Zanidatamab + Chemotherapy ± Tislelizumab for Stomach and Esophageal Cancer

(HERIZON-GEA-01 Trial)

Not currently recruiting at 548 trial locations

Overseen By Clinical Trial Disclosure & Transparency

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Jazz Pharmaceuticals

Must not be taking: HER2-targeted, Anti-PD-1, Anti-PD-L1, others

Disqualifiers: CNS metastases, Active hepatitis, HIV, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 2.5 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if the drug zanidatamab, used with chemotherapy and possibly the drug tislelizumab (an immune checkpoint inhibitor), is safer and more effective than the current treatment, trastuzumab, for advanced stomach and esophageal cancers. It specifically targets HER2-positive cancers, which have a protein that promotes cancer growth and cannot be treated with surgery or have spread to other body parts. The trial seeks participants with these specific cancer types who have not received previous treatments targeting HER2 or certain immune therapies. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, it does exclude participants who have had certain treatments before, like HER2-targeted therapy or specific immune therapies, so it's best to discuss your current medications with the trial team.

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

Previous studies demonstrated that zanidatamab is safe and manageable for patients, meaning they generally tolerated the treatment well. Research indicates that zanidatamab, whether used alone or with chemotherapy, was safe for patients who had already tried other treatments.

When combined with chemotherapy, zanidatamab provided lasting benefits, with effects continuing over time. Another study tested zanidatamab with a drug called tislelizumab and found it to be safe as well.

These findings suggest that both zanidatamab alone and in combination with tislelizumab are generally well-tolerated. While any treatment can have side effects, the data so far shows that these combinations are considered safe for people with similar conditions. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because zanidatamab, combined with chemotherapy and possibly tislelizumab, offers a fresh approach for treating stomach and esophageal cancer. Unlike standard treatments like trastuzumab, zanidatamab is a bispecific antibody that targets two sites on the HER2 protein, potentially leading to more effective cancer cell destruction. Additionally, the combination with tislelizumab, an immune checkpoint inhibitor, could further enhance the body's immune response against cancer cells. This dual-targeting strategy and immune system boost set these treatments apart, offering hope for improved outcomes in a challenging cancer landscape.

What evidence suggests that this trial's treatments could be effective for stomach and esophageal cancer?

Research has shown that zanidatamab may help treat HER2-positive cancers, such as those in the stomach and esophagus. One study found that patients receiving zanidatamab with chemotherapy lived an average of 12.5 months without cancer progression and had an overall survival of 36.5 months. Another study found that 84% of patients experienced tumor shrinkage. In this trial, some participants will receive zanidatamab with chemotherapy, while others will receive zanidatamab combined with another drug, tislelizumab. When used with tislelizumab, zanidatamab has shown lasting positive effects, suggesting potential long-term improvements. Overall, these findings suggest that zanidatamab, either alone or with tislelizumab, may effectively manage advanced HER2-positive stomach and esophageal cancers. ^{2 3 4 5 6}

Who Is on the Research Team?

Jonathan Grim, MD, PhD

Principal Investigator

Zymeworks Inc.

Are You a Good Fit for This Trial?

This trial is for adults with advanced HER2-positive stomach or esophageal cancers that can't be removed by surgery or have spread. Participants should be in good physical condition, with a performance status of 0-1 and proper organ function including heart health. They must not have untreated brain metastases, significant heart issues, HIV, recent other cancers, prior treatment with certain cancer drugs including HER2-targeted agents (unless it was for breast cancer over 5 years ago), or known SARS-CoV-2 infection.

Inclusion Criteria

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

My cancer is advanced stomach or esophagus cancer that cannot be removed by surgery and tests positive for HER2.

Assessable (measurable or non-measurable) disease as defined by RECIST 1.1

Exclusion Criteria

I have had chemotherapy for advanced stomach or esophagus cancer that couldn't be removed by surgery.

I have a history of or currently have leptomeningeal disease.

I do not have serious heart conditions like uncontrolled high blood pressure or heart failure.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive zanidatamab in combination with chemotherapy, with or without tislelizumab, or trastuzumab with chemotherapy

Up to 2.5 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 1 year

What Are the Treatments Tested in This Trial?

Interventions

• Cisplatin
• Oxaliplatin
• Tislelizumab
• Trastuzumab
• Zanidatamab

Trial Overview The study tests if zanidatamab combined with chemotherapy works better and is safer than trastuzumab plus chemotherapy in treating these cancers. Some patients will also receive tislelizumab to see if adding this drug improves outcomes. The effectiveness will be measured against the standard care for this type of cancer.

How Is the Trial Designed?

Group I: Arm C Experimental Treatment 6 Interventions

Zanidatamab and tislelizumab plus physician's choice of CAPOX or FP

Group II: Arm B Experimental Treatment 5 Interventions

Zanidatamab plus physician's choice of CAPOX or FP

Group III: Arm A Active Control 5 Interventions

Trastuzumab (Herceptin®) plus physician's choice of capecitabine plus oxaliplatin (CAPOX) or 5-fluorouracil (5-FU) plus cisplatin (FP)

Cisplatin is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Approved in United States as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Approved in Canada as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Approved in Japan as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Who Is Running the Clinical Trial?

Jazz Pharmaceuticals

Lead Sponsor

Trials

252

Recruited

35,100+

Bruce C. Cozadd

Jazz Pharmaceuticals

Chief Executive Officer since 2009

BA in Economics from Yale University, MBA from Stanford University

Dr. Austin

Jazz Pharmaceuticals

Chief Medical Officer since 2023

MD from the Royal College of Surgeons in Ireland

Zymeworks Inc.

Lead Sponsor

Trials

11

Recruited

2,400+

BeiGene, Ltd.

Collaborator

Trials

3

Recruited

1,000+

BeiGene

Industry Sponsor

Trials

216

Recruited

32,500+

BeOne Medicines LTD

Collaborator

BeOne Pharmaceutical Co., Ltd.

Collaborator

Published Research Related to This Trial

In a phase 3 study involving 649 patients with advanced oesophageal squamous cell carcinoma, tislelizumab combined with chemotherapy significantly improved median overall survival to 17.2 months compared to 10.6 months for the placebo group, demonstrating its efficacy as a first-line treatment.

The safety profile of tislelizumab was manageable, with treatment-related adverse events occurring in 97% of patients, similar to the placebo group, indicating that while there are risks, the benefits in survival may outweigh them.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (RATIONALE-306): a global, randomised, placebo-controlled, phase 3 study. Xu, J., Kato, K., Raymond, E., et al.[2023]

Cis-platinum is a highly effective chemotherapy agent used for various cancers, including testicular, ovarian, and bladder cancers, but it can cause dose-limiting kidney toxicity.

Recent advancements have identified methods to mitigate these toxic effects, allowing for the safe use of higher doses (up to 200 mg/m2) that significantly improve outcomes in patients with poor prognostic testicular cancer compared to standard doses (100 mg/m2).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacology and clinical applications of cis-platinum. Javadpour, N.[2019]

Cisplatin and carboplatin are both effective platinum-based chemotherapy agents, but they differ significantly in their side effects; cisplatin can cause severe kidney damage and neurotoxicity, while carboplatin is safer for renal function and has less neurotoxicity.

Carboplatin's toxicity profile allows for dose adjustments based on renal function, making it a more manageable option for patients, whereas cisplatin requires hydration protocols to mitigate its harmful effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative adverse effect profiles of platinum drugs. McKeage, MJ.[2018]

Zanidatamab, a bispecific monoclonal antibody targeting HER2, was found to be safe and well-tolerated in a phase 1 trial with 132 patients, showing no dose-limiting toxicities and a recommended dose of 20 mg/kg every 2 weeks.

The treatment resulted in a confirmed objective response in 37% of evaluable patients, indicating its potential efficacy across various solid tumors expressing HER2, including biliary tract and colorectal cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zanidatamab, a novel bispecific antibody, for the treatment of locally advanced or metastatic HER2-expressing or HER2-amplified cancers: a phase 1, dose-escalation and expansion study. Meric-Bernstam, F., Beeram, M., Hamilton, E., et al.[2022]

Tislelizumab, an immune checkpoint inhibitor, has shown promising results as a first-line treatment for a cisplatin-ineligible patient with metastatic urothelial carcinoma (mUC), achieving a complete response and over 16 months of progression-free survival.

This case is significant as it is the first report of tislelizumab being effective in a cisplatin-ineligible mUC patient with specific characteristics (PD-L1-negative, microsatellite stable, high tumor mutational burden), highlighting the need for further studies to evaluate its efficacy in similar patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Complete response to tislelizumab in a metastatic urothelial carcinoma after surgery associated with high tumor mutational burden: a case report. Jin, J., Yang, Q., Yu, Y., et al.[2023]

Cis-dichlorodiammineplatinum(II) can cause serious side effects such as nephrotoxicity, gastrointestinal issues (like nausea and vomiting), and myelosuppression, highlighting the need for careful monitoring during treatment.

Other potential side effects include ototoxicity (which can lead to hearing loss), anaphylactic reactions, and peripheral neuropathies, indicating that while the drug may be effective, its safety profile requires close attention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxic effects of cis-dichlorodiammineplatinum(II) in man. Von Hoff, DD., Schilsky, R., Reichert, CM., et al.[2022]

The HERIZON-GEA-01 study is a Phase III clinical trial designed to evaluate the effectiveness and safety of zanidatamab combined with chemotherapy, with or without tislelizumab, in treating advanced HER2-positive gastroesophageal adenocarcinomas (GEAs).

This trial aims to determine if dual targeting of HER2 and PD-1 pathways can provide better outcomes compared to the standard treatment of trastuzumab plus chemotherapy, potentially offering a new first-line treatment option for patients with limited existing therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

HERIZON-GEA-01: Zanidatamab + chemo ± tislelizumab for 1L treatment of HER2-positive gastroesophageal adenocarcinoma. Tabernero, J., Shen, L., Elimova, E., et al.[2022]

Pre-operative chemotherapy with Paclitaxel-Carboplatin followed by adjuvant immunotherapy using Nivolumab has significantly improved the management of locally advanced esophageal cancer, which historically has a poor prognosis.

Current trials are exploring the effectiveness of immunotherapy for non-operable esophageal cancers, while strategies like dose escalation and combining pre-operative chemo-radiotherapy with trastuzumab have not shown benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[News in gastrointestinal radiotherapy: The esophageal cancer]. Quéro, L., Besnard, C., Guillerm, S., et al.[2022]

In a study of 30 patients with locally advanced gastric cancer, the neoadjuvant therapy combining S-1, oxaliplatin, a PD-1 inhibitor, and apatinib (SOXPA) resulted in a high objective response rate of 66.7% and a remarkable disease control rate of 100%.

The treatment demonstrated a favorable safety profile, with most adverse events being mild, and no grade 4 adverse events reported, indicating that SOXPA is both effective and tolerable for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant PD-1 inhibitor and apatinib combined with S-1 plus oxaliplatin for locally advanced gastric cancer patients: a multicentered, prospective, cohort study. Xu, C., Xie, X., Kang, N., et al.[2023]

The combination of pemetrexed, platinum, and pembrolizumab shows manageable toxicity, with most severe adverse events occurring early in treatment and resolving within two weeks, indicating a favorable safety profile for long-term use.

While there was a slightly higher incidence of renal toxicity in patients receiving the pembrolizumab combination compared to those on pemetrexed alone, this did not increase with longer treatment durations, supporting the regimen's safety in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of pemetrexed plus platinum in combination with pembrolizumab for metastatic nonsquamous non-small cell lung cancer: A post hoc analysis of KEYNOTE-189. Garon, EB., Aerts, J., Kim, JS., et al.[2023]

The RATIONALE 311 study is a Phase III clinical trial that aims to assess the safety and efficacy of tislelizumab, an anti-PD-1 antibody, when combined with standard chemoradiotherapy for patients with inoperable localized esophageal squamous cell carcinoma (ESCC).

Tislelizumab is designed to reduce the risk of T-cell clearance and resistance to therapy by minimizing binding to macrophages, which may enhance its effectiveness in treating ESCC compared to traditional treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

RATIONALE 311: tislelizumab plus concurrent chemoradiotherapy for localized esophageal squamous cell carcinoma. Yu, R., Wang, W., Li, T., et al.[2022]

The maximum tolerated dose (MTD) for the combination of paclitaxel (TXL) and cisplatin (CDDP) was established at 18 mg/m2 for TXL, with a recommended dose of 16 mg/m2, indicating a safe dosage range for further studies.

In the phase II part of the study, the combination therapy showed a 25% response rate in patients with gastric cancer, with the most common severe side effect being neutropenia, affecting 65% of patients, but no cases of febrile neutropenia were reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I-II study of biweekly paclitaxel administration with fixed-dose-rate cisplatin in advanced gastric cancer. Yamaguchi, K., Shimamura, T., Komatsu, Y., et al.[2018]

Esophageal cancer is rapidly increasing in the U.S. and is aggressive, with poor survival rates from traditional treatments like surgery or chemoradiation alone.

New trials at Memorial Sloan-Kettering Cancer Center are exploring the use of weekly paclitaxel/cisplatin and irinotecan/cisplatin, which may reduce gastrointestinal toxicity while maintaining efficacy, compared to traditional cisplatin/5-FU regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined modality therapy in esophageal cancer: the Memorial experience. Anderson, SE., Minsky, BD., Bains, M., et al.[2018]

In a study of 45 patients with resectable esophageal squamous cell carcinoma (ESCC), the combination of the PD-1 inhibitor tislelizumab and chemotherapy resulted in a major pathological response (MPR) rate of 72% among those who underwent surgery, indicating strong antitumor activity.

The treatment was generally well-tolerated, with no treatment-related surgical delays or deaths reported, although 42.2% of patients experienced severe adverse events (grade 3-4) and 77.8% had postoperative complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tislelizumab combined with chemotherapy as neoadjuvant therapy for surgically resectable esophageal cancer: A prospective, single-arm, phase II study (TD-NICE). Yan, X., Duan, H., Ni, Y., et al.[2023]

In a study of 52 patients with locally advanced gastric cancer, the combination of paclitaxel and cisplatin (TC) as neoadjuvant chemotherapy was found to be safe, with no treatment-related deaths reported.

The treatment resulted in a significant pathological response rate of 34.6%, and 41.5% of patients survived for at least three years, indicating that TC is an effective option for this patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of paclitaxel and cisplatin as neoadjuvant chemotherapy for locally advanced gastric cancer. Tsuburaya, A., Nagata, N., Cho, H., et al.[2015]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.4013

4-year follow-up of a phase 2 trial. As of July 28, 2024, the median (range) follow-up was 48 (29-59) mo; 8 pts (17%) were on zani treatment and 19 (41%) in survival follow-up. ...

2. thelancet.com thelancet.com/journals/lanonc/article/PIIS1470-2045(25)00287-6/abstract

Zanidatamab plus chemotherapy as first-line treatment for ... The median progression-free survival was 12·5 months (95% CI 8·2–21·8) and median overall survival was 36·5 months (23·6–not estimable). The ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11871714/

Exploring Zanidatamab's efficacy across HER2-positive ... Zanidatamab has shown promising clinical outcomes in several HER2-positive cancers, including biliary tract, breast, gastric, and lung cancers.

4. cancernetwork.com cancernetwork.com/view/zanidatamab-displays-safety-efficacy-in-her2-expressing-gastric-cancer

Zanidatamab Displays Safety, Efficacy in HER2- ... Zanidatamab-hrii (Ziihera) with or without chemotherapy displayed a manageable safety profile and favorable efficacy outcomes in heavily pretreated patients ...

5. investor.jazzpharma.com investor.jazzpharma.com/news-releases/news-release-details/jazz-pharmaceuticals-reports-clinically-meaningful-long-term

Media Contact - Investors - Jazz Pharmaceuticals The overall prognosis for patients with GEA remains poor, with a global five-year survival rate of less than 30 percent for gastric cancer and ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT03929666

NCT03929666 | A Safety and Efficacy Study of ZW25 ... This is a multicenter, global, Phase 2, open-label, 2-part, first-line study to investigate the safety, tolerability, and anti-tumor activity of ZW25 ...