ASP2138 for Digestive System Cancers

Recruiting at 50 trial locations

Overseen By Astellas Pharma Global Development, Inc.

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Astellas Pharma Global Development, Inc.

Must not be taking: Immunosuppressants, Corticosteroids

Disqualifiers: HIV, Hepatitis B, CNS metastases, others

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

Compensation: Varies

Number of Visits: Unknown

398 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called ASP2138 for certain digestive system cancers, such as stomach, gastroesophageal junction (where the esophagus meets the stomach), and pancreatic cancers. Researchers aim to determine if ASP2138 can help the immune system attack tumors by targeting a specific protein on cancer cells. They seek to find the best dose of ASP2138, both alone and with standard cancer treatments, while ensuring its safety and tolerability. Suitable participants have advanced stomach, GEJ, or pancreatic cancer that cannot be surgically removed or has spread, and their tumors must have a specific marker called CLDN18.2. As a Phase 1 trial, this research focuses on understanding how ASP2138 works in people, offering participants the opportunity to be among the first to receive this new treatment.

Do I need to stop my current medications for the trial?

The trial information does not specify if you need to stop taking your current medications. However, it mentions that participants who have received other investigational agents or antineoplastic therapy within 21 days prior to the first dose are excluded. It's best to discuss your current medications with the trial team to get specific guidance.

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

Research is investigating ASP2138 as a potential treatment for various digestive system cancers. In early studies, researchers monitored patient responses when ASP2138 was used alone or with other cancer treatments. These studies aim to determine ASP2138's safety and tolerability.

Current research lacks detailed safety information for ASP2138 alone, as the study is in its early stages, focusing on dose optimization and side effect assessment.

When combined with treatments like pembrolizumab and mFOLFOX6, or ramucirumab and paclitaxel, past studies have shown these combinations are generally well-tolerated. These existing treatments are already known to be safe for similar cancers.

For the combination with mFOLFIRINOX, ASP2138 is being tested for pancreatic cancer. Researchers are still determining the optimal dose, so detailed safety information is not yet available.

Overall, the studies aim to identify the appropriate dose of ASP2138 and monitor for any medical issues, ensuring future trials can proceed safely. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about ASP2138 because it represents a potentially novel approach to treating digestive system cancers, particularly gastric, gastroesophageal junction (GEJ), and pancreatic cancers. Unlike the standard treatments, which often include chemotherapy regimens like mFOLFOX6 and mFOLFIRINOX, ASP2138 is being investigated for its unique ability to work in combination with these therapies and enhance their effectiveness. It is being tested in combination with pembrolizumab, an immunotherapy drug that helps the immune system attack cancer cells more effectively, and with chemotherapy drugs like ramucirumab and paclitaxel. By potentially offering a new mechanism of action and enhancing the effects of existing treatments, ASP2138 could improve outcomes for patients who may not respond well to current options.

What evidence suggests that ASP2138 could be an effective treatment for digestive system cancers?

Research has shown that ASP2138 targets a protein called Claudin 18.2, often found in tumors of the digestive system. This protein is linked to cancer growth and spread. By attaching to Claudin 18.2 and a protein on immune cells, ASP2138 may help the immune system attack tumors. Early studies have found Claudin 18.2 to be common in stomach, gastroesophageal junction (where the esophagus meets the stomach), and pancreatic cancers. This trial will evaluate ASP2138 in various treatment arms, including monotherapy and combination therapies, to determine its effectiveness in treating these cancers by boosting the body's natural defenses. ^{1 3 5 6 7}

Who Is on the Research Team?

Senior Director

Principal Investigator

Astellas Pharma Global Development, Inc.

Are You a Good Fit for This Trial?

Adults with advanced stomach, gastroesophageal junction, or pancreatic cancer that can't be removed by surgery or has spread are eligible. They must not be pregnant or breastfeeding and agree to contraception. Their tumors should express CLDN18.2 protein and they should have a life expectancy of at least 12 weeks.

Inclusion Criteria

I am a man who will use birth control during and for 6 months after treatment.

My tumor tested positive for CLDN18.2.

I have cancer in my stomach or where my esophagus meets my stomach.

Exclusion Criteria

I weigh less than 40 kg.

I have severe blockage in my stomach causing vomiting.

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

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Phase 1

Participants receive escalating doses of ASP2138 alone or in combination with standard cancer treatments to determine the maximum tolerated dose and recommended phase 2 dose.

Up to 15 months

Weekly visits during treatment cycles

Treatment Phase 1b

Participants receive ASP2138 at the recommended phase 2 dose to evaluate cancer response and safety.

Up to 21 months

Regular visits for safety checks and response evaluation

Follow-up

Participants are monitored for safety and effectiveness after treatment completion.

Several months, depending on individual health status

Several visits for health checks

What Are the Treatments Tested in This Trial?

Interventions

• ASP2138

Trial Overview The trial is testing ASP2138, which targets both the tumor cell and an immune cell protein to direct the immune system against the tumor. It's given as an infusion in two phases: first to find a safe dose by escalating amounts in small groups, then using those doses to see how different cancers respond.

How Is the Trial Designed?

Group I: Monotherapy Dose Expansion (Phase 1b) Pancreatic cancer Experimental Treatment 1 Intervention

Participants will receive ASP2138 at the candidate RP2D regimens determined in Monotherapy Dose Escalation arm.

Group II: Monotherapy Dose Expansion (Phase 1b) Gastric/GEJ cancer Experimental Treatment 1 Intervention

Participants will receive ASP2138 at the candidate RP2D regimens determined in Monotherapy Dose Escalation arm.

Group III: Monotherapy Dose Escalation (Phase 1) Experimental Treatment 1 Intervention

A dose escalation design will be used to determine the Maximum Tolerated Dose (MTD) and/ or the Recommended Phase 2 Dose (RP2D) regimens to be further evaluated in the Monotherapy Dose Expansion arms. Monotherapy Dose escalation part consists of six parts (Part A, B, C, D, E, and F), and approximately 86 patients would be enrolled in total. Participants will be assigned to sequentially escalating dose cohorts of ASP2138 in each part. The study will open with the Part A dosing schedule, while subsequent cohorts will be opened sequentially or in parallel based upon sponsor review of emerging data.

Group IV: Combination Therapy Dose Escalation (Phase 1) Part I - First line Pancreatic Cancer Experimental Treatment 5 Interventions

A dose escalation design will be used to determine the MTD and/ or the RP2D regimens to be further evaluated in the Combination Dose Expansion arms. Participants will be assigned to sequentially escalating dose cohorts of ASP2138 in combination with mFOLFIRINOX as first line therapy.

Group V: Combination Therapy Dose Escalation (Phase 1) Part H - Second-line Gastric/GEJ Cancer Experimental Treatment 3 Interventions

A dose escalation design will be used to determine the MTD and/ or the RP2D regimens to be further evaluated in the Combination Dose Expansion arms. Participants will be assigned to sequentially escalating dose cohorts of ASP2138 in combination with ramucirumab and paclitaxel as second line therapy.

Group VI: Combination Therapy Dose Escalation (Phase 1) Part G - First-line Gastric/GEJ Cancer Experimental Treatment 5 Interventions

A dose escalation design will be used to determine the MTD and/ or the RP2D regimens to be further evaluated in the Combination Dose Expansion arms. In combination dose escalation part G approximately 24 patients would be enrolled in total. Participants will be assigned to sequentially escalating dose cohorts of ASP2138 in combination with pembrolizumab and mFOLFOX6 as first line therapy.

Group VII: ASP2138 + mFOLFIRINOX Combination Therapy Dose Expansion (Phase 1b) Pancreatic Cancer Experimental Treatment 5 Interventions

Participants will receive candidate RP2D regimens of ASP2138 in combination with mFOLFIRINOX as first line therapy in pancreatic cancer determined in Combination Therapy Dose Escalation arm in combination with mFOLFIRINOX as first line therapy in pancreatic cancer.

Group VIII: ASP2138 + Ramucirumab & Paclitaxel Combination Therapy Dose Expansion (Phase 1b) Gastric/GEJ Cancer Experimental Treatment 3 Interventions

Participants will receive candidate RP2D regimens of ASP2138 in combination with ramucirumab and paclitaxel as second line therapy determined in Combination Therapy Dose Escalation arm.

Group IX: ASP2138 + Pembrolizumab & mFOLFOX6 Combination Therapy Dose Expansion (Phase 1b) Gastric/GEJ Cancer Experimental Treatment 5 Interventions

Participants will receive candidate RP2D regimens of ASP2138 in combination with pembrolizumab \& mFOLFOX6 as first line therapy determined in Combination Therapy Dose Escalation arm.

Group X: ASP2138 + Pembrolizumab & CAPOX CTDE Exploratory Cohort (Phase1b) Gastric/GEJ Cancer - Japan & Korea Experimental Treatment 4 Interventions

Participants will receive candidate RP2D regimens of ASP2138 in combination with pembrolizumab \& CAPOX as first line therapy determined in Combination Therapy Dose Escalation arm. CTDE: Combination Therapy Dose Expansion

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

Deleting p38-MAPK in the intestinal epithelium of mice led to a significant increase in tumor development, with epithelial-deleted mice developing an average of 3.7 tumors compared to 1.1 in wild-type mice, indicating that p38-MAPK plays a crucial role in suppressing tumorigenesis in the colon.

The study suggests that the increased tumor burden in p38-MAPK deficient mice is likely due to impaired cell cycle regulation rather than increased inflammation, highlighting the potential for targeting p38-MAPK as a therapeutic strategy in colorectal cancer, especially for patients with inflammatory bowel disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Deletion of p38-alpha mitogen-activated protein kinase within the intestinal epithelium promotes colon tumorigenesis. Wakeman, D., Schneider, JE., Liu, J., et al.[2021]

The response of colorectal cancer (CRC) to p38 inhibitors varies significantly between subgroups, with some experiencing tumor regression while others show increased growth, highlighting the complexity of targeting p38 MAP kinase in cancer therapy.

PP2AC expression levels can predict how CRC will respond to p38 inhibitors, and combining p38 and mTOR inhibitors may help overcome resistance, suggesting a promising biomarker-guided approach for treating metastatic CRC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PP2AC Level Determines Differential Programming of p38-TSC-mTOR Signaling and Therapeutic Response to p38-Targeted Therapy in Colorectal Cancer. Zhang, Y., Wang, X., Qin, X., et al.[2021]

Locally advanced colorectal cancer (CRC) stem cells show high levels of p38α, which is linked to poor patient outcomes, indicating that targeting p38α could improve disease-free and progression-free survival.

The p38α kinase inhibitor ralimetinib enhances the effectiveness of standard chemotherapy in CRC stem cells and shows potential for use in combination with other treatments, suggesting a new avenue for personalized therapy in CRC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacological targeting of the novel β-catenin chromatin-associated kinase p38α in colorectal cancer stem cell tumorspheres and organoids. Lepore Signorile, M., Grossi, V., Di Franco, S., et al.[2023]

The p38α signaling pathway plays a protective role in preventing colitis-associated colon cancer by maintaining the integrity of the intestinal epithelial barrier, as its downregulation leads to increased inflammation and epithelial damage.

Interestingly, while p38α helps prevent tumor formation in normal epithelial cells, its inhibition in cancerous colon cells can actually reduce tumor burden, highlighting its complex role in colorectal tumorigenesis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dual function of p38α MAPK in colon cancer: suppression of colitis-associated tumor initiation but requirement for cancer cell survival. Gupta, J., del Barco Barrantes, I., Igea, A., et al.[2022]

A study found that the -1628G variant allele of the p38β promoter SNP (rs2235356) is associated with nearly double the risk of developing sporadic colorectal cancer (CRC), based on a case-control analysis involving genotyping of participants.

The SNP affects the binding of transcription factors to the p38β promoter, suggesting that this genetic variant may influence CRC susceptibility through changes in gene regulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A genetic variation of the p38β promoter region is correlated with an increased risk of sporadic colorectal cancer. Huang, Q., Chen, D., Song, S., et al.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05365581

NCT05365581 | A Study of ASP2138 Given by Itself or ... ASP2138 in Combination with Pembrolizumab & CAPOX as First-line Therapy in Gastric/GEJ Cancer: Participant has history of (noninfectious) pneumonitis that ...

2. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2022-09348

A Study of ASP2138 Given by Itself or ... In this study, ASP2138 will either be given by itself, or given together with standard treatments for gastric, GEJ and pancreatic cancer. Pembrolizumab and ...

3. cancer.columbia.edu cancer.columbia.edu/cancer-types-care/clinical-trials/find-clinical-trial/phase-1-1b-study-asp2138-monotherapy-and-combination-pembrolizumab-and-mfolfox6-or-ramucirumab-and-paclitaxel-participants-metastatic-or-locally-advanced-unresectable-gastric-or-gastroesophageal

A Phase 1/1b Study of ASP2138 as Monotherapy and in ... The goal of this study is to see if a study drug called ASP2138 is safe and effective for people diagnosed with tumors known to have Claudin (CLDN) 18.2 ...

4. mskcc.org mskcc.org/cancer-care/clinical-trials/23-217

A Phase 1 Study of ASP2138 in People With Pancreatic ... Researchers are finding the best dose of ASP2138 to use in people with advanced digestive cancers. The people in this study have cancer of the pancreas, stomach ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9892960/

KEYNOTE-859: a Phase III study of pembrolizumab plus ... Combining pembrolizumab with chemotherapy has demonstrated efficacy and manageable safety in multiple tumor types, including gastric cancer [13,15–17]. Based on ...

6. ancora.ai ancora.ai/fr/details/NCT05365581

A Study of ASP2138 Given by Itself or Given With Other ... ASP2138 in Combination with Pembrolizumab & CAPOX as First-line Therapy in Gastric/GEJ Cancer: * Participant has history of (noninfectious) pneumonitis that ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7812199/

Safety and preliminary signs of efficacy with the combination ... Safety and preliminary signs of efficacy with the combination of pembrolizumab plus oxaliplatin and S-1 in Japanese gastric cancer patients. Maria Alsina ...