Regorafenib, With Cetuximab or Panitumumab, for the Treatment of Unresectable, Locally Advanced, or Metastatic Colorectal Cancer

A Randomized Phase II Study of Regorafenib Followed by Anti-EGFR Monoclonal Antibody Therapy Versus the Reverse Sequencing for Metastatic Colorectal Cancer Patients Previously Treated With Fluoropyrimidine, Oxaliplatin and Irinotecan (REVERCE II)

This phase II trial how well regorafenib and anti-EGFR therapy (cetuximab or panitumumab) works for the treatment of patients with colorectal cancer that cannot be removed by surgery (unresectable), has spread to nearby tissue or lymph nodes (locally advanced), or has spread to other places in the body (metastatic). Regorafenib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as cetuximab or panitumumab, may interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as irinotecan, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. The purpose of this research study is to compare the effects, good and/or bad, of taking regorafenib follow by cetuximab or panitumumab, to those that receive cetuximab or panitumumab before regorafenib.

Study Overview

• Status: Active, not recruiting
• Conditions: Metastatic Colorectal Adenocarcinoma; Stage IV Colorectal Cancer AJCC v8; Stage IVA Colorectal Cancer AJCC v8; Stage IVB Colorectal Cancer AJCC v8; Stage IVC Colorectal Cancer AJCC v8; Stage III Colorectal Cancer AJCC v8; Stage IIIA Colorectal Cancer AJCC v8; Stage IIIB Colorectal Cancer AJCC v8; Stage IIIC Colorectal Cancer AJCC v8; BRAF V600E Negative; KRAS Gene Mutation Negative; Locally Advanced Unresectable Colorectal Adenocarcinoma; NRAS Gene Mutation Negative
• Intervention / Treatment: Biological: Panitumumab; Drug: Irinotecan; Drug: Regorafenib; Biological: Cetuximab

Detailed Description

PRIMARY OBJECTIVE:

I. To compare the overall survival between evaluable patients who were randomized to receive regorafenib followed by anti-EGFR monoclonal antibody therapy compared to those that receive anti-EGFR monoclonal antibody followed by regorafenib.

SECONDARY OBJECTIVES:

I. To compare the first progression free survival (PFS1) of patients between evaluable patients who were randomized to receive regorafenib followed by anti-EGFR monoclonal antibody therapy compared to those that receive anti-EGFR monoclonal antibody followed by regorafenib II. To compare the second progression free survival (PFS2) of patients between evaluable patients who were randomized to receive regorafenib followed by anti-EGFR monoclonal antibody therapy compared to those that receive anti-EGFR monoclonal antibody followed by regorafenib.

III. To compare the sequential treatment progression free survival (stPFS) of patients between evaluable patients who were randomized to receive regorafenib followed by anti-EGFR monoclonal antibody therapy compared to those that receive anti-EGFR monoclonal antibody followed by regorafenib.

IV. To assess the frequency and severity of adverse events between evaluable patients who were randomized to receive regorafenib followed by anti-EGFR monoclonal antibody therapy compared to those that receive anti-EGFR monoclonal antibody followed by regorafenib.

V. To compare the objective response rate (ORR), while on initial treatment, between evaluable patients who were randomized to receive regorafenib followed by anti-EGFR monoclonal antibody therapy compared to those that receive anti-EGFR monoclonal antibody followed by regorafenib VI. To compare the objective response rate (ORR), while on sequential treatment, between evaluable patients who were randomized to receive regorafenib followed by anti-EGFR monoclonal antibody therapy compared to those that receive anti-EGFR monoclonal antibody prior to regorafenib.

CORRELATIVE RESEARCH OBJECTIVES:

I. To assess plasma pharmacodynamics biomarkers of response and resistance to therapy.

II. To explore any correlation between tissue and blood based biomarkers and clinical outcomes.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive regorafenib orally (PO) once daily (QD) on days 1-21. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Per the treating physician's discretion, patients who experience disease progression may initiate a treatment regimen consisting of cetuximab or panitumumab intravenously (IV) over 30-90 minutes on days 1 and 15. Patients may also receive irinotecan IV on days 1 and 15 as determined by the study doctor. Cycles repeat every 28 days until disease progression or unacceptable toxicity.

ARM B: Patients receive cetuximab or panitumumab IV over 30-90 minutes on days 1 and 15. Patients may also receive irinotecan IV on days 1 and 15 as determined by the study doctor. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Per the treating physician's discretion, patients who experience disease progression may initiate a treatment regimen consisting of regorafenib PO QD on days 1-21. Cycles repeat every 28 days until disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, and then every 3 months for up to 3 years after randomization.

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85259
      • Mayo Clinic in Arizona
  • California
    • Los Angeles, California, United States, 90033
      • USC / Norris Comprehensive Cancer Center
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • MedStar Georgetown University Hospital
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic in Florida
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University Hospital/Winship Cancer Institute
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Comprehensive Cancer Center
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa/Holden Comprehensive Cancer Center
    • Sioux City, Iowa, United States, 51101
      • Siouxland Regional Cancer Center
  • Kansas
    • Wichita, Kansas, United States, 67214
      • Cancer Center of Kansas
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska Medical Center
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Ohio
    • Toledo, Ohio, United States, 43623
      • Toledo Clinic Cancer Center
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15212
      • Allegheny General Hospital
  • Wisconsin
    • Marshfield, Wisconsin, United States, 54449
      • Marshfield Medical Center
    • Wauwatosa, Wisconsin, United States, 53226
      • Aurora Cancer Care-Milwaukee West

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Histologically proven, unresectable distant metastatic or locally advanced colorectal adenocarcinoma
• KRAS, NRAS wild type
• BRAF v600E wildtype
• Measurable disease
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2
• Life expectancy of >= 3 months per estimation of treating physician
• Absolute neutrophil count (ANC) >= 1200/mm^3 (obtained =< 7 days prior to randomization)
• Platelet count >= 75,000/mm^3 (obtained =< 7 days prior to randomization)
• Hemoglobin >= 9.0 g/dL (obtained =< 7 days prior to randomization)
• Total bilirubin =< 1.5 x upper limit of normal (ULN) (obtained =< 7 days prior to randomization)
• Alanine aminotransferase (ALT) and aspartate amino-transferase (AST) =< 2.5 x ULN (=< 5 x ULN for subjects with liver involvement of their cancer) (obtained =< 7 days prior to randomization)
• Serum creatinine =< 1.5 x ULN (obtained =< 7 days prior to randomization)

• International normalized ratio (INR)/partial thromboplastin time (PTT) =< 1.5 x ULN (obtained =< 7 days prior to randomization)

  • NOTE: Patients who are therapeutically treated with an agent such as warfarin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in coagulation parameters exists. Close monitoring of at least weekly evaluations will be performed until INR/PTT is stable based on a measurement that is pre-dose as defined by the local standard of care
• Alkaline phosphatase limit =< 2.5 x ULN (=< 5 x ULN for patients with liver involvement of their cancer) (obtained =< 7 days prior to randomization)

• Negative serum pregnancy test done =< 7 days prior to randomization for women of childbearing potential only.

  • NOTE: Post-menopausal women (defined as no menses for at least 1 year) and surgically sterilized women are not required to undergo a pregnancy test. The definition of adequate contraception will be based on the judgment of the treating physician
• Provide informed written consent
• Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study)
• Disease progression on or intolerable to any of the following: fluoropyrimidine, oxaliplatin and irinotecan
• Able to swallow and retain oral medication
• Willing to provide tissue and blood samples for correlative research purposes
• Willing to allow transfer of tissue and blood samples, clinical information, and outcome data collected from this trial for future research

Exclusion Criteria:

• Prior treatment with regorafenib, cetuximab or panitumumab
• Major surgical procedure, open biopsy, or significant traumatic injury =< 28 days prior to randomization

• Congestive heart failure > New York Heart Association (NYHA) class 2.

  • NOTE: Class 3 is defined as marked limitation in activity due to symptoms, even during less-than-ordinary activity, e.g., walking short distances (20-100m). They are comfortable at rest. Class 4 is defined as patients with severe limitations. Experiences symptoms even while at rest. Mostly bed bound
• Unstable angina (angina symptoms at rest), new-onset angina (begun =< 3 months prior to randomization) or myocardial infarction =< 6 months prior to randomization
• Cardiac arrhythmias requiring anti-arrhythmic therapy. Note: Pace makers, beta blockers or digoxin are permitted
• Uncontrolled hypertension. (Systolic blood pressure > 140 mmHg or diastolic pressure > 90 mmHg despite optimal medical management)
• History of or current pheochromocytoma
• Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism =< 6 months prior to randomization
• Ongoing infection > grade 2 National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0
• Known history of chronic hepatitis B or C
• Patients with seizure disorder requiring medication
• Symptomatic metastatic brain or meningeal tumors unless the patient is > 6 months from definitive therapy, has a negative imaging study within 4 weeks of randomization and is clinically stable with respect to the tumor at the time of randomization. Note: Patient must not be undergoing acute steroid therapy or taper (chronic steroid therapy is acceptable provided that the dose is stable for one month prior to and following screening radiographic studies)
• History of organ allograft (including corneal transplant)
• Evidence or history of bleeding diathesis or any hemorrhage or bleeding event > CTCAE v5.0 grade 3 =< 4 weeks prior to randomization
• Non-healing wound, ulcer, or bone fracture
• Substance abuse, medical, psychological or social conditions that may interfere with the patient?s participation in the study or evaluation of the study results
• High-frequency microsatellite instability (MSI-H) patients who have not received prior PD-1 monoclonal antibody (mAb) therapy
• Concurrent anti-cancer therapy =< 3 weeks from randomization (chemotherapy, radiation therapy, surgery, immunotherapy, biologic therapy, or tumor embolization)
• Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation
• Interstitial lung disease with ongoing signs and symptoms at the time of informed consent
• History of known persistent proteinuria of CTCAE v5.0 grade 3 or higher (>= 3.5 g/24 hrs)
• Any malabsorption condition
• Unresolved toxicity greater than CTCAE v5.0 grade 1 attributed to any prior therapy/procedure excluding alopecia and oxaliplatin induced neurotoxicity =< grade 2
• Albumin levels < 2.5 g/dl

• Any of the following because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects:

  • Pregnant women
  • Nursing women
  • Men or women of childbearing potential who are unwilling to employ adequate contraception
  • NOTE: Men and women of childbearing potential must agree to use adequate contraception beginning at the signing of the informed consent form (ICF) until at least 3 months after the last dose of study drug. The definition of adequate contraception will be based on the judgment of the principal investigator or a designated associate
• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the treating physician, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens
• Known history of human immunodeficiency virus (HIV) infection or active hepatitis B or C infection requiring treatment with antiviral therapy
• Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm
• Previous or concurrent cancer that is distinct in primary site or histology from colorectal cancer =< 3 years prior to randomization EXCEPT for cervical cancer in-situ, treated ductal carcinoma in situ of the breast, curatively treated nonmelanoma skin carcinoma, noninvasive aerodigestive neoplasms, or superficial bladder tumor (Ta [Non-invasive tumor], Tis [carcinoma in situ] and T1 [Tumor invades lamina propria]). Note: All cancer treatments for cancers that were distinct in a primary site other than colorectal must be completed at least 3 years prior to randomization (i.e., signature date of the informed consent form)
• Pleural effusion or ascites that causes respiratory compromise (>= CTCAE v5.0 grade 2 dyspnea)
• Any condition which, in the treating physician?s opinion, makes the subject unsuitable for trial participation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A (regorafenib); Patients receive regorafenib PO QD on days 1-21. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. If received as initial treatment, patients who experience disease progression may switch over to the other treatment regimen, per treating physician discretion.	Drug: Regorafenib; Given PO; Other Names: BAY 73-4506; Stivarga
Experimental: Arm B (cetuximab, panitumumab, irinotecan); Patients receive cetuximab or panitumumab IV over 30-90 minutes on days 1 and 15. Patients may also receive irinotecan IV on days 1 and 15 as determined by the study doctor. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. If received as initial treatment, patients who experience disease progression may switch over to the other treatment regimen, per treating physician discretion.	Biological: Panitumumab; Given IV; Other Names: ABX-EGF; ABX-EGF Monoclonal Antibody; ABX-EGF, Clone E7.6.3; MoAb ABX-EGF; Monoclonal Antibody ABX-EGF; Vectibix; Drug: Irinotecan; Given IV; Biological: Cetuximab; Given IV; Other Names: Erbitux; IMC-C225; Cetuximab Biosimilar CDP-1; Cetuximab Biosimilar CMAB009; Cetuximab Biosimilar KL 140; Chimeric Anti-EGFR Monoclonal Antibody; Chimeric MoAb C225; Chimeric Monoclonal Antibody C225

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival (OS)	The median OS and 95% confidence intervals in each arm will be reported.	Up to 3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
First progression-free survival (PFS)	The median first PFS and 95% confidence intervals in each arm will be reported.	Up to 3 years
Second PFS	The median second PFS and 95% confidence intervals in each arm will be reported.	Up to 3 years
Sequential treatment PFS	The median PFS while on sequential treatment and 95% confidence intervals in each arm will be reported.	Up to 3 years
Objective response rate	Point estimates and the corresponding 95% confidence intervals for the true success proportions in each arm will be reported.	Up to 3 years
Sequential treatment objective response rate	Point estimates and the corresponding 95% confidence intervals for the true success proportions will be reported.	Up to 3 years
Incidence of adverse events	The number of patients who experience a grade 3 or higher adverse event (Common Terminology Criteria for Adverse Events [CTCAE] version [v.] 5.0), regardless of attribution, will be reported by arm.	Up to 3 years

Collaborators and Investigators

• Sponsor: Academic and Community Cancer Research United
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Daniel H Ahn, Academic and Community Cancer Research United

Study record dates

Study Major Dates

• Study Start (Actual): March 3, 2020
• Primary Completion (Estimated): February 28, 2024
• Study Completion (Estimated): March 31, 2025

Study Registration Dates

• First Submitted: October 4, 2019
• First Submitted That Met QC Criteria: October 4, 2019
• First Posted (Actual): October 7, 2019

Study Record Updates

• Last Update Posted (Estimated): February 7, 2024
• Last Update Submitted That Met QC Criteria: February 5, 2024
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Adenocarcinoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Immunologic Factors; Topoisomerase Inhibitors; Topoisomerase I Inhibitors; Antibodies; Immunoglobulins; Irinotecan; Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Panitumumab; Cetuximab
• Other Study ID Numbers: ACCRU-GI-1809 (Other Identifier: Academic and Community Cancer Research United); P30CA015083 (U.S. NIH Grant/Contract); NCI-2019-06518 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No