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

Inclusion Criteria

• Subjects must have the nature of the study explained to them
• Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests, pharmacokinetic collections, and other requirements of the study
• Subjects must provide a signed and dated Institutional Review Board (IRB) approved written informed consent form (ICF) in accordance with regulatory and institutional guidelines for both the study and exploratory biomarker analyses (e.g., CMS4 and others) on archival tissue
• Subjects must provide a signed and dated Health Insurance Portability and Accountability Act (HIPAA) authorization
• The ICF and HIPAA authorization must be obtained before conducting any procedures that do not form a part of the subject’s normal care
• After signing the ICF and HIPAA Authorization, subjects will be evaluated for study eligibility during the screening period (no more than 28 days before study drug administration) according to the following further inclusion/exclusion criteria below
• Men and women, ages >= 18 years of age
• Histologically or cytologically confirmed adenocarcinoma of the colon or the rectum that is metastatic or unresectable
• Tumor is determined to be RAS-mutated (KRAS or NRAS) and microsatellite stable/proficient in mismatch repair, as assessed by immunohistochemistry (IHC) and/or polymerase chain reaction (PCR)/next generation sequencing (NGS) in a Clinical Laboratory Improvement Act (CLIA) environment
• Received at least two prior regimens of therapy for unresectable or metastatic CRC including fluoropyrimidine-, oxaliplatin-, and irinotecan-based regimens. Patients who relapse within 6 months of adjuvant chemotherapy composed of oxaliplatin and a fluoropyrimidine will have their adjuvant therapy count as one prior regimen
• For the expansion cohort, pre-treatment primary tumor tissue (i.e., archived paraffin embedded) or from an unresectable metastatic site must be available for biomarker analyses. Biopsy should be excisional or core needle. Fine needle aspirates or other cytology samples are insufficient
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Must have measurable disease with at least 1 unidimensional measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1
• Prior radiotherapy must have been completed at least 2 weeks prior to study drug administration
• White blood cell count (WBC) >= 3000/uL (should be obtained within 14 days prior to first dose)
• Neutrophils > =1500/uL (should be obtained within 14 days prior to first dose)
• Platelets >= 100,000/uL (should be obtained within 14 days prior to first dose)
• Hemoglobin >= 9.0 g/dL (may have been transfused) (should be obtained within 14 days prior to first dose)
• Creatinine =< 1.5 mg/dL (should be obtained within 14 days prior to first dose)
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 X upper limit of normal (ULN) for subject with no liver metastases = < 5 X ULN for subjects with liver metastases (should be obtained within 14 days prior to first dose)
• Bilirubin < 1.5 mg/dL (unless diagnosed with Gilbert’s syndrome, who can have total bilirubin < 3.0 mg/dL) (should be obtained within 14 days prior to first dose)
• International normalized ratio (INR) or prothrombin time test (PT) =< 1.5 X ULN unless the subject is receiving anticoagulant therapy (should be obtained within 14 days prior to first dose)
• Activated partial thromboplastin time (aPTT) or partial thromboplastin time (PTT) =< 1.5 X ULN unless the subject is receiving anticoagulant therapy (should be obtained within 14 days prior to first dose)
• Glomerular filtration rate (GFR) calculated by Cockcroft-Gault formula > 60 ml/min
• Life expectancy >= 12 weeks as judged by the treating physician
• Subject re-enrollment: This study permits the re-enrollment of a subject that has discontinued the study as a pre-treatment failure (i.e., subject has not been treated with SX-682). If re-enrolled, the subject must be re-consented

Exclusion Criteria

• Active brain metastases or leptomeningeal metastases. Subjects with brain metastases are eligible if these have been treated and there is no magnetic resonance imaging (magnetic resonance imaging [MRI] - except where contraindicated, in which computed tomography [CT] scan is acceptable) evidence of progression for at least 8 weeks after treatment is complete and within 28 days prior to first dose of study drug administration. An MRI is not required to rule out brain metastases or leptomeningeal metastases. There must also be no requirement for high doses of systemic corticosteroids that could result in immunosuppression (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration
• Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results. Specifically: * Subjects with active, non-infectious pneumonitis * Subjects with interstitial lung disease or a history of pneumonitis that required oral or intravenous glucocorticoids to assist with management * Subjects with clinically significant heart disease that affects normal activities. Clinically significant cardiovascular/ cerebrovascular disease as follows: cerebral vascular accident / stroke / carotid artery disease / transient ischemic attack (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (New York Heart Association Classification Class > II) or serious cardiac arrhythmia
• Prior malignancy active within the previous 3 years except for locally curable cancers 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
• Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll
• Subjects with a condition (including organ or bone marrow transplant) requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications. Inhaled or topical steroids, and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease
• Use of other investigational drugs (drugs not marketed for any indication) or medications at immunosuppressive doses within 28 days before study drug administration
• Prior exposure to any immune checkpoint blockade agent or any other immunomodulatory agent used for antineoplastic therapy for mCRC
• Anticancer treatment within 21 days before the start of trial treatment [e.g., cytoreductive therapy, radiotherapy (with the exception of palliative radiotherapy delivered in a normal organ-sparing technique), immune therapy, or cytokine therapy]
• Major surgery as determined by the investigator within 28 days before the start of trial treatment (prior diagnostic biopsy is permitted)
• Subjects who have received a live-virus vaccine within 30 days before study drug administration
• Treatment with botanical preparations (e.g., herbal supplements or traditional Chinese medicines) intended for general health support or to treat the disease under study within 2 weeks prior to randomization/treatment
• Patients who are taking any drug that is known to prolong corrected QT (QTc) interval within at least 2 weeks before the start of trial drug and during the conduct of the trial
• Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic infection (hepatitis B virus [HBV] surface antigen positive and HBV core antibody positive with reflex to positive HBV DNA or HBV core antibody positive alone with reflex to positive HBV DNA or positive hepatitis C virus [HCV] antibody with reflex to positive HCV RNA)
• Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
• Active tuberculosis (history of exposure or history of positive tuberculosis test plus presence of clinical symptoms, physical or radiographic findings)
• Electrocardiogram (ECG) demonstrating a QTc interval >= 470 msec or patients with congenital long QT syndrome
• History of allergy to study drug components (excipients: hydroxypropyl methylcellulose phthalate (hypromellose phthalate or HPMCP), microcrystalline cellulose, sodium croscarmellose, sodium lauryl sulfate, and silicon dioxide)
• History of severe hypersensitivity reaction to any monoclonal antibody (grade >= 3 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v5)
• History of anaphylaxis, or recent (within 5 months) history of uncontrolled asthma
• Women of childbearing potential (WOCBP) must use method(s) of contraception as indicated while on study and for 5 months after the last dose of SX-682 or nivolumab. A WOCBP is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or is not postmenopausal. Menopause is defined clinically as 12 months of amenorrhea in a woman over age 45 in the absence of other biological or physiological causes
• Women under the age of 62 with a history of being postmenopausal must have a documented serum follicle stimulating hormone, (FSH) level >= 40 mIU/mL
• Women must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 24 hours prior to the start of study drug
• Women must not be breastfeeding
• Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year while on study and for a period at least 6 months after the last dose of study drug
• Women who are not of childbearing potential and azoospermic men do not require contraception