ASP2138 for Digestive System Cancers

Recruiting at 39 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

378 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing a new drug called ASP2138 for adults with advanced stomach, gastroesophageal junction, or pancreatic cancer. ASP2138 helps the immune system target and attack cancer cells. The study aims to find a safe and effective dose and monitor any side effects. Participants will receive the drug through an IV or injection and will be closely monitored throughout the study.

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.

How does the drug ASP2138 work differently for digestive system cancers?

ASP2138 targets the p38 MAP kinase pathway, which plays a dual role in colorectal cancer by both suppressing tumor initiation and supporting cancer cell survival. This drug may offer a novel approach by potentially inhibiting cancer cell growth while also addressing inflammation-related tumorigenesis, making it different from standard treatments that do not specifically target this pathway. ^{1 2 3 4 5}

Research Team

Senior Director

Principal Investigator

Astellas Pharma Global Development, Inc.

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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.

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

Findings from Research

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]

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]

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]

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]

References

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

Deletion of p38-alpha mitogen-activated protein kinase within the intestinal epithelium promotes colon tumorigenesis. [2021]

2. Greece pubmed.ncbi.nlm.nih.gov

A genetic variation of the p38β promoter region is correlated with an increased risk of sporadic colorectal cancer. [2021]

3. United States 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. [2022]

4. Netherlands 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. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Pharmacological targeting of the novel β-catenin chromatin-associated kinase p38α in colorectal cancer stem cell tumorspheres and organoids. [2023]