraception prior to entering the program until at least 8 weeks after the last dose of study drug. The investigator or designee is required to advise the subject on how to achieve appropriate contraception. Adequate contraception is defined in the study as any medically recommended method (or combination of methods) according to standard treatment 2) Women of childbearing age must confirm a negative serum or urine pregnancy test within 7 days prior to initiating treatment and must agree to record a negative result prior to entering the study
Exclusion criteria
. 1. Prior exposure to any VEGFR tyrosine kinase inhibitor (e.g., regorafenib, apatinib, anlotinib, furoquinitinib, etc.) therapy 2. Received raltitrexed in the previous treatment 3. Patients with abnormal coagulation function or those treated with thrombolytic or anticoagulant drugs with a tendency to bleed from the gastrointestinal tract, including active peptic ulcer with fecal occult blood ++, vomiting blood or black stool within 3 months 4. Prior or concurrent cancers with a different primary site or histology than CRC within the enrollment year, except cured in situ cervical cancer, non-melanoma skin cancer, and superficial bladder tumors: staged Ta, Tis, and T1 5. Arterial or venous thrombotic or embolic events such ascerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 6 month before the start of study medication (except for adequately treated catheter-related venous thrombos is occurring more than one month before the start of study medication) 6. Major surgery, biopsy or significant traumatic damage within 28 days prior to the start of investigational treatment 7. Non-healing wound, non-healing ulcer, or non-healing bone fracture. 8. Patients with brain metastases and/or cancerous meningitis 9. Congestive heart failure \> New York Heart Association (NYHA) class 2. 10. Unstable angina (angina symptoms at rest), new onset angina (occurred within the last 3 months). Myocardial infarction within 6 months prior to the start of treatment. 11. Arrhythmias requiring antiarrhythmic therapy (beta-blockers or digoxin allowed) 12. Uncontrolled hypertension. (Systolic blood pressure \> 150 mmHg or diastolic blood pressure \> 90 mmHg despite optimal medical treatment) 13. Patients with pheochromocytoma 14. Pleural effusion or ascites causing restricted breathing (≥ CTCAE grade 2 dyspnea) 15. Known to have dihydropyrimidine dehydrogenase deficiency 16. Ongoing infection \> Grade 2 NCI CTCAE 17. Interstitial lung disease with ongoing signs and symptoms at the time of informed consent 18. Known hypersensitivity to any of the stidy drugs, study drug classes,or excipients in the formulation 19. The use of CYP3A4 inhibitors or inducers 20. Participation in another clinical trial within 4 weeks prior to enrollment and receipt of the investigational drug and any concomitant therapy containing the investigational drug 21. Received radiotherapy within 4 weeks prior to enrollment and the lesions observed in this study were in the target area of radiotherapy 22. Subjects with active tuberculosis (TB) who are on anti-tuberculosis treatment, or who have received anti-tuberculosis treatment within one year prior to screening 23. Comorbidities requiring long-term treatment with immunosuppressive drugs or systemic or topical corticosteroids at immunosuppressive doses (doses \>10 mg/day of prednisone or other isotonic hormones) 24. Received any anti-infective vaccine (e.g., influenza vaccine, varicella vaccine, Neocon vaccine, etc.) within 4 weeks prior to enrollment 25. Pregnancy or breastfeeding 26. Persistent proteinuria \>3.5g/24 hours by measuring the urine protein-creatinine ratio in random urine samples (grade 3, NCI-CTCAE version 5.0) 27. Positive for Human Immunodeficiency Virus (HIV) 28. Positive hepatitis B virus surface antigen (HBsAg) with positive HBV DNA copy number (quantitative test ≥ 1000 cps/ml) 29. Positive blood screen for chronic hepatitis C (positive for HCV antibodies) 30. Renal failure requiring hemodialysis or peritoneal dialysis 31. The degree of dehydration ≥ CTCAE version 5.0 level 1 32. Persons without legal capacity 33. Any other clinically significant disease or condition that, in the opinion of the investigator, could affect compliance with the protocol, or affect the subject's ability to sign an informed consent form (ICF), or is inappropriate for participation in this clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | one year | PFS, defined as the time from randomization to the first occurrence of disease progression as determined by the investigator with use of RECIST v1.1 or death from any cause, whichever occurs first. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | one year | ORR, determined using RECIST v1.1, defined as best overall response (CR or PR) across all assessment time points during the period from enrolment to termination of trial treatment. |
| Disease Control Rate (DCR) | one year | Determined using RECIST v1.1 criteria. |
| Overall Survival (OS) | two years | Duration from the date of initial treatment to the date of death due to any cause. |
| Incidence and severity of adverse events (AE) and serious adverse events (SAE) | two years | Incidence, nature, and severity of adverse events graded according to the NCI CTCAE v5.0. |
Contacts
Primary ContactYunpeng Liu, PhD
Backup ContactLing Xu, PhD
Outcome results
None listed