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 and Randomized Phase 2 Trial of Pidnarulex (CX-5461) and Cemiplimab (REGN2810) in Refractory Microsatellite Stable Colorectal Cancer
3 other identifiers
interventional
86
1 country
1
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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_1
Started Dec 2026
1 active site
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
August 28, 2025
CompletedFirst Posted
Study publicly available on registry
August 29, 2025
CompletedStudy Start
First participant enrolled
December 21, 2026
ExpectedPrimary Completion
Last participant's last visit for primary outcome
September 30, 2027
Study Completion
Last participant's last visit for all outcomes
September 30, 2027
April 20, 2026
April 1, 2026
9 months
August 28, 2025
April 17, 2026
Conditions
Outcome Measures
Primary Outcomes (3)
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.
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.
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.
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)
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)
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)
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)
From randomization until death from any cause, assessed up to 2 years
Pharmacokinetic (PK) parameters of pidnarulex (CX-5461)
Cycle (C) 1 day (D) 1, C1D8, C1D9, C1D15, C2D1, C2D15, C3D1, C6D1, C9D1, C12D1
- +2 more secondary outcomes
Other Outcomes (5)
Expression of MYC and CCNE1 (Phase 2)
At baseline
Stimulator of interferon genes (STING) pathway activation and immune cell profile (Phase 2)
At baseline and 30 days after last dose of study drug
Replication stress (Phase 2)
At baseline and 30 days after last dose of study drug
- +2 more other outcomes
Study Arms (3)
Phase I (cemiplimab, pidnarulex)
EXPERIMENTALPatients 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 COMPARATORPatients 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)
EXPERIMENTALPatients 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
Undergo blood sample collection
Given IV
Undergo PET/CT
Given IV
Undergo CT or PET/CT
Undergo MRI
Undergo tumor biopsy
Eligibility Criteria
You may qualify if:
- 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)
- +9 more criteria
You may not qualify if:
- 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
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (1)
JHU Sidney Kimmel Comprehensive Cancer Center LAO
Baltimore, Maryland, 21231, United States
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Wells A Messersmith
JHU Sidney Kimmel Comprehensive Cancer Center LAO
Study Design
- Study Type
- interventional
- Phase
- phase 1
- Allocation
- RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- SEQUENTIAL
- Sponsor Type
- NIH
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
August 28, 2025
First Posted
August 29, 2025
Study Start (Estimated)
December 21, 2026
Primary Completion (Estimated)
September 30, 2027
Study Completion (Estimated)
September 30, 2027
Last Updated
April 20, 2026
Record last verified: 2026-04
Data Sharing
- IPD Sharing
- Will share
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.