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

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ClinicalTrials.gov Identifier: NCT04117945
Recruitment Status : Recruiting
First Posted : October 7, 2019
Last Update Posted : November 19, 2020
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Academic and Community Cancer Research United

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
BRAF V600E Negative KRAS Gene Mutation Negative Locally Advanced Unresectable Colorectal Adenocarcinoma Metastatic Colorectal Adenocarcinoma NRAS Gene Mutation Negative Stage III Colorectal Cancer AJCC v8 Stage IIIA Colorectal Cancer AJCC v8 Stage IIIB Colorectal Cancer AJCC v8 Stage IIIC Colorectal Cancer AJCC v8 Stage IV Colorectal Cancer AJCC v8 Stage IVA Colorectal Cancer AJCC v8 Stage IVB Colorectal Cancer AJCC v8 Stage IVC Colorectal Cancer AJCC v8 Biological: Cetuximab Drug: Irinotecan Biological: Panitumumab Drug: Regorafenib Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 124 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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)
Actual Study Start Date : March 3, 2020
Estimated Primary Completion Date : February 28, 2023
Estimated Study Completion Date : March 31, 2025

Resource links provided by the National Library of Medicine


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: Cetuximab
Given IV
Other Names:
  • Cetuximab Biosimilar CDP-1
  • Cetuximab Biosimilar CMAB009
  • Cetuximab Biosimilar KL 140
  • Chimeric Anti-EGFR Monoclonal Antibody
  • Chimeric MoAb C225
  • Chimeric Monoclonal Antibody C225
  • Erbitux
  • IMC-C225

Drug: Irinotecan
Given IV

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




Primary Outcome Measures :
  1. Overall survival (OS) [ Time Frame: Up to 3 years ]
    The median OS and 95% confidence intervals in each arm will be reported.


Secondary Outcome Measures :
  1. First progression-free survival (PFS) [ Time Frame: Up to 3 years ]
    The median first PFS and 95% confidence intervals in each arm will be reported.

  2. Second PFS [ Time Frame: Up to 3 years ]
    The median second PFS and 95% confidence intervals in each arm will be reported.

  3. Sequential treatment PFS [ Time Frame: Up to 3 years ]
    The median PFS while on sequential treatment and 95% confidence intervals in each arm will be reported.

  4. Objective response rate [ Time Frame: Up to 3 years ]
    Point estimates and the corresponding 95% confidence intervals for the true success proportions in each arm will be reported.

  5. Sequential treatment objective response rate [ Time Frame: Up to 3 years ]
    Point estimates and the corresponding 95% confidence intervals for the true success proportions will be reported.

  6. Incidence of adverse events [ Time Frame: Up to 3 years ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

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): NCT04117945


Locations
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United States, Arizona
Mayo Clinic in Arizona Recruiting
Scottsdale, Arizona, United States, 85259
Contact: Clinical Trials Office    855-776-0015    mayocliniccancerstudies@mayo.edu   
Principal Investigator: Daniel H. Ahn         
United States, California
USC / Norris Comprehensive Cancer Center Recruiting
Los Angeles, California, United States, 90033
Contact: Fatima Siddiqui    323-865-0840      
Principal Investigator: Heinz-Josef Lenz         
United States, District of Columbia
MedStar Georgetown University Hospital Not yet recruiting
Washington, District of Columbia, United States, 20007
Contact: Benjamin A. Weinberg       baw12@gunet.georgetown.edu   
Principal Investigator: Benjamin A. Weinberg         
United States, Florida
Mayo Clinic in Florida Not yet recruiting
Jacksonville, Florida, United States, 32224
Contact: Angel Yedrysek       yedrysek.angel@mayo.edu   
Principal Investigator: Jason Starr, MD         
United States, Georgia
Emory University Hospital/Winship Cancer Institute Not yet recruiting
Atlanta, Georgia, United States, 30322
Contact: Christina S. Wu       christina.sing-ying.wu@emory.edu   
Principal Investigator: Christina S. Wu         
United States, Illinois
University of Chicago Comprehensive Cancer Center Not yet recruiting
Chicago, Illinois, United States, 60637
Contact: Daniel V. Catenacci       dcatenac@medicine.bsd.uchicago.edu   
Principal Investigator: Daniel V. Catenacci         
United States, Iowa
University of Iowa/Holden Comprehensive Cancer Center Not yet recruiting
Iowa City, Iowa, United States, 52242
Contact: Daniel J. Berg       daniel-j-berg@uiowa.edu   
Principal Investigator: Daniel J. Berg         
Siouxland Regional Cancer Center Recruiting
Sioux City, Iowa, United States, 51101
Contact: Tom Hoopingarner    712-252-9326    hoopingarnerT@jencc.com   
Principal Investigator: Donald B. Wender         
United States, Minnesota
Mayo Clinic Recruiting
Rochester, Minnesota, United States, 55905
Contact: Clinical Trials Referrals Office    855-776-0015    mayocliniccancerstudies@mayo.edu   
Principal Investigator: Zhaohui Jin         
United States, Missouri
Washington University School of Medicine Not yet recruiting
Saint Louis, Missouri, United States, 63110
Contact: Katrina S. Pedersen       kpedersen@wustl.edu   
Principal Investigator: Katrina S. Pedersen         
United States, Nebraska
University of Nebraska Medical Center Not yet recruiting
Omaha, Nebraska, United States, 68198
Contact: Kelsey A. Klute       kelsey.klute@unmc.edu   
Principal Investigator: Kelsey A. Klute         
United States, North Carolina
Duke University Medical Center Recruiting
Durham, North Carolina, United States, 27710
Contact: Ireka Burrus    919-668-1861    Ireka.burrus@duke.edu   
Principal Investigator: John H. Strickler         
United States, Pennsylvania
Allegheny General Hospital Recruiting
Pittsburgh, Pennsylvania, United States, 15212
Contact: Karen Derzic    412-330-6263    Karen.derzic@ahn.org   
Principal Investigator: Dulabh Monga, MD         
United States, Wisconsin
Marshfield Medical Center Not yet recruiting
Marshfield, Wisconsin, United States, 54449
Contact: Seth O. Fagbemi       fagbemi.seth@marshfieldclinic.org   
Principal Investigator: Seth O. Fagbemi         
Aurora Cancer Care-Milwaukee West Not yet recruiting
Wauwatosa, Wisconsin, United States, 53226
Contact: Federico Augusto H. Sanchez       federico.sanchez@aurora.org   
Principal Investigator: Federico Augusto H. Sanchez         
Sponsors and Collaborators
Academic and Community Cancer Research United
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Daniel H Ahn Academic and Community Cancer Research United
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Responsible Party: Academic and Community Cancer Research United
ClinicalTrials.gov Identifier: NCT04117945    
Other Study ID Numbers: ACCRU-GI-1809
NCI-2019-06518 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
ACCRU-GI-1809 ( Other Identifier: Academic and Community Cancer Research United )
P30CA015083 ( U.S. NIH Grant/Contract )
First Posted: October 7, 2019    Key Record Dates
Last Update Posted: November 19, 2020
Last Verified: July 2020

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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
Additional relevant MeSH terms:
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Colorectal Neoplasms
Adenocarcinoma
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Antineoplastic Agents, Immunological
Cetuximab
Panitumumab
Irinotecan
Antibodies
Immunoglobulins
Antibodies, Monoclonal
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action