What side effects are associated with this type of intervention?

Common treatments for Gastroesophageal Junction (GEJ) cancers, such as Zolbetuximab in combination with mFOLFOX6 (a regimen including oxaliplatin, leucovorin, and 5-fluorouracil), and pembrolizumab, often result in side effects like fatigue, nausea, diarrhea, decreased appetite, and musculoskeletal pain. Pembrolizumab, specifically, can cause immune-related adverse events such as pneumonitis, nephritis, and myasthenia gravis-like symptoms. Chemotherapy agents like oxaliplatin and 5-fluorouracil may lead to additional side effects including neuropathy, myelosuppression, and gastrointestinal disturbances.

What prior FDA approvals exist?

Prior FDA approvals for the treatment of Gastroesophageal Junction (GEJ) cancers include several targeted therapies and monoclonal antibodies. Trastuzumab, a monoclonal antibody targeting HER2, has been approved for HER2-positive GEJ adenocarcinomas. Pembrolizumab, an anti-PD-1 monoclonal antibody, has shown efficacy in PD-L1-positive advanced gastric and GEJ cancers and is approved for use in these settings. Other biologic therapies like pertuzumab and apatinib have also demonstrated increased overall and progression-free survival in clinical trials, contributing to their use in treating esophageal and gastric malignancies. These treatments share similarities with Zolbetuximab, which targets CLDN18.2, a novel target in GEJ cancer therapy.

What other types of research exist?

Promising alternatives to Zolbetuximab for Gastroesophageal Junction cancers include: 1) Nivolumab (an immune checkpoint inhibitor) in combination with mFOLFOX6, 2) Pembrolizumab (another immune checkpoint inhibitor) in combination with chemotherapy regimens like mFOLFOX6 or FLOT, and 3) Combination therapies involving fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT). These alternatives are being actively studied for their efficacy and safety in treating GEJ cancers.

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Chemotherapy

Zolbetuximab Combination Therapy for Stomach Cancer (ILUSTRO Trial)

Phase 2

Recruiting

Research Sponsored by Astellas Pharma Global Development, Inc.

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Cohorts 1-4: Estimated creatinine clearance ≥ 30 mL/min

Cohort 5: Serum creatinine ≤ 1.5 × ULN, or estimated creatinine clearance ≥ 50 mL/min for subjects with serum creatinine levels > 1.5 × ULN

Must not have

Cohort 2, 4 and 5 Only, subject has any of the following: Prior severe allergic reaction or intolerance to any component of mFOLFOX6 or FLOT chemotherapeutics in this study, Known dihydropyrimidine dehydrogenase deficiency (DPD), Known peripheral neuropathy > Grade 1 (absence of deep tendon reflexes as the sole neurological abnormality does not render the subject ineligible), Sinusoidal obstruction syndrome, formerly known as veno-occlusive disease, if present, should be stable or improving, History of clinically significant ventricular arrhythmias, QTc interval > 450 msec for male subjects; QTc interval > 470 msec for female subjects, History or family history of congenital long QT syndrome, Cardiac arrhythmias requiring anti-arrhythmic medications (Subjects with rate controlled atrial fibrillation for > 1 month prior to first dose of study treatment are eligible).

Subject has received radiotherapy for locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma ≤ 14 days (Cohorts 1 and 3A) and ≤ 28 days (Cohorts 2 and 4A or 4B) prior to start of study treatment and has NOT recovered from any related toxicity.

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to 72 months

Awards & highlights

Summary

This trial is testing zolbetuximab, a medicine that helps the immune system attack stomach and gastroesophageal cancers with a specific protein. It targets patients whose tumors have the CLDN18.2 protein, aiming to improve their response to treatment.

Who is the study for?

This trial is for adults with advanced or metastatic gastric or GEJ adenocarcinoma that tests positive for CLDN18.2. They should have a life expectancy of at least 12 weeks, meet specific lab criteria, and agree to contraception if applicable. Exclusions include severe allergies to similar drugs, recent immunosuppressive therapy, significant heart issues within the past 6 months, active infections requiring systemic treatment, other cancers needing treatment, and certain psychiatric or social conditions.

What is being tested?

The study is testing Zolbetuximab's effectiveness alone and in combination with chemotherapy (mFOLFOX6) plus/minus Nivolumab or Pembrolizumab on tumor response rate and progression-free survival. It will also assess safety/tolerability, effects on CLDN18.2 expression levels, pharmacokinetics of all drugs involved, quality of life impacts from treatments provided.

What are the potential side effects?

Potential side effects may include allergic reactions to Zolbetuximab or other monoclonal antibodies used in the trial; complications related to oxaliplatin such as nerve damage; digestive issues from fluorouracil; immune-related adverse events due to Pembrolizumab/Nivolumab like inflammation in organs; fatigue; increased risk of infection.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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My kidneys are working well enough (creatinine clearance ≥ 30 mL/min).

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My kidney function is within the required range.

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I haven't had any drug treatments for my advanced cancer.

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My tumor shows high CLDN18.2 expression.

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My tumor tests positive for CLDN18.2 with moderate to strong levels.

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My advanced disease has worsened after at least 2 treatments, including chemotherapy.

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I have never received checkpoint inhibitor therapy.

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I have been diagnosed with stomach or gastroesophageal junction cancer.

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My advanced disease has worsened after 2 treatments, including chemotherapy.

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My stomach cancer is not HER2 positive.

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My stomach or gastroesophageal cancer is at a specific stage and size, not spread far.

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

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I had radiotherapy for stomach cancer less than 14 or 28 days ago and still feel side effects.

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I have another cancer that needs treatment.

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I have severe or partial blockage in my stomach causing vomiting.

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I do not have severe stomach bleeding or untreated stomach ulcers.

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My cancer has spread to my brain or its coverings from my stomach.

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I have tested positive for HIV or active hepatitis B or C.

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I have an infection needing treatment that hasn't cleared in the last week.

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I have a history of autoimmune disease, lung disease, serious allergies to pembrolizumab or nivolumab, or other significant health issues.

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I haven't had serious heart issues like a heart attack or unstable angina in the last 6 months.

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I had major surgery less than 2 weeks ago and haven't fully recovered.

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I've had severe allergic reactions to specific cancer drugs before.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to 72 months

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to 72 months

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to 72 months for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Objective Response Rate (ORR) of zolbetuximab as a single agent by central review (Cohort 1)

Secondary study objectives

DCR of zolbetuximab as a single agent by independent central reader (Cohort 1A)

DCR of zolbetuximab in combination with mFOLFOX6 (with nivolumab) by investigator assessment (Cohort 4)

DCR of zolbetuximab in combination with mFOLFOX6 by Independent central reader (Cohort 2)

+70 more

Trial Design

5Treatment groups

Experimental Treatment

Group I: zolbetuximab (Cohort 1A)Experimental Treatment1 Intervention

Participants will be treated with zolbetuximab on a 21-day cycle in which zolbetuximab will be administered as a single agent every 3 weeks until disease progression, toxicity requiring cessation, start of another anti-cancer treatment or other treatment discontinuation criteria are met.

Group II: mFOLFOX6 plus zolbetuximab (Cohort 2)Experimental Treatment5 Interventions

Participants will be treated with zolbetuximab and mFOLFOX6 on a 42-day cycle in which zolbetuximab is administered on days 1 and 22, and mFOLFOX6 is administered on days 1, 15 and 29; however, for the first cycle, zolbetuximab will be administered on day 3 (instead of day 1) to allow for pharmacokinetic collection. Participants will receive up to 12 mFOLFOX6 treatments (4 cycles). Beginning at cycle 5, participants may continue on 5-FU and leucovorin or folinic acid along with zolbetuximab for the remainder of the study per investigator's discretion. mFOLFOX6 treatment includes oxaliplatin: intravenous \[IV\] infusion, leucovorin: IV infusion, fluorouracil bolus: IV bolus, fluorouracil infusion: continuous IV infusion.

Group III: Zolbetuximab in combination with mFOLFOX6 and nivolumab (Cohort 4A/4B)Experimental Treatment6 Interventions

Participants will be treated with zolbetuximab and mFOLFOX6, nivolumab on a 42-day cycle. Cohort 4A: Loading dose of zolbetuximab in combination with nivolumab and mFOLFOX6 on cycle 1 day 1, followed by zolbetuximab in combination with nivolumab and mFOLFOX6 q2w \[days 15 and 29\] (1 cycle = 6 weeks). Tolerability and safety of zolbetuximab in combination with nivolumab, mFOLFOX6 will be evaluated during the 3-week DLT assessment period. If cycle 1 dose is not tolerable, a lower dose of dose zolbetuximab in combination with nivolumab and mFOLFOX6 will be subsequently evaluated. Cohort 4B: Subjects will be treated with the combination of zolbetuximab, mFOLFOX6 and nivolumab at the dose deemed tolerable in Cohort 4A. Subjects will receive up to 12 mFOLFOX6 treatments (4 cycles). For Cohorts 4A and 4B, beginning at cycle 5, subjects may continue on 5-FU and leucovorin or folinic acid along with zolbetuximab and nivolumab for the remainder of the study per investigator's discretion.

Group IV: Zolbetuximab in combination with FLOT (Cohort 5)Experimental Treatment6 Interventions

Participants will be treated with zolbetuximab \& FLOT for a total of eight 2-week cycles. 4 cycles preoperatively \& 4 cycles postoperatively 6-12 weeks after surgery. Preoperative: Participants will receive zolbetuximab loading dose on cycle 1 day 1, followed by FLOT on cycle 1 day 2. For cycles 2-4, participants may receive zolbetuximab maintenance dose in combination with FLOT, dosed on day 1 of each cycle. However, dosing may be split over 2 days with zolbetuximab administration on day 1 \& FLOT on day 2. Post operative: Participants will receive zolbetuximab loading dose on cycle 5 day 1, followed by FLOT on cycle 5 day 2. For cycles 6-8, participants may receive zolbetuximab maintenance dose in combination with FLOT, dosed on day 1 of each cycle. However, dosing may be split over 2 days with zolbetuximab administration on day 1 and FLOT on day 2. For participants who experience a DLT during preoperative treatment on the loading dose, the postoperative loading dose may be lowered.

Group V: Pembrolizumab plus zolbetuximab (Cohort 3A)Experimental Treatment2 Interventions

Participants will be treated with zolbetuximab and pembrolizumab on a 21-day cycle. Loading dose of zolbetuximab will be administered at cycle 1, day 1 followed by maintenance dose of zolbetuximab once every 3 weeks (Q3W). Pembrolizumab will be administered to 3 to 6 subjects at a intravenously on day 1 of every 21-day cycle and will be infused 1 hour after the zolbetuximab infusion is completed. Tolerability and safety of zolbetuximab in combination with pembrolizumab will be evaluated during the 3-week dose-limiting toxicity (DLT) assessment period. If this cycle 1 dose is not tolerable, a lower dose of zolbetuximab in combination with pembrolizumab will subsequently be evaluated.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Docetaxel

1995

Completed Phase 4

~5620

zolbetuximab

2019

Completed Phase 2

~270

oxaliplatin

2002

Completed Phase 3

~6370

leucovorin

2005

Completed Phase 3

~1200

fluorouracil

1994

Completed Phase 3

~8440

Pembrolizumab

2017

Completed Phase 2

~2070

folinic acid

2009

Completed Phase 3

~580

nivolumab

2016

Completed Phase 3

~4960

0 / 24Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

The most common treatments for Gastroesophageal Junction (GEJ) cancers include monoclonal antibodies like Zolbetuximab, which targets CLDN18.2, a protein expressed in some GEJ cancers, leading to direct antitumor activity. Nivolumab and pembrolizumab are immune checkpoint inhibitors that target PD-1, enhancing the immune system's ability to attack cancer cells. Trastuzumab targets HER2, a protein overexpressed in some GEJ cancers, inhibiting tumor growth. These treatments are crucial for GEJ cancer patients as they offer targeted therapies that can improve response rates and survival outcomes by specifically attacking cancer cells while sparing normal tissues.

[A case of advanced esophagogastric junction cancer responding to pre-operative combination chemotherapy of docetaxel, cisplatin, S-1, and trastuzumab].