Summary

This phase III trial compares the addition of total ablative therapy to the usual systemic therapy versus the usual systemic therapy alone in treating patients with advanced colorectal cancer that has spread to up to 4 body sites (limited metastatic). The usual approach for patients who are not participating in a study is treatment with intravenous (through a vein) and/or oral medications (systemic therapy) to help stop the cancer sites from getting larger and the spread of the cancer to additional body sites. The ablative local therapy will consist of any combination of very focused, intensive radiotherapy called stereotactic ablative radiotherapy (SABR), surgical resection, or microwave ablation, which is a procedure where a needle is temporarily inserted in the tumor and heat is used to destroy the cancer cells. The addition of ablative local therapy to the usual approach of systemic therapy could be more effective than usual chemotherapy alone by increasing the life of patients with limited metastatic colorectal cancer.

Objectives

PRIMARY OBJECTIVE:
I. To evaluate and compare overall survival (OS) (measured from time of randomization) in patients with newly diagnosed oligometastatic colorectal cancer (oCRC) treated with total ablative therapy (TAT) in addition to standard of care (SOC) systemic therapy versus SOC systemic therapy.

SECONDARY OBJECTIVES:
I. To evaluate and compare event-free survival (EFS) (measured from time of randomization) between the two treatment arms.
II. To assess the adverse events (AE) profile within each of the two treatment arms.
III. To evaluate the time to local recurrence (TLR) (measured from completion of TAT) in patients with newly diagnosed oCRC treated with TAT + SOC systemic therapy.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM 1: Patients undergo TAT on study, consisting of any combination of SABR, surgical resection, or microwave ablation. Patients also receive SOC chemotherapy on study. Patients also undergo computed tomography (CT) or magnetic resonance imaging (MRI) or positron emission tomography (PET)/CT scans throughout the trial. Additionally, patients may undergo endoscopic exam and optional blood sample collection throughout the trial.

ARM 2: Patients receive SOC chemotherapy on study. Patients also undergo CT or MRI or PET/CT scans throughout the trial. Additionally, patients may undergo endoscopic exam and optional blood sample collection throughout the trial.

After completion of study treatment, patients are followed for 5 years from the date of registration.

Eligibility

1. Women and men of reproductive potential should agree to use an appropriate method of birth control throughout their participation in this study due to the teratogenic potential of the therapy utilized in this trial. Appropriate methods of birth control include abstinence, oral contraceptives, implantable hormonal contraceptives or double barrier method (diaphragm plus condom)
2. PRE-REGISTRATION (STEP 0): Pathologically proven diagnosis of colorectal adenocarcinoma with metastases (biopsy from primary tumor or metastatic site is acceptable)
3. PRE-REGISTRATION (STEP 0): No known microsatellite instable (MSI) tumor
4. PRE-REGISTRATION (STEP 0): No known BRAF V600E mutation
5. PRE-REGISTRATION (STEP 0): Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression. No known peritoneal and/or omental metastases. If radiologic studies suggest the presence of peritoneal disease, a diagnostic laparoscopy is recommended to verify the absence of peritoneal implants
6. PRE-REGISTRATION (STEP 0): Liver-only metastatic disease is NOT permitted. For patients with liver metastases, there must be at least one other site of metastasis in addition to the liver to be eligible for this study
7. PRE-REGISTRATION (STEP 0): Patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1
8. REGISTRATION (STEP 1): Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better
9. REGISTRATION (STEP 1): Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
10. REGISTRATION (STEP 1): A female of childbearing potential is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months)
11. REGISTRATION (STEP 1): Patients must have no overt evidence of disease progression during systemic therapy prior to registration
12. REGISTRATION (STEP 1): Not eligible for hepatic artery infusion pump (HAIP) therapy or benefit of HAIP therapy is undefined
13. REGISTRATION (STEP 1): Primary tumor is already resected OR patient has had a clinical complete response without surgical resection and no local regrowth (primary rectal tumors only) OR primary tumor is amenable to surgical resection, as determined by consultation and documentation with surgeon or documentation of discussion in the institutional multi-disciplinary tumor board where a surgeon confirms resectability. Patients with unresectable primary tumors are not eligible
14. REGISTRATION (STEP 1): Four (4) or fewer apparent sites of metastatic disease based on review by local medical team of radiographic imaging obtained following at least 12 weeks of systemic therapy. Of note, the primary tumor and associated regional lymph nodes do not count as one of the sites of disease. * Sites of metastatic disease must be radiographically evident, but pathologic confirmation is not required. * Metastatic lesions must be amenable to surgical resection, microwave ablation, SABR or any combination of these modalities. * Subcentimeter indeterminate lesions such as lung nodules < 5 mm in size may be considered metastases unless there are > 2 months of documented stability prior to the initiation of systemic therapy. * Single sites include: ** Each hemiliver (right and left), each lobe of the lungs, each adrenal gland, lymph nodes amenable to a single resection or treatment in a single SABR field, bone metastases amenable to treatment in a single SABR field
15. REGISTRATION (STEP 1): Patients must have measurable disease per RECIST v1.1
16. REGISTRATION (STEP 1): Patients must be receiving (or have received) first-line systemic therapy for metastatic disease for a minimum of 12 weeks and a maximum of 39 weeks
17. REGISTRATION (STEP 1): Prior definitive therapy, including adjuvant chemotherapy, must have been completed at least 6 months prior to diagnosis of metastatic disease
18. REGISTRATION (STEP 1): Not pregnant and not nursing, because this study involves an agent or treatment that has known genotoxic, mutagenic, and teratogenic effects. * Therefore, for women of childbearing potential only, a negative pregnancy test done =< 14 days prior to registration is required
19. REGISTRATION (STEP 1): Age >= 18 years
20. REGISTRATION (STEP 1): Eastern Cooperative Oncology Group (ECOG) performance status: 0-2
21. REGISTRATION (STEP 1): Absolute neutrophil count (ANC) >= 1,500/mm^3
22. REGISTRATION (STEP 1): Platelet count >= 50,000/mm^3
23. REGISTRATION (STEP 1): Creatinine =< 1.5 x upper limit of normal (ULN) OR calculated (calc.) creatinine clearance >= 30 mL/min * Calculated using the Cockcroft-Gault equation
24. REGISTRATION (STEP 1): Total bilirubin =< 1.5 x ULN
25. REGISTRATION (STEP 1): Aspartate aminotransferase (AST)(serum glutamic-oxaloacetic transaminase [SGOT]) / alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x ULN * In the event of metastatic liver disease, =< 5 x ULN
26. REGISTRATION (STEP 1): Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial. Note: HIV testing is not required for eligibility
27. REGISTRATION (STEP 1): No other planned concurrent investigational agents while on study

Treatment Sites in Georgia