ZN-A-1041 Combinations for Breast Cancer

Recruiting at 23 trial locations

Overseen By Ding Zhou, Ph.D

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Suzhou Zanrong Pharma Limited

Must not be taking: Antiepileptics, Corticosteroids

Disqualifiers: Progressive neurologic impairment, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial is testing a new drug called ZN-A-1041 to see if it is safe and effective for patients with advanced cancers that have a specific marker called HER2. The drug aims to find and destroy these cancer cells, even if they have spread to the brain.

Do I need to stop my current medications for this trial?

The trial protocol does not specify if you need to stop all current medications. However, there is a required 2-week interval between your last treatment with certain therapies (like tyrosine kinase inhibitors, chemotherapy, antibodies, or antibody-drug conjugates) and the start of the study drug. If you are on Herceptin, Perjeta, or PHESGO, you may continue these in some cases. Please consult with the trial team for specific guidance on your medications.

What data supports the idea that ZN-A-1041 Combinations for Breast Cancer is an effective drug?

The available research does not provide specific data on the effectiveness of ZN-A-1041 Combinations for Breast Cancer. Instead, it focuses on other aspects of breast cancer, such as the role of certain genes like ZNF217 and ZNF703 in cancer progression and resistance to treatment. These studies suggest potential targets for therapy but do not directly address the effectiveness of ZN-A-1041 Combinations. Therefore, there is no direct evidence from the provided information to support the effectiveness of ZN-A-1041 Combinations for Breast Cancer. ^{1 2 3 4 5}

What safety data is available for ZN-A-1041 and related breast cancer treatments?

The provided research does not contain specific safety data for ZN-A-1041 or its related treatments such as Herceptin, Trastuzumab, and others. The studies focus on different aspects of breast cancer biology and potential therapeutic targets, but do not address the safety profiles of these treatments. For safety data, it would be necessary to consult clinical trial results or safety studies specifically evaluating these drugs. ^{1 3 4 6 7}

Is the drug ZN-A-1041 a promising treatment for breast cancer?

The information provided does not directly mention ZN-A-1041 or its effects on breast cancer. Therefore, we cannot determine if ZN-A-1041 is a promising treatment based on the given research articles. ^{1 3 4 8 9}

Research Team

Anders Carey K, MD

Principal Investigator

Duke Cancer Institute

Eligibility Criteria

This trial is for adults with advanced HER2-positive solid tumors, including breast and gastric cancers. Participants must have tried certain treatments like Trastuzumab or a taxane without success, or be intolerant to them. Those with brain metastases can join if they meet specific criteria regarding prior treatments and stability of their condition.

Inclusion Criteria

If you have cancer that has spread to your brain, you must have previously received treatment for HER2-positive breast or gastric cancer. You cannot have had recent local treatment, unless your disease is stable or progressing. If you have had previous treatment with certain medications, you must wait at least 2 weeks before starting this trial.

I am fully active or can carry out light work.

I don't need immediate brain treatment and either had stable brain treatment over 2-4 weeks ago or never had it.

Exclusion Criteria

I have a brain lesion that needs immediate treatment.

I am experiencing worsening neurological symptoms like headaches or blurred vision.

I am taking more than 2 mg of dexamethasone daily for brain metastases.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

4 weeks

Phase 1a: Dose Escalation (Monotherapy)

Dose escalation with ZN-A-1041 monotherapy using a modified 3+3 design across 7 planned dose levels

21 days per cycle

Phase 1b: Dose Escalation (Combination Therapy)

Dose escalation with ZN-A-1041 in combination with other therapies using a traditional 3+3 design

21 days per cycle

Phase 1c: Dose Expansion (Combination Therapy)

Dose expansion with ZN-A-1041 in combination with other therapies based on recommended doses from Phase 1b

21 days per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Herceptin (Monoclonal Antibodies)
• Perjeta (Monoclonal Antibodies)
• PHESGO (Other)
• T-DM1 (Monoclonal Antibodies)
• T-Dxd (Antibody-Drug Conjugate)
• ZN-A-1041 (Other)

Trial Overview The trial tests ZN-A-1041 alone or in combination with other cancer drugs (T-DM1, PHESGO/Herceptin plus Perjeta, T-Dxd) at various doses to assess safety, tolerability, how the body processes the drug (pharmacokinetics), and effectiveness against HER2-positive tumors.

Participant Groups

Group I: ZN-A-1041 800mg Experimental Treatment 1 Intervention

Phase 1a: Subjects will be given ZN-A-1041 orally 800mg Bid, for 21days as one cycle

Group II: ZN-A-1041 600mg Experimental Treatment 1 Intervention

Phase 1a: Subjects will be given ZN-A-1041 orally 600mg Bid, for 21days as one cycle

Group III: ZN-A-1041 50mg Experimental Treatment 1 Intervention

Phase 1a: Subjects will be given ZN-A-1041 orally 50mg Bid, for 21days as one cycle

Group IV: ZN-A-1041 400mg Experimental Treatment 1 Intervention

Phase 1a: Subjects will be given ZN-A-1041 orally 400mg Bid, for 21days as one cycle

Group V: ZN-A-1041 200mg Experimental Treatment 1 Intervention

Phase 1a: Subjects will be given ZN-A-1041 orally 200mg Bid, for 21days as one cycle

Group VI: ZN-A-1041 100mg Experimental Treatment 1 Intervention

Phase 1a: Subjects will be given ZN-A-1041 orally 100mg Bid, for 21days as one cycle

Group VII: ZN-A-1041 1000mg Experimental Treatment 1 Intervention

Phase 1a: Subjects will be given ZN-A-1041 orally 1000mg Bid, for 21days as one cycle

Group VIII: 1c: ZN-A-1041 + T-Dxd 5.4 mg/kg iv. Experimental Treatment 1 Intervention

Phase 1c Arm2: The dose levels of ZN-A-1041 in the Phase 1c study will be the recommended doses determined in the Phase 1b study.

Group IX: 1c: ZN-A-1041 + T-DM1 3.6 mg/kg iv. Experimental Treatment 1 Intervention

Phase 1c Arm1: The dose levels of ZN-A-1041 in the Phase 1c study will be the recommended doses determined in the Phase 1b study.

Group X: 1c: ZN-A-1041 + Herceptin plus Perjeta/PHESGO Experimental Treatment 1 Intervention

Phase 1c Arm3: The dose levels of ZN-A-1041 in the Phase 1c study will be the recommended doses determined in the Phase 1b study.

Group XI: 1b: ZN-A-1041 + T-Dxd 5.4 mg/kg iv. Experimental Treatment 1 Intervention

Phase 1b Arm2: 1. If the MTD of ZN-A-1041 is identified in Phase 1a study: The 2 tentative dose levels of ZN-A-1041 are MTD-1 (Level 1) and MTD (Level 2) 2. If the MTD is still not reached at the maximum dose level in Phase 1a study, the maximum dose level of ZN-A-1041 in Phase 1a will be used in Phase 1b study.

Group XII: 1b: ZN-A-1041 + T-DM1 3.6 mg/kg iv. Experimental Treatment 1 Intervention

Phase 1b Arm1: 1. If the MTD of ZN-A-1041 is identified in Phase 1a study: The 2 tentative dose levels of ZN-A-1041 are MTD-1 (Level 1) and MTD (Level 2) 2. If the MTD is still not reached at the maximum dose level in Phase 1a study, the maximum dose level of ZN-A-1041 in Phase 1a will be used in Phase 1b study.

Group XIII: 1b: ZN-A-1041 + PHESGO / Herceptin plus Perjeta Experimental Treatment 1 Intervention

Phase 1b Arm3: 1. If the MTD of ZN-A-1041 is identified in Phase 1a study: The 2 tentative dose levels of ZN-A-1041 are MTD-1 (Level 1) and MTD (Level 2) 2. If the MTD is still not reached at the maximum dose level in Phase 1a study, the maximum dose level of ZN-A-1041 in Phase 1a will be used in Phase 1b study.

Who Is Running the Clinical Trial?

Suzhou Zanrong Pharma Limited

Lead Sponsor

Trials

2

Recruited

290+

Findings from Research

The study developed an antisense oligonucleotide (ASO) that effectively downregulates the ZNF703 gene, which is linked to resistance against endocrine therapies in luminal B breast cancers, potentially improving treatment outcomes.

Inhibition of ZNF703 not only decreased cancer cell proliferation and induced apoptosis but also enhanced the effectiveness of cisplatin, suggesting a promising combination therapy for patients with this aggressive breast cancer subtype.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ZNF703 mRNA-Targeting Antisense Oligonucleotide Blocks Cell Proliferation and Induces Apoptosis in Breast Cancer Cell Lines. Udu-Ituma, S., Adélaïde, J., Le, TK., et al.[2023]

ZNF217 is identified as a candidate oncogene in breast cancer, associated with poor prognosis, and its overexpression leads to increased cancer cell self-renewal, motility, and metastasis.

The nucleoside analogue triciribine effectively inhibits tumor growth and chemotherapy resistance in ZNF217-overexpressing cancer cells, suggesting it could be a personalized treatment option for patients with high ZNF217 levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The transcription factor ZNF217 is a prognostic biomarker and therapeutic target during breast cancer progression. Littlepage, LE., Adler, AS., Kouros-Mehr, H., et al.[2021]

ZNF652 is significantly up-regulated in breast cancer tissues compared to adjacent tissues, with its expression linked to more aggressive forms of breast cancer and distant metastasis, indicating its potential as a biomarker for disease severity.

Overexpression of ZNF652 enhances breast cancer cell proliferation, invasion, and migration, while its knockdown reduces these effects, suggesting that targeting ZNF652 could be a promising strategy for breast cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[High expression of ZNF652 promotes carcinogenesis and progression of breast cancer]. Lei, T., Xiao, B., He, Y., et al.[2021]

Malignant breast tumor cells (T47D) have significantly higher zinc levels than non-malignant cells (MCF-10A) and rely on the zinc transporter ZnT2 to sequester excess zinc, which protects them from cytotoxicity.

Suppressing ZnT2 in these tumor cells leads to increased cytoplasmic zinc levels, triggering apoptosis and reducing cell viability and tumor formation by about 25%, suggesting that targeting zinc compartmentalization could be a new strategy for breast cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ZnT2-overexpression represses the cytotoxic effects of zinc hyper-accumulation in malignant metallothionein-null T47D breast tumor cells. Lopez, V., Foolad, F., Kelleher, SL.[2013]

The study identified a new splice variant of the oncogene ZNF217, called ZNF217-ΔE4, in primary breast tumors, showing a positive correlation with the wild-type ZNF217, suggesting its potential role in breast cancer progression.

Combining the expression levels of both ZNF217-ΔE4 and ZNF217-WT may serve as a novel prognostic biomarker, providing better stratification of breast cancer patients and aiding in therapeutic decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exploring the Significance of the Exon 4-Skipping Isoform of the ZNF217 Oncogene in Breast Cancer. Bellanger, A., Le, DT., Vendrell, J., et al.[2021]

Restoring wild type p53 function in BRCA1 deficient breast cancer using zinc metallochaperones (ZMCs) like ZMC1 shows promise, as it significantly improves survival in murine models with specific TP53 mutations.

A new formulation of ZMC1 (Zn-1) enhances zinc delivery and efficacy, and when combined with olaparib, it effectively inhibits tumor growth, suggesting a novel therapeutic strategy for treating triple negative breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic targeting of BRCA1 and TP53 mutant breast cancer through mutant p53 reactivation. Na, B., Yu, X., Withers, T., et al.[2023]

Tamoxifen resistance in estrogen receptor-positive breast cancer is linked to increased levels of zinc and the zinc transporter ZIP7, which enhances growth factor receptor activation and promotes tumor growth and invasion.

Targeting ZIP7 can reduce intracellular zinc levels, effectively blocking the activation of key growth factor signaling pathways, suggesting a potential new therapeutic strategy to overcome resistance and improve treatment outcomes in breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ZIP7-mediated intracellular zinc transport contributes to aberrant growth factor signaling in antihormone-resistant breast cancer Cells. Taylor, KM., Vichova, P., Jordan, N., et al.[2022]

In a study of 17 clinical breast cancer specimens, the expression levels of the ZNF217 oncogene were found to significantly correlate with Oncotype DX® Recurrence Scores, indicating its potential role in predicting cancer recurrence.

The findings suggest that measuring ZNF217 mRNA and protein levels could provide valuable insights into the aggressiveness of ER-positive invasive breast cancer, aiding in treatment decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The ZNF217 Biomarker Predicts Low- and High-Risk Oncotype DX® Recurrence Score in ER-Positive Invasive Breast Cancers. Cohen, PA., Loudig, O., Liu, C., et al.[2020]

ZNF711 expression is decreased in breast cancer and is negatively correlated with estrogen receptor (ER) levels while positively correlated with HER-2 expression, indicating its potential role in breast cancer pathology.

Patients with higher ZNF711 expression have a poorer prognosis, suggesting that ZNF711 could serve as a valuable biomarker for predicting outcomes and guiding targeted therapies in breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Significance of ZNF711 in Human Breast Cancer. Li, X., Tian, L., Zhang, L., et al.[2022]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

ZNF703 mRNA-Targeting Antisense Oligonucleotide Blocks Cell Proliferation and Induces Apoptosis in Breast Cancer Cell Lines. [2023]

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

The transcription factor ZNF217 is a prognostic biomarker and therapeutic target during breast cancer progression. [2021]

3. China pubmed.ncbi.nlm.nih.gov

[High expression of ZNF652 promotes carcinogenesis and progression of breast cancer]. [2021]

4. Ireland pubmed.ncbi.nlm.nih.gov

ZnT2-overexpression represses the cytotoxic effects of zinc hyper-accumulation in malignant metallothionein-null T47D breast tumor cells. [2013]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Exploring the Significance of the Exon 4-Skipping Isoform of the ZNF217 Oncogene in Breast Cancer. [2021]

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

Therapeutic targeting of BRCA1 and TP53 mutant breast cancer through mutant p53 reactivation. [2023]

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

ZIP7-mediated intracellular zinc transport contributes to aberrant growth factor signaling in antihormone-resistant breast cancer Cells. [2022]

8. Switzerland pubmed.ncbi.nlm.nih.gov

The ZNF217 Biomarker Predicts Low- and High-Risk Oncotype DX® Recurrence Score in ER-Positive Invasive Breast Cancers. [2020]

9. New Zealand pubmed.ncbi.nlm.nih.gov

Clinical Significance of ZNF711 in Human Breast Cancer. [2022]