ZW171 for Mesothelioma

No longer recruiting at 18 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test the safety and effectiveness of a new treatment called ZW171 for certain advanced cancers that express a protein called mesothelin. The focus is on cancers that have spread or cannot be surgically removed and have not responded to standard treatments. Individuals diagnosed with such advanced cancers, who have stopped responding to or cannot tolerate existing treatments, might be suitable candidates for this trial. As a Phase 1 trial, participants will be among the first to receive this new treatment, aiding researchers in understanding its effects in people.

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.

Is there any evidence suggesting that ZW171 is likely to be safe for humans?

Research has shown that ZW171, a treatment for certain cancers, encountered safety issues. One study found that development of ZW171 stopped because the risks outweighed the benefits for patients with ovarian and lung cancers. Early trials revealed safety problems, despite promising lab results. Although ZW171 showed potential, these concerns halted its development for those cancers. Prospective participants should consider this information when thinking about joining a trial for ZW171. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for mesothelioma, which often include chemotherapy drugs like pemetrexed and cisplatin, ZW171 is unique because it targets a new pathway that could potentially slow or stop the growth of cancer cells more effectively. Researchers are excited about ZW171 because it employs a novel mechanism of action that might lead to better outcomes for patients who have not responded well to existing therapies. Additionally, ZW171 could offer a new hope for extending survival and improving quality of life in mesothelioma patients, a group that currently has limited treatment options.

What evidence suggests that ZW171 might be an effective treatment for mesothelioma?

Research has shown that ZW171 targets cancers with a protein called mesothelin, found in many tumors, including mesothelioma. ZW171 is a unique antibody that connects with two different targets simultaneously, potentially enhancing its ability to attack cancer cells. Early lab studies demonstrated its effectiveness against cancer cells, suggesting it could address challenges faced by other treatments. However, later human trials revealed that the risks outweighed the benefits, halting its development. Despite early promise, ZW171 did not meet expectations for safety and effectiveness in treating cancer. ^{2 4 6 7 8}

Who Is on the Research Team?

Pranshul Chauhan, MSc, MB, BCh, BAO

Principal Investigator

Zymeworks BC Inc.

Are You a Good Fit for This Trial?

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 have had a transplant of stem cells or an organ in the last 5 years.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

Group I: ZW171 Experimental Treatment 1 Intervention

Who Is Running the Clinical Trial?

Zymeworks BC Inc.

Lead Sponsor

Trials

6

Recruited

1,300+

Published Research Related to This Trial

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]

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]

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]

Citations

1.

targetedonc.com

targetedonc.com/view/clinical-focus-zymeworks-discontinues-development-of-zw171-in-phase-1-trial

Zymeworks Discontinues Development of ZW171 in Phase ...

Zymeworks discontinued ZW171 development due to an unfavorable benefit-risk profile in phase 1 trials, despite promising preclinical data. The ...

2.

onclive.com

onclive.com/view/development-to-discontinue-for-zw171-in-gynecologic-thoracic-and-gi-cancer

Development to Discontinue for ZW171 in Gynecologic, ...

“While this is a disappointing outcome given the promising preclinical activity observed with ZW171, we are deeply grateful to the patients, ...

3.

synapse.patsnap.com

synapse.patsnap.com/article/zymeworks-begins-phase-1-trial-of-zw171-for-advanced-mesothelin-cancers

Zymeworks Begins Phase 1 Trial of ZW171 for Advanced ...

The trial is designed to quickly generate clinical data to establish ZW171's differentiated product profile compared to other mesothelin- ...

4.

clinicaltrials.gov

clinicaltrials.gov/study/NCT06523803

NCT06523803 | A Study of ZW171 in Participants With ...

A type of eligibility criteria that indicates whether people who do not have the condition/disease being studied can participate in that clinical study. ... An ...

5.

zymeworks.com

zymeworks.com/wp-content/uploads/2023/04/ZW171-Poster_AACR-2023.pdf

ZW171, a T Cell-Engaging, Bispecific Antibody for the ...

Collectively, these data suggest that ZW171 could overcome the issues impeding the success of other TCEs developed to treat solid tumors and provide the ...

6.

zymeworks.com

zymeworks.com/wp-content/uploads/2023/05/PEGS-2023-ZW171-Engineering-and-preclin-dev-Piscitelli-final.pdf

A 2+1 Format Anti-MSLN T Cell Engager

activity and safety, ZW171, was selected for development. AlphaFold model of MSLN. 1. Morello, A., Sadelain, M., & Adusumilli, P.S. (2016). Mesothelin ...

7.

trial.medpath.com

trial.medpath.com/news/8610477e9850654b/zymeworks-discontinues-zw171-mesothelin-targeted-t-cell-engager-after-phase-1-safety-concerns

Zymeworks Discontinues ZW171 Mesothelin-Targeted T Cell ...

Zymeworks Discontinues ZW171 Mesothelin-Targeted T Cell Engager After Phase 1 Safety Concerns · Key Insights · Phase 1 Trial Results Drive ...

8.

aacrjournals.org

aacrjournals.org/cancerres/article/83/7_Supplement/2942/724302/Abstract-2942-ZW171-a-T-cell-engaging-bispecific

Abstract 2942: ZW171, a T cell-engaging, bispecific antibody ...

Collectively, these data suggest that ZW171 has the potential to be an efficacious and safe therapeutic for the treatment of MSLN-expressing ...