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Regorafenib Plus FOLFIRI With Irinotecan Dose Escalated in Patients With Previously Treated Metastatic Colorectal Cancer

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ClinicalTrials.gov Identifier: NCT03880877
Recruitment Status : Recruiting
First Posted : March 19, 2019
Last Update Posted : March 21, 2019
Sponsor:
Information provided by (Responsible Party):
Jaw-Yuan Wang, MD, PhD, Kaohsiung Medical University Chung-Ho Memorial Hospital

Brief Summary:
A prospective, multicenter, randomized in a 2:1 ratio, controlled, clinical trial with two parallel arms will be conducted to compare irinotecan dose escalated FOLFIRI according to UGT1A1 genotyping plus 120 mg regorafenib with 120 mg regorafenib alone in previously treated patients with metastatic colorectal cancer (mCRC).

Condition or disease Intervention/treatment Phase
Metastatic Colorectal Cancer Drug: Regorafenib Genetic: UGT1A1 genotyping (TA6/TA6) Genetic: UGT1A1 genotyping (TA6/TA7) Genetic: UGT1A1 genotyping (TA7/TA7) Drug: Leucovorin and 5-FU Phase 2

Detailed Description:

Primary objective:

Progression-free survival

Secondary objective:

Overall survival, best objective response, disease control rate, time to progression, duration of treatment and adverse events

Number of Subjects: 153 patients with metastatic colorectal cancer treated with regorafenib and FOLFIRI as a third- or fourth-line setting.

Plan of the Study:

  1. This is a prospective, multicenter, randomized in a 2:1 ratio, controlled study.
  2. Study Schedule Study date: the time getting approval letter issued by both regulatory authority and institutional review board (IRB). Duration of the study: 4 years.
  3. Duration of Treatment: Treatment was administered until disease progressed.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 153 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Regorafenib Plus FOLFIRI With Irinotecan Dose Escalated According to UGT1A1 Genotyping Versus Regorafenib Monotherapy in Patients With Previously Treated Metastatic Colorectal Cancer: A Prospective, Randomized, Controlled Study
Actual Study Start Date : February 26, 2019
Estimated Primary Completion Date : March 1, 2021
Estimated Study Completion Date : December 31, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Regorafenib plus FOLFIRI

Regimen for treatment consists of irinotecan (180 mg/m2 as a 120-min IV infusion for UGT1A1 genotyping (TA6/TA6) and UGT1A1 genotyping (TA6/TA7); 120 mg/m2 as a 120-min IV infusion for UGT1A1 genotyping (TA7/TA7)), followed by Leucovorin (400 mg/m2 IV infusion over 2 hours), and fluorouracil (5-FU) (2800 mg/m2 IV infusion over a 46-hour period), repeated every 2 weeks.

After every 2 cycles of each different dose of irinotecan, if adverse events (AEs) are under the grade 2, we will escalate the dose of 30 mg/m2. The estimated maximal dose of irinotecan is 260 mg/m2 for UGT1A1 genotyping (TA6/TA6); 240 mg/m2 for UGT1A1 genotyping (TA6/TA7); 180 mg/m2 for UGT1A1 genotyping (TA7/TA7).

Regorafenib is administered at adjusted dosage of 120 mg daily for 3 weeks in a 4-week cycle.

Drug: Regorafenib
Regorafenib is administered at dose of 120 mg daily for 3 weeks in a 4-week cycle
Other Name: stivarga

Genetic: UGT1A1 genotyping (TA6/TA6)
The dosage of irinotecan in FOLFIRI is escalated from 180mg/m2 to 260 mg/m2

Genetic: UGT1A1 genotyping (TA6/TA7)
The dosage of irinotecan in FOLFIRI is escalated from 180mg/m2 to 240 mg/m2

Genetic: UGT1A1 genotyping (TA7/TA7)
The dosage of irinotecan in FOLFIRI is escalated from 120mg/m2 to180 mg/m2

Drug: Leucovorin and 5-FU
Leucovorin (400 mg/m2 IV infusion over 2 hours), and 5-FU (2800 mg/m2 IV infusion over a 46-hour period)

Active Comparator: Regorafenib
Regorafenib is administered at adjusted dosage of 120 mg daily for 3 weeks in a 4-week cycle.
Drug: Regorafenib
Regorafenib is administered at dose of 120 mg daily for 3 weeks in a 4-week cycle
Other Name: stivarga




Primary Outcome Measures :
  1. Progression-free survival [ Time Frame: From date of initiation of treatment until the date of first documented progression, assessed up to 23 months ]
    Time from treatment to disease progresses and lives


Secondary Outcome Measures :
  1. Overall survival [ Time Frame: From date of initiation of treatment until the date of death from any cause, assessed up to 23 months ]
    Time from treatment to death of patients

  2. Best objective response [ Time Frame: From date of initiation of treatment until the date of disease progression, assessed up to 23 months ]
    best response recorded during treatment

  3. Disease control rate [ Time Frame: From date of initiation of treatment until the date of disease progression, assessed up to 23 months ]
    Rate of best objective response, including complete response, partial response and stable disease

  4. Time to progression [ Time Frame: From date of initiation of treatment until the date of disease progression, assessed up to 23 months ]
    Time from treatment to disease progresses

  5. Duration of treatment [ Time Frame: From date of initiation of treatment until the date of disease progression, assessed up to 23 months ]
    Time from initiation to termination of treatment



Information from the National Library of Medicine

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Ages Eligible for Study:   20 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Cyto-/histological confirmed mCRC
  2. Patients who have been previously treated with, or are not considered candidates for, other locally approved standard treatment(s) and for whom the decision has been made per investigator's routine treatment practice to prescribe regorafenib as 3rd line (RAS mutant) or 4th line (RAS wild type) therapy
  3. Aged no less than 20 years, at the time of acquisition of informed consent
  4. Eastern Cooperative Oncology Group (ECOG) performance score of 0-1
  5. Patients with measurable or non-measurable disease in the colon or rectum, according to RECIST criteria version 1.1
  6. Life expectancy more than 12 weeks
  7. Women with childbearing potential must agree to perform adequate contraception measures since informed consent till a least 12 weeks after the last study drug administration.

    The investigators or designee are requested to advise the patient to achieve adequate birth control.

  8. Adequate organ and bone marrow function as defined below:

    • Total bilirubin <= 1.5 x the upper limit of normal (ULN)
    • Alanine amino-transferase (ALT) and aspartate amino-transferase (AST) <= 2.5 x ULN (<= 5 x ULN for patients with liver metastases)
    • Alkaline phosphatase (ALP) <= 2.5 x ULN (<= 5 x ULN for patients with liver metastases)
    • Amylase and lipase <= 1.5 x ULN
    • Serum creatinine <= 1.5 x ULN
    • Glomerular filtration rate (GFR) >= 30 mL/min/1.73 m2, according to the modified diet in renal disease (MDRD) abbreviated formula
    • International normalized ratio (INR)/partial thromboplastin time (PTT) <= 1.5 x ULN
    • Platelet counts >= 100,000/mm3
    • Hemoglobin level >= 9 g/dL
    • Absolute neutrophil counts >= 1,500/mm3
  9. Ability to understand and willingness to sign written Informed Consent Form (ICF)

Exclusion Criteria:

  1. Prior treatment with regorafenib within 28 days
  2. Other concurrent cancer or prior treatment for other carcinomas within the last five years, except curatively treated non-melanoma skin cancer, superficial bladder tumors, and cervical cancer in-situ
  3. Extended field radiotherapy within 28 days or limited radiotherapy within 14 days prior to randomization
  4. Major surgery within 28 days prior to start of study treatment (diagnostic biopsy, laparotomy, line placement is not considered as major surgery)
  5. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, myocardial infarction in the past 12 months, active gastrointestinal bleeding, central nervous system disorders or psychiatric illness/social situation that would limit compliance with study requirements or judged to be ineligible for the study by the investigator
  6. History of myocardial infarction, deep venous or arterial thrombosis, or cardiovascular accident (CVA) during the last 6 months
  7. Uncontrolled cardiac arrhythmias, unstable angina, or newly-onset angina within 3 months prior to study entry
  8. Uncontrolled hypertension despite optimal management (systolic blood pressure > 150 mmHg or diastolic pressure > 90 mmHg)
  9. Patients with known central nervous system (CNS) metastases
  10. Having received any investigational agents or participating in any investigational drug study within 4 weeks prior to study enrollment
  11. Pregnant or breast-feeding female (a pregnancy test must be performed on all female patients with child-bearing potential within 7 days of treatment initiation, and the result must be negative)
  12. Inability to take oral medications
  13. Poor compliance as judged by the investigator

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03880877


Contacts
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Contact: Jaw-Yuan Wang, PhD +886-7-3122805 cy614112@ms14.hinet.net; jayuwa@cc.kmu.edu.tw

Locations
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Taiwan
Chung-Ho Memorial Hospital, Kaohsiung Medical University: Recruiting
Kaohsiung, Taiwan, 807
Contact: Jaw-Yuan Wang, PhD       chunpin870132@yahoo.com.tw   
Principal Investigator: Jaw-Yuan Wang, Ph.D.         
Principal Investigator: Jaw-Yuan Wang, PhD         
Sponsors and Collaborators
Kaohsiung Medical University Chung-Ho Memorial Hospital
Investigators
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Study Chair: Jaw-Yuan Wang, PhD Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University

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Responsible Party: Jaw-Yuan Wang, MD, PhD, Professor, Vice Superintendent, Kaohsiung Medical University Chung-Ho Memorial Hospital
ClinicalTrials.gov Identifier: NCT03880877     History of Changes
Other Study ID Numbers: KMUHIRB-F(II)-20190032
First Posted: March 19, 2019    Key Record Dates
Last Update Posted: March 21, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Jaw-Yuan Wang, MD, PhD, Kaohsiung Medical University Chung-Ho Memorial Hospital:
metastatic colorectal cancer
FOLFIRI
regorafenib

Additional relevant MeSH terms:
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Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Irinotecan
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents