SX-682 and Nivolumab for the Treatment of RAS-Mutated, MSS Unresectable or Metastatic Colorectal Cancer, the STOPTRAFFIC-1 Trial

Inclusion Criteria:

1. Written Informed Consent and HIPAA Authorization

2. Subjects must have the nature of the study explained to them.

3. Non-English speaking patients will be eligible for participation withinvolvement of the MD Anderson Language Assistance department in the informedconsent process (per MD Anderson SOP 04_Informed Consent Process).

4. Subjects must be willing and able to comply with scheduled visits, treatmentschedule, laboratory tests, pharmacokinetic collections, and other requirementsof the study.

5. Subjects must provide a signed and dated IRB approved written informed consentform (ICF) in accordance with regulatory and institutional guidelines for boththe study and exploratory biomarker analyses (e.g., CMS4 and others) onarchival tissue.

6. Subjects must provide a signed and dated Health Insurance Portability andAccountability Act (HIPAA) authorization.

7. The ICF and HIPAA authorization must be obtained before conducting anyprocedures that do not form a part of the subject's normal care.

8. After signing the ICF and HIPAA Authorization, subjects will be evaluated forstudy eligibility during the Screening Period (no more than 28 days beforestudy drug administration) according to the following further

inclusion/exclusion criteria:

2. Target Population

3. Men and women, ages > 18 years of age. Both men and women of all races andethnic groups, regardless of preferred language, are eligible for this trial.

4. Histologically or cytologically confirmed adenocarcinoma of the colon or therectum that is metastatic or unresectable.

5. Tumor is determined to be RAS-mutated (KRAS or NRAS) and microsatellitestable/proficient in mismatch repair, as assessed by IHC and/or PCR/NGS in aCLIA environment.

6. Received at least two prior regimens of therapy for unresectable or metastaticCRC including fluoropyrimidine-, oxaliplatin-, and irinotecan-based regimens.Patients who relapse within 6 months of adjuvant chemotherapy composed ofoxaliplatin and a fluoropyrimidine will have their adjuvant therapy count asone prior regimen.

7. For the expansion cohort, pre-treatment primary tumor tissue (i.e., archivedparaffin-embedded) or from an unresectable metastatic site must be availablefor biomarker analyses. Biopsy should be excisional or core needle. Fine needleaspirates or other cytology samples are insufficient.

8. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 (Appendix 1).

9. Must have measurable disease with at least 1 unidimensional measurable lesionper RECIST v1.1 (see Appendix 2).

10. Prior radiotherapy must have been completed at least 2 weeks prior to studydrug administration.

11. Screening laboratory values must meet the following criteria and should beobtained within 14 days prior to first dose:WBC > 3000/µL Neutrophils > 1500/ µL Platelets > 100,000/µL Hemoglobin > 9.0g/dL (may have been transfused) Creatinine < 1.5 mg/dL AST/ALT < 2.5 X ULN forsubject with no liver metastases < 5 X ULN for subjects with liver metastasesBilirubin < 1.5 mg/dL (unless diagnosed with Gilbert's syndrome, who can havetotal bilirubin < 3.0 mg/dL) INR or PT < 1.5 X ULN unless the subject isreceiving anticoagulant therapy aPTT or PTT < 1.5 X ULN unless the subject isreceiving anticoagulant therapy

12. Glomerular filtration rate (GFR) calculated by Cockcroft-Gault formula >60ml/min.

13. Life expectancy > 12 weeks as judged by the treating physician.

14. Subject Re-enrollment: This study permits the re-enrollment of a subject thathas discontinued the study as a pre-treatment failure (i.e., subject has notbeen treated with SX-682). If re-enrolled, the subject must be re-consented.

Exclusion Criteria

1. Target Disease Exceptions a) Active brain metastases or leptomeningeal metastases. Subjects with brainmetastases are eligible if these have been treated and there is no magneticresonance imaging (MRI - except where contraindicated, in which CT scan isacceptable) evidence of progression for at least 8 weeks after treatment is completeand within 28 days prior to first dose of study drug administration. An MRI is notrequired to rule out brain metastases or leptomeningeal metastases. There must alsobe no requirement for high doses of systemic corticosteroids that could result inimmunosuppression (> 10 mg/day prednisone equivalents) for at least 2 weeks prior tostudy drug administration. b) Patients with bulky liver metastases (liver metastases >3cm) are not eligible.

2. Medical History and Concurrent Diseases a) Any serious or uncontrolled medical disorder that, in the opinion of theinvestigator, may increase the risk associated with study participation or studydrug administration, impair the ability of the subject to receive protocol therapy,or interfere with the interpretation of study results. Specifically: a. Subjects with active, non-infectious pneumonitis. b. Subjects with interstitiallung disease or a history of pneumonitis that required oral or intravenousglucocorticoids to assist with management. c. Subjects with clinically significant heart disease that affects normalactivities. Clinically significant cardiovascular/ cerebrovascular disease asfollows: cerebral vascular accident / stroke / carotid artery disease / transientischemic attack (<6 months prior to enrollment), myocardial infarction (<6 monthsprior to enrollment), unstable angina, congestive heart failure (New York HeartAssociation Classification Class >II) or serious cardiac arrhythmia. b) Prior malignancy active within the previous 3 years except for locally curablecancers that have been apparently cured, such as basal or squamous cell skin cancer,superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast. c) Subjects with active, known or suspected autoimmune disease (Appendix 3).Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due toautoimmune condition only requiring hormone replacement, psoriasis not requiringsystemic treatment, or conditions not expected to recur in the absence of anexternal trigger are permitted to enroll. d) Subjects with a condition (including organ or bone marrow transplant) requiringsystemic treatment with either corticosteroids (> 10 mg daily prednisoneequivalents) or other immunosuppressive medications. Inhaled or topical steroids,and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted inthe absence of active autoimmune disease. e) Use of other investigational drugs (drugs not marketed for any indication) ormedications at immunosuppressive doses within 28 days before study drugadministration. f) Prior exposure to any immune checkpoint blockade agent or any otherimmunomodulatory agent used for antineoplastic therapy for mCRC. g) Anticancer treatment within 21 days before the start of trial treatment [e.g.,cytoreductive therapy, radiotherapy (with the exception of palliative radiotherapydelivered in a normal organ-sparing technique), immune therapy, or cytokinetherapy]. Note: Patients on maintenance anti-hormonal treatment to preventrecurrence and secondary cancers are eligible for participation. h) Major surgery as determined by the investigator within 28 days before the startof trial treatment (prior diagnostic biopsy is permitted). i) Subjects who have received a live-virus vaccine within 30 days before study drugadministration. j) Treatment with botanical preparations (e.g., herbal supplements or traditionalChinese medicines) intended for general health support or to treat the disease understudy within 2 weeks prior to randomization/treatment. k) Patients who are taking any drug that is known to prolong QTc interval within atleast 2 weeks before the start of trial drug and during the conduct of the trial. l) Individuals lacking the ability, based on reasonable medical judgment, tounderstand and appreciate the nature and consequences of participation in this studywill not be eligible for participation