Circulating Cell-Free Tumor DNA Testing in Guiding Treatment for Patients With Advanced or Metastatic Colorectal Cancer

PRIMARY OBJECTIVES:

I. To evaluate the ability of early change in circulating tumor-derived deoxyribonucleic acid
(ctDNA) (ctDNA-early dynamic changes [EDC] or A ctDNA) during systemic therapy in metastatic
colorectal cancer (mCRC) to predict radiographic progression (only standard of care [SOC]
arm).

II. To evaluate differences in clinically significant treatment-related adverse events
(TRAEs) of interest (grade 3/4 toxicity per National Cancer Institute (NCI)-Common
Terminology Criteria for Adverse Events (CTCAE) version 4.0, intolerable grade 2 toxicity or
any toxicity requiring dose reduction) between SOC and ctDNA arm.

SECONDARY OBJECTIVES:

I. To evaluate differences in patient-reported outcomes (PROs) between SOC and ctDNA arm.

II. To compare Response Evaluation Criteria in Solid Tumors (RECIST) duration of complete
response (DCR) (partial response [PR] and stable disease [SD]) between SOC and ctDNA arm.

III. To evaluate differences in overall survival (OS) between SOC and ctDNA arm.

IV. To evaluate differences between SOC and ctDNA arm with regards to emergency severity
indices (ESIs): Hospitalizations/emergency room visits.

V. To evaluate differences between SOC and ctDNA arm with regards to ESIs: Need for medical
interventions (blood transfusions and intravenous [IV] hydration).

VI. To evaluate cost-effectiveness associated with both strategies, i.e. SOC strategy and
ctDNA strategy in treatment of mCRC.

VII. To compare time to deterioration of Eastern Cooperative Oncology Group (ECOG)
performance status (PS) between SOC and ctDNA arms.

VIII. To compare time to deterioration of PROs between SOC and ctDNA arms. IX. To evaluate
differences in proportion of patients referred to clinical trial after completion of therapy
between SOC and ctDNA arms.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients undergo ctDNA testing and depending on the results receive either regorafenib
orally (PO) on days 1-21, trifluridine and tipiracil hydrochloride (TAS-102) PO twice daily
(BID) on days 1-5 and 8-12, or regorafenib PO on days 1-21 and TAS-102 PO BID on days 1-5 and
8-12. Treatment repeats every 28 days in the absence of disease progression or unacceptable
toxicity.

ARM II: Patients receive regorafenib or TAS-102 per standard of care. Treatment continues in
the event of disease stability or regression as per discretion of treating physician or
absence of disease progression.

After completion of study treatment, patients are followed up at 2 weeks and then monthly for
up to 18 months.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed colorectal cancer.

- Patients must have advanced or metastatic disease with no curative options.

- Patients must have radiographically evaluable disease.

- Patients must have had at least 2 prior therapies for mCRC (including fluorouracil
[5-FU], oxaliplatin, irinotecan, bevacizumab; cetuximab/panitumumab [for RAS wild type
(WT) patients]) and have either progressed on or intolerant to these agents or use of
these agents is contraindicated.

- Patients must be clinically eligible for either regorafenib or TAS-102 as per their
treating physician.

- Patients must have a negative serum pregnancy test done less than are equal to 14 days
prior to randomization for women of childbearing potential only. Women of child
bearing potential and men must agree to use adequate contraception (hormonal or
barrier method of birth control; abstinence) prior to study entry for the duration of
study participation.

- Patients must have ability to complete questionnaire(s) by themselves or with
assistance.

- Patients must have ability to provide informed written consent.

- Patients must be willing to return to enrolling institution for follow-up as per study
schedule.

- Patients must be willing to provide blood samples for correlative studies.

- Any of the following: Pregnant or nursing women, men or women of childbearing
potential who are unwilling to employ adequate contraception.

- Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment
of the investigator, 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.

Exclusion Criteria:

- Patient who have received prior TAS-102 are eligible to enroll on the study if they
can receive regorafenib and vice-versa. Otherwise these patients will be excluded from
the study.

- Congestive heart failure > New York Heart Association (NYHA) class 2, unstable angina
(angina symptoms at rest), new-onset angina (begun within the last 3 months) or
myocardial infarction less than 3 months prior to randomization.

- Ongoing infection > grade 2 CTCAE version 4.0.

- Symptomatic metastatic brain or meningeal tumors unless the patient is > 3 months from
definitive therapy, has a negative imaging study within 4 weeks of randomization and
is clinically stable with respect to brain lesions 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]).

- Renal failure requiring hematological or peritoneal dialysis.

- Patients unable to swallow oral medications.