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

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

Trial Summary

What is the purpose of this trial?

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 cancer. During the Dose Escalation portion of the study, different dose levels of CA-4948 in combination with FOLFOX/nivolumab will be evaluated by BOIN algorithm. Dose Expansion will include Cohorts A and B. Expansion Cohort A will enroll up to 12 patients with HER2 negative gastric, GEJ, and esophageal cancer at the expansion dose of CA-4948 determined during Dose Escalation and will use the same treatment regimen of FOLFOX/nivolumab. Expansion Cohort B will investigate CA-4948 at the dose determined during Dose Escalation in combination with FOLFOX/pembrolizumab and trastuzumab in up to 12 patients with HER2 positive disease; however, the initial 6 patients will be considered safety lead-in to confirm the safety and tolerability of this combination; if determined to be safe, an additional 6 patients will be enrolled for a total of 12 in Cohort B.

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.

What data supports the effectiveness of the drugs used in the CA-4948 + Chemotherapy/Immunotherapy trial for stomach and esophageal cancer?

Research shows that 5-Fluorouracil (5-FU) combined with folinic acid (leucovorin) or interferon has shown higher remission rates in gastric cancer compared to 5-FU alone. 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. ^{1 2 3 4 5}

Is the combination of CA-4948 and chemotherapy/immunotherapy safe for humans?

The safety of 5-fluorouracil (5-FU) and its combinations with leucovorin (a form of folic acid) has been studied in patients with colorectal and gastric cancer, showing it can be used safely in these conditions. However, specific safety data for CA-4948 combined with these treatments in stomach and esophageal cancer is not provided in the available research. ^{6 7 8 9 10}

What makes the drug CA-4948 combined with chemotherapy/immunotherapy unique for stomach and esophageal cancer?

This treatment is unique because it combines CA-4948, a novel drug, with established chemotherapy and immunotherapy agents like 5-FU, Leucovorin, Oxaliplatin, Nivolumab, and Pembrolizumab, potentially enhancing the effectiveness of standard treatments for stomach and esophageal cancer. ^{1 2 11 12 13}

Research Team

Patrick Grierson

Principal Investigator

Washington University School of Medicine

Eligibility Criteria

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.

I am 18 years old or older.

My bone marrow and organs are functioning normally.

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

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]

References

1. United States 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. [2018]

2. England pubmed.ncbi.nlm.nih.gov

S-1 for the treatment of gastrointestinal cancer. [2022]

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

Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer. [2022]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Doxifluridine as palliative treatment in advanced gastric and pancreatic cancer patients. [2018]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Phase II trial of neoadjuvant cisplatin, 5-fluorouracil and interferon-alpha in operable squamous cell carcinoma of the esophagus. [2013]

6. England 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. [2019]

7. Switzerland 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. [2013]

8. Switzerland 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. [2017]

9. United States 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. [2017]

10. Germany pubmed.ncbi.nlm.nih.gov

A phase II and pharmacokinetic study of first line S-1 for advanced gastric cancer in Taiwan. [2022]

11. Korea (South) pubmed.ncbi.nlm.nih.gov

cDNA microarray analysis of differential gene expression in gastric cancer cells sensitive and resistant to 5-fluorouracil and cisplatin. [2021]

12. England pubmed.ncbi.nlm.nih.gov

Capecitabine in the treatment of esophageal and gastric cancers. [2015]

13. England pubmed.ncbi.nlm.nih.gov

Pharmacogenomics of fluorouracil -based chemotherapy toxicity. [2015]