Metastatic Colon Cancer, Stage III Colon Cancer
Conditions
Keywords
Metastatic colon Cancer, Stage III Colon Cancer
Brief summary
This research study is comparing two standard of care treatment options based on blood test results for participants who have metastatic colon cancer. The names of the potential treatments involved in this study are: * Active surveillance * FOLFIRI treatment * Nivolumab treatment * Encorafenib/Binimetinib/Cetuximab treatment * Trastuzumab + Pertuzumab
Detailed description
The FDA (the U.S. Food and Drug Administration) has approved FOLFIRI, comprised of Irinotecan, Leucovorin, and 5-Fluorouracil, as a treatment option for metastatic colon cancer in the Stage IV setting. * After diagnosis and surgical removal of tumors, individuals with metastatic colon cancer commonly receive what is called adjuvant chemotherapy treatment, commonly utilizing treatment plans called FOLFOX, CAPOX, or therapy with 5-Fluorouracil. * If all the cancer is not killed, the investigators may be able to detect tumor in the blood called circulating tumor DNA (ctDNA). This is genetic material unique to metastatic colon cancer that may be present in the blood stream, and it can be identified through a ctDNA blood test. If ctDNA is present in the blood stream, it is commonly called micro-metastatic disease (meaning disease that can't be seen detected by CT scans but may be there in the blood). Cancer researchers believe that ctDNA in the blood stream may be an indicator that cancer is more likely to recur. * After initial adjuvant chemotherapy, it is standard for individuals to begin active surveillance, where they do not receive further treatment but instead undergo frequent tumor imaging scans to see if their cancer is stable, growing, or coming back. The investigators plan to see if additional therapy, where FOLFIRI (comprised of Irinotecan, Leucovorin, and 5-Fluorouracil) is administered can decrease recurrence. Typically, FOLFIRI is given when the disease is visibly recurrent. * In addition, the investigators plan to include study groups of adjuvant nivolumab treatment and adjuvant Encorafenib/Binimetinib/Cetuximab treatment to see if these treatments can decrease recurrence. The FDA has not approved either of these as a treatment options for metastatic colon cancer in the Stage IV setting. * Patients who have a greater than normal number of genetic markers called microsatellites are called MSI-H. Because tumor cells with these features tend to have more genetic mutations than tumor cells without them, they are more likely to be recognized by the immune system. 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 your immune system and controls parts of your 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 is one of the first effective regimens to target the BRAF V600E-mutation in colon 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 slows down their growth and communication However, in this research study, the investigators are * determining whether there are differences in cancer recurrence in ctDNA positive participants treated with additional therapy versus put on active surveillance. * determining whether there are differences in health in ctDNA positive participants treated with additional therapy versus put on active surveillance. * examining whether patients who undergo further therapy experience changes in the ctDNA levels.
Interventions
DRUGFOLFIRI Protocol
FOLFIRI cycle will be two weeks (14 days) long, with FOLFIRI administered on Days 1-3. Participants will receive up to 12 two-week cycles (for a total of 24 weeks) of FOLFIRI chemotherapy.
OTHERACTIVE SURVEILLANCE
Will be followed with observation and monitoring with imaging, tumor markers, and ctDNA collections
DRUGNivolumab Protocol
Nivolumab cycle will be four weeks (28 days) long, with Nivolumab administered on day 1. Participants will receive up to 12 four-week cycles (for a total of 48 weeks) of Nivolumab treatment.
DRUGEncorafenib/Binimetinib/Cetuximab Protocol
Encorafenib/Binimetinib will be taken orally every day and Cetuximab will be administered intravenously on day 1 of each cycle. Cycles are 14 days long. Participants will receive up to 12 two-week cycles (for a total of 24 weeks) of Encorafenib/Binimetinib/Cetuximab.
Trastuzumab (Herceptin) is received by intravenous administration and Pertuzumab is received intravenously by infusion on Day 1 of each cycle. Cycles are 21 days long. Participants will receive up to 8 cycles of Trastuzumab and Pertuzumab.
Sponsors
Stand Up To Cancer
Massachusetts General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants must have histologically confirmed resected Stage III adenocarcinoma of the colon. Any T \[Tx, T1, T2, T3, or T4-\], N1-2M0. * Participants must have completely resected disease. In patients with tumor adherent to adjacent structures, en block RO resection must be documented. * Entire tumor must be in the colon (rectal involvement is excluded). * Participants 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. * Participants must not have received prior neoadjuvant chemotherapy. * Age ≥18 years. * ECOG performance status ≤1. * Life expectancy of greater than 3 months. * Participants must have normal organ and marrow function as defined below: * leukocytes ≥3,000/mcL * absolute neutrophil count ≥1,500/mcL * platelets ≥100,000/ mcL * total bilirubin within normal institutional limits. For patients with Gilbert's syndrome, total bilirubin must be ≤ 2 and documented as elevated indirect bilirubin. * AST(SGOT)/ALT(SGPT) ≤3 (AST) or ≤ 3 (ALT) × institutional upper limit of normal * creatinine within normal institutional limits OR * creatinine clearance ≥40 mL/min/1.73 m2 for participants with creatinine levels above institutional normal by Cockroft-Gault formula. * In order to be eligible for the ctDNA positive cohort, women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG). * 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, in order to be eligible for the ctDNA positive cohort, 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, ie, who are postmenopausal or surgically sterile as well as azoospermic men, do not require contraception. * Participants must have documentation of microsatellite instability status. Testing by NGS, 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. * Participant's circulating tumor DNA (ctDNA) assay (Guardant Reveal-Guardant Health) must satisfy assay specific quality control metrics to generate a result. * In order to be eligible for the ctDNA positive cohort, patient must be ctDNA positive following adjuvant therapy using the CLIA certified Guardant Reveal assay. ctDNA positive will be defined as positive based on having a tumor derived signal in the cfDNA that passes calling threshold (ctDNA detected). * Ability to understand and the willingness to sign a written informed consent document. Trastuzumab and Pertuzumab Specific Inclusion Criteria for HER2 cohort * HER2 overexpression/amplification as shown by NGS sequencing, IHC/FISH or Tumor with 3+ by IHC or 2+ by IHC and HER2/cep17 ratio \>2 by FISH. * AST(SGOT) ≤ 1.25 and ALT(SGPT) ≤ 1.25 × institutional upper limit of normal * Participants of childbearing potential must use effective contraceptive methods during and for 7 months after the last dose of HER2-targeted therapy * History of other malignancies within the 5 years prior to study registration, except for the following: carcinoma in situ of the cervix, carcinoma in situ of the colon, melanoma in situ, and basal cell and squamous cell carcinomas of the skin (\*malignancies occurring more than 5 years prior to study entry are permitted if curatively treated with surgery alone). * LVEF ≥ 55% measured by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) within 12 weeks of treatment start.
Exclusion criteria
* Patients who are receiving additional investigational therapy or on another investigational protocol * Patients who have confirmed metastatic disease per CT. * Patients who are unable to get any standard adjuvant therapy * Patients who have received more than 6 months of standard adjuvant therapy at the time of study entry. * With the exception of standard of care adjuvant therapy, patient 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 (ENCO/BINI/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. * (ctDNA positive cohort only). 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 Inclusion Criteria for MSI-H Cohort: * Must have documentation of microsatellite instability status. NGS, 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. * Patients must have detectable ctDNA (Guardant Reveal assay) post standard adjuvant therapy in order to be in this cohort. Nivolumab Specific
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Disease-free survival (DFS) | 5 years | Disease-free survival (DFS) between ctDNA-positive patients treated with additional treatment of FOLFIRI and ctDNA-positive patients who are untreated |
| Clearance rate of ctDNA | 7 Months | Compare the clearance rate of ctDNA in ctDNA-positive patients between patients treated with additional treatment of FOLFIRI and those who are untreated |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease-free survival (DFS) of Arm 4: Nivolumab Treatment | 5 years | Determine the disease-free survival (DFS) of ctDNA-positive patients treated with nivolumab in an exploratory MSI/mismatch repair deficient cohort |
| Clearance rate of ctDNA of Arm 5: Encorafenib/Binimetinib/Cetuximab Treatment | 7 months | Determine the clearance rate of ctDNA-positive patients treated with encorafenib, binimetinib, and cetuximab in an exploratory BRAF V600E cohort. |
| Disease-free survival (DFS) of Arm 5: Encorafenib/Binimetinib/Cetuximab Treatment | 5 years | Determine the disease-free survival DFS of ctDNA-positive patients treated with encorafenib, binimetinib, and cetuximab, in an exploratory BRAF V600E cohort. |
| Overall Survival (OS) Rate | 5 years | Overall survival (OS) between ctDNA-positive patients treated with additional adjuvant therapy (Arm 1) and ctDNA-positive patients who are untreated (Arm 2) |
| Lead time to recurrence | 5 years | Compare lead time to recurrence and sensitivity of predicting recurrence between ctDNA and tumor markers |
| Disease-free survival (DFS) of Arm 6: Herceptin/Perjeta | 5 years | Determine the DFS ctDNA-positive patients treated Herceptin/Perjeta |
| Clearance rate of Arm 6: Herceptin/Perjeta | 7 months | Determine the clearance rate of ctDNA-positive patients treated Herceptin/Perjeta |
| ctDNA clearance as Marker | 13 Months | Examine the correlation of ctDNA clearance as a surrogate marker for disease burden |
| Clearance rate of ctDNA of Arm 4: Nivolumab Treatment | 13 months | Determine clearance rate of ctDNA-positive patients treated with nivolumab in an exploratory MSI/mismatch repair deficient cohort |
Countries
United States
Contacts
Primary ContactAparna Parikh, MD
Outcome results
None listed