Pidnarulex for Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: Pregnancy, Lactation, Cirrhosis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 4

Duration: Up to 3 years

40 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but you cannot participate if you are taking strong CYP3A4 inhibitors or inducers, as they may interact with the study drug. It's best to discuss your current medications with the trial team to determine eligibility.

What data supports the effectiveness of the drug Pidnarulex for cancer?

The research does not provide direct evidence about Pidnarulex, but it highlights the effectiveness of paclitaxel, a similar cancer drug, which has shown significant activity in various cancers, including ovarian and breast cancer. Paclitaxel's success in combination therapies suggests that Pidnarulex might also be effective when used with other agents. ^{1 2 3 4 5}

Is Pidnarulex safe for humans?

Pidnarulex, also known as CX-5461, has been shown to cause significant genetic changes in human cells, which could be harmful. This suggests potential safety concerns, as these changes are more extensive than those caused by known environmental cancer-causing agents. ^{6 7 8 9 10}

Research Team

A P Chen

Principal Investigator

National Cancer Institute LAO

Eligibility Criteria

This trial is for adults with solid tumors that have spread and worsened after at least one prior treatment. They must have a tumor measurable by medical imaging, be able to undergo a biopsy, and be in decent physical shape (able to perform light activities). Blood counts and liver function need to meet specific levels.

Inclusion Criteria

My total bilirubin levels are within the normal range.

I have Gilbert's syndrome with a bilirubin level up to 3 mg/dl.

My cancer has spread and worsened after at least one treatment.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Patients receive pidnarulex IV over 60 minutes on days 1 and 8 of each 28-day cycle. Patients also undergo CT or MRI, biopsy, and collection of blood samples throughout the trial.

Up to 3 years

2 visits per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

4 weeks

1 visit (in-person)

Treatment Details

Interventions

• Pidnarulex

Trial Overview The trial is testing the safety, side effects, and best dose of Pidnarulex (CX-5461), an oral drug designed to block enzymes involved in cell division and DNA repair. This could potentially kill cancer cells. The study includes tests like echocardiography, MRI, CT scans, biopsies, and biospecimen collection.

Participant Groups

Group I: Treatment (pidnarulex) Experimental Treatment 6 Interventions

Patients receive pidnarulex 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 CT or MRI, biopsy, and collection of blood samples throughout the trial. Patients may undergo ECHO at screening and then as clinically indicated.

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

Panobinostat, a histone deacetylase inhibitor, shows significant synergy with gemcitabine and paclitaxel, and particularly strong synergistic effects when combined with doxorubicin and carboplatin in treating metastatic ovarian cancer cell lines.

The study utilized in vitro assays on three ovarian cancer cell lines (SK-OV3, CaOV-3, and ES-2) to identify effective drug combinations, suggesting that these combinations could enhance treatment efficacy and warrant further clinical investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The histone deacetylase inhibitor panobinostat demonstrates marked synergy with conventional chemotherapeutic agents in human ovarian cancer cell lines. Budman, DR., Tai, J., Calabro, A., et al.[2021]

In a study of 138 patients with relapsing epithelial ovarian cancer, paclitaxel treatment resulted in a 28% overall response rate, with 14% achieving a complete response, indicating its potential efficacy as a second-line treatment.

The treatment was well-tolerated with no serious toxicity reported, and patients with platinum-sensitive tumors and good performance status had significantly better survival outcomes, highlighting the importance of patient selection for optimal results.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term results from a phase II study of single agent paclitaxel (Taxol) in previously platinum treated patients with advanced ovarian cancer: the Nordic experience. Tropé, C., Hogberg, T., Kaern, J., et al.[2020]

The novel paclitaxel-aminoguanidine conjugate significantly improves water solubility compared to paclitaxel alone, enhancing its potential effectiveness against metastatic breast cancer.

This conjugate not only releases both paclitaxel and aminoguanidine within cancer cells but also demonstrates stronger cytotoxicity, increased apoptosis, and superior anti-metastatic effects compared to either drug used separately.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synthesis and Biological Evaluation of Paclitaxel-aminoguanidine Conjugates for Suppressing Breast Cancer. Dai, Y., Zhang, Y., Zhang, L., et al.[2023]

Paclitaxel has shown significant efficacy in treating various cancers, with response rates of 24%-30% in platinum refractory ovarian cancer and up to 62% in untreated advanced breast cancer, indicating its potential as a key chemotherapy agent.

The drug's unique mechanism of action, along with its ability to be combined with other therapies, suggests it can be effectively used in early-stage disease and has demonstrated superiority over standard treatments in ovarian and lung cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paclitaxel (Taxol®): A new natural product with major anticancer activity. De Furia, MD.[2012]

A mathematical framework using virtual clinical trial simulations was developed to evaluate the effectiveness of combinatorial treatments for overcoming platinum resistance in high-grade serous ovarian cancer.

The study found that drugs designed to resensitize chemoresistant cells were more effective than those that simply trigger cell death or enhance platinum availability, highlighting the importance of targeting specific resistance mechanisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Virtual clinical trials identify effective combination therapies in ovarian cancer. Kozłowska, E., Vallius, T., Hynninen, J., et al.[2021]

CX-5461, a chemotherapeutic agent, is being fast-tracked for clinical studies targeting cancers with BRCA1, BRCA2, and PALB2 mutations, showing promise for synthetic lethality in BRCA-deficient cells.

However, the drug also causes significant nonselective mutagenesis in various cell lines, raising safety concerns as the levels of mutations exceed those caused by known environmental carcinogens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The chemotherapeutic drug CX-5461 is a potent mutagen in cultured human cells. Koh, GCC., Boushaki, S., Zhao, SJ., et al.[2023]

A meta-analysis of 53 Phase II/III/IV trials involving nearly 20,000 patients revealed that molecular target anticancer drugs significantly increase the risk of serious adverse events (SAEs) by 57% and fatal adverse events (FAEs) by 51% compared to placebo.

The overall incidence rates for SAEs and FAEs were found to be 26.9% and 2.3%, respectively, highlighting the need for careful monitoring and preventive measures for patients receiving these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk of serious adverse event and fatal adverse event with molecular target anticancer drugs in cancer patients: A meta-analysis. Wang, Z., Yang, X., Wang, J., et al.[2020]

MetaADEDB 2.0 is an updated online database that now includes 744,709 drug-adverse drug event (ADE) associations, representing a 40% increase from its previous version, making it a more comprehensive resource for researchers.

The new version features a user-friendly web interface, enhancing accessibility for drug safety assessments and studies in drug discovery and development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MetaADEDB 2.0: a comprehensive database on adverse drug events. Yu, Z., Wu, Z., Li, W., et al.[2021]

The Adverse Drug Reaction Classification System-Target Profile (ADReCS-Target) is a new database that compiles extensive information on adverse drug reactions (ADRs), including 66,573 relationships between drugs, proteins, genes, and genetic variations, which can aid in understanding drug safety.

A case study using ADReCS-Target identified key genes (HLA, C1QA, and APOA1) associated with drug-induced rashes, suggesting these could be potential targets for monitoring and preventing such adverse reactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ADReCS-Target: target profiles for aiding drug safety research and application. Huang, LH., He, QS., Liu, K., et al.[2019]

In a study of 176 patients with idiopathic pulmonary fibrosis treated with either pirfenidone or nintedanib, adverse drug reactions (ADRs) were reported in 78.3% of those on pirfenidone and 70.5% on nintedanib, indicating a high incidence of side effects for both medications.

The incidence of serious ADRs was about 33 per 100 person-years for both drugs, while non-serious ADRs were more frequent, with 102 per 100 person-years for pirfenidone and 130 per 100 person-years for nintedanib, highlighting the need for careful monitoring of patients on these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world safety profiles of pirfenidone and nintedanib in idiopathic pulmonary fibrosis patients. Fournier, D., Jouneau, S., Bouzillé, G., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

The histone deacetylase inhibitor panobinostat demonstrates marked synergy with conventional chemotherapeutic agents in human ovarian cancer cell lines. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Long-term results from a phase II study of single agent paclitaxel (Taxol) in previously platinum treated patients with advanced ovarian cancer: the Nordic experience. [2020]

3. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Synthesis and Biological Evaluation of Paclitaxel-aminoguanidine Conjugates for Suppressing Breast Cancer. [2023]

4. Germany pubmed.ncbi.nlm.nih.gov

Paclitaxel (Taxol®): A new natural product with major anticancer activity. [2012]

5. England pubmed.ncbi.nlm.nih.gov

Virtual clinical trials identify effective combination therapies in ovarian cancer. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

The chemotherapeutic drug CX-5461 is a potent mutagen in cultured human cells. [2023]

7. India pubmed.ncbi.nlm.nih.gov

Risk of serious adverse event and fatal adverse event with molecular target anticancer drugs in cancer patients: A meta-analysis. [2020]

8. England pubmed.ncbi.nlm.nih.gov

MetaADEDB 2.0: a comprehensive database on adverse drug events. [2021]

9. England pubmed.ncbi.nlm.nih.gov

ADReCS-Target: target profiles for aiding drug safety research and application. [2019]

10. England pubmed.ncbi.nlm.nih.gov

Real-world safety profiles of pirfenidone and nintedanib in idiopathic pulmonary fibrosis patients. [2022]