Zolbetuximab Combination Therapy for Stomach Cancer

(ILUSTRO Trial)

Recruiting at 20 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

143 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

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.

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 Zolbetuximab combination therapy safe for humans?

In a Phase 1 trial with Japanese patients, Zolbetuximab showed no dose-limiting toxicities or severe drug-related side effects, with most side effects being mild and related to the digestive system. ^{1 2 3 4 5}

What makes the drug Zolbetuximab combination therapy unique for stomach cancer?

Zolbetuximab is unique because it targets a specific protein called Claudin 18.2, which is found in certain stomach cancers, and works by helping the immune system kill cancer cells. This makes it different from other treatments that do not specifically target this protein. ^{1 3 4 6 7}

What data supports the effectiveness of the drug Zolbetuximab Combination Therapy for Stomach Cancer?

The SPOTLIGHT trial showed that zolbetuximab, when combined with chemotherapy, improved progression-free survival (the time during which the cancer does not get worse) and overall survival in patients with a specific type of stomach cancer that is positive for claudin 18.2 and negative for HER2. ^{1 2 4 6 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

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

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

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. England pubmed.ncbi.nlm.nih.gov

CLDN18.2 expression and its impact on prognosis and the immune microenvironment in gastric cancer. [2023]

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

Zolbetuximab Improves Survival in Gastric Cancer. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Comparison of Claudin 18.2 expression in primary tumors and lymph node metastases in Japanese patients with gastric adenocarcinoma. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT): a multicentre, randomised, double-blind, phase 3 trial. [2023]

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

Claudin18.2 expression and clinicopathological features in cytology effusion specimens from gastric adenocarcinoma: A comparative study with tissue specimens. [2023]

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

ILUSTRO: Phase II Multicohort Trial of Zolbetuximab in Patients with Advanced or Metastatic Claudin 18.2-Positive Gastric or Gastroesophageal Junction Adenocarcinoma. [2023]

7. England pubmed.ncbi.nlm.nih.gov

Phase 1 trial of zolbetuximab in Japanese patients with CLDN18.2+ gastric or gastroesophageal junction adenocarcinoma. [2023]

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

Patient-reported outcomes from the phase II FAST trial of zolbetuximab plus EOX compared to EOX alone as first-line treatment of patients with metastatic CLDN18.2+ gastroesophageal adenocarcinoma. [2021]