Regorafenib Plus Raltitrexed as Third-line Treatment in Advanced Colorectal Cancer Patients
Primary Purpose
Regorafenib, Raltitrexed, Colorectal Neoplasms
Status
Not yet recruiting
Phase
Phase 1
Locations
Study Type
Interventional
Intervention
Regorafenib
Raltitrexed
Sponsored by
About this trial
This is an interventional treatment trial for Regorafenib
Eligibility Criteria
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.
Sites / Locations
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Regorafenib combined with Raltitrexed
Arm Description
Regorafenib: 120mg/d,Po,qd,d1-d21,Every 4 weeks Raltitrexed: 3mg/㎡,ivgtt,d1,Every 3 weeks
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
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.
Disease Control Rate (DCR)
Determined using RECIST v1.1 criteria.
Overall Survival (OS)
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)
Incidence, nature, and severity of adverse events graded according to the NCI CTCAE v5.0.
Full Information
NCT ID
NCT05426811
First Posted
June 16, 2022
Last Updated
June 24, 2022
Sponsor
China Medical University, China
Collaborators
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
1. Study Identification
Unique Protocol Identification Number
NCT05426811
Brief Title
Regorafenib Plus Raltitrexed as Third-line Treatment in Advanced Colorectal Cancer Patients
Official Title
Regorafenib Plus Raltitrexed as Third-line Treatment in Advanced Colorectal Cancer Patients:An Open-label, Single-arm, Multicenter Phase I/II Study
Study Type
Interventional
2. Study Status
Record Verification Date
June 2022
Overall Recruitment Status
Not yet recruiting
Study Start Date
July 1, 2022 (Anticipated)
Primary Completion Date
July 1, 2025 (Anticipated)
Study Completion Date
December 30, 2025 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
China Medical University, China
Collaborators
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
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
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).
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Regorafenib, Raltitrexed, Colorectal Neoplasms, Third-line Treatment
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Model Description
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
50 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Regorafenib combined with Raltitrexed
Arm Type
Experimental
Arm Description
Regorafenib:
120mg/d,Po,qd,d1-d21,Every 4 weeks
Raltitrexed:
3mg/㎡,ivgtt,d1,Every 3 weeks
Intervention Type
Drug
Intervention Name(s)
Regorafenib
Other Intervention Name(s)
Stivarga
Intervention Description
Regorafenib:120mg/d,Po,qd,d1-d21,Every 4 weeks
Intervention Type
Drug
Intervention Name(s)
Raltitrexed
Other Intervention Name(s)
Sai wei jian
Intervention Description
Raltitrexed:3mg/㎡,ivgtt,d1,Every 3 weeks
Primary Outcome Measure Information:
Title
Progression-free Survival (PFS)
Description
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.
Time Frame
one year
Secondary Outcome Measure Information:
Title
Objective Response Rate (ORR)
Description
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.
Time Frame
one year
Title
Disease Control Rate (DCR)
Description
Determined using RECIST v1.1 criteria.
Time Frame
one year
Title
Overall Survival (OS)
Description
Duration from the date of initial treatment to the date of death due to any cause.
Time Frame
two years
Title
Incidence and severity of adverse events (AE) and serious adverse events (SAE)
Description
Incidence, nature, and severity of adverse events graded according to the NCI CTCAE v5.0.
Time Frame
two years
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Yunpeng Liu, PhD
Phone
86-24-83282312
Email
cmu_trial@163.com
First Name & Middle Initial & Last Name or Official Title & Degree
Ling Xu, PhD
Email
cmuxuling@163.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Yunpeng Liu, PhD
Organizational Affiliation
First Hospital of China Medical University
Official's Role
Principal Investigator
12. IPD Sharing Statement
Plan to Share IPD
No
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Regorafenib Plus Raltitrexed as Third-line Treatment in Advanced Colorectal Cancer Patients
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