Metastatic Colorectal AdenocarcinomaPhase 1/2NCT07147231
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
A Phase 1/2 study testing Biopsy Procedure, Biospecimen Collection and Cemiplimab in people with Metastatic Colorectal Adenocarcinoma and Refractory Colorectal Adenocarcinoma, run by National Cancer Institute (NCI) at 7 sites in United States.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Metastatic Colorectal Adenocarcinoma, Refractory Colorectal Adenocarcinoma, Stage III Colorectal Cancer AJCC v8
- What is being tested?
- Biopsy Procedure, Biospecimen Collection and Cemiplimab
- Type of treatment
- Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 86 participants
- Where
- 7 sitesUnited States
- Study dates
- 10 Aug 2026to 30 Sep 2027
- Phase
- Phase 1/2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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
Who cannot join
- 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
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- 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)
Trial locations and contacts
7 sites in 1 country. Contact the study team or a site near you to ask about taking part.
7 sites in 1 country
United States7 sites, 7 recruiting
- Recruiting
Emory University Hospital Midtown
Atlanta, Georgia, 30308
Site Public Contact, 888-946-7447
Olumide B. Gbolahan
- Recruiting
Emory University Hospital/Winship Cancer Institute
Atlanta, Georgia, 30322
Site Public Contact, 404-778-1868
Olumide B. Gbolahan
- Recruiting
Emory Saint Joseph's Hospital
Atlanta, Georgia, 30342
Site Public Contact, 404-851-7115
Olumide B. Gbolahan
- Recruiting
UCHealth University of Colorado Hospital
Aurora, Colorado, 80045
Site Public Contact, 720-848-0650
Wells A. Messersmith
- Recruiting
University of Maryland/Greenebaum Cancer Center
Baltimore, Maryland, 21201
Site Public Contact, 800-888-8823
Daniel Shu
- Recruiting
Johns Hopkins University/Sidney Kimmel Cancer Center
Baltimore, Maryland, 21287
Site Public Contact, 410-955-8804, jhcccro@jhmi.edu
Eric Christenson
- Recruiting
MedStar Georgetown University Hospital
Washington D.C., District of Columbia, 20007
Site Public Contact, 202-444-2223
Benjamin A. Weinberg
About this study
Official title: A Phase 1 and Randomized Phase 2 Trial of Pidnarulex (CX-5461) and Cemiplimab (REGN2810) in Refractory Microsatellite Stable Colorectal Cancer
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.
Read the detailed description
PRIMARY OBJECTIVES:
- To establish the recommended phase 2 dose of pidnarulex (CX-5461) with anti-programmed cell death protein 1 (PD-1) in phase 1, and to determine safety and tolerability of pidnarulex (CX-5461) alone, and in combination with anti-PD-1 in phases 1 and 2.
II. To determine the progression-free survival (PFS) of pidnarulex (CX-5461) alone and in combination with anti-PD-1 in patients with refractory liver metastatic microsatellite stable (MSS) colorectal cancer (CRC) associated with replication stress in phase 2.
SECONDARY OBJECTIVES:
- To observe and record anti-tumor activity. II. To compare the objective response rate (ORR) and disease control rate (DCR) of patients treated with pidnarulex (CX-5461) alone and in combination with anti-PD-1 in phase 2.
III. To compare the duration of response (DoR) of patients treated with pidnarulex (CX-5461) alone and in combination with anti-PD-1 in phase 2.
IV. To compare the overall survival (OS) of patients treated with pidnarulex (CX-5461) alone and in combination with anti-PD-1 in phase 2.
- To evaluate plasma pharmacokinetic (PK) profiles of pidnarulex (CX-5461) alone and in combination with anti-PD-1.
VI. To evaluate the plasma PK profile of cemiplimab. VII. To explore gene signature patterns at baseline or following treatment that may suggest, response to pidnarulex (CX-5461) alone or in combination with anti-PD-1, by whole exome sequencing (WES) and ribonucleic acid (RNA) sequencing in tumor tissue and cell-free deoxyribonucleic acid (DNA) in peripheral blood in phase 2.
EXPLORATORY OBJECTIVES:
- To evaluate the baseline expression of MYC and CCNE1 in tumor tissue and its association with response to treatment, as identified by immunohistochemistry in phase 2.
II. To evaluate the stimulator of interferon genes (STING) pathway activation and immune cell profile in the tumor at baseline and after treatment with pidnarulex (CX-5461) alone or in combination with anti-PD-1, and its association with response to treatment, as identified by immunohistochemistry in phase 2.
III. To evaluate replication stress at baseline and after treatment, and its association with response to treatment, as identified by immunohistochemistry in phase 2.
IV. To explore pidnarulex (CX-5461) target engagement, as identified by 47S pre-ribosomal ribonucleic acid (rRNA) in-situ hybridization in phase 2.
- To explore DNA alterations in circulating-tumor deoxyribonucleic acid (ctDNA) and their potential correlation with response to treatment in phase 2.
OUTLINE: This is a phase I, dose-escalation study of pidnarulex in combination with cemiplimab followed by a phase II study.
PHASE I:
Patients receive cemiplimab intravenously (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 computed tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography (PET)/CT throughout the trial.
PHASE II: Patients are randomized to 1 of 2 arms.
ARM I: 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.
ARM II: 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.
After completion of study treatment, patients are followed up at 30 days and then every 3 months for 2 years.
- Conditions
- Metastatic Colorectal Adenocarcinoma, Refractory Colorectal Adenocarcinoma, Stage III Colorectal Cancer AJCC v8, Stage IV Colorectal Cancer AJCC v8, Unresectable Colorectal Adenocarcinoma
- Being tested
- Biopsy Procedure, Biospecimen Collection, Cemiplimab, Computed Tomography, Magnetic Resonance Imaging
- Medical subject headings
- Colorectal Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Biopsy ProcedureProcedure or surgery
Also called Biopsy, BIOPSY_TYPE, Bx
Undergo tumor biopsy
Biospecimen CollectionProcedure or surgery
Also called Biological Sample Collection, Biospecimen Collected, Sample Collection, Specimen Collection
Undergo blood sample collection
CemiplimabBiological
Also called Cemiplimab RWLC, Cemiplimab-rwlc, Libtayo, REGN 2810
Given IV
Computed TomographyProcedure or surgery
Also called CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography
Undergo CT or PET/CT
Magnetic Resonance ImagingProcedure or surgery
Also called Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan
Undergo MRI
PidnarulexDrug
Also called CX-5461, CX5461, Pol I Inhibitor CX5461, RNA Pol I Inhibitor CX5461
Given IV
Positron Emission TomographyProcedure or surgery
Also called Medical Imaging, Positron Emission Tomography, PET, PET Scan, Positron emission tomography (procedure)
Undergo PET/CT
| Study group | Role | What they receive |
|---|---|---|
| Phase I (cemiplimab, pidnarulex) | Experimental | 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. Receives: Procedure: Biospecimen Collection; Biological: Cemiplimab; Procedure: Computed Tomography; Procedure: Magnetic Resonance Imaging; Drug: Pidnarulex; Procedure: Positron Emission Tomography |
| Phase II arm I (pidnarulex) | Active comparator | 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. Receives: Procedure: Biopsy Procedure; Procedure: Biospecimen Collection; Procedure: Computed Tomography; Procedure: Magnetic Resonance Imaging; Drug: Pidnarulex; Procedure: Positron Emission Tomography |
| Phase II arm II (cemiplimab, pidnarulex) | Experimental | 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. Receives: Procedure: Biopsy Procedure; Procedure: Biospecimen Collection; Biological: Cemiplimab; Procedure: Computed Tomography; Procedure: Magnetic Resonance Imaging; Drug: Pidnarulex; Procedure: Positron Emission Tomography |
What is being measured
The primary outcome is the main question the study is designed to answer.
Recommended phase 2 dose (RP2D) of pidnarulex (CX-5461) with anti-programmed cell death protein 1 (anti-PD-1) (Phase 1)
The Bayesian optimal interval design will be employed to identify the RP2D of pidnarulex (CX-5461) in combination with anti-PD-1.
Measured: Up to 28 days
Incidence of adverse events, serious adverse events, and dose limiting toxicities
Will evaluate safety and tolerability of pidnarulex (CX-5461) alone and in combination with anti-PD-1 in phases 1-2. Safety and tolerability will be summarized via descriptive statistics, including adverse events, serious adverse events, and dose limiting toxicities.
Measured: Up to 30 days after last dose of study drug
Progression-free survival (PFS) (Phase II)
Will evaluate PFS of pidnarulex (CX-5461) alone and in combination with anti-PD-1 in patients with refractory liver metastatic microsatellite stable colorectal cancer associated with replication stress in phase 2. PFS will be compared between the 2 treatment groups following the futility boundary on hazard ratio (HR) derived by using a Hwang-Shih-DeCani spending function with gamma = -2.909. The Kaplan-Meier method will be used to estimate median PFS, PFS rates at different time points, and their 95% confidence intervals (CIs), using the Brookmeyer Crowley's method. The HR and the corresponding two-sided 95% CI will be estimated in a stratified Cox regression model. Stratification factors are consistent with those used at randomization. Subgroup analysis will be performed to assess the consistency of treatment effect across subgroups.
Measured: 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
Secondary outcomes (7)
Objective response rate (ORR) (Phase 2)
Will evaluate the ORR of patients treated with pidnarulex (CX-5461) alone and in combination with anti-PD-1 in phase 2. Defined as the proportion (%) of patients with confirmed complete response (CR) or partial response (PR) as assessed according to RECIST v1.1. ORR will be compared to historical control following Simon's two stage design for the within-arm analysis. The cumulative frequency estimated ORR with corresponding 95% CI will be reported.
Measured: Up to disease progression or subsequent anticancer therapy, or until the last evaluable tumor assessment in the absence of disease progression, assessed up to 2 years
Disease control rate (DCR) (Phase 2)
Will evaluate the DCR of patients treated with pidnarulex (CX-5461) alone and in combination with anti-PD-1 in phase 2.Defined as the proportion (%) of patients with confirmed CR, PR or stable disease as assessed according to RECIST v1.1. The cumulative frequency estimated DCR with corresponding 95% CI will be reported.
Measured: Up to disease progression or subsequent anticancer therapy, or until the last evaluable tumor assessment in the absence of disease progression, assessed up to 2 years
Duration of response (DOR) (Phase 2)
Will evaluate the DOR of patients treated with pidnarulex (CX-5461) alone and in combination with anti-PD-1 in phase 2. Will be evaluated only for patients who achieve CR or PR. DOR will be summarized descriptively using the Kaplan-Meier method.
Measured: From the first recorded response (confirmed CR or PR) to the first recorded disease progression (according to RECIST v1.1) or death from any cause, whichever occurs first, assessed up to 2 years
Overall survival (OS) (Phase 2)
Will evaluate the OS of patients treated with pidnarulex (CX-5461) alone and in combination with anti-PD-1 in phase 2. OS will be summarized descriptively using the Kaplan-Meier method.
Measured: From randomization until death from any cause, assessed up to 2 years
Pharmacokinetic (PK) parameters of pidnarulex (CX-5461)
Will evaluate the PK parameters of pidnarulex (CX-5461) when given alone and in combination with anti-PD-1, including volume of distribution, area under the curve, maximum serum concentration, serum half-life, and accumulation. Will be reported descriptively. Will be analyzed with both non-compartmental and nonlinear mixed effects approaches. Will also be compared between the randomized arms.
Measured: Cycle (C) 1 day (D) 1, C1D8, C1D9, C1D15, C2D1, C2D15, C3D1, C6D1, C9D1, C12D1
PK parameters of cemiplimab (REGN2810)
Will evaluate the PK parameters of cemiplimab (REGN2810), including clearance. Will be reported descriptively. Will be analyzed with both non-compartmental and nonlinear mixed effects approaches.
Measured: C1D1, C1D8, C1D9, C1D15, C2D1, C2D15, C3D1, C6D1, C9D1, C12D1
Gene signature patterns (Phase 2)
Will evaluate gene signature patterns at baseline or following treatment that may suggest response to pidnarulex (CX-5461) alone or in combination with anti-PD-1, by whole exome sequencing and ribonucleic acid sequencing in tumor tissue and cell-free deoxyribonucleic acid (DNA) in peripheral blood in phase 2.
Measured: At baseline and 30 days after last dose of study drug
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 Aug 2025
- Study start10 Aug 2026
- Primary completion30 Sep 2027 (estimated)
- Study completion30 Sep 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Metastatic Colorectal AdenocarcinomaStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Sequential
- Model description
- In phase 1, patients will be treated with pidnarulex (CX-5461) in combination with cemiplimab (REGN2810) to determine the pidnarulex (CX-5461) RP2D. In phase 2 (randomized), patients will be randomized to receive either pidnarulex (CX-5461) alone or in combination with anti-PD-1, to evaluate the primary endpoint of progression-free survival.
- Masking
- None (open label)
- Enrolment
- 86 participants (estimated)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Wells A Messersmith, Principal investigator, JHU Sidney Kimmel Comprehensive Cancer Center LAO
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07147231
- Sponsor's protocol ID
- NCI-2025-06058
- Other IDs
- NCI-2025-06058, 10716, 10716, UM1CA186691
- Status last verified
- Aug 2026
- First submitted
- 28 Aug 2025
- Last updated
- 9 Sep 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.
Study at a glance
From the registry record, last updated by the sponsor on 9 Sep 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase 1 and Randomized Phase 2 Trial of Pidnarulex (CX-5461) and Cemiplimab (REGN2810) in Refractory Microsatellite Stable Colorectal Cancer
- ClinicalTrials.gov ID
- NCT07147231
- Acronym / sponsor ID
- NCI-2025-06058
- Conditions
- Metastatic Colorectal Adenocarcinoma, Refractory Colorectal Adenocarcinoma, Stage III Colorectal Cancer AJCC v8, Stage IV Colorectal Cancer AJCC v8, Unresectable Colorectal Adenocarcinoma
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 86 participants (estimated)
- Lead sponsor
- National Cancer Institute (NCI)US National Institutes of Health
- Study start
- 10 Aug 2026 (actual)
- Primary completion
- 30 Sep 2027 (estimated)
- Study completion
- 30 Sep 2027 (estimated)
- First posted
- 29 Aug 2025 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
PRIMARY OBJECTIVES:
- To establish the recommended phase 2 dose of pidnarulex (CX-5461) with anti-programmed cell death protein 1 (PD-1) in phase 1, and to determine safety and tolerability of pidnarulex (CX-5461) alone, and in combination with anti-PD-1 in phases 1 and 2.
II. To determine the progression-free survival (PFS) of pidnarulex (CX-5461) alone and in combination with anti-PD-1 in patients with refractory liver metastatic microsatellite stable (MSS) colorectal cancer (CRC) associated with replication stress in phase 2.
SECONDARY OBJECTIVES:
- To observe and record anti-tumor activity. II. To compare the objective response rate (ORR) and disease control rate (DCR) of patients treated with pidnarulex (CX-5461) alone and in combination with anti-PD-1 in phase 2.
III. To compare the duration of response (DoR) of patients treated with pidnarulex (CX-5461) alone and in combination with anti-PD-1 in phase 2.
IV. To compare the overall survival (OS) of patients treated with pidnarulex (CX-5461) alone and in combination with anti-PD-1 in phase 2.
- To evaluate plasma pharmacokinetic (PK) profiles of pidnarulex (CX-5461) alone and in combination with anti-PD-1.
VI. To evaluate the plasma PK profile of cemiplimab. VII. To explore gene signature patterns at baseline or following treatment that may suggest, response to pidnarulex (CX-5461) alone or in combination with anti-PD-1, by whole exome sequencing (WES) and ribonucleic acid (RNA) sequencing in tumor tissue and cell-free deoxyribonucleic acid (DNA) in peripheral blood in phase 2.
EXPLORATORY OBJECTIVES:
- To evaluate the baseline expression of MYC and CCNE1 in tumor tissue and its association with response to treatment, as identified by immunohistochemistry in phase 2.
II. To evaluate the stimulator of interferon genes (STING) pathway activation and immune cell profile in the tumor at baseline and after treatment with pidnarulex (CX-5461) alone or in combination with anti-PD-1, and its association with response to treatment, as identified by immunohistochemistry in phase 2.
III. To evaluate replication stress at baseline and after treatment, and its association with response to treatment, as identified by immunohistochemistry in phase 2.
IV. To explore pidnarulex (CX-5461) target engagement, as identified by 47S pre-ribosomal ribonucleic acid (rRNA) in-situ hybridization in phase 2.
- To explore DNA alterations in circulating-tumor deoxyribonucleic acid (ctDNA) and their potential correlation with response to treatment in phase 2.
OUTLINE: This is a phase I, dose-escalation study of pidnarulex in combination with cemiplimab followed by a phase II study.
PHASE I:
Patients receive cemiplimab intravenously (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 computed tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography (PET)/CT throughout the trial.
PHASE II: Patients are randomized to 1 of 2 arms.
ARM I: 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.
ARM II: 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.
After completion of study treatment, patients are followed up at 30 days and then every 3 months for 2 years.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 3
- Model description
- In phase 1, patients will be treated with pidnarulex (CX-5461) in combination with cemiplimab (REGN2810) to determine the pidnarulex (CX-5461) RP2D. In phase 2 (randomized), patients will be randomized to receive either pidnarulex (CX-5461) alone or in combination with anti-PD-1, to evaluate the primary endpoint of progression-free survival.
| Arm | Type | Receives |
|---|---|---|
| Phase I (cemiplimab, pidnarulex) | Experimental | Procedure: Biospecimen Collection, Biological: Cemiplimab, Procedure: Computed Tomography, Procedure: Magnetic Resonance Imaging, Drug: Pidnarulex, Procedure: Positron Emission TomographyPatients 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. |
| Phase II arm I (pidnarulex) | Active comparator | Procedure: Biopsy Procedure, Procedure: Biospecimen Collection, Procedure: Computed Tomography, Procedure: Magnetic Resonance Imaging, Drug: Pidnarulex, Procedure: Positron Emission TomographyPatients 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. |
| Phase II arm II (cemiplimab, pidnarulex) | Experimental | Procedure: Biopsy Procedure, Procedure: Biospecimen Collection, Biological: Cemiplimab, Procedure: Computed Tomography, Procedure: Magnetic Resonance Imaging, Drug: Pidnarulex, Procedure: Positron Emission TomographyPatients 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (24 listed)
- 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
Key exclusion criteria (12 listed)
- 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 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Biopsy ProcedureAlso: Biopsy, BIOPSY_TYPE, BxUndergo tumor biopsy | Procedure or surgery | Phase II arm I (pidnarulex), Phase II arm II (cemiplimab, pidnarulex) |
| Biospecimen CollectionAlso: Biological Sample Collection, Biospecimen Collected, Sample Collection, Specimen CollectionUndergo blood sample collection | Procedure or surgery | Phase I (cemiplimab, pidnarulex), Phase II arm I (pidnarulex), Phase II arm II (cemiplimab, pidnarulex) |
| CemiplimabAlso: Cemiplimab RWLC, Cemiplimab-rwlc, Libtayo, REGN 2810Given IV | Biological | Phase I (cemiplimab, pidnarulex), Phase II arm II (cemiplimab, pidnarulex) |
| Computed TomographyAlso: CAT, CAT Scan, Computed Axial Tomography, Computerized Axial TomographyUndergo CT or PET/CT | Procedure or surgery | Phase I (cemiplimab, pidnarulex), Phase II arm I (pidnarulex), Phase II arm II (cemiplimab, pidnarulex) |
| Magnetic Resonance ImagingAlso: Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging ScanUndergo MRI | Procedure or surgery | Phase I (cemiplimab, pidnarulex), Phase II arm I (pidnarulex), Phase II arm II (cemiplimab, pidnarulex) |
| PidnarulexAlso: CX-5461, CX5461, Pol I Inhibitor CX5461, RNA Pol I Inhibitor CX5461Given IV | Drug | Phase I (cemiplimab, pidnarulex), Phase II arm I (pidnarulex), Phase II arm II (cemiplimab, pidnarulex) |
| Positron Emission TomographyAlso: Medical Imaging, Positron Emission Tomography, PET, PET Scan, Positron emission tomography (procedure)Undergo PET/CT | Procedure or surgery | Phase I (cemiplimab, pidnarulex), Phase II arm I (pidnarulex), Phase II arm II (cemiplimab, pidnarulex) |
Primary outcome
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
The Bayesian optimal interval design will be employed to identify the RP2D of pidnarulex (CX-5461) in combination with anti-PD-1.
Incidence of adverse events, serious adverse events, and dose limiting toxicities
Time frame: Up to 30 days after last dose of study drug
Will evaluate safety and tolerability of pidnarulex (CX-5461) alone and in combination with anti-PD-1 in phases 1-2. Safety and tolerability will be summarized via descriptive statistics, including adverse events, serious adverse events, and dose limiting toxicities.
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
Will evaluate PFS of pidnarulex (CX-5461) alone and in combination with anti-PD-1 in patients with refractory liver metastatic microsatellite stable colorectal cancer associated with replication stress in phase 2. PFS will be compared between the 2 treatment groups following the futility boundary on hazard ratio (HR) derived by using a Hwang-Shih-DeCani spending function with gamma = -2.909. The Kaplan-Meier method will be used to estimate median PFS, PFS rates at different time points, and their 95% confidence intervals (CIs), using the Brookmeyer Crowley's method. The HR and the corresponding two-sided 95% CI will be estimated in a stratified Cox regression model. Stratification factors are consistent with those used at randomization. Subgroup analysis will be performed to assess the consistency of treatment effect across subgroups.
7 secondary outcomes
Objective response rate (ORR) (Phase 2)
Time frame: Up to disease progression or subsequent anticancer therapy, or until the last evaluable tumor assessment in the absence of disease progression, assessed up to 2 years
Disease control rate (DCR) (Phase 2)
Time frame: Up to disease progression or subsequent anticancer therapy, or until the last evaluable tumor assessment in the absence of disease progression, assessed up to 2 years
Duration of response (DOR) (Phase 2)
Time frame: From the first recorded response (confirmed CR or PR) to the first recorded disease progression (according to RECIST v1.1) or death from any cause, whichever occurs first, assessed up to 2 years
Overall survival (OS) (Phase 2)
Time frame: From randomization until death from any cause, assessed up to 2 years
Pharmacokinetic (PK) parameters of pidnarulex (CX-5461)
Time frame: Cycle (C) 1 day (D) 1, C1D8, C1D9, C1D15, C2D1, C2D15, C3D1, C6D1, C9D1, C12D1
PK parameters of cemiplimab (REGN2810)
Time frame: C1D1, C1D8, C1D9, C1D15, C2D1, C2D15, C3D1, C6D1, C9D1, C12D1
Gene signature patterns (Phase 2)
Time frame: At baseline and 30 days after last dose of study drug
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Sep 2026.
- Individual participant dataSharing planned: Yes. NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Wells A Messersmith principal investigator
JHU Sidney Kimmel Comprehensive Cancer Center LAO
7 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Biopsy Procedure, Biospecimen Collection and Cemiplimab in people with Metastatic Colorectal Adenocarcinoma and Refractory Colorectal Adenocarcinoma, run by National Cancer Institute (NCI) at 7 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 24 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 9 Sep 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 7 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Each site lists its own contact: choose the nearest one under Trial locations. AzTrials does not enrol participants or take referrals.
What does the 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). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Sep 2026.