Zolbetuximab Combination Therapy for Stomach Cancer

(ILUSTRO Trial)

Not currently recruiting at 25 trial locations

Overseen By Astellas Pharma Global Development

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Astellas Pharma Global Development, Inc.

Must not be taking: Immunosuppressants, Corticosteroids

Disqualifiers: Autoimmune disease, CNS metastases, Heart condition, others

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

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

Compensation: Varies

Number of Visits: 5

Duration: Up to 24 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment called zolbetuximab for stomach cancer and gastroesophageal junction cancer. Researchers aim to determine how effectively zolbetuximab controls tumors, either alone or with other treatments like chemotherapy or different cancer-fighting drugs. Zolbetuximab targets a specific protein found in most tumors of this cancer type, aiming to trigger the immune system to attack the tumor. Ideal participants are adults whose cancer has spread and contains the protein Claudin 18.2. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot participate if you need medicines to suppress your immune system or if you have certain medical conditions. It's best to discuss your specific medications with the study doctors.

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

Research has shown that zolbetuximab, whether used alone or with other treatments, is generally well-tolerated. In studies, patients with advanced stomach or gastroesophageal junction cancer found zolbetuximab to be safe. For example, when combined with chemotherapy, zolbetuximab did not introduce any new safety issues compared to chemotherapy alone.

Similarly, when used with mFOLFOX6 (a type of chemotherapy) or pembrolizumab (an immune system drug), zolbetuximab did not present new safety problems. Common side effects included nausea, vomiting, and loss of appetite, which are typical with many cancer treatments. The FDA has approved zolbetuximab for use with chemotherapy in certain stomach cancers, supporting its safety.

Overall, while side effects can occur, studies have shown that zolbetuximab is safe in various combinations. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for stomach cancer that typically involve chemotherapy drugs like fluorouracil, oxaliplatin, and folinic acid, the study treatments incorporate zolbetuximab, which is an exciting addition. Zolbetuximab is unique because it targets a protein called CLDN18.2, which is abundant in stomach cancer cells but not in most normal tissues. This targeted approach promises to attack cancer cells more precisely, potentially leading to fewer side effects. Researchers are also testing combinations of zolbetuximab with other agents like pembrolizumab and nivolumab, which are immunotherapy drugs. These combinations might boost the immune system's ability to fight cancer, offering new hope for more effective treatment options.

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

This trial will evaluate various combinations of zolbetuximab with other treatments for stomach cancer. Studies have shown that zolbetuximab can effectively target and attack stomach cancers with the protein Claudin 18.2. In this trial, participants in different arms will receive zolbetuximab combined with different therapies.

One arm will test zolbetuximab with the chemotherapy treatment mFOLFOX6, which has shown promising results in treating advanced stomach and gastroesophageal junction cancers. Another arm will evaluate zolbetuximab with pembrolizumab, an immunotherapy drug, which may further boost its effectiveness by helping the immune system fight cancer cells. Early research suggests that zolbetuximab could significantly help control tumor growth in these types of cancers. ^{1 3 6 7 8}

Who Is on the Research Team?

Global Medical Lead

Principal Investigator

Astellas Pharma Global Development, Inc.

Are You a Good Fit for This Trial?

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.

Inclusion Criteria

My cancer can be measured and was checked within the last 28 days.

I agree to use contraception for 6 months after my last treatment.

Female subject must agree not to breastfeed starting at screening and throughout the study period, and for 6 months after the final study drug administration.

Exclusion Criteria

I have not taken any immune-weakening medication, including steroids, in the last 14 days.

Subject has known immediate or delayed hypersensitivity or contraindication to any component of study treatment.

Subject has psychiatric illness or social situations that would preclude study compliance.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive zolbetuximab as monotherapy or in combination with chemotherapy and/or immunotherapy in cycles

Up to 24 months

Visits every 2-6 weeks depending on treatment cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 16 months

Clinic visits and telephone health checks every 3 months

Survival Follow-up

Participants in certain cohorts are monitored for overall survival

Up to 72 months

What Are the Treatments Tested in This Trial?

Interventions

• Fluorouracil
• Folinic Acid
• Nivolumab
• Oxaliplatin
• Pembrolizumab
• Zolbetuximab

Trial Overview 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.

How Is the Trial Designed?

Group I: zolbetuximab (Cohort 1A) Experimental Treatment 1 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 Treatment 5 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 Treatment 6 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 Treatment 6 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 Treatment 2 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.

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

Approved in United States as 5-Fluorouracil for:

• Colorectal cancer
• Breast cancer
• Stomach cancer
• Pancreatic cancer
• Skin cancer

Approved in European Union as 5-Fluorouracil for:

• Colorectal cancer
• Breast cancer
• Stomach cancer
• Pancreatic cancer

Approved in Canada as 5-Fluorouracil for:

• Colorectal cancer
• Breast cancer
• Stomach cancer
• Pancreatic cancer

Who Is Running the Clinical Trial?

Astellas Pharma Global Development, Inc.

Lead Sponsor

Trials

204

Recruited

123,000+

Tadaaki Taniguchi

Astellas Pharma Global Development, Inc.

Chief Medical Officer

M.D., Ph.D.

Naoki Okamura

Astellas Pharma Global Development, Inc.

Chief Executive Officer

Not available

Published Research Related to This Trial

In a study of 263 gastric cancer samples from Japanese patients, 87% of primary tumors and 80% of lymph node metastases expressed the biomarker CLDN18.2, indicating a high prevalence that supports the use of zolbetuximab as a treatment option.

Moderate-to-strong expression of CLDN18.2 was found in 52% of primary tumors and 45% of lymph node metastases, particularly in high-grade tumors and those of the diffuse histological subtype, suggesting that zolbetuximab could be particularly effective in these cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of Claudin 18.2 expression in primary tumors and lymph node metastases in Japanese patients with gastric adenocarcinoma. Rohde, C., Yamaguchi, R., Mukhina, S., et al.[2022]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39699854/

Efficacy and Safety of Zolbetuximab in Gastric Cancer Zolbetuximab's targeted action, combined with manageable adverse effects, positions it as a promising therapy for advanced gastric cancer.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03504397

NCT03504397 | A Study to Compare Zolbetuximab ... This study will give more information about how well zolbetuximab works when given with chemotherapy in adults with advanced stomach cancer or GEJ cancer.

3. fda.gov fda.gov/drugs/resources-information-approved-drugs/fda-approves-zolbetuximab-clzb-chemotherapy-gastric-or-gastroesophageal-junction-adenocarcinoma

FDA approves zolbetuximab-clzb with chemotherapy FDA approves zolbetuximab-clzb with chemotherapy for gastric or gastroesophageal junction adenocarcinoma · Efficacy and Safety · Expedited ...

4. nejm.org nejm.org/doi/full/10.1056/NEJMc2409512

Zolbetuximab in Gastric or Gastroesophageal Junction ... Zolbetuximab plus chemotherapy resulted in longer progression-free survival and overall survival than placebo plus chemotherapy among patients with HER2- ...

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.4036

Final overall survival results from phase 3 SPOTLIGHT ... Zolbetuximab + mFOLFOX6 continued to demonstrate statistically significant and clinically meaningful improvement in PFS and OS vs PBO + mFOLFOX6, with no new ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT06902545?intr=zolbetuximab&rank=4

A Study to Observe the Safety of VYLOY (Zolbetuximab) in ... The main aim of the study is to collect information in a real-world setting about the safety of VYLOY in people with gastric cancer or GEJ cancer in clinics in ...

7. clinicaltrials.astellas.com clinicaltrials.astellas.com/study/8951-CL-0103

A study of zolbetuximab (IMAB362) in adults with gastric ... The main aim of this study is to check how well zolbetuximab controls tumors when given by itself. Adults with cancer in and around the stomach or ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6771222/

A multicentre, phase IIa study of zolbetuximab as a single ... Zolbetuximab monotherapy was well tolerated and exhibited antitumour activity in patients with CLDN18.2-positive advanced gastric or GEJ adenocarcinomas, with ...