Regorafenib, With Cetuximab or Panitumumab, for the Treatment of Unresectable, Locally Advanced, or Metastatic Colorectal Cancer
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The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. |
| ClinicalTrials.gov Identifier: NCT04117945 |
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Recruitment Status :
Recruiting
First Posted : October 7, 2019
Last Update Posted : January 13, 2023
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Sponsor:
Academic and Community Cancer Research United
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Academic and Community Cancer Research United
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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 |
Show detailed description
| 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 |
|---|---|
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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.
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Drug: Regorafenib
Given PO
Other Names:
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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.
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Biological: Cetuximab
Given IV
Other Names:
Drug: Irinotecan Given IV Biological: Panitumumab Given IV
Other Names:
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Primary Outcome Measures :
- 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 :
- 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.
- Second PFS [ Time Frame: Up to 3 years ]The median second PFS and 95% confidence intervals in each arm will be reported.
- 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.
- 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.
- 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.
- 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.
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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)
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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)
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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
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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
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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
| 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 | Recruiting |
| Washington, District of Columbia, United States, 20007 | |
| Contact: Meghan Mavredes 202-687-6653 mm4780@georgetown.edu | |
| Principal Investigator: Benjamin A. Weinberg | |
| United States, Florida | |
| Mayo Clinic in Florida | Recruiting |
| Jacksonville, Florida, United States, 32224 | |
| Contact: Lashundra Stewart 904-953-9792 Stewart.Lashundra@mayo.edu | |
| Principal Investigator: Jeremy Jones, MD | |
| United States, Georgia | |
| Emory University Hospital/Winship Cancer Institute | Recruiting |
| Atlanta, Georgia, United States, 30322 | |
| Contact: KJ Lee 404-778-3173 kyungjong.lee@emory.edu | |
| Principal Investigator: Olatunji Alese | |
| United States, Illinois | |
| University of Chicago Comprehensive Cancer Center | Recruiting |
| Chicago, Illinois, United States, 60637 | |
| Contact: University of Chicago V. Cancer Team 855-702-8222 cancerclinicaltrials@bsd.uchicago.edu | |
| Principal Investigator: Ardaman Shergill | |
| United States, Iowa | |
| University of Iowa/Holden Comprehensive Cancer Center | Recruiting |
| Iowa City, Iowa, United States, 52242 | |
| Contact: Mary Schall 319-356-3516 mary-schall@uiowa.edu | |
| Principal Investigator: Saima Sharif, MD | |
| 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, Kansas | |
| Cancer Center of Kansas | Not yet recruiting |
| Wichita, Kansas, United States, 67214 | |
| Contact: Pat Stone 316-613-4313 pat.stone@cancercenterofkansas.com | |
| Principal Investigator: Shaker Dakhil, M.D. | |
| 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, Nebraska | |
| University of Nebraska Medical Center | Recruiting |
| Omaha, Nebraska, United States, 68198 | |
| Contact: Amanda Smith 760-793-1020 Amandasmith1@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, Ohio | |
| Toledo Clinic Cancer Center | Recruiting |
| Toledo, Ohio, United States, 43623 | |
| Contact: Pam Shoup 419-214-4236 pshoup@toledoclinic.com | |
| Principal Investigator: Rex Mowat | |
| 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 | Recruiting |
| Marshfield, Wisconsin, United States, 54449 | |
| Contact: Barbaraann Gildenzopf, RN 1-800-782-8581 ext. 4-3048 gildenzopf.barbara@marshfieldclinic.org | |
| Principal Investigator: Seth O. Fagbemi | |
| Aurora Cancer Care-Milwaukee West | Recruiting |
| Wauwatosa, Wisconsin, United States, 53226 | |
| Contact: Karen Cheek Karen.cheek@aah.org | |
| Principal Investigator: Antony Ruggeri | |
Sponsors and Collaborators
Academic and Community Cancer Research United
National Cancer Institute (NCI)
Investigators
| Principal Investigator: | Daniel H Ahn | Academic and Community Cancer Research United |
| 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: | January 13, 2023 |
| Last Verified: | September 2022 |
| 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 |