ZEN003694 for Squamous Cell Lung Cancer

Recruiting at 6 trial locations

Overseen By Paul Paik, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: CYP3A4 inducers, CYP1A2 substrates, P-gp inhibitors, Factor Xa/IIa inhibitors

Disqualifiers: Cardiac disease, Active infections, Others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 2 years

13 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test whether the drug ZEN003694 can effectively treat individuals with advanced squamous cell lung cancer that has a specific genetic mutation called NSD3. ZEN003694 blocks certain proteins that may slow or stop cancer growth. This trial may suit those whose squamous cell lung cancer has spread or returned after treatment and who have undergone specific prior therapies. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

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

The trial requires stopping medications that are strong inducers or inhibitors of CYP3A4 and substrates of CYP1A2 with a narrow therapeutic window at least 7 days before starting the study drug. If you're on these medications, you may need to stop them. The protocol does not specify other medications, so consult with the trial team for guidance.

Is there any evidence suggesting that ZEN003694 is likely to be safe for humans?

Research has shown that ZEN003694, a drug known as a BET inhibitor, has been tested in over 550 patients. These studies found strong evidence that the drug is safe for humans, even with long-term use and without major issues. Although specific safety data for treating squamous cell lung cancer is lacking, evidence from other uses suggests it is generally well-tolerated. This makes it a promising option for those considering participation in a clinical trial for this treatment. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for squamous cell lung cancer?

Unlike the standard treatments for squamous cell lung cancer, which typically include chemotherapy, radiation, and immunotherapy, ZEN003694 offers a novel approach by targeting bromodomain and extra-terminal (BET) proteins. These proteins are involved in regulating gene expression, and inhibiting them can disrupt cancer cell growth. Researchers are excited about ZEN003694 because it has the potential to specifically target cancer cells with fewer side effects, offering a more precise and potentially more effective treatment option. Additionally, its oral administration on a unique 5 days on/2 days off schedule could improve patient quality of life compared to traditional continuous treatments.

What evidence suggests that ZEN003694 might be an effective treatment for squamous cell lung cancer?

Research has shown that ZEN003694, administered to participants in this trial, targets a specific change in the NSD3 gene to treat advanced squamous cell lung cancer. This drug acts as a BET inhibitor, blocking proteins that assist the NSD3 gene in promoting tumor growth. By blocking these proteins, ZEN003694 may slow or halt cancer growth. Early results suggest this method could be effective, but further research is necessary to confirm its effectiveness in people. ^{1 2 5 6 7}

Who Is on the Research Team?

Paul Paik

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

Adults with advanced squamous cell lung cancer and NSD3 gene mutation can join this trial. They must have had prior chemotherapy and immunotherapy, be able to swallow capsules, and not be pregnant or breastfeeding. Stable brain metastases are okay. Participants need proper organ function, no recent heart attacks or surgeries, and cannot have HIV/HBV/HCV or other significant health issues.

Inclusion Criteria

Contraception should be considered for a non-pregnant female partner of childbearing potential

I am not breastfeeding and will not be during the study.

I am not pregnant and agree to regular pregnancy tests during the study.

Exclusion Criteria

My heart's pumping ability is below normal.

I am taking medication that strongly affects liver enzymes.

Historically positive for HIV, HBV, or HCV or with active infections

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ZEN003694 60mg po qd on a 5 days on/2 days off schedule in an every 21-day cycle

2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• ZEN003694

Trial Overview The study is testing ZEN003694's effectiveness for squamous cell lung cancer with an NSD3 mutation. It's a BET inhibitor that may slow down tumor growth by blocking proteins involved in cancer progression.

How Is the Trial Designed?

Group I: ZEN003694 Experimental Treatment 1 Intervention

All patients enrolled on the study will undergo treatment with ZEN003694 60mg po qd on a 5 days on/2 days off schedule in an every 21-day cycle. All assessments, including drug dosing, have a window of +/- 7 days unless otherwise noted.

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Zenith Epigenetics

Industry Sponsor

Trials

10

Recruited

590+

Published Research Related to This Trial

In a study of 197 patients with non-small-cell lung cancer (NSCLC), squamous NSCLC (SQ-NSCLC) showed a higher presence of CD8+ tumor infiltrating lymphocytes (TILs) in the cancer nests compared to nonsquamous NSCLC (non-SQ-NSCLC), which may influence treatment response and prognosis.

The degree of CD8+ TIL infiltration was identified as a significant positive predictor for overall survival in both SQ-NSCLC and non-SQ-NSCLC, suggesting that the immune microenvironment differs between these cancer types and impacts patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune Microenvironment Differences Between Squamous and Non-squamous Non-small-cell Lung Cancer and Their Influence on the Prognosis. Meng, X., Gao, Y., Yang, L., et al.[2019]

Squamous cell lung cancer (sqCLC) is challenging to treat due to factors like older patient age, late-stage diagnosis, and high comorbidity rates, leading to median survival times of only 9 to 11 months.

Recent advancements in targeted therapies, including monoclonal antibodies and immunotherapies, have shown modest survival benefits for sqCLC patients, highlighting the need for ongoing research into actionable molecular targets and effective treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Incremental Innovation and Progress in Advanced Squamous Cell Lung Cancer: Current Status and Future Impact of Treatment. Langer, CJ., Obasaju, C., Bunn, P., et al.[2018]

Squamous-cell carcinomas of the lung (SQCLCs) have evolved from being the most common subtype of non-small-cell lung cancers to being less prevalent than adenocarcinomas, with a notable shift towards peripheral squamous tumors.

Recent discoveries of specific genetic abnormalities, such as SOX2 amplification and mutations in NFE2L2 and KEAP1, have led to the development of targeted therapies, marking a significant advancement in treatment options for SQCLCs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Squamous-cell carcinomas of the lung: emerging biology, controversies, and the promise of targeted therapy. Drilon, A., Rekhtman, N., Ladanyi, M., et al.[2022]

Targeted therapies for non-small cell lung cancer (NSCLC) have significantly improved treatment options, but their effectiveness can be compromised by issues like poor patient adherence and adverse events.

The review highlights the need for standardized monitoring protocols for the various toxicities associated with these therapies, which can include skin, gastrointestinal, lung, and heart-related side effects, to ensure better patient management and treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeted Toxicities: Protocols for Monitoring the Adverse Events of Targeted Therapies Used in the Treatment of Non-Small Cell Lung Cancer. Hines, JB., Bowar, B., Levine, E., et al.[2023]

In a study of 205 patients with advanced non-small cell lung cancer (NSCLC) receiving anti-PD-1/PD-L1 therapy, the incidence of checkpoint inhibitor pneumonitis (CIP) was found to be 19%, significantly higher than the 3%-5% reported in clinical trials.

The study identified tumor histologic type as a potential risk factor for developing CIP, with a median onset time of 82 days and severe outcomes associated with higher-grade CIP, highlighting the need for improved monitoring and management strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pneumonitis in Non-Small Cell Lung Cancer Patients Receiving Immune Checkpoint Immunotherapy: Incidence and Risk Factors. Suresh, K., Voong, KR., Shankar, B., et al.[2019]

In a phase 3 clinical trial involving 355 patients with advanced squamous non-small-cell lung cancer (sq-NSCLC), the combination of tislelizumab and chemotherapy significantly improved progression-free survival (PFS) compared to chemotherapy alone, with PFS of 7.6 months for the combination versus 5.5 months for chemotherapy alone.

The addition of tislelizumab also resulted in higher objective response rates (ORR) and longer duration of response, while maintaining a manageable safety profile, with no deaths directly attributed to tislelizumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tislelizumab Plus Chemotherapy vs Chemotherapy Alone as First-line Treatment for Advanced Squamous Non-Small-Cell Lung Cancer: A Phase 3 Randomized Clinical Trial. Wang, J., Lu, S., Yu, X., et al.[2022]

Squamous cell carcinoma of the lung, which makes up 20-30% of non-small cell lung cancers, has historically been treated similarly to non-squamous types, despite differences in disease characteristics.

Recent advancements in immunotherapy targeting immune checkpoints, such as CTLA-4 and PD-1 pathways, show promise in restoring immune responses against squamous NSCLC, indicating a potential shift in treatment strategies for this subtype.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Unmet needs in squamous cell carcinoma of the lung: potential role for immunotherapy. Stinchcombe, TE.[2021]

Recent research has made significant strides in understanding squamous cell lung cancer (SCC), identifying new genomic and signaling pathways that could lead to targeted therapies.

Emerging prognostic gene signatures and predictive biomarkers are paving the way for innovative clinical trials, such as the Lung-MAP master protocol, aimed at improving treatment options for patients with advanced SCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Squamous cell lung cancer: from tumor genomics to cancer therapeutics. Gandara, DR., Hammerman, PS., Sos, ML., et al.[2023]

Lung squamous cell carcinoma (SQCC) is a major subtype of non-small-cell lung cancer linked to tobacco smoking, and recent advancements in genomic characterization using next-generation sequencing (NGS) have revealed distinct DNA modifications that could lead to new treatment targets.

Currently, targeted therapies have not been effectively implemented for lung SQCC, but ongoing research aims to identify specific genetic alterations that may pave the way for novel targeted treatments in the future.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New developments in the treatment of squamous cell lung cancer. Filipits, M.[2014]

In a meta-analysis of 4413 patients from 8 randomized controlled trials, PD-1/PD-L1 inhibitors showed a significantly lower risk of all-grade adverse events (66.20% vs. 86.08%) and high-grade adverse events (14.26% vs. 43.53%) compared to chemotherapy, indicating a better safety profile.

While PD-1/PD-L1 inhibitors are generally safer, they are associated with a unique set of immune-related adverse events (irAEs) that can be severe, such as pneumonitis and thyroid dysfunction, which clinicians need to monitor closely to manage patient quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of PD-1/PD-L1 inhibitors in the treatment of non-small cell lung cancer: a meta-analysis of randomized controlled trials. Luo, W., Wang, Z., Tian, P., et al.[2021]

In a phase II trial involving 47 patients with extensive-stage small cell lung cancer, docetaxel demonstrated efficacy with a 23% partial response rate and a median overall survival of 9 months.

The treatment was generally well tolerated, although 58% of patients experienced grade 4 neutropenia, indicating that while docetaxel is effective, it can cause significant blood-related side effects that need to be managed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of docetaxel in previously untreated extensive-stage small cell lung cancer: a Southwest Oncology Group phase II trial. Hesketh, PJ., Crowley, JJ., Burris, HA., et al.[2018]

The combination of docetaxel and gemcitabine did not improve survival rates compared to docetaxel alone in patients with previously treated non-small-cell lung cancer (NSCLC), with median survival times being similar at 10.3 months and 10.1 months, respectively.

The trial was halted early due to a higher incidence of interstitial lung disease (ILD) and three treatment-related deaths in the combination group, indicating that docetaxel alone remains the safer and standard second-line treatment for NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase III trial of docetaxel plus gemcitabine versus docetaxel in second-line treatment for non-small-cell lung cancer: results of a Japan Clinical Oncology Group trial (JCOG0104). Takeda, K., Negoro, S., Tamura, T., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05607108

A Study of ZEN003694 in People With Squamous Cell ... The purpose of this study is to find out whether ZEN003694 is an effective treatment for people with advanced squamous cell lung cancer with a mutation in ...

2. withpower.com withpower.com/trial/phase-2-lung-neoplasms-10-2022-5410a

ZEN003694 for Squamous Cell Lung Cancer The purpose of this study is to find out whether ZEN003694 is an effective treatment for people with advanced squamous cell lung cancer with a mutation in ...

3. mskcc.org mskcc.org/cancer-care/clinical-trials/22-286

A Phase II Study of ZEN003694 in People with Advanced ... The purpose of this study is to assess the safety and effectiveness of the investigational drug ZEN003694 in people with advanced squamous cell lung cancer.

4. zenithepigenetics.com zenithepigenetics.com/newsroom/news-releases?article=60

News Releases - zenithepigenetics We are developing ZEN-3694 for the treatment of two aggressive rare cancers with very poor prognosis and no effective approved therapies.

5. centerwatch.com centerwatch.com/clinical-trials/listings/NCT05607108/a-study-of-zen003694-in-people-with-squamous-cell-lung-cancer

A Study of ZEN003694 in People With Squamous Cell ... The purpose of this study is to find out whether ZEN003694 is an effective treatment for people with advanced squamous cell lung cancer with ...

6. ctv.veeva.com ctv.veeva.com/study/a-study-of-zen003694-in-people-with-squamous-cell-lung-cancer

A Study of ZEN003694 in People With Squamous Cell Lung ... The purpose of this study is to find out whether ZEN003694 is an effective treatment for people with advanced squamous cell lung cancer with ...

7. cancernetwork.com cancernetwork.com/view/zen-3694-earns-fda-orphan-drug-designation-in-nut-carcinoma

ZEN-3694 Earns FDA Orphan Drug Designation in NUT ... Across more than 550 patients who have received ZEN-3694 to date, developers have observed robust signs of on-target safety, chronic dosing, ...