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Perioperative Zanidatamab and Tislelizumab with Chemotherapy for Patients with HER2‑Positive Locally Advanced Operable Gastroesophageal Adenocarcinoma

Verified siteRegistered drugNo placebo

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What is this trial about?

A plain-language summary of the goals, design and what participants do

The study focuses on patients with Gastroesophageal adenocarcinoma that is HER2-positive, a type of cancer that starts in the lining of the stomach or the lower part of the esophagus and has a specific protein on the cancer cells. The treatment being tested combines the experimental antibody zanidatamab with a standard chemotherapy regimen called FLOT, which is given through an intravenous infusion (a drip into a vein). In some participants, the immune‑targeting drug tislelizumab may also be added to explore its effect.

The main goal of the trial is to see whether the combination is safe and can be given before surgery, and to determine if it can increase the chance that no cancer cells are left in the tissue removed during the operation, known as a pathological complete response (meaning the tumor disappears under the microscope). Participants will receive several cycles of the infusion treatment over a few months, followed by surgery to remove the tumor, and then they will be monitored for any side effects and for how well the cancer responds. The study follows patients from the first dose through the surgery period and continues to track their health for a period after treatment.

The research process

The trial runs in 8 steps – from screening to follow-up. Each step says what happens and what the team monitors.

Step 1
Enrollment and consent
After joining the study, you will sign a consent form that explains the purpose of the trial and the procedures involved.
Your eligibility for the trial will be confirmed by reviewing your medical history and test results.
Step 2
Baseline assessments
A series of examinations, blood tests, and imaging studies will be performed to document the status of your gastroesophageal adenocarcinoma and to establish a reference point before treatment begins.
Step 3
Start neoadjuvant treatment (phase 1b safety run‑in)
You will receive zanidatamab by intravenous infusion together with the chemotherapy regimen called f l o t.
zanidatamab is given as an infusion on day 1 of each treatment cycle; the exact dose is determined by the study protocol.
f l o t consists of four chemotherapy drugs (fluorouracil, leucovorin, oxaliplatin, and docetaxel) delivered by infusion, also on day 1 of each cycle.
Treatment cycles are repeated every two weeks, and the neoadjuvant phase includes four cycles.
Some patients may also receive tislelizumab, another intravenous drug, to explore its effect; the decision to add it is made by the study team based on safety observations.
Step 4
Safety monitoring during neoadjuvant therapy
At each visit you will have physical examinations, blood tests, and assessments for any side effects.
The study team will record any safety events that occur during the first four cycles to decide whether treatment can continue.
Step 5
Response evaluation before surgery
After the four neoadjuvant cycles, imaging studies will be repeated to evaluate how the tumor has responded to the combined therapy.
The results help determine whether you are ready for surgical removal of the tumor.
Step 6
Surgery
You will undergo an operation to remove the tumor from the gastroesophageal region.
The goal is a complete resection, meaning no visible cancer remains after the procedure.
Step 7
Post‑operative (adjuvant) therapy
Following recovery from surgery, you will continue to receive the same combination of zanidatamab and f l o t for additional cycles, as defined by the study protocol.
The number of adjuvant cycles and the exact dosing schedule are determined by the investigators based on your individual response and tolerance.
Step 8
Follow‑up and long‑term monitoring
After completing all treatment cycles, you will attend regular follow‑up visits where imaging and clinical assessments are performed.
These visits track event‑free survival (time until disease progression, relapse, or death) and overall survival (time until death from any cause).
Follow‑up continues for the duration of the study, which may extend several years.

Who can join the trial?

15 criteria

Provide voluntary written informed consent before any screening procedures are done.
Have blood test results that show:
- Absolute neutrophil count (a type of white blood cell) ≥ 2.0 × 10⁹/L.
- Platelet count (cells that help blood clot) ≥ 100 × 10⁹/L and no platelet transfusions or medications that raise platelets (thrombopoietic growth factors) in the past 30 days.
- Hemoglobin (the protein that carries oxygen in red blood cells) ≥ 8 g/dL; if you have chronic anemia, occasional red blood cell transfusions are allowed.
- Heart function measured by an echocardiogram (ultrasound of the heart) shows a left ventricular ejection fraction (LVEF) of at least 50 %.
- Be at least 18 years old at the time you sign the consent form.
- Use a highly effective birth‑control method (such as implants, injectables, combined oral contraceptives, certain IUDs, abstinence, or a partner who has had a vasectomy) throughout the period you might be at risk from the study treatment.
- Have a WHO‑ECOG performance status of 0 or 1 (meaning you are fully active or able to carry out light work but are up and about).
- Have a confirmed diagnosis of operable gastroesophageal adenocarcinoma that is HER2‑positive (tested as HER2 IHC 3+ or HER2 IHC 2+ with ISH‑positive results).
- Have disease that is localized and considered resectable (able to be removed by surgery) and be judged fit for peri‑operative treatment (treatment given around the time of surgery) by a multidisciplinary team of doctors.
- Be able to receive the standard chemotherapy regimen that forms the backbone of the study treatment.
- Show adequate liver function:
  - AST (an enzyme that indicates liver health) ≤ 2.5 times the normal upper limit.
  - ALT (another liver enzyme) ≤ 2.5 times the normal upper limit.
  - Total bilirubin (a substance processed by the liver) ≤ 1.5 times the normal upper limit, or ≤ 2.5 times if you have Gilbert’s disease (a mild liver condition).
  - Show adequate kidney function with an estimated glomerular filtration rate (eGFR) > 50 mL/min (a measure of how well the kidneys filter blood).

Who cannot join the trial?

10 criteria

Having already received chemotherapy, immunotherapy, targeted therapy or radiation treatment.
Having an active autoimmune disease (where the immune system attacks the body) or a history of such disease that could flare up, except for controlled type 1 diabetes, hypothyroidism managed with hormone pills, controlled celiac disease, skin conditions like vitiligo, psoriasis or alopecia that do not need systemic medication, or other diseases unlikely to return without a trigger.
Having squamous cell cancer of the esophagus (a flat‑cell cancer in the tube that carries food).
Having metastatic (cancer that has spread) or unresectable (cannot be removed by surgery) gastroesophageal cancer.
Being allergic (hypersensitive) to the study drug zanidatamab or any of its ingredients such as Polysorbate 20, disodium succinate, succinic acid, or sucrose.
Having a known deficiency of the enzyme DPD (which helps break down certain chemotherapy drugs).
Having an active infection that needs treatment with medicines given through the bloodstream, or having HIV infection, or testing positive for hepatitis B surface antigen, or having active hepatitis C infection. (If only hepatitis C antibodies are positive but the virus is not detectable, this may be allowed.) Serious infections within 4 weeks before the first dose, such as bloodstream infection, severe pneumonia treated with IV antibiotics for ≥ 2 weeks, or any infection treated with IV antibiotics within 2 weeks or oral antibiotics within 1 week before the first dose, also exclude participation.
Having a history of major heart problems, such as a heart attack or unstable chest pain within the past 6 months, dangerous heart rhythm requiring treatment, uncontrolled high blood pressure (hypertension), or symptoms of heart failure.
Having had another cancer within the past 5 years, except for low‑risk cancers such as cervical carcinoma in situ, localized non‑melanoma skin cancer, or other cancers that were fully treated and are not expected to affect life expectancy beyond 5 years.
Currently taking part in another clinical trial that uses an investigational drug or device.

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Verified sites

All sites with verified contact details – recruitment status may not be available; ask directly

Algemeen Ziekenhuis Delta
Verified
Roeselare, Belgium
Katholieke Universiteit te Leuven
Responsive
Leuven, Belgium
Universitair Ziekenhuis Gent
Responsive
Gent, Belgium

Trial locations

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Investigated drugs

zanidatamab
is a laboratory‑made protein that attaches to the HER2 receptor found on some stomach and esophagus cancers. By binding to HER2, it helps the immune system recognize and attack the cancer cells. In this trial it is given through an IV infusion together with standard chemotherapy to see if the combination works better than chemotherapy alone.
tislelizumab
is a type of immunotherapy called a PD‑1 inhibitor. It works by releasing the “brakes” on the body’s own immune cells so they can more effectively destroy cancer cells. The drug is delivered by IV infusion and is being studied to determine if adding it to the treatment plan is safe and helpful for patients with HER2‑positive gastroesophageal cancer.
FLOT chemotherapy
is a standard treatment that combines four chemotherapy medicines: 5‑fluorouracil, leucovorin, oxaliplatin, and docetaxel. These drugs work together to stop cancer cells from growing and to kill them. In the study, FLOT is given before surgery, and the researchers want to see if adding zanidatamab (and possibly tislelizumab) improves the chances that the tumor disappears completely after treatment.

What is already known about the treatment

Tislelizumab
This drug is given by intravenous infusion as a concentrate that is mixed with fluid before use. It is an approved immune‑checkpoint inhibitor used for several advanced cancers such as bladder and lung cancer, and is being studied in gastroesophageal adenocarcinoma. It works by attaching to the PD‑1 protein on immune cells, stopping the cancer from turning off the immune response, which helps the body attack the tumor. Tislelizumab belongs to the class of PD‑1 blocking monoclonal antibodies.
Zanidatamab
Zanidatamab is administered by intravenous infusion and is supplied as a solution for injection. It is still an investigational medicine, currently evaluated in clinical trials for HER2‑positive, locally advanced operable gastroesophageal adenocarcinoma. The drug is a bispecific antibody that binds two different sites on the HER2 protein, blocking growth signals and marking the cancer cells for immune destruction. It is classified as a HER2‑directed bispecific antibody.

Investigated diseases

Gastroesophageal adenocarcinoma - It is a cancer that originates in the glandular cells lining the lower esophagus and upper stomach. The tumor usually starts as a small lesion that can grow larger and invade deeper layers of the tissue. As it expands, it may spread to nearby lymph nodes and eventually to other parts of the body. The disease can move from a localized stage to an advanced stage as cancer cells travel beyond the original site.