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

Trial Summary

What is the purpose of this trial?

This is an open-label, multi-center, phase 1b study designed to determine a tolerable dose of CX-5461 administered by IV infusion on Day 1 and Day 8 of a 28-day cycle in patients with selected solid tumours and associated mutations for future Phase II trials. The safety and tolerability of CX-5461, preliminary evidence of antitumor effect and the effect of CX-5461 on the Health-Related Quality of Life (HRQoL) will also be evaluated. The study will also evaluate the predictive value of mutational signatures and explore the significance of dynamic changes in ctDNA levels and plasma DNA methylome profiling in this study's exploratory cohort.

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.

What data supports the effectiveness of the drug CX-5461 for treating solid cancers?

Research shows that CX-5461, a drug that blocks a protein called RNA polymerase I, can stop cancer cells from growing by interfering with their ability to make certain proteins. In studies with mice, CX-5461 has shown promise in slowing down the growth of solid tumors, suggesting it could be effective in treating solid cancers. ^{1 2 3 4 5}

Is CX-5461 safe for use in humans?

CX-5461 has been tested in humans with advanced blood cancers and found to be safe at certain doses, with manageable side effects like skin reactions. It has shown potential for use in solid tumors as well, based on studies in mice. ^{1 2 3 4 5}

What makes the drug CX-5461 unique for treating solid cancers?

CX-5461 is unique because it is the first drug to selectively inhibit RNA polymerase I, which is responsible for ribosomal RNA synthesis, a process often upregulated in cancer cells. Unlike many cancer treatments, it is orally administered and works by inducing a stress response in the nucleolus of cancer cells, potentially offering a new way to target solid tumors. ^{1 2 3 4 6}

Research Team

Jin-Ding Huang, PhD

Principal Investigator

Senhwa Biosciences

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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 BRCA2 and/or PALB2 mutation 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 BRCA2 and/or PALB2 mutation 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+

Findings from Research

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]

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]

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]

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 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]

References

1. United States 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. [2020]

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

Targeting RNA polymerase I with an oral small molecule CX-5461 inhibits ribosomal RNA synthesis and solid tumor growth. [2016]

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

Inhibition of RNA polymerase I transcription initiation by CX-5461 activates non-canonical ATM/ATR signaling. [2018]

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

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

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

CX-5461 induces radiosensitization through modification of the DNA damage response and not inhibition of RNA polymerase I. [2022]

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

Discovery of CX-5461, the First Direct and Selective Inhibitor of RNA Polymerase I, for Cancer Therapeutics. [2021]