CX-5461 for Solid Cancers

Recruiting at 7 trial locations

Overseen By Hylee Lee

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Senhwa Biosciences, Inc.

Must not be taking: QT-prolonging drugs, CYP3A4 modulators

Disqualifiers: Brain metastases, Active infection, HIV, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 15

Duration: 24 weeks

52 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests CX-5461, a new treatment for certain solid cancers, such as pancreatic, ovarian, prostate, and breast cancer. The main goal is to determine a safe dose and evaluate its effectiveness against these cancers. The trial also examines how the treatment affects quality of life and checks for specific genetic markers that might predict patient response. Individuals with confirmed cancer in these areas and specific genetic mutations, like BRCA1/2 or PALB2, might be suitable candidates. Participants will receive the treatment through an IV on specific days within a 28-day cycle. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot take other systemic anti-cancer therapies or medications that prolong the QT/QTc interval while participating in the study.

Is there any evidence suggesting that CX-5461 is likely to be safe for humans?

In earlier studies, CX-5461 has shown promise by stopping cancer cells from producing the proteins necessary for growth. Research suggests it can damage cancer cells, particularly those associated with certain genetic changes.

Participants in past studies generally tolerated CX-5461 well, with most not experiencing severe side effects. However, some encountered common reactions to cancer treatments, such as nausea or fatigue. This trial is in an early phase, so researchers are still determining the safest dose.

For those considering participation in a trial with CX-5461, this information provides an overview of what to expect. However, consulting a doctor for personalized advice is essential. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about CX-5461 because it represents a novel approach to treating solid cancers like pancreatic, ovarian, prostate, and breast cancers. Unlike standard treatments that often involve chemotherapy or targeted therapies aimed at inhibiting growth signals, CX-5461 is unique because it targets RNA polymerase I transcription, a process crucial for cancer cell survival. This new mechanism of action could potentially overcome resistance seen with current treatments and offer a fresh therapeutic angle. Moreover, CX-5461 is administered through a 60-minute IV infusion, which may provide a more controlled and direct delivery of the drug to cancer cells. This innovative approach could pave the way for more effective treatment options for patients with specific genetic mutations.

What evidence suggests that CX-5461 could be an effective treatment for solid cancers?

Research has shown that CX-5461 may help treat certain solid cancers. In an earlier study, four patients—three with breast cancer and one with ovarian cancer—experienced tumor shrinkage, known as a partial response, resulting in an overall response rate of 10%. CX-5461 targets a specific part of the cancer cell's DNA, the G-quadruplex, to inhibit cancer growth. Although no approved drugs currently exist like it, early trials suggest this treatment might be effective for cancers with certain genetic changes. Participants in this trial will receive CX-5461 at either 250mg/m2 or 325mg/m2, depending on their cohort, to further evaluate its effectiveness and safety. ^{6 7 8 9 10}

Who Is on the Research Team?

Jason Huang, MD

Principal Investigator

Senhwa Biosciences

Are You a Good Fit for This Trial?

Adults with certain solid tumors (pancreas, prostate, breast, ovary) and specific genetic mutations (BRCA1/2 or PALB2) can join this trial. They must have measurable disease progression recently and be in good enough health to follow the study plan for over 3 months. Women of childbearing age need a negative pregnancy test and agree to use contraception.

Inclusion Criteria

My test shows a genetic mutation linked to cancer, confirmed by a certified lab.

My cancer did not worsen within 6 months after platinum chemotherapy OR it worsened within 6 months of the last platinum dose.

Your blood test shows that you have enough infection-fighting white blood cells.

Exclusion Criteria

A marked baseline prolongation of QT/QTc interval

You have a weakened immune system.

I am not currently on any other cancer treatments.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive CX-5461 via IV infusion on Day 1 and Day 8 of a 28-day cycle

24 weeks

2 visits per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 months

Every 12 weeks for 2 years

Exploratory

Evaluation of mutational signatures and ctDNA levels for treatment response

24 weeks

Blood samples collected at specified intervals

What Are the Treatments Tested in This Trial?

Interventions

• CX-5461

Trial Overview The trial is testing CX-5461 given by IV on two days every four weeks to find a safe dose for future studies. It will look at how well it's tolerated, its effect on tumor size, quality of life impact, and explore changes in ctDNA levels and DNA methylation patterns.

How Is the Trial Designed?

Group I: Main Study Cohort patients receiving CX-5461 at 325mg/m2 Experimental Treatment 1 Intervention

After confirming the dose of 250mg/m2 to be safe and tolerable, eligible patients with histologically confirmed pancreatic, ovarian, prostate, or breast cancers with pathogenic/likely pathogenic germline or somatic BRCA1/2 and/or PALB2 mutation and/or genetic alterations in the specified genes will be enrolled to receive CX-5461 at a dosing concentration of 325mg/m2, delivered as a 60-minute IV infusion on Day 1 and Day 8 of a 28-day cycle.

Group II: Main Study Cohort patients receiving CX-5461 at 250mg/m2 Experimental Treatment 1 Intervention

Eligible patients with histologically confirmed pancreatic, ovarian, prostate, or breast cancers with pathogenic/likely pathogenic germline or somatic BRCA1/2 and/or PALB2 mutation and/or genetic alterations in the specified genes will be enrolled to receive CX-5461 at a dosing concentration of 250mg/m2, delivered as a 60-minute IV infusion on Day 1 and Day 8 of a 28-day cycle.

Group III: Exploratory cohort patients receiving CX-5461 at 325mg/m2 Experimental Treatment 1 Intervention

After confirming the dose of 250mg/m2 to be safe and tolerable, eligible patients with ovarian cancer and pathogenic/likely pathogenic BRCA1 and/or other HRD-associated mutation will be enrolled to receive CX-5461 at a dosing concentration of 325 mg/m2, delivered as a 60-minute IV infusion on Day 1 and Day 8 of a 28-day cycle.

Group IV: Exploratory cohort patients receiving CX-5461 at 250mg/m2 Experimental Treatment 1 Intervention

Eligible patients with ovarian cancer and pathogenic/likely pathogenic BRCA1 and/or other HRD-associated mutation will be enrolled to receive CX-5461 at a dosing concentration of 250 mg/m2, delivered as a 60-minute IV infusion on Day 1 and Day 8 of a 28-day cycle.

CX-5461 is already approved in United States for the following indications:

Approved in United States as CX-5461 for:

• None approved yet; Fast Track designation for BRCA1/2, PALB2, or HRD mutations in breast or ovarian cancer

Who Is Running the Clinical Trial?

Senhwa Biosciences, Inc.

Lead Sponsor

Trials

9

Recruited

530+

Published Research Related to This Trial

CX-5461, a selective inhibitor of ribosomal RNA transcription, was found to be safe and effective in a phase I study involving advanced hematologic cancers, with a maximum tolerated dose of 170 mg/m2 and manageable side effects like palmar-plantar erythrodysesthesia.

The treatment showed promising antitumor activity, with one patient achieving a prolonged partial response and others maintaining stable disease, indicating its potential as a therapeutic option for various hematologic malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-in-Human RNA Polymerase I Transcription Inhibitor CX-5461 in Patients with Advanced Hematologic Cancers: Results of a Phase I Dose-Escalation Study. Khot, A., Brajanovski, N., Cameron, DP., et al.[2020]

The investigational drug CX-5461, which inhibits RNA polymerase I, has shown promising results in extending survival in mouse models of aggressive acute myeloid leukemia and multiple myeloma.

This study suggests that CX-5461 may offer a new therapeutic option for patients with these types of cancer that do not respond to standard treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CX-5461 inhibits RNA Pol I in blood cancers. [2016]

CX-5461, a small molecule inhibitor of RNA polymerase I, enhances the effectiveness of radiation therapy in cancer cells, showing dose enhancement factors of 1.2-1.3 across various tumor types in a study involving four different cell lines.

The combination of CX-5461 and radiation leads to cell death through mitotic catastrophe rather than apoptosis, and it appears to inhibit DNA repair mechanisms, which could improve outcomes in cancer treatment when used together.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CX-5461 induces radiosensitization through modification of the DNA damage response and not inhibition of RNA polymerase I. Lehman, SL., Schwartz, KR., Maheshwari, S., et al.[2022]

CX-5461 inhibits RNA polymerase I, leading to selective p53-mediated apoptosis in tumor cells, and is currently being tested in clinical trials for advanced hematological malignancies.

The drug also triggers p53-independent cell cycle checkpoints through ATM/ATR signaling, and combining CX-5461 with ATM/ATR inhibitors enhances treatment effectiveness in p53-null tumors, which typically resist single-agent therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhibition of RNA polymerase I transcription initiation by CX-5461 activates non-canonical ATM/ATR signaling. Quin, J., Chan, KT., Devlin, JR., et al.[2018]

CX-5461 is the first potent and selective inhibitor of RNA polymerase I (Pol I) transcription, which is crucial for the accelerated growth of cancer cells, making it a promising anticancer therapeutic.

Preclinical studies show that CX-5461 is orally bioavailable and effective in reducing tumor growth, indicating its potential for treating various types of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Discovery of CX-5461, the First Direct and Selective Inhibitor of RNA Polymerase I, for Cancer Therapeutics. Haddach, M., Schwaebe, MK., Michaux, J., et al.[2021]

CX-5461 is a potent small-molecule inhibitor that selectively targets RNA polymerase I (Pol I) to block rRNA synthesis in cancer cells, which is crucial for their proliferation.

In preclinical studies, CX-5461 demonstrated the ability to induce senescence and autophagy in solid tumor cell lines without causing apoptosis, and it showed effective antitumor activity in mouse models, making it a promising candidate for clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting RNA polymerase I with an oral small molecule CX-5461 inhibits ribosomal RNA synthesis and solid tumor growth. Drygin, D., Lin, A., Bliesath, J., et al.[2016]

Citations

1. nature.com nature.com/articles/s41467-022-31199-2

Results of the phase I CCTG IND.231 trial of CX-5461 in ... Four patients had confirmed PR (3 patients with breast and 1 with ovarian cancer) (ORR 4/40 = 10%, 95% CI: 2.8–23.7); all patients with PR had ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12007140/

The G-quadruplex ligand CX-5461 - PubMed Central - NIH In 2017, it was discovered that CX-5461 could bind and stabilize G4 DNA structures in vitro, dispute the progression of DNA replication result ...

3. clinicaltrialvanguard.com clinicaltrialvanguard.com/news/rna-polymerase-i-clinical-trials-a-promising-2025-report/

RNA Polymerase I Clinical Trials: A Promising 2025 Report No approved RNA Polymerase I inhibitors are on the market, but the lead asset, pindnarulex (CX-5461), has advanced into Phase I/II across ...

4. dfhcc.harvard.edu dfhcc.harvard.edu/fileadmin/media/ETCTN/02_Developing_an_ETCTN_Study/PTMA_Requests/Pidnarulex_NSC_845292_PTMA.pdf

FOR CONDUCTING CLINICAL TRIALS USING ... First-in-human RNA polymerase I transcription inhibitor CX-5461 in patients with advanced hematologic cancers: Results of a phase I dose-escalation study.

5. aacrjournals.org aacrjournals.org/cancerdiscovery/article/9/8/1036/41936/First-in-Human-RNA-Polymerase-I-Transcription

First-in-Human RNA Polymerase I Transcription Inhibitor CX ... A phase I dose-escalation study evaluates the safety and pharmacokinetics of the RNA Polymerase I inhibitor CX-5461 in patients with advanced hematologic.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT07137416

Testing the Safety of the Combination of Anti-Cancer Drugs ... Testing the Safety of the Combination of Anti-Cancer Drugs CX-5461 ... 2 (HER2)-Positive Solid Tumors and Breast Cancer. ClinicalTrials.gov ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4025669/

Discovery of CX-5461, the First Direct and Selective ... The preclinical data support the development of CX-5461 as an anticancer drug with potential for activity in several types of cancer. Keywords: CX-5461, rRNA, ...

8. nature.com nature.com/articles/s41588-023-01602-9

The chemotherapeutic drug CX-5461 is a potent mutagen ... Targeting RNA polymerase I with an oral small molecule CX-5461 inhibits ribosomal RNA synthesis and solid tumor growth. Cancer Res. 71, 1418– ...

9. ascopubs.org ascopubs.org/doi/10.1200/JCO.2022.40.4_suppl.TPS622

Phase 1b expansion study of CX-5461 in patients with ... CX-5461, a G-quadruplex stabilizer, employs an alternative mechanism in destabilizing the DNA replication fork to promote DNA damage resulting ...

10. merckmillipore.com merckmillipore.com/IE/en/product/RNA-Polymerase-I-Inhibitor-II-CX-5461-CAS-1138549-36-6-Calbiochem,EMD_BIO-509265

RNA Polymerase I Inhibitor II, CX-5461 While Pol I inhibition by CX-5461 is shown to result in p53-dependent apoptosis in cancer cells of hematopoietic origin, cell death by CX-5461 treatment in ...