Testing the Effectiveness of the Anti-cancer Drug Pidnarulex (CX-5461), in Combination With Another Anti-cancer Drug Cemiplimab (REGN2810), in Treating Refractory Microsatellite Stable Colorectal Cancer

Inclusion Criteria:

• Patients must have pathologically confirmed colorectal adenocarcinoma that isunresectable and/or metastatic and for which standard curative or palliativemeasures do not exist or are no longer effective

• Patients must have measurable disease as defined by Response Evaluation Criteria inSolid Tumors (RECIST) version (v) 1.1

• Patients must have pathologically confirmed proficient mismatch repair proteins (pMMR) and/or not microsatellite-high status (non-MSI-H). This may be confirmed bylocal tissue testing of the primary tumor and/or any metastatic lesion utilizingapproved immunohistochemistry (for mismatch repair status) and/or polymerase chainreaction or next generation sequencing (for microsatellite status) assays.Historical (i.e., previously obtained) biopsy mismatch repair (MMR) andmicrosatellite instability (MSI) status may be utilized. If historical tissue isavailable, MMR and/or MSI testing may be performed on that tissue if not donepreviously. Clinical documentation of the patient's MMR and/or MSI status in themedical record may also be utilized to determine MMR and/or MSI status for thepurposes of eligibility. pMMR results for eligibility testing must be availableprior to study enrollment and no eligibility testing will be conducted on study

• Phase 2 patients must have at least one liver metastasis at study entry (by imagingand/or histology, per investigator assessment); this metastasis does not need to bemeasurable

• Phase 2 patients must have local/standard of care tumor molecular testing (tumortissue or circulating tumor DNA) demonstrating MYC amplification ordeleterious/likely deleterious FBXW7 mutation, as defined in the report

• Phase 2 patients must have at least one tumor lesion amenable to biopsy

• Patients must undergo a washout period of 28 days for epidermal growth factorreceptor (EGFR) inhibitors, including cetuximab and panitumumab

• Patients must have progressed on or have intolerance to (if eligible and notcontraindicated per treating investigator) fluoropyrimidine, oxaliplatin,irinotecan, bevacizumab, and epidermal growth factor receptor (EGFR) inhibitor.These are standard of care treatments for this patient population with provensurvival benefit, so it would not be appropriate for patients to enroll in thistrial without this criterion being met. Subsequent standard of care treatments (trifluridine/tipiracil, fruquintinib, and regorafenib) have a very modestimprovement on survival of only a few months compared to placebo and thus clinicaltrial options are commonly sought after oxaliplatin and irinotecan but before theseother agents

• Age ≥ 18 years. Because no dosing or adverse event data are currently available onthe use of pidnarulex (CX-5461) in combination with cemiplimab in patients < 18years of age, children are excluded from this study

• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%)

• Absolute neutrophil count ≥ 1,500/mcL

• Platelets ≥ 100,000/mcL

• Hemoglobin ≥ 9 g/dL

• Total bilirubin ≤ 1.5 × upper limit of normal (ULN) (however, patients with knownGilbert disease who have serum bilirubin level of up to 3 mg/dl may be enrolled)

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) ≤ 3 × institutional ULN, (5 × ULN for patients with liver involvement)

• Glomerular filtration rate (GFR) ≥ 50 mL/min/1.73 m^2

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviraltherapy with undetectable viral load within 6 months are eligible for this trial

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBVviral load must be undetectable on suppressive therapy, if indicated

• Patients with a history of hepatitis C virus (HCV) infection must have been treatedand cured. For patients with HCV infection who are currently on treatment, they areeligible if they have an undetectable HCV viral load

• Patients with treated brain metastases are eligible if follow-up brain imaging aftercentral nervous system (CNS)-directed therapy shows no evidence of progression for ≥ 1 month after treatment of the brain metastases

• Patients with a prior or concurrent malignancy whose natural history or treatmentdoes not have the potential to interfere with the safety or efficacy assessment ofthe investigational regimen are eligible for this trial

• Patients with known history or current symptoms of cardiac disease, or history oftreatment with cardiotoxic agents, should have a clinical risk assessment of cardiacfunction using the New York Heart Association Functional Classification. To beeligible for this trial, patients should be class II or better

• The effects of that pidnarulex (CX-5461) on the developing human fetus are unknown.Based on its mechanism of action, cemiplimab (REGN2810) can cause fetal harm whenadministered to a pregnant woman. Animal studies have demonstrated that inhibitionof the PD-1/PD-L1 pathway can lead to increased risk of immune-mediated rejection ofthe developing fetus resulting in fetal death. For these reasons, women ofchild-bearing potential and men must agree to use adequate contraception (hormonalor barrier method of birth control; abstinence) 14 days prior to study entry, forthe duration of study participation and for at least 4 months after the last dose ofcemiplimab (REGN2810) and 6 months after the last dose of pidnarulex (CX-5461).Sexual abstinence is considered a highly effective method only if defined asrefraining from heterosexual intercourse during the entire period of risk associatedwith the study intervention. The reliability of sexual abstinence needs to beevaluated in relation to the duration of the study and the preferred and usuallifestyle of the participant. Should a woman become pregnant or suspect she ispregnant while she or her partner is participating in this study, she should informher treating physician immediately. Women should not breastfeed while takingcemiplimab (REGN2810) for at least 4 months after cessation of treatment, and forpidnarulex (CX-5461), for 6 months after cessation of treatment. Women should notdonate eggs for 14 days prior to the study, for the duration of study participation,and 6 months after completion of pidnarulex (CX-5461) and cemiplimab (REGN2810).Male patients must also agree to not donate sperm for 14 days prior to the study,for the duration of study participation, and 6 months after completion of pidnarulex (CX-5461) and cemiplimab (REGN2810) administration

• Ability to understand and the willingness to sign a written informed consentdocument. Legally authorized representatives may sign and give informed consent onbehalf of study participants

Exclusion Criteria:

• Patients with active autoimmune diseases, defined as requiring systemic treatment inthe past 2 years with use of disease modifying agents, corticosteroids, orimmunosuppressive drugs. Replacement therapy (eg; thyroxine, insulin, physiologiccorticosteroid replacement therapy for adrenal or pituitary insufficiency) is notconsidered a form of systemic treatment

• Patients with prior treatment with an RNA polymerase inhibitor, G quadruplexstabilizer, or immunotherapy. This includes prior treatment with a PD-1 or PD-L1inhibitor agent

• Presence of known photosensitivity disorders

• Patients who do not agree to use sunglasses and sunscreen (≥ sun protectivefactor (SPF) 50 to ultraviolet B (UVB) and a high degree of protection againstultraviolet A (UVA) if exposed to sunlight during the study and for 4 weeksafter the last dose are not eligible. Patients may also not use sun tanningbeds during the study, and within 4 weeks after the last dose

• Patients with a history of cicatricial conjunctivitis or active ocular surfacedisease (as evaluated by ophthalmologist as needed; routine eye exam for all studyparticipants is not needed)

• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia

• Patients who are receiving any other investigational agents

• Patients with a history of allergic reactions attributed to compounds of similarchemical or biologic composition to pidnarulex (CX-5461) and cemiplimab

• Patients who use strong CYP3A4 inhibitors or strong CYP3A4 inducers. Pidnarulex (CX-5461) has been shown to be metabolized primarily by the CYP3A4 enzyme.Inhibitors and substrates of these enzymes can increase pidnarulex (CX-5461) plasmaconcentrations while inducers of these enzymes can decrease pidnarulex (CX-5461)plasma concentrations

• Patients who are taking corticosteroids at a dose greater than 10 mg of prednisonedaily or other immunosuppressive or disease-modifying agents, as this may reduceefficacy of an immunotherapy regimen

• Patients with uncontrolled intercurrent illness or any other significantcondition(s) that would make participation in this protocol unreasonably hazardous

• Pregnant and lactating women are excluded from this study. The exclusion is based onthe potential risk of adverse effects of pidnarulex (CX-5461) on fetal developmentand newborn health. The safety of pidnarulex (CX-5461) has not been established inpregnant or lactating women, and there is a possibility that the drug could causeharm to the developing fetus or be transferred to the infant through breast milk.Additionally, the physiological changes that occur during pregnancy and lactationcould alter the pharmacokinetics and pharmacodynamics of pidnarulex (CX-5461),leading to unpredictable drug exposure and efficacy. There is also an increased riskof immune-mediated rejection of the developing fetus with cemiplimab (REGN2810)