Recruiting
Phase 1
Phase 2

Pidnarulex & Cemiplimab

Sponsor:

National Cancer Institute (NCI)

Code:

NCT07147231

Conditions

Metastatic Colorectal Adenocarcinoma

Refractory Colorectal Adenocarcinoma

Stage III Colorectal Cancer AJCC v8

Stage IV Colorectal Cancer AJCC v8

Unresectable Colorectal Adenocarcinoma

Eligibility Criteria

Sex: All

Age: 18+

Healthy Volunteers: Not accepted

Interventions

Biopsy Procedure

Biospecimen Collection

Cemiplimab

Computed Tomography

Magnetic Resonance Imaging

Study Details

Brief summary:

This phase I/II trial studies the side effects and best dose of pidnarulex when given together with cemiplimab and to see how well it works in treating patients with microsatellite stable (MSS) colorectal cancer (CRC) that does not respond to treatment (refractory). Pidnarulex may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as cemiplimab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving pidnarulex with cemiplimab may be safe, tolerable and/or effective in treating patients with refractory MSS CRC.

Conditions

Metastatic Colorectal Adenocarcinoma

Refractory Colorectal Adenocarcinoma

Stage III Colorectal Cancer AJCC v8

Stage IV Colorectal Cancer AJCC v8

Unresectable Colorectal Adenocarcinoma

Study ID

NCT07147231

Start date

Aug 10, 2026

Status verified date

Aug, 2026

Completion date

Sep 30, 2027

Anticipated

Primary completion date

Sep 30, 2027

Anticipated

Eligibility Criteria

Eligibility Criteria

Sex: All

Age: 18+

Healthy Volunteers: Not accepted

Inclusion Criteria:

  • Patients must have pathologically confirmed colorectal adenocarcinoma that is unresectable and/or metastatic and for which standard curative or palliative measures do not exist or are no longer effective
  • Patients must have measurable disease as defined by Response Evaluation Criteria in Solid 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 by local tissue testing of the primary tumor and/or any metastatic lesion utilizing approved immunohistochemistry (for mismatch repair status) and/or polymerase chain reaction or next generation sequencing (for microsatellite status) assays. Historical (i.e., previously obtained) biopsy mismatch repair (MMR) and microsatellite instability (MSI) status may be utilized. If historical tissue is available, MMR and/or MSI testing may be performed on that tissue if not done previously. Clinical documentation of the patient's MMR and/or MSI status in the medical record may also be utilized to determine MMR and/or MSI status for the purposes of eligibility. pMMR results for eligibility testing must be available prior 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 imaging and/or histology, per investigator assessment); this metastasis does not need to be measurable
  • Phase 2 patients must have local/standard of care tumor molecular testing (tumor tissue or circulating tumor DNA) demonstrating MYC amplification or deleterious/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 factor receptor (EGFR) inhibitors, including cetuximab and panitumumab
  • Patients must have progressed on or have intolerance to (if eligible and not contraindicated 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 proven survival benefit, so it would not be appropriate for patients to enroll in this trial without this criterion being met. Subsequent standard of care treatments (trifluridine/tipiracil, fruquintinib, and regorafenib) have a very modest improvement on survival of only a few months compared to placebo and thus clinical trial options are commonly sought after oxaliplatin and irinotecan but before these other agents
  • Age ≥ 18 years. Because no dosing or adverse event data are currently available on the use of pidnarulex (CX-5461) in combination with cemiplimab in patients < 18 years 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 known Gilbert 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-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
  • For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
  • Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
  • Patients with treated brain metastases are eligible if follow-up brain imaging after central 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 treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
  • Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible 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 when administered to a pregnant woman. Animal studies have demonstrated that inhibition of the PD-1/PD-L1 pathway can lead to increased risk of immune-mediated rejection of the developing fetus resulting in fetal death. For these reasons, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) 14 days prior to study entry, for the duration of study participation and for at least 4 months after the last dose of cemiplimab (REGN2810) and 6 months after the last dose of pidnarulex (CX-5461). Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study intervention. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Women should not breastfeed while taking cemiplimab (REGN2810) for at least 4 months after cessation of treatment, and for pidnarulex (CX-5461), for 6 months after cessation of treatment. Women should not donate 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 consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants

Exclusion Criteria:

  • Patients with active autoimmune diseases, defined as requiring systemic treatment in the past 2 years with use of disease modifying agents, corticosteroids, or immunosuppressive drugs. Replacement therapy (eg; thyroxine, insulin, physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment
  • Patients with prior treatment with an RNA polymerase inhibitor, G quadruplex stabilizer, or immunotherapy. This includes prior treatment with a PD-1 or PD-L1 inhibitor agent
  • Presence of known photosensitivity disorders

  • Patients who do not agree to use sunglasses and sunscreen (≥ sun protective factor (SPF) 50 to ultraviolet B (UVB) and a high degree of protection against ultraviolet A (UVA) if exposed to sunlight during the study and for 4 weeks after the last dose are not eligible. Patients may also not use sun tanning beds during the study, and within 4 weeks after the last dose
  • Patients with a history of cicatricial conjunctivitis or active ocular surface disease (as evaluated by ophthalmologist as needed; routine eye exam for all study participants 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 similar chemical 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) plasma concentrations 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 prednisone daily or other immunosuppressive or disease-modifying agents, as this may reduce efficacy of an immunotherapy regimen
  • Patients with uncontrolled intercurrent illness or any other significant condition(s) that would make participation in this protocol unreasonably hazardous
  • Pregnant and lactating women are excluded from this study. The exclusion is based on the potential risk of adverse effects of pidnarulex (CX-5461) on fetal development and newborn health. The safety of pidnarulex (CX-5461) has not been established in pregnant or lactating women, and there is a possibility that the drug could cause harm to the developing fetus or be transferred to the infant through breast milk. Additionally, the physiological changes that occur during pregnancy and lactation could alter the pharmacokinetics and pharmacodynamics of pidnarulex (CX-5461), leading to unpredictable drug exposure and efficacy. There is also an increased risk of immune-mediated rejection of the developing fetus with cemiplimab (REGN2810)

Study Design

Enrollment

86 participants

Anticipated

Allocation

Randomized

Intervention Model

Sequential

Primary purpose

Treatment

Interventions and Outcome Measures

Arms

experimental: Phase I (cemiplimab, pidnarulex)

Patients receive cemiplimab IV over 30 minutes on days 1 and 15 of each cycle and pidnarulex IV over 60 minutes on days 1 and 8 of each cycle. Cycles repeat every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection on study and CT, MRI, or PET/CT throughout the trial.

active comparator: Phase II arm I (pidnarulex)

Patients receive pidnarulex IV over 60 minutes on days 1 and 8 of each cycle. Cycles repeat every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo tumor biopsy and CT, MRI, or PET/CT throughout the trial. Additionally, patients undergo blood sample collection on study.

experimental: Phase II arm II (cemiplimab, pidnarulex)

Patients receive cemiplimab IV over 30 minutes on days 1 and 15 of each cycle and pidnarulex IV over 60 minutes on days 1 and 8 of each cycle. Cycles repeat every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo tumor biopsy and CT, MRI, or PET/CT throughout the trial. Additionally, patients undergo blood sample collection on study.

Interventions

Biopsy Procedure

Undergo tumor biopsy

Biospecimen Collection

Undergo blood sample collection

Cemiplimab

Given IV

Computed Tomography

Undergo CT or PET/CT

Magnetic Resonance Imaging

Undergo MRI

Pidnarulex

Given IV

Positron Emission Tomography

Undergo PET/CT

Primary outcome measure

  • Recommended phase 2 dose (RP2D) of pidnarulex (CX-5461) with anti-programmed cell death protein 1 (anti-PD-1) (Phase 1) [ Time Frame: Up to 28 days ]
  • Incidence of adverse events, serious adverse events, and dose limiting toxicities [ Time Frame: Up to 30 days after last dose of study drug ]
  • Progression-free survival (PFS) (Phase II) [ Time Frame: From randomization until disease progression (as assessed by Response Evaluation Criteria in Solid Tumors [RECIST] version [v] 1.1) or death from any cause, whichever occurs first, assessed up to 2 years ]

Central Contacts and Locations

Locations

UCHealth University of Colorado Hospital

Recruiting

Aurora, Colorado, United States, 80045

Contacts

Site Public Contact

720-848-0650

Principal Investigator:

Wells A. Messersmith

MedStar Georgetown University Hospital

Recruiting

Washington D.C., District of Columbia, United States, 20007

Contacts

Site Public Contact

202-444-2223

Principal Investigator:

Benjamin A. Weinberg

Emory University Hospital Midtown

Recruiting

Atlanta, Georgia, United States, 30308

Contacts

Site Public Contact

888-946-7447

Principal Investigator:

Olumide B. Gbolahan

Emory University Hospital/Winship Cancer Institute

Recruiting

Atlanta, Georgia, United States, 30322

Contacts

Site Public Contact

404-778-1868

Principal Investigator:

Olumide B. Gbolahan

Emory Saint Joseph's Hospital

Recruiting

Atlanta, Georgia, United States, 30342

Contacts

Site Public Contact

404-851-7115

Principal Investigator:

Olumide B. Gbolahan

University of Maryland/Greenebaum Cancer Center

Recruiting

Baltimore, Maryland, United States, 21201

Contacts

Site Public Contact

800-888-8823

Principal Investigator:

Daniel Shu

Johns Hopkins University/Sidney Kimmel Cancer Center

Recruiting

Baltimore, Maryland, United States, 21287

Contacts

Site Public Contact

410-955-8804jhcccro@jhmi.edu

Principal Investigator:

Eric Christenson

More Information

Sponsor

National Cancer Institute (NCI)

Last update posted

Sep 9, 2026

Last verified

Aug, 2026

Trial information was received from ClinicalTrials.gov and was last updated on 2026-09-10. This information was provided to ClinicalTrials.gov by National Cancer Institute (NCI) on 2026-09-09.