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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

ConditionsMetastatic Colorectal AdenocarcinomaRefractory Colorectal AdenocarcinomaStage III Colorectal Cancer AJCC v8Stage IV Colorectal Cancer AJCC v8Unresectable Colorectal Adenocarcinoma
Trial statusRecruiting
Trial phasePhase 1, Phase 2
Trial typeInterventional
Biological sexAll
Age18+
SponsorNational Cancer Institute (NCI)

About this trial

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.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

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

Disqualifiers

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

Trial design

Design model

Sequential

Treatments tested in this trial

  • Biopsy Procedure

    Procedure/Surgery

    Undergo tumor biopsy

  • Biospecimen Collection

    Procedure/Surgery

    Undergo blood sample collection

  • Cemiplimab

    Biological/Vaccine

    Given IV

  • Computed Tomography

    Procedure/Surgery

    Undergo CT or PET/CT

  • Magnetic Resonance Imaging

    Procedure/Surgery

    Undergo MRI

  • Pidnarulex

    Drug

    Given IV

  • Positron Emission Tomography

    Procedure/Surgery

    Undergo PET/CT

Treatment groups

86 Participants
are divided into 3 treatment groups
Group A: Phase I (cemiplimab, pidnarulex)Experimental treatment 6 interventions
Group B: Phase II arm I (pidnarulex)Active comparator 6 interventions
Group C: Phase II arm II (cemiplimab, pidnarulex)Experimental treatment 7 interventions

Trial outcomes

Primary outcomes

1

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.

Time frame
Up to 28 days
2

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.

Time frame
Up to 30 days after last dose of study drug
3

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.

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

Secondary outcomes

1

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.

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
2

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.

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
3

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.

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
4

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.

Time frame
From randomization until death from any cause, assessed up to 2 years

Other outcomes

1

Expression of MYC and CCNE1 (Phase 2)

Will evaluate baseline expression of MYC and CCNE1 in tumor tissue and its association with response to treatment, as identified by immunohistochemistry in phase 2. Will be evaluated and correlated with safety and efficacy outcomes.

Time frame
At baseline
2

Stimulator of interferon genes (STING) pathway activation and immune cell profile (Phase 2)

Will evaluate 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. Will be correlated with safety and efficacy outcomes.

Time frame
At baseline and 30 days after last dose of study drug
3

Replication stress (Phase 2)

Will evaluate replication stress at baseline and after treatment, and its association with response to treatment, as identified by immunohistochemistry in phase 2. Will be correlated with safety and efficacy outcomes.

Time frame
At baseline and 30 days after last dose of study drug
4

Pidnarulex (CX-5461) target engagement (Phase 2)

Will evaluate pidnarulex (CX-5461) target engagement, as identified by 47S pre-ribosomal ribonucleic acid in-situ hybridization in phase 2. Will be correlated with safety and efficacy outcomes.

Time frame
Up to 30 days after last dose of study drug

Sponsors and contacts

Click on the lead sponsor to view all of their trials.

National Cancer Institute (NCI)

Lead sponsor

Source ClinicalTrials.gov
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