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Early Identification and Treatment of Occult Metastatic Disease in Stage III Colorectal Cancer

Trial Status: Active

This phase III trial studies how well either FOLFIRI (leucovorin, fluorouracil, and irinotecan), active surveillance, nivolumab, or encorafenib, binimetinib, and cetuximab work in decreasing recurrence (chance of the cancer coming back) in patients with stage III colorectal cancer who are ctDNA positive. If all the cancer is not killed after initial treatment, bloods tests may be able to detect tumor DNA in the blood called circulating tumor DNA (ctDNA). This is genetic material unique to the cancer that may be present in the blood stream and can be identified through a ctDNA blood test. Cancer researchers believe that ctDNA in the blood stream may be an indicator that cancer is more likely to recur. Chemotherapy drugs, such as leucovorin, fluorouracil, and irinotecan, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Nivolumab is an anti-PD-1 antibody. It works by attaching to and blocking a molecule called PD-1. PD-1 is a protein that is present on different types of cells in the immune system and controls parts of the immune system by shutting it down. Antibodies that block PD-1 can potentially prevent PD-1 from shutting down the immune system, thus potentially allowing immune cells to recognize and destroy cancer cells. Encorafenib in combination with binimetinib and cetuximab may target the BRAF V600E-mutation in colorectal cancer. When this mutation is present, it switches on pathway called the MAPK pathway which stimulates cell division and leads to uncontrolled cell growth. Encorafenib, binimetinib and cetuximab target different parts of this important signaling pathway in tumor cells with this mutation and may slow down their growth and communication. Encorafenib and binimetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Cetuximab is a monoclonal antibody that may interfere with the ability of tumor cells to grow and spread. This study is being done to determine whether there are differences in cancer recurrence in ctDNA positive patients treated with additional therapy versus put on active surveillance.

Inclusion Criteria

  • PRE-SCREENING: Participants must have histologically confirmed resected stage III adenocarcinoma of colorectal. Any T [Tx, T1, T2, T3, or T4-], N1-2MO; including NC
  • PRE-SCREENING: Patients must be receiving or planning to receive standard adjuvant chemotherapy per the discretion of the treating physician. Standard therapy includes leucovorin calcium (calcium folinate), 5-fluorouracil and oxaliplatin (FOLFOX), capecitabine and oxaliplatin (CAPOX), or therapy with fluorouracil (5FU) analog alone will be permitted if it constitutes appropriate standard therapy in the opinion of the treating physician
  • PRE-SCREENING: Patients must have sufficient tumor tissue available for molecular profiling, defined as at least 10 x 5 micron sections of formalin-fixed paraffin-embedded (FFPE) tumor tissue or the equivalent
  • PRE-SCREENING: Eastern Cooperative Oncology Group (ECOG) performance status =< 1
  • PRE-SCREENING: Ability to understand and the willingness to sign a written informed consent document
  • PRE-SCREENING: Patients must not have received prior neoadjuvant chemotherapy
  • SCREENING: Participants must have histologically confirmed resected stage III adenocarcinoma of colorectal. Any T [Tx, T1, T2, T3, or T4-], N1-2MO; including NC
  • SCREENING: Patient must have completed resected disease. In patients with tumor adherent to adjacent structures, en block RO resection must be documented
  • SCREENING: Entire tumor must be in the colon (rectal involvement is excluded)
  • SCREENING: Patients must have completed standard adjuvant chemotherapy per the discretion of the treating physician. Standard therapy includes FOLFOX, CAPOX, or therapy with 5FU analog alone will be permitted if it constitutes appropriate standard therapy in the opinion of the treating physician
  • SCREENING: Patients must not have received prior neoadjuvant chemotherapy
  • SCREENING: ECOG performance status =< 1
  • SCREENING: Life expectancy of greater than 3 months
  • SCREENING: Leukocytes >= 3,000/mcL
  • SCREENING: Absolute neutrophil count >= 1,500/mcL
  • SCREENING: Platelets >= 100,000/ mcL
  • SCREENING: Total bilirubin within normal institutional limits
  • SCREENING: Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase [SGPT]) =< 3 (AST) or =< 3 (ALT) x institutional upper limit of normal
  • SCREENING: Creatinine within normal institutional limits OR creatinine clearance >= 40 mL/min/1.73 m^2 for participants with creatinine levels above institutional normal by Cockcroft-Gault formula
  • SCREENING: Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG])
  • SCREENING: The effects on the developing human fetus are unknown. For this reason and because 5FU, capecitabine, oxaliplatin, irinotecan, leucovorin, nivolumab, and cetuximab are known to be teratogenic, females of child-bearing potential (FOCBP) and males must be willing to abstain from heterosexual activity or use 2 forms of effective contraception (fail rate of less than 1% per year, hormonal or barrier method of birth control) from time of informed consent until 5 months (FOCBP) and 7 months (males) after the last dose of study treatment. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Women who are not of childbearing potential, i.e., who are postmenopausal or surgically sterile as well as azoospermic men, do not require contraception
  • SCREENING: Patient must have documentation of mismatch repair deficiency (dMMR). Abnormal immunohistochemistry (IHC) staining for dMMR (MMR protein expression (MLH1, MSH2, MSH6, PMS2) where loss of one or more protein indicated dMMR) is acceptable as is MSI assessment via polymerase chain reaction (PCR). This may be done locally per local standards
  • SCREENING: Patient’s circulating tumor DNA (ctDNA) assay (LUNAR-Guardant Health) must satisfy assay specific quality control metrics to generate a result
  • SCREENING: In order to be eligible for the ctDNA positive cohort, patient must be ctDNA positive following adjuvant therapy using the Clinical Laboratory Improvement Act (CLIA) certified Guardant Health LUNAR assay. ctDNA positive will be defined as positive based on having a tumor derived signal in the cfDNA that passes calling threshold (“ctDNA detected”)
  • SCREENING: Ability to understand and the willingness to sign a written informed consent document
  • NIVOLUMAB SPECIFIC INCLUSION CRITERIA FOR MSI-H COHORT: Must have documentation of microsatellite instability status. Both PCR based assessment and immunohistochemistry (IHC) are acceptable. Presence of deficient (d) DNA mismatch repair (dMMR) may be assessed by IHC for MMR protein expression (MLH1, MSH2, MSH6, PMS2) where loss of one or more proteins indicated dMMR. This may be done locally
  • NIVOLUMAB SPECIFIC INCLUSION CRITERIA FOR MSI-H COHORT: Patients must have detectable ctDNA (Guardant Health LUNAR assay) post standard adjuvant therapy in order to be in this cohort
  • ENCORAFENIB, BINIMETINIB, AND CETUXIMAB SPECIFIC INCLUSION CRITERIA FOR BRAF MUTANT COHORT: Presence of BRAFV600E in tumor tissue previously determined by IMPACT at any time prior to Screening
  • ENCORAFENIB, BINIMETINIB, AND CETUXIMAB SPECIFIC INCLUSION CRITERIA FOR BRAF MUTANT COHORT: Patients must have detectable ctDNA (Guardant Health LUNAR assay) post standard adjuvant therapy in order to be in this cohort
  • ENCORAFENIB, BINIMETINIB, AND CETUXIMAB SPECIFIC INCLUSION CRITERIA FOR BRAF MUTANT COHORT: Hemoglobin >= 9 g/dL (5.58 mmol/L)
  • ENCORAFENIB, BINIMETINIB, AND CETUXIMAB SPECIFIC INCLUSION CRITERIA FOR BRAF MUTANT COHORT: Total bilirubin =< 1.5 (25.65 umol/L)
  • ENCORAFENIB, BINIMETINIB, AND CETUXIMAB SPECIFIC INCLUSION CRITERIA FOR BRAF MUTANT COHORT: Platelets >= 100,000/uL

Exclusion Criteria

  • Patients who are receiving additional investigational therapy or on another investigational protocol
  • Patients who have confirmed metastatic disease per computed tomography (CT)
  • Patients who are unable to get any standard adjuvant therapy
  • Patient who have received more than 3-6 months of standard adjuvant therapy at the time of study entry
  • Received anticancer therapy including chemotherapy, immunotherapy, or antineoplastic biologic therapy (e.g., cetuximab, bevacizumab etc.), within 30 days prior to start of study treatment
  • Patients who are MSI-high or have a BRAF V600E mutation are excluded from Arm 1 (FOLFIRI) and Arm 2 (Active Surveillance)
  • Patients with a BRAFV600E mutation and who are MSI-high are excluded from Arm 5 (encorafenib [ENCO]/binimetinib [BINI]/cetuximab [CETUX])
  • Has uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
  • Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 6 months for woman and 6 months for men, after the last dose of trial treatment
  • Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin and squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer
  • Has an active infection requiring systemic therapy
  • NIVOLUMAB SPECIFIC EXCLUSION CRITERIA FOR MSI-H COHORT: Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other forms of immunosuppressive therapy within 7 days prior to the first dose of nivolumab treatment. Subject requiring systemic steroids are excluded from the trial. The use of physiologic doses of corticosteroids may be approved after discussion with the sponsor
  • NIVOLUMAB SPECIFIC EXCLUSION CRITERIA FOR MSI-H COHORT: Has a known history of active TB (Bacillus tuberculosis)
  • NIVOLUMAB SPECIFIC EXCLUSION CRITERIA FOR MSI-H COHORT: Hypersensitivity to nivolumab or any of is excipients
  • NIVOLUMAB SPECIFIC EXCLUSION CRITERIA FOR MSI-H COHORT: Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., =< Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier
  • NIVOLUMAB SPECIFIC EXCLUSION CRITERIA FOR MSI-H COHORT: Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
  • NIVOLUMAB SPECIFIC EXCLUSION CRITERIA FOR MSI-H COHORT: Patients that require supplemental oxygen are excluded
  • NIVOLUMAB SPECIFIC EXCLUSION CRITERIA FOR MSI-H COHORT: Patients who are known human immunodeficiency virus positive (HIV+) positive are eligible if their CD4+ count is >= 350/μL for at least 3 months and they have an undetectable viral load. In addition, patient must be currently receiving highly active antiretroviral therapy (HAART) and have been on therapy for at least 3 months prior to study entry, under the care of an Infectious Diseases specialist. Patients should have no history of an acquired immunodeficiency syndrome (AIDS)-defining opportunistic infection
  • NIVOLUMAB SPECIFIC EXCLUSION CRITERIA FOR MSI-H COHORT: Patients known hepatitis B and hepatitis C must be under the care of viral hepatitis expert consultant. Patients with hepatitis B are required to be treated with anti-hepatitis B virus (HBV) treatment (e.g., entecavir) and have an HBV viral load < 100 IU/mL. Patients with hepatitis C need to have received prior and/or ongoing hepatitis C treatment
  • NIVOLUMAB SPECIFIC EXCLUSION CRITERIA FOR MSI-H COHORT: Has received a live vaccine within 30 days of planned start of study therapy * Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed
  • ENCORAFENIB, BINIMETINIB, AND CETUXIMAB SPECIFIC EXCLUSION CRITERIA FOR BRAF MUTANT COHORT: Patients with a BRAFV600E mutation and who are MSI-H are excluded from Arm 5 (ENCO/BINI/CETUX)
  • ENCORAFENIB, BINIMETINIB, AND CETUXIMAB SPECIFIC EXCLUSION CRITERIA FOR BRAF MUTANT COHORT: Prior therapy with a BRAF inhibitor (e.g., encorafenib, dabrafenib, vemurafenib) and/or a MEK inhibitor (e.g., binimetinib, trametinib, cobimetinib)
  • ENCORAFENIB, BINIMETINIB, AND CETUXIMAB SPECIFIC EXCLUSION CRITERIA FOR BRAF MUTANT COHORT: Known hypersensitivity or contraindication to any component of binimetinib or encorafenib or their excipients
  • ENCORAFENIB, BINIMETINIB, AND CETUXIMAB SPECIFIC EXCLUSION CRITERIA FOR BRAF MUTANT COHORT: The patient has a history of allergic reactions attributed to compounds of chemical or biologic composition similar to those of cetuximab, or has red meat allergy or tick bit history
  • ENCORAFENIB, BINIMETINIB, AND CETUXIMAB SPECIFIC EXCLUSION CRITERIA FOR BRAF MUTANT COHORT: Inability to swallow and retain study drug
  • ENCORAFENIB, BINIMETINIB, AND CETUXIMAB SPECIFIC EXCLUSION CRITERIA FOR BRAF MUTANT COHORT: Participants who have undergone major surgery (e.g., in-patient procedures) =< 6 weeks prior to start of study treatment or who have not recovered from side effects of such procedure
  • ENCORAFENIB, BINIMETINIB, AND CETUXIMAB SPECIFIC EXCLUSION CRITERIA FOR BRAF MUTANT COHORT: Participants who have had radiotherapy =< 14 days prior to start of study treatment or who have not recovered from side effects of such procedure. * Note: Palliative radiation therapy must be complete 7 days prior to the first dose of study treatment
  • ENCORAFENIB, BINIMETINIB, AND CETUXIMAB SPECIFIC EXCLUSION CRITERIA FOR BRAF MUTANT COHORT: Patient has not recovered to =< Grade 1 from toxic effects of prior therapy before starting study treatment. * Note: Stable chronic conditions (=< Grade 2) that are not expected to resolve (such as neuropathy, myalgia, alopecia, prior therapy-related endocrinopathies) are exceptions and may enroll
  • ENCORAFENIB, BINIMETINIB, AND CETUXIMAB SPECIFIC EXCLUSION CRITERIA FOR BRAF MUTANT COHORT: Impaired cardiovascular function or clinically significant cardiovascular disease including, but not limited to, any of the following: * History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty or stenting) < 6 months prior to Screening; * Congestive heart failure requiring treatment (New York Heart Association class >= 2); * Left ventricular ejection fraction (LVEF) < 50% as determined by multigated acquisition scan (MUGA) or echocardiogram (ECHO); * Uncontrolled hypertension defined as persistent systolic blood pressure >= 150 mmHg or diastolic blood pressure >= 100 mmHg despite current therapy; * History or presence of clinically significant cardiac arrhythmias (including resting bradycardia, uncontrolled atrial fibrillation or uncontrolled paroxysmal supraventricular tachycardia); * Triplicate average baseline corrected QT (QTc) interval >= 480 ms
  • ENCORAFENIB, BINIMETINIB, AND CETUXIMAB SPECIFIC EXCLUSION CRITERIA FOR BRAF MUTANT COHORT: Impairment of gastrointestinal function or disease which may significantly alter the absorption of study drug (e.g., active ulcerative disease, uncontrolled vomiting or diarrhea, malabsorption syndrome, small bowel resection with decreased intestinal absorption), or recent (=< 3 months) history of a partial or complete bowel obstruction, or other conditions that will interfere significantly with the absorption of oral drugs
  • ENCORAFENIB, BINIMETINIB, AND CETUXIMAB SPECIFIC EXCLUSION CRITERIA FOR BRAF MUTANT COHORT: Known history of acute or chronic pancreatitis
  • ENCORAFENIB, BINIMETINIB, AND CETUXIMAB SPECIFIC EXCLUSION CRITERIA FOR BRAF MUTANT COHORT: Concurrent neuromuscular disorder that is associated with elevated creatine kinase (CK) (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy)
  • ENCORAFENIB, BINIMETINIB, AND CETUXIMAB SPECIFIC EXCLUSION CRITERIA FOR BRAF MUTANT COHORT: History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes); history of retinal degenerative disease
  • ENCORAFENIB, BINIMETINIB, AND CETUXIMAB SPECIFIC EXCLUSION CRITERIA FOR BRAF MUTANT COHORT: Current use of a prohibited medication (including herbal medications, supplements, or foods), or use of a prohibited medication =< 1 week prior to the start of study treatment
  • ENCORAFENIB, BINIMETINIB, AND CETUXIMAB SPECIFIC EXCLUSION CRITERIA FOR BRAF MUTANT COHORT: History of thromboembolic or cerebrovascular events =< 12 weeks prior to the first dose of study treatment. Examples include transient ischemic attacks, cerebrovascular accidents, hemodynamically significant (i.e. massive or sub-massive) deep vein thrombosis or pulmonary emboli * Note: Patients with either deep vein thrombosis or pulmonary emboli that does not result in hemodynamic instability are allowed to enroll as long as they are on a stable dose of anticoagulants for at least 4 weeks * Note: Patients with thromboembolic events related to indwelling catheters or other procedures may be enrolled
  • ENCORAFENIB, BINIMETINIB, AND CETUXIMAB SPECIFIC EXCLUSION CRITERIA FOR BRAF MUTANT COHORT: Concurrent or previous other malignancy within 2 years of study entry, except adequately treated basal or squamous cell skin cancer, prostate intraepithelial neoplasm, carcinoma in-situ of the cervix, Bowen’s disease and Gleason 6 prostate cancer
  • ENCORAFENIB, BINIMETINIB, AND CETUXIMAB SPECIFIC EXCLUSION CRITERIA FOR BRAF MUTANT COHORT: Known history of positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
  • ENCORAFENIB, BINIMETINIB, AND CETUXIMAB SPECIFIC EXCLUSION CRITERIA FOR BRAF MUTANT COHORT: Evidence of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection * Note: Patients with laboratory evidence of cleared HBV or HCV infection may be enrolled * Note: Patients with no prior history of HBV infection who have been vaccinated against HBV and who have a positive antibody against hepatitis B surface antigen as the only evidence of prior exposure may be enrolled

Massachusetts

Boston
Brigham and Women's Hospital
Status: ACTIVE
Contact: Marios Giannakis
Dana-Farber Cancer Institute
Status: ACTIVE
Contact: Marios Giannakis
Massachusetts General Hospital Cancer Center
Status: ACTIVE
Contact: Aparna Raj Parikh
Phone: 617-724-4000

PRIMARY OBJECTIVES:

I. To compare disease-free survival (DFS) between circulating tumor deoxyribonucleic acid (ctDNA)-positive patients treated with additional treatment of leucovorin calcium (calcium folinate), 5-fluorouracil, and irinotecan (FOLFIRI) and ctDNA-positive patients who are untreated.

II. To compare the clearance rate of ctDNA in ctDNA-positive patients between patients treated with additional treatment of FOLFIRI and those who are untreated.

SECONDARY OBJECTIVES:

I. To compare the overall survival (OS) between ctDNA-positive patients treated with additional adjuvant therapy (Arm 1) and ctDNA-positive patients who are untreated (Arm 2).

II. To determine the clearance rate of ctDNA-positive patients treated with nivolumab in an exploratory microsatellite instability (MSI)/mismatch repair deficient cohort.

III. To determine the DFS of ctDNA-positive patients treated with nivolumab in an exploratory MSI/mismatch repair deficient cohort.

IV. To determine the clearance rate of ctDNA-positive patients treated with encorafenib, binimetinib, and cetuximab in an exploratory BRAF V600E cohort.

V. To determine the DFS of ctDNA-positive patients treated with encorafenib, binimetinib, and cetuximab, in an exploratory BRAF V600E cohort.

VI. To examine the correlation of ctDNA clearance as a surrogate marker for disease burden.

VII. To compare lead time to recurrence and sensitivity of predicting recurrence between ctDNA and tumor markers.

OUTLINE: Patients with positive ctDNA are randomized to either Arm I or Arm II. Patients with negative ctDNA are assigned to Arm III. Patients with positive ctDNA and a BRAF V600E mutation are assigned to Arm IV. Patients with positive ctDNA who are MSI-H are assigned to Arm V.

ARM I: Patients with positive ctDNA receive irinotecan hydrochloride intravenously (IV) over 90 minutes, leucovorin IV over 2 hours, and fluorouracil IV push followed by continuous infusion over 46-48 hours. Treatment repeats every 14 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

ARM II: Patients with positive ctDNA undergo standard of care active surveillance once monthly for 6 months.

ARM III: Patients with negative ctDNA undergo standard of care active surveillance and will be monitored every 3 months with ctDNA for the first two years on study.

ARM IV: Patients with positive ctDNA and a BRAF V600E mutation receive nivolumab IV over 30 minutes on day 1. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

ARM V: Patients with positive ctDNA and are MSI-H receive encorafenib orally (PO) once daily (QD), binimetinib PO twice daily (BID), and cetuximab IV on days 1 and 8. Treatment repeats every 14 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, every 12 weeks during years 1-3, every 24 weeks during years 4-5, then every 48 weeks thereafter.

Trial Phase Phase III

Trial Type Treatment

Lead Organization
Dana-Farber Harvard Cancer Center

Principal Investigator
Aparna Raj Parikh

  • Primary ID 18-397
  • Secondary IDs NCI-2020-01521
  • Clinicaltrials.gov ID NCT03803553