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

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.

PRIMARY OBJECTIVES:

I. 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:

I. 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.

V. 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:

I. 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.

V. 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.

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)