ZW171 for Mesothelioma

Recruiting at 12 trial locations

Overseen By Zymeworks Clinical Trial Resource

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Zymeworks BC Inc.

Must not be taking: High-dose corticosteroids

Disqualifiers: Additional malignancy, Transplant, Uncontrolled renal, others

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

Compensation: Varies

Number of Visits: Unknown

160 Participants Needed

Trial Summary

What is the purpose of this trial?

This study is being done to find out if ZW171 is safe and can treat participants with advanced (locally advanced \[inoperable\] and/or metastatic) mesothelin-expressing cancers.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What makes the treatment ZW171 unique for mesothelioma?

ZW171 is unique because it uses a zinc-based compound to enhance the body's immune response against tumors by neutralizing the tumor's acidic environment and promoting the activity of immune cells, without relying on traditional inflammatory cytokines that can cause side effects. ^{1 2 3 4 5}

Research Team

Pranshul Chauhan, MSc, MB, BCh, BAO

Principal Investigator

Zymeworks BC Inc.

Eligibility Criteria

This trial is for individuals with advanced or metastatic cancers that express mesothelin, meaning their cancer cells have a specific protein. Details on who can join are not fully provided, but typically participants need to meet certain health standards and may be required to have tried other treatments first.

Inclusion Criteria

My organs are functioning well.

I am fully active or restricted in physically strenuous activity but can do light work.

My heart's left ventricle pumps well, with an efficiency of 50% or more.

Exclusion Criteria

I am on high-dose steroids or immunosuppressants for an autoimmune disease.

I do not have uncontrolled kidney, pancreas, or liver issues, except for allowed conditions.

I don't have major side effects from past cancer treatments, except for hair loss.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Part 1: Safety and Tolerability Evaluation

Evaluation of the safety and tolerability of ZW171

Up to 3 weeks

Part 2: Anti-tumor Activity Evaluation

Evaluation of the anti-tumor activity of ZW171 while continuing to evaluate safety and tolerability

Up to approximately 2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• ZW171

Trial Overview The study is testing ZW171's safety and effectiveness in treating advanced or metastatic mesothelin-expressing cancers. It aims to determine the appropriate dosage and observe any potential benefits in shrinking or controlling the cancer.

Participant Groups

Group I: ZW171 Experimental Treatment 1 Intervention

Who Is Running the Clinical Trial?

Zymeworks BC Inc.

Lead Sponsor

Trials

6

Recruited

1,300+

Findings from Research

Cancer cells often rely on iron, making them more vulnerable to a type of cell death called ferroptosis, but some tumors show resistance to this process due to lipid peroxidation.

The study identified that the protein ZRANB1 plays a crucial role in this resistance by regulating the expression of SLC7A11, which affects glutathione synthesis and lipid peroxidation, suggesting that targeting ZRANB1 could enhance ferroptosis in treatment-resistant tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The deubiquitinase ZRANB1 is an E3 ubiquitin ligase for SLC7A11 and regulates ferroptotic resistance. Huang, S., Zhang, Q., Zhao, M., et al.[2023]

The study introduces a novel Zn2+ doped layered double hydroxide (Zn-LDH) adjuvant that effectively neutralizes the acidic tumor microenvironment and enhances antitumor immunity without the use of traditional inflammatory cytokines, significantly inhibiting tumor growth and metastasis in mice.

Zn-LDH promotes a pro-inflammatory immune response by activating M1 macrophages and cytotoxic T cells, while also inducing immunogenic cell death through the cGas-STING signaling pathway, showcasing its potential as a safe and effective immunotherapy for solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Peritumorally Injected Immunomodulating Adjuvant Elicits Robust and Safe Metalloimmunotherapy against Solid Tumors. Zhang, L., Zhao, J., Hu, X., et al.[2022]

Zinc is crucial for the process of ferroptosis, a type of cell death linked to oxidative stress, in breast and renal cancer cells, as shown by experiments involving zinc chelation and supplementation.

The study identified the gene SLC39A7, which encodes the ZIP7 protein responsible for zinc transport, as a key regulator of ferroptosis; inhibiting ZIP7 protects cells from ferroptosis by causing endoplasmic reticulum stress, suggesting potential therapeutic targets for diseases related to ferroptosis and zinc imbalances.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zinc transporter ZIP7 is a novel determinant of ferroptosis. Chen, PH., Wu, J., Xu, Y., et al.[2021]

HECW1 promotes ferroptosis in glioma cells by enhancing iron accumulation and lipid peroxidation, while ZNF350 counteracts these effects, indicating a regulatory axis between these two proteins.

The study reveals that HECW1 regulates the degradation of ZNF350, which in turn activates NCOA4-mediated ferroptosis, providing insights into potential therapeutic strategies for glioma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

HECW1 induces NCOA4-regulated ferroptosis in glioma through the ubiquitination and degradation of ZNF350. Lin, Y., Gong, H., Liu, J., et al.[2023]

Zeolite imidazole frameworks (ZIFs) are effective carriers for nucleic acids in cancer therapy, offering high loading efficiency and the ability to respond to specific conditions like pH and certain molecules (ATP, GSH).

This review highlights the potential of ZIFs in improving the delivery of gene therapy and nucleic acid-based diagnostics, addressing challenges like low cellular uptake and degradation, which are critical for enhancing cancer treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synthesis and application of zeolitic imidazolate frameworks-based nucleic acid delivery system in tumor diagnosis and therapy: a review. Wang, L., Liang, Z., Li, D., et al.[2023]

References

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

The deubiquitinase ZRANB1 is an E3 ubiquitin ligase for SLC7A11 and regulates ferroptotic resistance. [2023]

2. Germany pubmed.ncbi.nlm.nih.gov

A Peritumorally Injected Immunomodulating Adjuvant Elicits Robust and Safe Metalloimmunotherapy against Solid Tumors. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Zinc transporter ZIP7 is a novel determinant of ferroptosis. [2021]

4. England pubmed.ncbi.nlm.nih.gov

HECW1 induces NCOA4-regulated ferroptosis in glioma through the ubiquitination and degradation of ZNF350. [2023]

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

Synthesis and application of zeolitic imidazolate frameworks-based nucleic acid delivery system in tumor diagnosis and therapy: a review. [2023]