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About
This phase I trial tests the safety, side effects, and best dose of pidnarulex (CX-5461) in treating patients with solid tumors that have spread from where it first started (primary site) to other places in the body (metastatic). Pidnarulex is an oral inhibitor of ribonucleic acid polymerase I, with potential antineoplastic activity. It blocks a certain enzyme needed for cell division and deoxyribonucleic acid (DNA) repair and may kill cancer cells.
Full description
PRIMARY OBJECTIVE:
I. To assess whether pidnarulex induces a Rad51 response, which will be determined by an integral biomarker of percentage of cells with Rad51 nuclear foci in tumor biopsy specimens in patients with and without homologous repair deficiency (HRD) genetic mutations.
SECONDARY OBJECTIVES:
I. To determine the safety and tolerability of pidnarulex. II. To determine the overall response rate (complete responses plus partial responses) in patients with advanced, refractory solid tumors.
III. To measure the pharmacokinetics of pidnarulex. IV. To evaluate other DNA damage and repair signaling markers including Top2, G4 stabilization, RPA32, pSer33-RPA32, γH2AX, 53BP1, pSer8-RPA32, pKap1m and pNBS1.
EXPLORATORY OBJECTIVE:
I. To examine genomic alterations in circulating tumor DNA (ctDNA) that may be associated with response or resistance.
OUTLINE:
Patients receive pidnarulex intravenously (IV) over 60 minutes on days 1 and 8 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) or magnetic resonance imaging (MRI), biopsy, and collection of blood samples throughout the trial. Patients may undergo echocardiography (ECHO) at screening and then as clinically indicated.
After completion of study treatment, patients are followed up at 30 days.
Enrollment
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Inclusion criteria
Patients must have histologically confirmed solid tumors with metastatic disease that have progressed after ≥ 1 line of prior therapy for which no standard treatment is available that has been shown to improve survival.
Patients must have a molecular testing report to assess HRD mutation status prior to enrollment.
Patients must have measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1, with at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥ 20 mm (≥ 2 cm) by chest x-ray or as ≥ 10 mm (≥ 1 cm) with CT scan, MRI, or calipers by clinical exam).
Patients must have a tumor site amenable to biopsy.
Age ≥ 18 years of age.
Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (Karnofsky ≥ 70%).
Absolute neutrophil count ≥ 1,500/mcL.
Hemoglobin ≥ 9 g/dL.
Platelets ≥ 100,000/mcL.
Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN).
International normalized ratio (INR) or activated partial thromboplastin time (aPTT) ≤ 1.5 institutional upper limit of normal (ULN).
Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic-pyruvic transaminase [SGPT]) ≤ 3 x institutional ULN.
Potassium ≥ lower limit of normal (LLN).
Magnesium ≥ LLN.
Ionized or corrected calcium ≥ LLN.
Creatinine ≤ 1.5 x institutional ULN OR creatinine clearance levels ≥ 60 ml/min based on the Cockcroft-Gault formula.
Oxygen (O2) saturation > 90% on room air.
Prior standard or investigational therapy must have been completed ≥ 4 weeks or ≥ 5 half-lives of the prior agent (whichever is shorter) prior to enrollment; the exception is ≥ 2 weeks since any investigational agent administered (at a sub-therapeutic dose) as part of a phase 0 study.
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.
Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured.
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 are eligible for this trial if, in the judgement of the principal investigator, the malignancy and its treatment do 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 2B or better.
The effects of pidnarulex on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) 14 days prior to study entry and for the duration of study participation and for at least 6 months after the last dose of study drug. 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 pidnarulex and for 6 months after cessation of treatment. Men treated or enrolled on this protocol must also agree to use adequate contraception 14 days prior to the study, for the duration of study participation, and 6 months after completion of pidnarulex administration.
Willingness to provide blood and biopsy samples for research purposes.
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
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40 participants in 1 patient group
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Data sourced from clinicaltrials.gov
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