Chemotherapy and/or Metastasectomy in Treating Participants With Metastatic Colorectal Adenocarcinoma With Lung Metastases

PRIMARY OBJECTIVES:

I. To compare recurrence-free survival in patients with "low risk" lung-limited metastatic
colorectal cancer (mCRC) undergoing pulmonary metastasectomy with or without perioperative
chemotherapy.

II. To compare overall survival in patients with "high risk" lung-limited mCRC receiving
systemic chemotherapy with or without surgical resection.

SECONDARY OBJECTIVES:

I. To compare grade 3 and 4 adverse events in patients receiving surgical resection and/or
chemotherapy in the management of lung-limited mCRC.

EXPLORATORY OBJECTIVES:

I. To evaluate for changes in circulating tumor deoxyribonucleic acid (DNA) following
surgical resection and/or systemic chemotherapy in patients with lung-limited mCRC.

OUTLINE: Participants are assigned to 1 of 2 risk groups (low or high).

GROUP 1 (LOW RISK): Participants are randomized to 1 of 2 groups.

GROUP 1A: Participants receive standard of care chemotherapy for 3 months prior to and 3
months after undergoing metastasectomy in the absence of disease progression or unacceptable
toxicity.

GROUP 1B: Participants undergo metastasectomy.

GROUP 2 (HIGH RISK): All high risk participants receive standard of care chemotherapy for 3
months in the absence of disease progression or unacceptable toxicity. Participants without
progressive disease after 3 months are then randomized to 1 of 2 groups.

GROUP 2A: Participants undergo metastasectomy.

GROUP 2B: Participants continue standard of care chemotherapy for 6 months in the absence of
disease progression or unacceptable toxicity. Participants with stable disease or
radiographic response after 6 months may then cross over to Group 2A.

After completion of study treatment, participants are followed up periodically for up to 5
years.

Inclusion Criteria:

1. Histological confirmation of colorectal adenocarcinoma.

2. Metastatic colorectal cancer involving the lung classified as measurable according to
RECIST 1.1 criteria.

3. Diagnosis of colorectal metastasis to lung made either histologically with
trans-thoracic needle biopsy or clinically based on radiographic imaging.

4. Identification as a medically appropriate candidate for surgical resection of the lung
metastasis (metastases) according to the evaluating cardiothoracic surgeon. Standard
justification for deeming a patient medically operable based on: (a) Pulmonary reserve
adequate to tolerate complete resection of all intrathoracic disease, as deemed by
thoracic surgeon, which may be determined by: Baseline FEV1 > 40% predicted,
post-operative predicted FEV1 > 30% predicted, DLCO > 40% predicted, absent baseline
hypoxemia and/or hypercapnia, exercise oxygen consumption > 50% predicted, absent
severe pulmonary hypertension, absent severe cerebral, cardiac, or peripheral vascular
disease, and absent severe chronic heart disease. (b) Ability to tolerate surgical
resection and acceptable operative risk as deemed by thoracic surgeon based on
performance status and medical comorbidities

5. Identification as a medically appropriate candidate for systemic chemotherapy at the
discretion of the evaluating medical oncologist.

6. Resection/definitive therapy of primary colorectal tumor with no suspicion of
recurrence. Prior radiation to a rectal adenocarcinoma is permitted.

7. Age >/= 18 years.

8. ECOG performance status (Appendix A) of 0 or 1.

9. Ability to provide informed consent for participation.

10. Patients must have normal organ and marrow function as defined: Leukocytes >/=
2,000/mcL; absolute neutrophil count >/= 1,000/mcL; hemoglobin >/= 9.0 gm/dL; platelet
count >/= 100,000/mcL; total bilirubin (ULN) (except patients with Gilbert Syndrome, who can have total bilirubin <3.0
mg/dL); AST(SGOT)/ALT(SGPT) clearance (CrCl >/= 50 mL/min (if using the Cockcroft-Gault formula below): Female
CrCl = (140 - age in years) x weight in kg x 0.85 72 x serum creatinine in mg/dL Male
CrCl = (140 - age in years) x weight in kg x 1.00 72 x serum creatinine in mg/dL

11. Patients (men and women) of child bearing potential should use an effective (for them)
method of birth control throughout their participation in this study.

Exclusion Criteria:

1. History of tumor involvement at other metastatic sites (e.g., liver, distant lymph
nodes, pleural effusion) within 12 months of planned operation. Prior surgical
resection for metastatic disease at other (non-pulmonary) sites is permitted provided
that the surgery was performed at least one year prior to date of screening with no
evidence of recurrence.

2. Presence of intact primary colorectal adenocarcinoma (or of an anastomotic
recurrence).

3. Previous radiotherapy to a lung metastasis that is still detectable radiographically.

4. Known DPD deficiency that would preclude the patient from tolerating 5-fluorouracil
chemotherapy.

5. Prior intolerance of systemic therapies used as standard regimens in the treatment of
metastatic CRC that would prohibit further receipt of systemic chemotherapy and/or
biologic agents - e.g.,5-fluorouracil, oxaliplatin, irinotecan, anti-VEGF therapies
(e.g., bevacizumab, ramucirumab), or anti-EGFR therapies (e.g., cetuximab,
panitumumab, for patients with RAS wild-type colorectal tumors).

6. Prior therapy with regorafenib or TAS-102 for metastatic/unresectable colorectal
cancer.

7. Synchronous primary or prior malignancy in the past 5 years other than nonmelanomatous
skin cancer or in situ cancer.

8. Pregnant or lactating women, as treatment involves unforeseeable risks to the embryo
or fetus.