CA-4948 + Chemotherapy/Immunotherapy for Stomach & Esophageal Cancer

Recruiting at 1 trial location

Overseen By Patrick Grierson

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Washington University School of Medicine

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: Other malignancy, Organ transplant, others

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

Compensation: Varies

Number of Visits: 28

42 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment combination for individuals with advanced stomach or esophageal cancer that cannot be surgically removed. Researchers are testing the safety and optimal dose of a drug called CA-4948 (an experimental treatment) in combination with chemotherapy and immunotherapy drugs. Participants are grouped based on whether their cancer is HER2 positive or negative, which relates to a protein affecting cancer growth. Ideal candidates have advanced stomach or esophageal cancer and have not received prior treatment for their condition. The trial aims to find better ways to manage this challenging type of cancer. As a Phase 1 trial, the research focuses on understanding how the treatment 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 to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you must not be using alternative, holistic, or botanical formulations for cancer treatment, and certain HIV medications may be contraindicated due to drug interactions. It's best to discuss your current medications with the trial team.

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

Previous studies have tested CA-4948 alone and with other drugs, showing it to be safe and tolerable. However, complete safety information for CA-4948 combined with the drugs in this trial, such as FOLFOX (a type of chemotherapy), nivolumab, pembrolizumab, and trastuzumab, is not yet available.

This phase 1 trial primarily examines the safety of CA-4948 when used with these treatments. Phase 1 trials are the first step in understanding safety and help determine the best dose that avoids serious side effects.

FOLFOX treats other cancers and is generally safe when monitored. Nivolumab and pembrolizumab help the immune system fight cancer and have been used in other treatments, with usually manageable side effects. Trastuzumab is often used for HER2 positive cancers and has a well-known safety profile.

In summary, while some evidence suggests CA-4948 could be safe, this trial will provide more detailed safety information as it progresses. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the treatments being tested for stomach and esophageal cancer because they combine innovative approaches with standard chemotherapy and immunotherapy. CA-4948 is a novel agent that targets interleukin-1 receptor-associated kinase 4 (IRAK4), potentially disrupting cancer cell signaling pathways and enhancing the effectiveness of other treatments. Unlike standard options, which primarily rely on chemotherapy drugs like FOLFOX, these combinations introduce CA-4948 with immunotherapy agents like Pembrolizumab and Nivolumab, which help the immune system better recognize and attack cancer cells. Additionally, the inclusion of Trastuzumab in one arm targets HER2-positive tumors specifically, which could provide a more tailored and effective treatment for certain patients. Overall, these combinations aim to improve outcomes by attacking cancer from multiple angles.

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

This trial studies CA-4948 in combination with standard treatments like FOLFOX and PD-1 inhibitors for stomach and esophageal cancers. Earlier studies have shown that CA-4948 might help overcome chemotherapy resistance, a major challenge for advanced cancers. For instance, combining 5-Fluorouracil (5-FU) with folinic acid has resulted in higher remission rates in stomach cancer compared to 5-FU alone. Early evidence supports CA-4948's ability to enhance the effectiveness of traditional cancer treatments, offering hope for patients with hard-to-treat cancers. Participants in this trial will receive CA-4948 with different regimens, including FOLFOX and either Nivolumab or Pembrolizumab, with some also receiving Trastuzumab. ^{1 3 4 6 7}

Who Is on the Research Team?

Patrick Grierson

Principal Investigator

Washington University School of Medicine

Are You a Good Fit for This Trial?

Adults with advanced, inoperable or metastatic stomach, gastroesophageal junction, or esophageal cancer. They must not have had previous systemic treatment for their cancer and should be in good physical condition (ECOG 0-1). Participants need normal organ and bone marrow function and known HER2 status. Women of childbearing potential and men must agree to use contraception.

Inclusion Criteria

I had palliative radiation therapy over 10 days ago.

My bone marrow and organs are functioning normally.

I have had up to two rounds of FOLFOX chemotherapy.

Exclusion Criteria

I am not on any experimental drugs, or it has been 7 days since my last dose.

I have an autoimmune disease.

I have not received a live vaccine in the last 30 days.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Different dose levels of CA-4948 in combination with FOLFOX/nivolumab are evaluated using the BOIN algorithm

14 months

Every 14 days

Dose Expansion

Expansion Cohorts A and B receive CA-4948 at the dose determined during Dose Escalation with FOLFOX/nivolumab or FOLFOX/pembrolizumab and trastuzumab

14 months

Every 14 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

What Are the Treatments Tested in This Trial?

Interventions

• 5-FU
• CA-4948
• Leucovorin
• Nivolumab
• Oxaliplatin
• Pembrolizumab
• Trastuzumab

Trial Overview The trial is testing CA-4948 combined with FOLFOX chemotherapy and a PD-1 inhibitor (nivolumab or pembrolizumab), with an additional option of trastuzumab for those with HER2 positive disease. It includes dose escalation to find the safest dose followed by expansion cohorts based on HER2 status.

How Is the Trial Designed?

Group I: Dose Expansion Cohort B (CA4948 + FOLFOX + Pembrolizumab + Trastuzumab) Experimental Treatment 4 Interventions

* CA4948 (dose will be the recommended dose found in the dose escalation portion of study) twice daily by mouth Standard of care mFOLFOX7 every 14 days. Pembrolizumab on day 1 of every 3 cycles. Trastuzumab every 14 days. * Each cycle is 14 days.

Group II: Dose Expansion Cohort A (CA4948 + FOLFOX + Nivolumab) Experimental Treatment 3 Interventions

* CA4948 (dose will be the recommended phase II dose found in the dose escalation portion of study) twice daily by mouth. Standard of care mFOLFOX7 every 14 days. Nivolumab every 14 days. * Each cycle is 14 days.

Group III: Dose Escalation (CA4948 + FOLFOX + Nivolumab) Experimental Treatment 3 Interventions

* CA4948 (dose will depend on dose level assigned) twice daily by mouth. Standard of care mFOLFOX7 every 14 days. Nivolumab every 14 days. * Each cycle is 14 days.

5-FU is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Fluorouracil for:

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

Approved in European Union as Fluorouracil for:

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

Approved in Canada as Fluorouracil for:

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

Approved in Japan as Fluorouracil for:

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

Who Is Running the Clinical Trial?

Washington University School of Medicine

Lead Sponsor

Trials

2,027

Recruited

2,353,000+

The Foundation for Barnes-Jewish Hospital

Collaborator

Trials

43

Recruited

6,600+

Curis, Inc.

Industry Sponsor

Trials

17

Recruited

1,100+

Published Research Related to This Trial

The ECF regimen (epirubicin, cisplatin, and protracted venous infusion fluorouracil) showed a significantly higher overall response rate of 45% compared to 21% for the FAMTX regimen (5-FU, doxorubicin, and methotrexate) in a study of 274 patients with advanced esophagogastric cancer.

Patients treated with ECF had a median survival of 8.9 months, which was longer than the 5.7 months observed with FAMTX, along with better quality of life scores at 24 weeks, indicating that ECF is a more effective and tolerable treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer. Webb, A., Cunningham, D., Scarffe, JH., et al.[2022]

S-1, an oral chemotherapy drug combining tegafur with modulators, has shown advantages over standard 5-FU-based treatments for gastric cancer in large Phase III studies, making it a recommended option in treatment guidelines.

S-1, either alone or in combination with cisplatin, is non-inferior to traditional 5-FU regimens while offering greater convenience and reduced toxicity, highlighting its potential for higher efficacy in treating gastrointestinal cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

S-1 for the treatment of gastrointestinal cancer. Satoh, T., Sakata, Y.[2022]

5-Fluorouracil (5-FU) combined with folinic acid (FA) or alpha-interferon (IFN) has shown improved clinical activity in treating esophageal and gastric cancers compared to 5-FU alone, with 27% objective remissions reported in esophageal cancer.

In advanced gastric cancer, the combination of 5-FU/FA and 5-FU/IFN resulted in higher remission rates, with some studies reporting response rates exceeding 50% when combined with other chemotherapy agents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biochemical modulation of 5-fluorouracil by folinic acid or alpha-interferon with and without other cytostatic drugs in gastric, esophageal, and pancreatic cancer. Wilke, H., Stahl, M., Schmoll, HJ., et al.[2018]

The study identified 69 and 45 genes associated with resistance to 5-fluorouracil (5-FU) and cisplatin in gastric cancer cells, respectively, highlighting specific gene expression changes that contribute to chemotherapy resistance.

Using cDNA microarray analysis, the research suggests that understanding these gene expression profiles could help predict drug responses and inform personalized treatment strategies to combat drug resistance in gastric cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

cDNA microarray analysis of differential gene expression in gastric cancer cells sensitive and resistant to 5-fluorouracil and cisplatin. Ahn, MJ., Yoo, YD., Lee, KH., et al.[2021]

The combination of oral doxifluridine (d-FUR) and l-leucovorin showed some efficacy in treating gastric cancer, with a 15% objective response rate in a study of 50 patients, primarily those previously treated with 5-FU.

While the treatment was well tolerated with moderate toxicity, including 14% experiencing severe diarrhea, the results for pancreatic cancer were less promising, with only a 4% response rate, consistent with existing literature on fluoropyrimidines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Doxifluridine as palliative treatment in advanced gastric and pancreatic cancer patients. Di Bartolomeo, M., Bajetta, E., Somma, L., et al.[2018]

Certain genetic mutations, particularly three rare DPYD mutations, are linked to severe toxicity from 5-fluorouracil (5-FU), a common chemotherapy drug used for various cancers, indicating the importance of genetic screening in patients before treatment.

A common haplotype (hapB3) and specific variants in the TYMS gene are associated with increased risk of severe toxicity, suggesting that understanding a patient's genetic background could help predict and manage adverse reactions to 5-FU and its derivatives.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacogenomics of fluorouracil -based chemotherapy toxicity. Matsusaka, S., Lenz, HJ.[2015]

In a study of 30 patients with resectable esophageal squamous cell carcinoma, a chemotherapy regimen combining 5-fluorouracil, cisplatin, and interferon-alpha showed promising results, with a median overall survival of 26.3 months.

The treatment led to a complete pathological response in 4 out of 23 patients who underwent esophagectomy, indicating significant effectiveness, although there was one toxic death due to esophageal perforation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of neoadjuvant cisplatin, 5-fluorouracil and interferon-alpha in operable squamous cell carcinoma of the esophagus. Bazarbashi, S., Abdelsalam, M., Amin, T., et al.[2013]

An individual patient data meta-analysis of 4960 colorectal cancer patients showed that oral fluoropyrimidines (o-FPs) significantly improve disease-free survival compared to surgery alone, with a risk ratio of 0.830.

o-FPs were particularly effective in improving survival rates for rectal cancer and Dukes' C colorectal cancer, indicating their potential as a beneficial adjuvant therapy in these specific patient groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjuvant therapy with oral fluoropyrimidines as main chemotherapeutic agents after curative resection for colorectal cancer: individual patient data meta-analysis of randomized trials. Sakamoto, J., Hamada, C., Kodaira, S., et al.[2019]

In a study involving 42 patients with metastatic colorectal cancer, the combination of 5-fluorouracil (5-FU) and sodium folinate (S-FA) administered via a continuous 24-hour infusion was found to be a safe and effective second-line treatment, achieving a 9% objective response rate and halting tumor progression in 74% of patients.

The treatment resulted in a median survival of 14.7 months and a median time to tumor progression of 5.7 months, with manageable side effects including grade III/IV diarrhea in 19% of patients, indicating that the new formulation allows for convenient simultaneous administration of both drugs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Second-line treatment of advanced colorectal cancer with a weekly simultaneous 24-hour infusion of 5-fluorouracil and sodium-folinate: a multicentre phase II trial. Kuhfahl, J., Steinbrecher, C., Wagner, T., et al.[2013]

In a study of 51 patients with metastatic colorectal cancer, the combination of 5-fluorouracil (5-FU) and sodium-folinic acid (S-FA) resulted in a 37.2% objective response rate, with 3.9% achieving complete remission and 33.3% showing partial remission.

The treatment demonstrated a median survival of 16.5 months and a median time to tumor progression of 8.5 months, with manageable toxicity levels, making S-FA a convenient and effective option for outpatient therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of a weekly 24-hour infusion with 5-fluorouracil and simultaneous sodium-folinic acid in the first-line treatment of metastatic colorectal cancer. Hartung, G., Hofheinz, RD., Wein, A., et al.[2017]

In a study involving 981 patients with metastatic colorectal cancer, the combination of eniluracil (EU) and fluorouracil (5-FU) showed a median overall survival of 13.3 months, which was not statistically equivalent to the 14.5 months observed with the standard treatment of 5-FU and leucovorin (LV).

Both treatment regimens were well tolerated, with similar rates of severe diarrhea (19% for EU/5-FU vs. 16% for 5-FU/LV) and significantly lower rates of severe granulocytopenia in the EU/5-FU group (5% vs. 47% for 5-FU/LV), indicating a potentially safer profile for EU/5-FU despite its inferior progression-free survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized, open-label, phase III study of a 28-day oral regimen of eniluracil plus fluorouracil versus intravenous fluorouracil plus leucovorin as first-line therapy in patients with metastatic/advanced colorectal cancer. Schilsky, RL., Levin, J., West, WH., et al.[2017]

Capecitabine, an oral chemotherapy drug, is effective in treating esophageal and stomach cancers and can be used interchangeably with intravenous 5-fluorouracil, offering similar or even superior efficacy.

Ongoing research is focused on understanding the molecular mechanisms of these cancers to optimize capecitabine's use and improve treatment outcomes for patients with different tumor characteristics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Capecitabine in the treatment of esophageal and gastric cancers. Popa, EC., Shah, MA.[2015]

In a study of 34 Taiwanese patients with advanced gastric cancer, S-1 showed an overall response rate of 35.3% and a median overall survival of 9.8 months, indicating its efficacy as a treatment option.

The study highlighted the importance of accurately assessing renal function before S-1 therapy, as treatment-related mortality occurred in patients with underestimated renal function, emphasizing the need for careful monitoring in those with low body mass.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II and pharmacokinetic study of first line S-1 for advanced gastric cancer in Taiwan. Chen, JS., Chao, Y., Hsieh, RK., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05187182

CA-4948 in Combination With FOLFOX/PD-1 Inhibitor ... This is a phase I trial of CA-4948 in combination with FOLFOX/PD-1 inhibitor with or without trastuzumab for unresectable gastric, GEJ, and esophageal ...

2. curis.com curis.com/wp-content/uploads/2024/05/Phase-I-Trial-of-Emavusertib-Containing-Combinations-in-Gastric-and-Esophageal-Cancer-ASCO-2022-TiP-Poster.pdf

Phase-I-Trial-of-Emavusertib-Containing-Combinations-in- ... These data provide strong rationale to add CA-4948 to systemic therapy for advanced GI cancers, where chemotherapy resistance is inevitable and benefit of PD-1 ...

3. withpower.com withpower.com/trial/phase-1-esophageal-neoplasms-1-2022-d9629

CA-4948 + Chemotherapy/Immunotherapy for Stomach & ... In esophageal cancer, 5-FU combined with interferon resulted in a 27% remission rate in a study, indicating it may be more effective than 5-FU alone.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT03328078

Study Details | NCT03328078 | CA-4948-101: Open-Label, ... This is a multi-center, open-label study to evaluate the safety, pharmacokinetics (PK), and anti-cancer activity of oral administration of emavusertib alone ...

5. aacrjournals.org aacrjournals.org/mct/article/20/12_Supplement/P243/675964/Abstract-P243-The-IRAK4-inhibitor-CA-4948

Abstract P243: The IRAK4 inhibitor CA-4948 demonstrates ... Our study goal was to evaluate CA-4948 efficacy in a syngeneic preclinical model of primary CNS B cell lymphoma (A20), supporting future ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT03328078

Study Details | NCT03328078 | CA-4948-101: Open-Label, ... This is a multi-center, open-label study to evaluate the safety, pharmacokinetics (PK), and anti-cancer activity of oral administration of emavusertib alone ...

7. trials.braintumor.org trials.braintumor.org/trials/NCT03328078

CA-4948-101 - Clinical Trial Finder This is a multi-center, open-label study to evaluate the safety, pharmacokinetics (PK), and anti-cancer activity of oral administration of emavusertib alone or ...