ZN-A-1041 Combinations for Breast Cancer

Not currently recruiting at 51 trial locations

Overseen By Ding Zhou, Ph.D

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Hoffmann-La Roche

Must not be taking: Antiepileptics, Corticosteroids

Disqualifiers: Progressive neurologic impairment, others

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

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called ZN-A-1041 for individuals with advanced HER2-positive breast cancer, where cancer cells have an excess of HER2 protein, aiding their growth. The trial examines ZN-A-1041 both alone and with other cancer drugs to assess its safety and effectiveness. Participants should have advanced or metastatic HER2-positive breast cancer and must have previously tried unsuccessful treatments. Those with new, untreated, or stable brain tumors may also qualify. The study seeks to provide new treatment options for those who have exhausted other possibilities. As a Phase 1 and Phase 2 trial, this research aims to understand how the treatment works in people and measure its effectiveness in an initial, smaller group, offering participants a chance to explore new treatment possibilities.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that ZN-A-1041 could be a promising treatment for HER2-positive cancer. Early studies have found it safe and effective. Designed to reach the brain, this drug is important for treating cancer that has spread there. So far, studies have not identified any major safety concerns.

ZN-A-1041 is being tested with other treatments like PHESGO or T-DM1, which the FDA has already approved for other uses, ensuring their safety is well-known. Another treatment in this trial, T-Dxd, has also demonstrated safety in practice.

This trial is in the early stages, focusing mainly on safety. Participants will receive increasing doses to determine the highest safe dose, allowing researchers to closely monitor for any side effects. Overall, early data suggests that ZN-A-1041 and its combinations are well-tolerated. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

ZN-A-1041 is unique because it targets breast cancer differently than traditional methods like chemotherapy or hormone therapy. While many current treatments focus on inhibiting hormone receptors or damaging cancer DNA, ZN-A-1041 is designed to work with existing therapies like PHESGO, Herceptin, Perjeta, T-DM1, and T-Dxd to potentially enhance their effectiveness. Researchers are excited about ZN-A-1041 because it could offer a new approach to managing breast cancer, particularly for patients whose cancers are resistant to existing treatments. By combining ZN-A-1041 with these established drugs, there’s hope for improved outcomes and potentially fewer side effects, offering more personalized treatment options for patients.

What evidence suggests that this trial's treatments could be effective for breast cancer?

Research has shown that ZN-A-1041 could effectively treat HER2-positive cancers, particularly those that have metastasized to the brain. In this trial, participants in different arms will receive ZN-A-1041 alongside other treatments. One arm will test ZN-A-1041 combined with T-DM1, a treatment for HER2-positive breast cancer that has shown promise in early studies. Another arm will evaluate ZN-A-1041 paired with T-Dxd (trastuzumab deruxtecan), which has produced positive early results against breast cancer, including cases with brain metastasis. These findings suggest that ZN-A-1041, whether used alone or with other treatments in this trial, could help combat advanced HER2-positive tumors. ^{1 3 5 6 7}

Who Is on the Research Team?

Clinical Trials

Principal Investigator

Hoffmann-La Roche

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Herceptin
• Perjeta
• PHESGO
• T-DM1
• T-Dxd
• ZN-A-1041

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.

How Is the Trial Designed?

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

Phase 1c Arm2: The recommended dose combination for Phase 1c will be determined by the Investigator and the Sponsor based on the data from Phase 1b.

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

Phase 1c Arm1: The recommended dose combination for Phase 1c will be determined by the Investigator and the Sponsor based on the data from Phase 1b.

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

Phase 1c Arm3: The recommended dose combination for Phase 1c will be determined by the Investigator and the Sponsor based on the data from Phase 1b.

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

Phase 1b Arm1: 1. If the maximum tolerated dose (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 VI: 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.

Group VII: 1a: ZN-A-1041 Experimental Treatment 1 Intervention

Phase 1a: Participants will receive escalating doses of ZN-A-1041 orally twice a day (BID) at pre-defined dosing regimens to determine the maximum tolerated dose (MTD).

Who Is Running the Clinical Trial?

Hoffmann-La Roche

Lead Sponsor

Trials

2,482

Recruited

1,107,000+

Headquarters

Basel, Switzerland

Known For

Precision medicine

Top Products

Avastin, Herceptin, Rituxan, Accu-Chek

Dr. Levi Garraway

Hoffmann-La Roche

Chief Medical Officer since 2019

MD from the University of Basel

Dr. Thomas Schinecker

Hoffmann-La Roche

Chief Executive Officer since 2023

PhD in Molecular Biology from New York University

Suzhou Zanrong Pharma Limited

Lead Sponsor

Trials

2

Recruited

290+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

Citations

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ascopubs.org

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Preclinical and early clinical data of ZN-1041, a best-in- ...

ZN-1041 alone demonstrated dose-dependent and significant anti-tumor activity when compared to tucatinib in BM model. ZN-1041 could synergize ...

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aacrjournals.org

aacrjournals.org/clincancerres/article/31/12_Supplement/PS8-01/753559/Abstract-PS8-01-ZN-1041-a-potential-best-in-class

Abstract PS8-01: ZN-1041, a potential best-in-class BBB ...

ZN-1041, a potential best-in-class BBB Penetrable HER2 Inhibitor, has high antitumor activity in patients with Breast Cancer with CNS Metastases ...

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clinicaltrials.gov

clinicaltrials.gov/study/NCT04487236

Trial of ZN-A-1041 Enteric Capsules in Patients With HER2 ...

This will be a phase 1, multicenter, open-label trial to evaluate the safety, tolerability, PK and efficacy of ZN-A-1041 as a monotherapy or in combination ...

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cancernetwork.com

cancernetwork.com/view/novel-her2-tki-shows-preliminary-activity-in-breast-cancer-brain-metastases

Novel HER2 TKI Shows Preliminary Activity in Breast ...

ZN-1041, administered alone or in combination with trastuzumab (Herceptin) and capecitabine, demonstrated encouraging preliminary efficacy and tolerability.

5.

ascopubs.org

ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.1041

Preclinical and early clinical data of ZN-1041 in ...

ZN-1041 is a brain permeable, selective HER2-targeted oral tyrosine kinase inhibitor. Preclinical studies have demonstrated efficacy and safety of ZN-1041.

6.

asco.org

asco.org/abstracts-presentations/ABSTRACT398550

Preclinical and early clinical data of ZN-1041, a best-in- ...

ZN-1041 is a best-in-class HER2 inhibitor designed to be delivered across the blood-brain barrier (BBB) with high selectivity and broader safety margin to treat ...

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clinicaltrials.gov

clinicaltrials.gov/study/NCT05593094

NCT05593094 | A Phase 1 Trial of ZN-A-1041 Enteric ...

This will be a Phase 1, multicenter, open-label trial to evaluate the safety, tolerability, PK and efficacy of ZN-A-1041 as a monotherapy or in combination ...