Zenocutuzumab for Solid Tumors

Not currently recruiting at 70 trial locations

Overseen By Merus Inquiries

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Partner Therapeutics, Inc.

Disqualifiers: Pregnancy, Infection, HIV, Hepatitis, 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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 36 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to evaluate the safety and effectiveness of a new treatment, zenocutuzumab (also known as MCLA-128), for individuals with solid tumors that have a specific genetic change called NRG1 fusion. The study administers zenocutuzumab to participants to determine if it helps shrink or control their tumors. Individuals with pancreatic cancer, non-small cell lung cancer, or other solid tumors may qualify if their tumors have this genetic change and they have not succeeded with standard treatments. Participants will receive the treatment every two weeks through an IV. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group of people.

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

The trial protocol does not specify if you need to stop taking your current medications. However, you must not have taken any anti-cancer medication or investigational drugs within 14 days or 5 half-lives before the first dose of the study drug, whichever is shorter.

Will I have to stop taking my current medications?

The trial requires that you stop taking any anti-cancer medication or investigational drugs at least 14 days before starting the study treatment. If your current medication is not an anti-cancer drug, the protocol does not specify whether you need to stop it.

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

Research has shown that zenocutuzumab, a treatment for solid tumors with an NRG1 fusion, has been tested for safety in patients with certain cancers, such as pancreatic cancer and non-small cell lung cancer (NSCLC). In these studies, about 23% of patients with pancreatic cancer experienced serious side effects. This indicates that while the treatment can be effective, some individuals did experience significant reactions.

Zenocutuzumab has received fast-track approval from the FDA for certain conditions, reflecting confidence in its safety for specific uses. However, reactions to the treatment can vary among individuals. Overall, the treatment is generally well-tolerated, but, like any cancer treatment, it carries some risks. Patients should consult their doctor to understand what this might mean for them. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Zenocutuzumab is unique because it targets NRG1 gene fusions, a genetic alteration found in certain solid tumors, including pancreatic adenocarcinoma and non-small cell lung cancer (NSCLC). Unlike traditional treatments, which might focus on chemotherapy or radiation, zenocutuzumab acts as a bispecific antibody, precisely targeting and inhibiting the HER3 receptor pathway activated by NRG1 fusions. This targeted approach has the potential to be more effective and have fewer side effects than conventional therapies. Researchers are excited because this precision treatment could offer a new option for patients who have limited effective treatments available, especially those with tumors driven by these specific genetic changes.

What evidence suggests that zenocutuzumab might be an effective treatment for solid tumors with NRG1 fusion?

Research has shown that zenocutuzumab yields promising results for treating cancers with a specific genetic change called NRG1 fusion. This trial includes separate treatment arms for advanced non-small cell lung cancer (NSCLC) and pancreatic cancer, both with NRG1 fusion, where zenocutuzumab has improved outcomes for many patients. The drug is generally well-tolerated, with mostly mild side effects. Zenocutuzumab is a bispecific antibody, targeting two proteins that often aid cancer growth, thereby helping to stop tumor growth. While still under testing for other types of solid tumors in this trial, current data supports its potential in combating these challenging cancers. ^{6 7 8 9 10}

Who Is on the Research Team?

Alison Schram, MD

Principal Investigator

Memorial Sloan Kettering Medical Center

Are You a Good Fit for This Trial?

This trial is for adults with advanced solid tumors that have a specific genetic change called an NRG1 fusion. They should have tried standard treatments or be unsuitable for them, and must not be pregnant or breastfeeding. Participants need to have a life expectancy of at least 12 weeks, stable organ function, and no serious heart conditions or uncontrolled infections.

Inclusion Criteria

I can provide a new or old sample of my tumor for testing.

Not pregnant or nursing

Your liver enzyme levels and bilirubin levels should be within certain limits. If you have liver spread of cancer, slightly higher levels are allowed. If you have Gilbert's syndrome, higher bilirubin levels are allowed.

Exclusion Criteria

Pregnant or lactating

I have HIV or untreated Hepatitis B, or I've been treated for Hepatitis C with no detectable virus now.

I have brain metastases that are causing symptoms or are unstable.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

4 weeks

Treatment

Participants receive intravenous infusion of 750 mg of zenocutuzumab (MCLA-128) every 2 weeks in 28-day treatment cycles

36 months

Bi-weekly visits for infusion

Follow-up

Participants are monitored for safety and effectiveness after treatment, with quarterly checks for survival data

24 months

What Are the Treatments Tested in This Trial?

Interventions

• Zenocutuzumab (MCLA-128)

Trial Overview The study tests Zenocutuzumab (MCLA-128), focusing on its safety, how the body processes it, and its effectiveness against tumors with NRG1 fusions. It's an early-stage trial involving dose adjustments to find the right balance between safety and efficacy.

How Is the Trial Designed?

Group I: Part 2 Solid tumour (basket) harboring NRG1 fusion Experimental Treatment 1 Intervention

Participants will receive intravenous infusion of 750 mg of zenocutuzumab (MCLA-128) (the recommended Phase 2 dose (RP2D)) every 2 weeks.

Group II: Part 2 Pancreatic adenocarcinoma harboring NRG1 fusion Experimental Treatment 1 Intervention

Participants will receive intravenous infusion of 750 mg of zenocutuzumab (MCLA-128) (the recommended Phase 2 dose (RP2D)) every 2 weeks.

Group III: Part 2 NSCLC cancer harboring NRG1 fusion Experimental Treatment 1 Intervention

Participants will receive intravenous infusion of 750 mg of zenocutuzumab (MCLA-128) (the recommended Phase 2 dose (RP2D)) every 2 weeks.

Zenocutuzumab (MCLA-128) is already approved in United States for the following indications:

Approved in United States as Bizengri for:

• Non-small cell lung cancer harboring a neuregulin 1 gene fusion
• Pancreatic adenocarcinoma harboring a neuregulin 1 gene fusion

Who Is Running the Clinical Trial?

Partner Therapeutics, Inc.

Lead Sponsor

Trials

7

Recruited

820+

Merus N.V.

Lead Sponsor

Trials

10

Recruited

2,700+

Published Research Related to This Trial

In a pilot study involving 6 patients with relapsed/refractory diffuse large B cell lymphoma (DLBCL), the use of 89Zr-labeled rituximab-PET showed a positive correlation between tumor uptake of the imaging agent and CD20 expression in tumor biopsies, suggesting it could serve as a useful imaging biomarker for assessing CD20 targeting.

The study found that intense tumor uptake of 89Zr-rituximab corresponded with positive CD20 expression in most patients, indicating that this imaging technique may help predict the effectiveness of rituximab therapy, although further research is needed to confirm these findings and their clinical implications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Performance of 89Zr-Labeled-Rituximab-PET as an Imaging Biomarker to Assess CD20 Targeting: A Pilot Study in Patients with Relapsed/Refractory Diffuse Large B Cell Lymphoma. Jauw, YW., Zijlstra, JM., de Jong, D., et al.[2018]

89Zr-matuzumab was developed as a PET imaging probe to monitor treatment responses in colorectal cancer, showing high uptake in EGFR-positive tumors and confirming its binding to noncompeting epitopes of EGFR.

The nimotuzumab-PEG6-DM1 antibody-drug conjugate demonstrated significantly improved efficacy in targeting colorectal cancer cells, achieving complete tumor remission in 2 out of 3 mice treated, indicating its potential as an effective therapeutic option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Simultaneous Imaging and Therapy Using Epitope-Specific Anti-Epidermal Growth Factor Receptor (EGFR) Antibody Conjugates. Tikum, AF., Nambisan, AK., Ketchemen, JP., et al.[2022]

In a phase II study involving 110 patients with advanced clear cell renal cell carcinoma (ccRCC), pembrolizumab demonstrated a 36.4% objective response rate, indicating significant antitumor activity as a first-line treatment.

The treatment was generally well-tolerated, with 30% of patients experiencing grade 3-5 adverse events, primarily colitis and diarrhea, which aligns with safety profiles observed in other cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Open-Label, Single-Arm Phase II Study of Pembrolizumab Monotherapy as First-Line Therapy in Patients With Advanced Clear Cell Renal Cell Carcinoma. McDermott, DF., Lee, JL., Bjarnason, GA., et al.[2022]

Polatuzumab vedotin is an antibody-drug conjugate that has shown significant clinical activity and an acceptable safety profile in treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL), particularly when combined with anti-CD20 monoclonal antibodies and chemotherapy.

The recent POLARIX trial suggests that polatuzumab may also be effective in frontline treatment for DLBCL, potentially changing its role in managing patients who have not responded to standard therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Polatuzumab vedotin in relapsed / refractory aggressive B-cell lymphoma. Varma, G., Wang, J., Diefenbach, C.[2022]

In phase I trials, matuzumab showed some efficacy in treating EGFR-positive cancers, with a 23% response rate in patients with advanced non-small cell lung cancer (NSCLC) when combined with paclitaxel.

Panitumumab did not demonstrate any benefit in NSCLC patients in a randomized phase II trial, and the absence of a biomarker to identify responsive patients limits its further investigation in this cancer type.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antibodies to the epidermal growth factor receptor in non small cell lung cancer: current status of matuzumab and panitumumab. Socinski, MA.[2019]

In a phase 3 trial involving 879 patients with untreated intermediate-risk or high-risk diffuse large B-cell lymphoma (DLBCL), the modified regimen pola-R-CHP (which replaces vincristine with polatuzumab vedotin) showed a significantly higher progression-free survival rate at 2 years (76.7%) compared to the standard R-CHOP regimen (70.2%).

The overall survival rates at 2 years were similar between the pola-R-CHP and R-CHOP groups (88.7% vs. 88.6%), indicating that while pola-R-CHP may reduce the risk of disease progression, it does not significantly improve overall survival compared to the standard treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Polatuzumab Vedotin in Previously Untreated Diffuse Large B-Cell Lymphoma. Tilly, H., Morschhauser, F., Sehn, LH., et al.[2022]

This first-in-human study involving 6 patients with HER2-positive metastatic breast cancer demonstrated that 89Zr-pertuzumab PET/CT is safe, with no reported toxicities during the trial.

The imaging technique effectively visualized HER2-positive metastases, confirming its potential for assessing HER2 status in lesions that are difficult to biopsy, and it accurately identified HER2-positive brain metastases in one patient, which was later confirmed by surgical resection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-in-Human Human Epidermal Growth Factor Receptor 2-Targeted Imaging Using 89Zr-Pertuzumab PET/CT: Dosimetry and Clinical Application in Patients with Breast Cancer. Ulaner, GA., Lyashchenko, SK., Riedl, C., et al.[2019]

The study successfully developed an immuno-PET imaging agent, 89Zr-DFO-pertuzumab, which effectively binds to HER2 and allows for visualization of HER2-expressing tumors, demonstrating its potential to monitor therapeutic responses in breast cancer.

In trastuzumab-resistant JIMT-1 breast cancer models, 89Zr-DFO-pertuzumab showed significantly reduced uptake in tumors treated with the HSP90 inhibitor 17-DMAG, indicating its ability to assess treatment efficacy and HER2 downregulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic Response Monitoring with 89Zr-DFO-Pertuzumab in HER2-Positive and Trastuzumab-Resistant Breast Cancer Models. Kang, M., Shin, JI., Han, S., et al.[2022]

A 68-year-old patient with stage IV lung adenocarcinoma showed an unexpected positive response to paclitaxel after failing treatment with pembrolizumab, an anti-PD-1 immunotherapy.

The patient experienced a response duration of over fourteen months with paclitaxel, suggesting that combining or sequencing chemotherapy with immunotherapy may enhance treatment effectiveness in certain cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Prolonged response with paclitaxel after immunotherapy by pembrolizumab in lung cancer]. Zapata, E., Mennecier, B., Leduc, C., et al.[2017]

Zenocutuzumab (Zeno) is a bispecific antibody that targets both HER2 and HER3, showing promising efficacy in treating NRG1 fusion-positive cancers, as demonstrated in both cell line models and patient cases.

In a small cohort of three patients with chemotherapy-resistant NRG1 fusion-positive cancers, two patients with pancreatic cancer experienced significant and lasting responses to Zeno, remaining on treatment for over 12 months, highlighting its potential as a novel therapeutic option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zenocutuzumab, a HER2xHER3 Bispecific Antibody, Is Effective Therapy for Tumors Driven by NRG1 Gene Rearrangements. Schram, AM., Odintsov, I., Espinosa-Cotton, M., et al.[2023]

In a study of 1506 patients with metastatic renal cell carcinoma (mRCC), those treated with the combination of axitinib and pembrolizumab (axi/pembro) showed a median overall survival (OS) of 28.9 months compared to 24.3 months for those treated with ipilimumab and nivolumab (ipi/nivo), although this difference was not statistically significant for the entire population.

Patients with favorable risk disease (IMDC favorable risk strata) experienced improved survival with axi/pembro, suggesting that this combination may be particularly beneficial for certain patient groups, even though overall survival rates were similar across both treatment groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative Effectiveness of Front-Line Ipilimumab and Nivolumab or Axitinib and Pembrolizumab in Metastatic Clear Cell Renal Cell Carcinoma. Zarrabi, KK., Handorf, E., Miron, B., et al.[2023]

Zenocutuzumab, a bispecific antibody, is currently being tested in a phase I/II study and has shown early signs of effectiveness in patients with tumors that have NRG1 fusions.

The treatment appears especially promising for younger patients with NRG1 fusion-positive pancreatic ductal adenocarcinoma, a type of cancer that is often difficult to treat.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zenocutuzumab Shines in PDAC. [2022]

Patritumab deruxtecan (HER3-DXd) is a promising new treatment for EGFR-mutated non-small cell lung cancer (NSCLC) that has progressed after standard therapies, showing antitumor activity and a tolerable safety profile in an ongoing phase I study.

HER3-DXd targets the HER3 receptor, which is often overexpressed in EGFR-mutated NSCLC, and is currently being further evaluated in a global phase II trial (HERTHENA-Lung01) to confirm its efficacy in patients who have already received other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

HERTHENA-Lung01: a phase II study of patritumab deruxtecan (HER3-DXd) in previously treated metastatic EGFR-mutated NSCLC. Yu, HA., Yang, JC., Hayashi, H., et al.[2023]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39908431/

Efficacy of Zenocutuzumab in NRG1 Fusion-Positive Cancer Zenocutuzumab showed efficacy in patients with advanced NRG1 fusion-positive cancer, notably NSCLC and pancreatic cancer, with mainly low-grade adverse events.

2. nejm.org nejm.org/doi/abs/10.1056/NEJMoa2405008

Efficacy of Zenocutuzumab in NRG1 Fusion–Positive Cancer Zenocutuzumab showed efficacy in patients with advanced NRG1 fusion–positive cancer, notably NSCLC and pancreatic cancer, with mainly low-grade adverse events.

3. cancer.gov cancer.gov/news-events/cancer-currents-blog/2025/fda-zenocutuzumab-lung-and-pancreatic-cancers-nrg1-alteration

Bizengri Approved to Treat Some Lung, Pancreatic Cancers FDA has approved zenocutuzumab (Bizengri) to treat lung and pancreatic cancers with a rare genetic alteration called an NRG1 fusion.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT02912949

NCT02912949 | A Study of Zenocutuzumab (MCLA-128) in ... Part 2 new patient populations examine: Group F: Patients with NSCLC with documented NRG1 fusion; Group G: Patients with pancreatic adenocarcinoma with ...

5. ir.merus.nl ir.merus.nl/news-releases/news-release-details/new-england-journal-medicine-publishes-efficacy-zenocutuzumab

Efficacy of Zenocutuzumab in NRG1 Fusion-Positive Cancer Zenocutuzumab demonstrated durable efficacy in patients with advanced NRG1+ cancer, notably NSCLC and pancreatic adenocarcinoma, with a favorable safety ...

6. fda.gov fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-zenocutuzumab-zbco-non-small-cell-lung-cancer-and-pancreatic

FDA grants accelerated approval to zenocutuzumab-zbco For pancreatic adenocarcinoma, ORR was 40% (95% CI: 23%, 59%) and the DOR range was 3.7 months to 16.6 months. In the pooled safety population, ...

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2024/761352s001lbl.pdf

Page 1 of 21 - accessdata.fda.gov Table 5 summarizes the adverse reactions in the eNRGy study in patients with NRG1 gene fusion positive pancreatic adenocarcinoma. Table 5: Adverse Reactions (≥ ...

8. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40834284/

Unveiling the Potential of Zenocutuzumab: A Breakthrough ... This editorial explores the clinical potential of zenocutuzumab in reshaping treatment strategies for NSCLC and pancreatic adenocarcinoma.

9. oncodaily.com oncodaily.com/drugs/zenocutuzumab-merus-overview

Zenocutuzumab: Uses in Cancer, Side Effects, Dosages ... Zenocutuzumab has demonstrated promising efficacy in NRG1 fusion-positive cancers, particularly NSCLC and pancreatic cancer. In the phase 2 ...

10. partnertx.com partnertx.com/new-england-journal-of-medicine-publishes-results-of-global-multicenter-enrgy-study-evaluating-zenocutuzumab-zbco-bizengri-in-nrg1-cancer/

New England Journal of Medicine Publishes Results ... Serious adverse reactions occurred in 23% of patients with NRG1 Gene Fusion Positive Pancreatic Adenocarcinoma who received BIZENGRI. There ...