Zanidatamab + Chemotherapy ± Tislelizumab for Stomach and Esophageal Cancer
(HERIZON-GEA-01 Trial)
Recruiting in Palo Alto (17 mi)
+506 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 3
Recruiting
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.
12345What 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.
678910What 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.
1112131415Eligibility 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
+2 more
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.
+8 more
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
Participant Groups
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.
3Treatment groups
Experimental Treatment
Active Control
Group I: Arm CExperimental Treatment6 Interventions
Zanidatamab and tislelizumab plus physician's choice of CAPOX or FP
Group II: Arm BExperimental Treatment5 Interventions
Zanidatamab plus physician's choice of CAPOX or FP
Group III: Arm AActive Control5 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Princess Margaret Cancer CentreToronto, Canada
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Who Is Running the Clinical Trial?
Jazz PharmaceuticalsLead Sponsor
Zymeworks Inc.Lead Sponsor
BeiGene, Ltd.Collaborator
BeiGeneIndustry Sponsor
References
[News in gastrointestinal radiotherapy: The esophageal cancer]. [2022]Esophageal cancers continue to have a poor prognosis, even if this has improved over the past 25 years due to better management. Pre-operative chemotherapy with Paclitaxel-Carboplatin followed by adjuvant immunotherapy with Nivolumab represents a major advance in the management of locally advanced oesophageal cancer. Pre-operatively, chemo-radiotherapy can be performed in combination with FOLFOX or Paclitaxel-Carboplatin. Several trials are currently ongoing to evaluate the benefit of immunotherapy in non-operable cancers. In contrast, dose escalation in locally advanced non-operable tumors and the combination of pre-operative chemo-radiotherapy with trastuzumab have not been shown to be beneficial.
Neoadjuvant PD-1 inhibitor and apatinib combined with S-1 plus oxaliplatin for locally advanced gastric cancer patients: a multicentered, prospective, cohort study. [2023]Programmed cell death protein 1 (PD-1) inhibitor and apatinib have been utilized in metastatic gastric cancer patients. The current study aimed to further investigate the efficacy and safety of neoadjuvant S-1 plus oxaliplatin combined with PD-1 inhibitor and apatinib (SOXPA) in locally advanced gastric cancer (LAGC) patients.
Combined modality therapy in esophageal cancer: the Memorial experience. [2018]Over the past 20 years in the United States, esophageal cancer has shown the most rapid rate of increase of any solid tumor malignancy. Esophageal cancer is an aggressive disease, and poor survival is achieved with surgery or chemoradiation therapy alone. Ongoing trials are investigating the use of preoperative chemoradiation followed by surgical resection. Chemoradiation employing a combination of cisplatin and a continuous infusion of 5-fluorouracil (5-FU) is the most commonly used therapy. The significant gastrointestinal toxicity of traditional cisplatin/5-FU-based regimens has prompted the evaluation of new agents in combined-modality therapy. The Memorial Sloan-Kettering Cancer Center has conducted chemoradiation trials with weekly paclitaxel/cisplatin and irinotecan/cisplatin, and the results suggest that this regimen has the potential to improve the therapeutic index without compromising efficacy. Randomized trials are now being conducted to evaluate the tolerance and efficacy of paclitaxel/cisplatin in comparison with paclitaxel/5-FU combined with radiotherapy in locally advanced esophageal cancer. The incorporation of these non-5-FU-based therapies with novel biologic agents is planned.
Phase II trial of paclitaxel and cisplatin as neoadjuvant chemotherapy for locally advanced gastric cancer. [2015]Paclitaxel-cisplatin (TC) combination is effective and well tolerated in patients with unresectable gastric cancer. We investigated the efficacy and safety of TC for locally advanced gastric cancers in a neoadjuvant setting.
Tislelizumab combined with chemotherapy as neoadjuvant therapy for surgically resectable esophageal cancer: A prospective, single-arm, phase II study (TD-NICE). [2023]Clinical benefit of neoadjuvant immunotherapy in resectable esophageal squamous cell carcinoma (ESCC). remains unclear. This study evaluated the efficacy and safety of the programmed death 1 (PD-1) inhibitor tislelizumab combined with chemotherapy as neoadjuvant therapy in patients with resectable ESCC.
Toxic effects of cis-dichlorodiammineplatinum(II) in man. [2022]Administration of cis-dichlorodiammineplatinum(II) may be associated with a number of serious side effects, including nephrotoxicity, gastroeintestinal side effects (nausea, vomiting, and diarrhea), myelosuppression, and occasional transient elevations in liver function tests. In addition, ototoxicity (tinnitus and hearing loss), anaphylactic reactions, peripheral neuropathies, and hypomagnesemia with resulting tetany may also be encountered. The toxic potential of this new agent necessitates careful clinical monitoring during treatment.
Pharmacology and clinical applications of cis-platinum. [2019]Cis-platinum is one of the most efficacious platinum group metals. This agent is widely used in combination with cancer chemotherapy including urologic, gynecologic, esophageal, and head and neck cancers. The initial experience indicated dose-limiting renal nephrotoxicity. However, recent knowledge through animal and clinical experiments have led to finding ways to prevent the undesirable toxicities of this agent even in high doses. The clinical utilization of cisplatinum in various cancers, including testicular, ovarian, bladder, prostate, esophageal, have been encouraging. The use of high-dose cis-platinum (200 mg/m2) has had important therapeutic impact on patients with poor prognostic testicular cancer when compared with the conventional dosage (100 mg/m2). The current use and future potential of this anticancer metal and its potential analogs are reviewed.
Phase I-II study of biweekly paclitaxel administration with fixed-dose-rate cisplatin in advanced gastric cancer. [2018]Both paclitaxel (TXL) and cisplatin (CDDP) show efficacy against gastric cancer. The aim of this phase I-II study was to determine the maximum tolerated dose (MTD) and to evaluate the toxicity and efficacy of combination chemotherapy with these two agents.
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]This post hoc analysis assessed the safety of pemetrexed and platinum in combination with pembrolizumab, including time-to-onset and time-to-resolution of all-cause any-grade and grade ≥3 adverse events (AEs) and renal AEs.
Comparative adverse effect profiles of platinum drugs. [2018]Since the discovery of the biologically active platinum complexes 30 years ago, 2 agents have become widely established in clinical oncology practice. Both cisplatin and carboplatin are platinum(II) complexes with 2 ammonia groups in the cis- position. However, they differ in their solubility, chemical reactivity, dichloride or alicyclic oxygenated leaving groups, pharmacokinetics and toxicology. Cisplatin causes severe renal tubular damage and reduces glomerular filtration, and requires concurrent saline hydration and mannitol diuresis to eliminate potentially lethal and unacceptable damage to the kidneys. Carboplatin, at conventional doses, causes no decrease in glomerular filtration and only minor transient elevations in urinary enzymes. Cisplatin is the most emetic cancer drug in common use, while nausea and vomiting associated with carboplatin are moderately severe. Serotonin release from enterochromaffin gut mucosal cells and stimulation of serotonin 5-HT3-receptors mediates acute emesis. Selective inhibitors of the 5-HT3-receptor protect against cisplatin- and carboplatin-induced nausea and vomiting. Peripheral neurotoxicity is the most dose-limiting problem associated with cisplatin. Loss of vibration sense, paraesthesia and sensory ataxia comes on after several treatment cycles. Carboplatin, however, is relatively free from peripheral neurotoxicity. Audiometry shows cisplatin-induced ototoxicity in 75 to 100% of patients, which may be associated with tinnitus and hearing loss. Ototoxicity is rare with conventional dose carboplatin therapy. Monitoring hearing with audiograms may identify early signs before significant impairment occurs. Cisplatin causes mild haematological toxicity to all 3 blood lineages. Haematological toxicity is dose-limiting for carboplatin, with thrombocytopenia being a greater problem than leucopenia. Although carboplatin is not toxic to the kidney, renal function markedly affects the severity of carboplatin-induced thrombocytopenia. The major clearance mechanism of cisplatin is irreversible binding in plasma and tissues, while carboplatin is cleared by glomerular filtration. Metabolism of cisplatin to aqua, amino acid and protein species is extensive, whereas carboplatin exists mainly as the free unchanged form. Strong relationships between carboplatin renal clearance, glomerular filtration rate, area under the plasma concentration-time curve (AUC) of filterable platinum and severity of thrombocytopenia have prompted dose adjustment according to renal function. New analogues such as JM216 offer the potential advantages of oral administration and few nonhaematological toxicities. Analogues based on the diaminocyclohexane ligand have encountered problematic neurotoxicity.
HERIZON-GEA-01: Zanidatamab + chemo ± tislelizumab for 1L treatment of HER2-positive gastroesophageal adenocarcinoma. [2022]HER2-positive gastroesophageal adenocarcinomas (GEAs) are common cancers with high mortality and the treatment options for advanced/metastatic disease are limited. Zanidatamab and tislelizumab are novel monoclonal antibodies targeting HER2 and PD-1, respectively, and have shown encouraging antitumor activity in early phase studies in multiple cancers, including GEA. Preliminary data suggest that dual targeting of the HER2 and PD-1 pathways could further improve upon the results achieved with targeting either pathway alone. Here, we describe the design of HERIZON-GEA-01, a global, randomized, open-label, active-comparator, Phase III study to evaluate and compare the efficacy and safety of zanidatamab plus chemotherapy with or without tislelizumab to the standard of care (trastuzumab plus chemotherapy) as first-line treatment for patients with advanced/metastatic HER2-positive GEAs.
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]HER2-targeted therapies have substantially improved outcomes for patients with HER2-positive breast and gastric or gastro-oesophageal junction cancers. Several other cancers exhibit HER2 expression or amplification, suggesting that HER2-targeted agents can have broader therapeutic impact. Zanidatamab is a humanised, bispecific monoclonal antibody directed against two non-overlapping domains of HER2. The aim of this study was to evaluate the safety and anti-tumour activity of zanidatamab across a range of solid tumours with HER2 expression or amplification.
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]The options for first-line treatment of advanced oesophageal squamous cell carcinoma are scarce, and the outcomes remain poor. The anti-PD-1 antibody, tislelizumab, has shown antitumour activity in previously treated patients with advanced oesophageal squamous cell carcinoma. We report interim analysis results from the RATIONALE-306 study, which aimed to assess tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma.
Complete response to tislelizumab in a metastatic urothelial carcinoma after surgery associated with high tumor mutational burden: a case report. [2023]Metastatic urothelial carcinoma (mUC) is associated with poor prognosis. Cisplatin-based combination chemotherapy is the preferred initial regimen for patients with mUC. However, a substantial proportion of patients cannot receive cisplatin-based chemotherapy due to renal impairment or other comorbidities. Currently, immune checkpoint inhibitors (ICI) showed to be effective in cisplatin-ineligible mUC patients on first-line treatment. Tislelizumab is an anti-human programmed death receptor-1 monoclonal IgG4 antibody, which was specifically engineered to minimize binding to FcɣR on macrophages to abrogate antibody-dependent phagocytosis. But there is no report of tislelizumab as a first-line treatment for cisplatin-ineligible patients with mUC currently. Here, we report a cisplatin-ineligible mUC patient with PD-L1-negative, microsatellite stable (MSS), high tumor mutational burden (TMB-H) obtained complete response receiving tislelizumab therapy after laparoscopic debulking surgery. Progression-free survival has exceeded 16 months since treatment with tislelizumab. To our knowledge, this is the first reported case of cisplatin-ineligible mUC patient with PD-L1-negative, MSS and TMB-H who responded well to tislelizumab as a first-line treatment. However, we still need more studies to assess the efficacy of tislelizumab as a first-line treatment in cisplatin-ineligible mUC patients and to confirm predictive values of TMB for efficacy of tislelizumab.
RATIONALE 311: tislelizumab plus concurrent chemoradiotherapy for localized esophageal squamous cell carcinoma. [2022]Definitive chemoradiotherapy is the standard of care for inoperable locoregionally advanced esophageal squamous cell carcinoma (ESCC). Immune checkpoint inhibitors such as anti-PD-1/PD-L1 antibodies have led to a paradigm shift in advanced, metastatic ESCC treatment; however, the effect of incorporating checkpoint inhibitors in the definitive management of ESCC is unclear. Tislelizumab is an anti-PD-1 antibody specifically engineered to minimize FcɣR binding on macrophages to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy. The RATIONALE 311 study described here (BGB-A317-311; NCT03957590) is a registrational multicenter, double-blind, placebo-controlled, randomized, Phase III clinical trial designed to evaluate the efficacy and safety of tislelizumab combined with concurrent chemoradiotherapy in patients with inoperable localized ESCC.