CX-5461 for Solid Cancers
Recruiting in Palo Alto (17 mi)
+7 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Senhwa Biosciences, Inc.
Must not be taking: QT-prolonging drugs, CYP3A4 modulators
Disqualifiers: Brain metastases, Active infection, HIV, others
No Placebo Group
Approved in 1 Jurisdiction
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.12345
Is CX-5461 safe for use in humans?
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.12346
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.
See 25 more
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.
See 19 more
Trial 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 (RNA Polymerase I Inhibitor)
Trial OverviewThe 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
4Treatment groups
Experimental Treatment
Group I: Main Study Cohort patients receiving CX-5461 at 325mg/m2Experimental Treatment1 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/m2Experimental Treatment1 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/m2Experimental Treatment1 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/m2Experimental Treatment1 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University of California, Los AngelesSanta Monica, CA
Centre hospitalier de l'Université de Montréal (CHUM)Montréal, Canada
H. Lee Moffitt Cancer Center and Research Institute HospitalTampa, FL
Dana Farber Cancer InstituteBoston, MA
More Trial Locations
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Who Is Running the Clinical Trial?
Senhwa Biosciences, Inc.Lead Sponsor
References
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]RNA polymerase I (Pol I) transcription of ribosomal RNA genes (rDNA) is tightly regulated downstream of oncogenic pathways, and its dysregulation is a common feature in cancer. We evaluated CX-5461, the first-in-class selective rDNA transcription inhibitor, in a first-in-human, phase I dose-escalation study in advanced hematologic cancers. Administration of CX-5461 intravenously once every 3 weeks to 5 cohorts determined an MTD of 170 mg/m2, with a predictable pharmacokinetic profile. The dose-limiting toxicity was palmar-plantar erythrodysesthesia; photosensitivity was a dose-independent adverse event (AE), manageable by preventive measures. CX-5461 induced rapid on-target inhibition of rDNA transcription, with p53 activation detected in tumor cells from one patient achieving a clinical response. One patient with anaplastic large cell lymphoma attained a prolonged partial response and 5 patients with myeloma and diffuse large B-cell lymphoma achieved stable disease as best response. CX-5461 is safe at doses associated with clinical benefit and dermatologic AEs are manageable. SIGNIFICANCE: CX-5461 is a first-in-class selective inhibitor of rDNA transcription. This first-in-human study establishes the feasibility of targeting this process, demonstrating single-agent antitumor activity against advanced hematologic cancers with predictable pharmacokinetics and a safety profile allowing prolonged dosing. Consistent with preclinical data, antitumor activity was observed in TP53 wild-type and mutant malignancies.This article is highlighted in the In This Issue feature, p. 983.
Targeting RNA polymerase I with an oral small molecule CX-5461 inhibits ribosomal RNA synthesis and solid tumor growth. [2016]Deregulated ribosomal RNA synthesis is associated with uncontrolled cancer cell proliferation. RNA polymerase (Pol) I, the multiprotein complex that synthesizes rRNA, is activated widely in cancer. Thus, selective inhibitors of Pol I may offer a general therapeutic strategy to block cancer cell proliferation. Coupling medicinal chemistry efforts to tandem cell- and molecular-based screening led to the design of CX-5461, a potent small-molecule inhibitor of rRNA synthesis in cancer cells. CX-5461 selectively inhibits Pol I-driven transcription relative to Pol II-driven transcription, DNA replication, and protein translation. Molecular studies demonstrate that CX-5461 inhibits the initiation stage of rRNA synthesis and induces both senescence and autophagy, but not apoptosis, through a p53-independent process in solid tumor cell lines. CX-5461 is orally bioavailable and demonstrates in vivo antitumor activity against human solid tumors in murine xenograft models. Our findings position CX-5461 for investigational clinical trials as a potent, selective, and orally administered agent for cancer treatment.
Inhibition of RNA polymerase I transcription initiation by CX-5461 activates non-canonical ATM/ATR signaling. [2018]RNA polymerase I (Pol I)-mediated transcription of the ribosomal RNA genes (rDNA) is confined to the nucleolus and is a rate-limiting step for cell growth and proliferation. Inhibition of Pol I by CX-5461 can selectively induce p53-mediated apoptosis of tumour cells in vivo. Currently, CX-5461 is in clinical trial for patients with advanced haematological malignancies (Peter Mac, Melbourne). Here we demonstrate that CX-5461 also induces p53-independent cell cycle checkpoints mediated by ATM/ATR signaling in the absence of DNA damage. Further, our data demonstrate that the combination of drugs targeting ATM/ATR signaling and CX-5461 leads to enhanced therapeutic benefit in treating p53-null tumours in vivo, which are normally refractory to each drug alone. Mechanistically, we show that CX-5461 induces an unusual chromatin structure in which transcriptionally competent relaxed rDNA repeats are devoid of transcribing Pol I leading to activation of ATM signaling within the nucleoli. Thus, we propose that acute inhibition of Pol transcription initiation by CX-5461 induces a novel nucleolar stress response that can be targeted to improve therapeutic efficacy.
CX-5461 inhibits RNA Pol I in blood cancers. [2016]In a preclinical study, the investigational drug CX-5461, which blocks the protein RNA polymerase I, extended survival in mouse models of highly aggressive acute myeloid leukemia and multiple myeloma refractory to standard therapy.
CX-5461 induces radiosensitization through modification of the DNA damage response and not inhibition of RNA polymerase I. [2022]Increased ribosome biogenesis is a distinguishing feature of cancer cells, and small molecule inhibitors of ribosome biogenesis are currently in clinical trials as single agent therapy. It has been previously shown that inhibiting ribosome biogenesis through the inhibition of nuclear export of ribosomal subunits sensitizes tumor cells to radiotherapy. In this study, the radiosensitizing potential of CX-5461, a small molecule inhibitor of RNA polymerase I, was tested. Radiosensitization was measured by clonogenic survival assay in a panel of four tumor cell lines derived from three different tumor types commonly treated with radiation. 50 nM CX-5461 radiosensitized PANC-1, U251, HeLa, and PSN1 cells with dose enhancement factors in the range of 1.2-1.3. However, 50 nM CX-5461 was not sufficient to inhibit 45S transcription alone or in combination with radiation. The mechanism of cell death with the combination of CX-5461 and radiation occurred through mitotic catastrophe and not apoptosis. CX-5461 inhibited the repair and/or enhanced the initial levels of radiation-induced DNA double strand breaks. Understanding the mechanism of CX-5461-induced radiosensitization should be of value in the potential application of the CX-5461/radiotherapy combination in cancer treatment.
Discovery of CX-5461, the First Direct and Selective Inhibitor of RNA Polymerase I, for Cancer Therapeutics. [2021]Accelerated proliferation of solid tumor and hematologic cancer cells is linked to accelerated transcription of rDNA by the RNA polymerase I (Pol I) enzyme to produce elevated levels of rRNA (rRNA). Indeed, upregulation of Pol I, frequently caused by mutational alterations among tumor suppressors and oncogenes, is required for maintenance of the cancer phenotype and forms the basis for seeking selective inhibitors of Pol I as anticancer therapeutics. 2-(4-Methyl-[1,4]diazepan-1-yl)-5-oxo-5H-7-thia-1,11b-diaza-benzo[c]fluorene-6-carboxylic acid (5-methyl-pyrazin-2-ylmethyl)-amide (CX-5461, 7c) has been identified as the first potent, selective, and orally bioavailable inhibitor of RNA Pol I transcription with in vivo activity in tumor growth efficacy models. The preclinical data support the development of CX-5461 as an anticancer drug with potential for activity in several types of cancer.