Regorafenib Plus Raltitrexed as Third-line Treatment in Advanced Colorectal Cancer Patients

Study Overview
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Brief Summary
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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
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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).

Official Title
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Regorafenib Plus Raltitrexed as Third-line Treatment in Advanced Colorectal Cancer Patients：An Open-label, Single-arm, Multicenter Phase I/II Study

Conditions
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Regorafenib, Raltitrexed, Colorectal Neoplasms, Third-line Treatment

Intervention / Treatment
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* Drug: Regorafenib
* Drug: Raltitrexed


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Sign a consent form Age> 18 years Pathological diagnosis as metastatic colorectal adenocarcinoma 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. Measurable disease according to RECIST ECOG score 0-1 points Life expectancy ≥3 months ALT and AST< 2.5 times the upper limit of normal (ULN), patients with liver metastases < 5 times ULN Serum albumin ≥ 3.0g/ dL Serum ALP <2.5 times ULN Total bilirubin <l.5mg / dL Estimated creatinine clearance (CLcr) ≥30mL/min as calculated using the Cockcroft-Gault equation Lipase≤1.5x the ULN Neutrophil absolute count (ANC) ≥1500/mm³, hemoglobin (Hb)>9g/dl, platelets> 10000/mm³ 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. Prior exposure to any VEGFR tyrosine kinase inhibitor (e.g., regorafenib, apatinib, anlotinib, furoquinitinib, etc.) therapy Received raltitrexed in the previous treatment 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 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 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) Major surgery, biopsy or significant traumatic damage within 28 days prior to the start of investigational treatment Non-healing wound, non-healing ulcer, or non-healing bone fracture. Patients with brain metastases and/or cancerous meningitis Congestive heart failure > New York Heart Association (NYHA) class 2. 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. Arrhythmias requiring antiarrhythmic therapy (beta-blockers or digoxin allowed) Uncontrolled hypertension. (Systolic blood pressure > 150 mmHg or diastolic blood pressure > 90 mmHg despite optimal medical treatment) Patients with pheochromocytoma Pleural effusion or ascites causing restricted breathing (≥ CTCAE grade 2 dyspnea) Known to have dihydropyrimidine dehydrogenase deficiency Ongoing infection > Grade 2 NCI CTCAE Interstitial lung disease with ongoing signs and symptoms at the time of informed consent Known hypersensitivity to any of the stidy drugs, study drug classes,or excipients in the formulation The use of CYP3A4 inhibitors or inducers 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 Received radiotherapy within 4 weeks prior to enrollment and the lesions observed in this study were in the target area of radiotherapy Subjects with active tuberculosis (TB) who are on anti-tuberculosis treatment, or who have received anti-tuberculosis treatment within one year prior to screening 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) Received any anti-infective vaccine (e.g., influenza vaccine, varicella vaccine, Neocon vaccine, etc.) within 4 weeks prior to enrollment Pregnancy or breastfeeding Persistent proteinuria >3.5g/24 hours by measuring the urine protein-creatinine ratio in random urine samples (grade 3, NCI-CTCAE version 5.0) Positive for Human Immunodeficiency Virus (HIV) Positive hepatitis B virus surface antigen (HBsAg) with positive HBV DNA copy number (quantitative test ≥ 1000 cps/ml) Positive blood screen for chronic hepatitis C (positive for HCV antibodies) Renal failure requiring hemodialysis or peritoneal dialysis The degree of dehydration ≥ CTCAE version 5.0 level 1 Persons without legal capacity 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Regorafenib combined with Raltitrexed<br>Regorafenib: 120mg/d，Po，qd,d1-d21，Every 4 weeks Raltitrexed: 3mg/㎡，ivgtt，d1，Every 3 weeks | Drug: Regorafenib<br>* Regorafenib:120mg/d，Po，qd,d1-d21，Every 4 weeks<br>* Other names: Stivarga;Drug: Raltitrexed<br>* Raltitrexed:3mg/㎡，ivgtt，d1，Every 3 weeks<br>* Other names: Sai wei jian;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | 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. | one year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | 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. | one year | 
| Disease Control Rate (DCR) | Determined using RECIST v1.1 criteria. | one year | 
| Overall Survival (OS) | Duration from the date of initial treatment to the date of death due to any cause. | two years | 
| Incidence and severity of adverse events (AE) and serious adverse events (SAE) | Incidence, nature, and severity of adverse events graded according to the NCI CTCAE v5.0. | two years |