Zanidatamab + Chemotherapy ± Tislelizumab for Stomach and Esophageal Cancer

(HERIZON-GEA-01 Trial)

Recruiting at 507 trial locations

Overseen By Clinical Trial Disclosure & Transparency

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Waitlist Available

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

Pivotal Trial (Near Approval)

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This trial is testing zanidatamab combined with chemotherapy, and sometimes with another drug called tislelizumab, to see if it works better than the current treatment. It targets patients with advanced HER2-positive stomach and esophageal cancers that can't be treated with surgery or standard treatments. The goal is to help the immune system find and destroy cancer cells more effectively. Zanidatamab is a novel HER2-targeting agent being evaluated for its efficacy in advanced HER2-positive 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. 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.

What data supports the effectiveness of this drug combination for stomach and esophageal cancer?

Research shows that combining chemotherapy with immunotherapy, like PD-1 inhibitors such as tislelizumab, can be effective in treating advanced gastric and esophageal cancers. Studies have found that combinations like paclitaxel and cisplatin are effective and well-tolerated in gastric cancer, and ongoing trials are exploring similar combinations for esophageal cancer. ^{1 2 3 4 5}

What are the safety concerns for the treatment involving Zanidatamab, Chemotherapy, and Tislelizumab for stomach and esophageal cancer?

The treatment may have serious side effects, including kidney damage, nausea, vomiting, hearing loss, and nerve damage. Careful monitoring is needed to manage these risks. ^{6 7 8 9 10}

What makes the drug combination of Zanidatamab, Chemotherapy, and Tislelizumab unique for stomach and esophageal cancer?

This drug combination is unique because it targets both the HER2 and PD-1 pathways, which are involved in cancer growth, using novel monoclonal antibodies Zanidatamab and Tislelizumab. This dual targeting approach has shown promising results in improving treatment outcomes compared to targeting either pathway alone. ^{11 12 13 14 15}

Research Team

Jonathan Grim, MD, PhD

Principal Investigator

Zymeworks Inc.

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• Cisplatin (Chemotherapy)
• Oxaliplatin (Chemotherapy)
• Tislelizumab (Monoclonal Antibodies)
• Trastuzumab (Monoclonal Antibodies)
• Zanidatamab (Monoclonal Antibodies)

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.

Participant Groups

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 Canada, Japan for the following indications:

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+

Findings from Research

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]

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 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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

References

1. France pubmed.ncbi.nlm.nih.gov

[News in gastrointestinal radiotherapy: The esophageal cancer]. [2022]

2. Germany 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. [2023]

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

Combined modality therapy in esophageal cancer: the Memorial experience. [2018]

4. Germany pubmed.ncbi.nlm.nih.gov

Phase II trial of paclitaxel and cisplatin as neoadjuvant chemotherapy for locally advanced gastric cancer. [2015]

5. United States 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). [2023]

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

Toxic effects of cis-dichlorodiammineplatinum(II) in man. [2022]

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

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

8. Japan pubmed.ncbi.nlm.nih.gov

Phase I-II study of biweekly paclitaxel administration with fixed-dose-rate cisplatin in advanced gastric cancer. [2018]

9. Ireland 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. [2023]

10. New Zealand pubmed.ncbi.nlm.nih.gov

Comparative adverse effect profiles of platinum drugs. [2018]

11. England pubmed.ncbi.nlm.nih.gov

HERIZON-GEA-01: Zanidatamab + chemo ± tislelizumab for 1L treatment of HER2-positive gastroesophageal adenocarcinoma. [2022]

12. England 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. [2022]

13. England 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. [2023]

14. England 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. [2023]

15. England pubmed.ncbi.nlm.nih.gov

RATIONALE 311: tislelizumab plus concurrent chemoradiotherapy for localized esophageal squamous cell carcinoma. [2022]