Chemotherapy + Immunotherapy for Esophageal Cancer

Overseen By Mariela Blum

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Antibiotics, Immunosuppressants, Immunostimulants, others

Disqualifiers: Metastatic cancer, Squamous cell carcinoma, Uncontrolled diabetes, Active angina, 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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 15

40 Participants Needed

Trial Summary

What is the purpose of this trial?

To learn if atezolizumab in combination with oxaliplatin and 5-fluorouracil (5-FU), when given before surgery, can help to control esophageal and/or gastroesophageal cancer. To learn if adding tiragolumab to the above drug combination can help to control the disease.

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

The trial does not specify if you need to stop taking your current medications. However, it does mention that patients should not have had prior chemotherapy or radiation therapy, and certain medications like systemic immunosuppressive agents should not be used close to the start of the trial. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drugs Atezolizumab, Tecentriq, Fluorouracil, 5-Fluorouracil, 5-FU, Adrucil, Carac, Efudex, Fluoroplex, Oxaliplatin, Eloxatin for esophageal cancer?

Research shows that combinations including fluorouracil (5-FU) and oxaliplatin have been effective in treating advanced esophageal cancer, with studies indicating good response rates. Additionally, similar treatments using 5-FU with other drugs have shown promising results in esophageal cancer. ^{1 2 3 4 5}

Is the combination of chemotherapy and immunotherapy generally safe for treating esophageal cancer?

The combination of chemotherapy drugs like 5-Fluorouracil (5-FU) and Oxaliplatin has been studied for safety in various cancer treatments, including esophageal cancer. In one study, 53% of patients experienced significant side effects, but these were considered manageable. Another study found that a combination of 5-FU and Oxaliplatin with other treatments was safe for esophageal cancer, suggesting a generally manageable safety profile. ^{6 7 8 9 10}

How is the drug combination of Atezolizumab, Fluorouracil, and Oxaliplatin unique for esophageal cancer?

This treatment combines chemotherapy with immunotherapy, using Atezolizumab (an immune system booster) alongside Fluorouracil and Oxaliplatin (chemotherapy drugs), which is different from traditional chemotherapy alone. This combination aims to enhance the body's immune response against cancer cells while also directly targeting them with chemotherapy. ^{1 3 8 11 12}

Research Team

Mariela Blum

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for adults with localized esophageal or gastroesophageal adenocarcinoma who haven't had prior treatments. They must have certain blood and organ function levels, not be pregnant or breastfeeding, use contraception, and be medically fit for surgery. People with specific other health conditions or cancers are excluded.

Inclusion Criteria

My white blood cell count is healthy without needing medication.

No supraclavicular, or para-aortic nodal enlargement unless biopsy negative

My hemoglobin level is at least 9 g/dL, possibly after a transfusion.

Exclusion Criteria

My cancer is not classified as T1aN0, T4b, or M1.

I tested negative for HBsAg and positive for HBcAb.

I do not have uncontrolled diabetes, heart issues, high blood pressure, or mental health conditions that would prevent my participation.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Neoadjuvant Treatment

Participants receive Atezolizumab +/- Tiragolumab with Oxaliplatin and 5-Fluorouracil IV on Days 1 and 15 of each 28-day cycle for a total of 6 doses

12 weeks

6 visits (in-person)

Surgery

Participants undergo surgery to remove localized esophageal and gastroesophageal adenocarcinoma

1 week

1 visit (in-person)

Adjuvant Treatment

Participants receive Atezolizumab +/- Tiragolumab on Day 1 of each 21-day cycle

24-48 weeks

8-16 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 3 years

Treatment Details

Interventions

• Atezolizumab
• Fluorouracil
• Oxaliplatin

Trial Overview The study tests if atezolizumab combined with chemotherapy (oxaliplatin and fluorouracil) before surgery can control cancer better than current methods. It also examines the addition of tiragolumab to this combination to see if it offers further benefits.

Participant Groups

Group I: Cohort 2- Atezolizumab plus and Tiragolumab with Oxaliplatin and 5-fluorouracil (5-FU) Experimental Treatment 5 Interventions

The combination of Atezolizumab + Tiragolumab with Oxaliplatin and 5-Flourouracil IV on Days 1 and 15 of each 28-day cycle for total of 6 doses followed by surgery followed by Atezolizumab + Tiragolumab on Day 1 of each 21-day cycle for a total of 48 weeks.

Group II: Cohort 1-Atezolizumab combination with Oxaliplatin and 5-fluorouracil (5-FU) Experimental Treatment 4 Interventions

The combination of Atezolizumab with Oxaliplatin and 5-Fluorouracil IV on Days 1 and 15 of each 28-day cycle for total of 6 doses followed by surgery followed by Atezolizumab on Day 1 of each 21-day cycle for total of 24 weeks

Atezolizumab is already approved in United States, European Union for the following indications:

Approved in United States as Tecentriq for:

• Melanoma
• Hepatocellular carcinoma
• Small cell lung cancer
• Non-small cell lung cancer
• Urothelial carcinoma

Approved in European Union as Tecentriq for:

• Melanoma
• Hepatocellular carcinoma
• Small cell lung cancer
• Non-small cell lung cancer
• Urothelial carcinoma

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a phase II trial involving 40 patients with advanced esophageal cancer, the combination of interferon alfa-2a (IFN) and fluorouracil (FU) resulted in a response rate of 27%, indicating it is an effective treatment option.

The treatment was generally well-tolerated, with manageable side effects primarily consisting of fatigue and mild myelosuppression, and the median duration of response was 6.4 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interferon alfa-2a and fluorouracil in the treatment of patients with advanced esophageal cancer. Kelsen, D., Lovett, D., Wong, J., et al.[2018]

In a study of 35 patients with advanced esophageal cancer, the combination of oxaliplatin, leucovorin, and fluorouracil demonstrated a 40% overall response rate, indicating significant anti-tumor activity.

While the treatment was effective, it also had notable side effects, including a 29% incidence of severe neutropenia and 26% experiencing significant peripheral neuropathy, highlighting the need for careful monitoring of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of oxaliplatin, leucovorin and fluorouracil in patients with advanced carcinoma of the esophagus. Mauer, AM., Kraut, EH., Krauss, SA., et al.[2020]

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]

In a meta-analysis of 1231 patients, pembrolizumab and paclitaxel showed no significant difference in effectiveness for treating advanced gastroesophageal cancer, with similar objective response rates.

Both treatments can be considered viable options for patients, as they provide comparable time to response and similar rates of partial response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab versus paclitaxel for previously treated, advanced gastro-esophageal junction cancer: A systematic review and meta-analysis of randomized clinical trials. Swed, S., Shaheen, N., Hafez, W., et al.[2022]

In a study of 62 patients with advanced esophageal squamous cell carcinoma, the combination of cetuximab with cisplatin and 5-fluorouracil (CF) showed a median overall survival of 9.5 months compared to 5.5 months for CF alone, suggesting improved efficacy.

Cetuximab did not significantly increase severe side effects, except for a higher incidence of rash and diarrhea, indicating that it can be safely combined with CF chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab plus cisplatin-5-fluorouracil versus cisplatin-5-fluorouracil alone in first-line metastatic squamous cell carcinoma of the esophagus: a randomized phase II study of the Arbeitsgemeinschaft Internistische Onkologie. Lorenzen, S., Schuster, T., Porschen, R., et al.[2022]

The maximum-tolerated dose (MTD) of S-1 for patients with advanced solid tumors was determined to be 40 mg/m², with diarrhea identified as the main dose-limiting toxicity, especially in patients with extensive prior chemotherapy.

S-1 demonstrated a linear pharmacokinetic profile for 5-FU, with some patients experiencing significant tumor reduction, indicating potential efficacy in treating certain cancers, warranting further Phase II trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I clinical and pharmacokinetic study of oral S-1 in patients with advanced solid tumors. van Groeningen, CJ., Peters, GJ., Schornagel, JH., et al.[2022]

The combination of neoadjuvant 5-fluorouracil, oxaliplatin, and lapatinib with radiation therapy is safe for patients with localized HER2-positive esophagogastric adenocarcinoma, as shown in a nonrandomized trial with 12 participants.

The pathologic complete response (pCR) rate was 8%, indicating some effectiveness, but the study was limited by low patient enrollment, suggesting that further evaluation in a larger group is needed to better assess efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase II Study with Lead-In Safety Cohort of 5-Fluorouracil, Oxaliplatin, and Lapatinib in Combination with Radiation Therapy as Neoadjuvant Treatment for Patients with Localized HER2-Positive Esophagogastric Adenocarcinomas. Shepard, G., Arrowsmith, ER., Murphy, P., et al.[2018]

In a phase 3 trial involving 551 patients with advanced esophageal squamous cell carcinoma (ESCC), the combination of serplulimab (an anti-PD-1 antibody) and chemotherapy significantly improved progression-free survival (PFS) compared to placebo plus chemotherapy, with a median PFS of 5.8 months versus 5.3 months.

The same combination also significantly prolonged overall survival (OS), with a median OS of 15.3 months for serplulimab plus chemotherapy compared to 11.8 months for the placebo group, while maintaining a manageable safety profile with similar rates of severe adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-line serplulimab or placebo plus chemotherapy in PD-L1-positive esophageal squamous cell carcinoma: a randomized, double-blind phase 3 trial. Song, Y., Zhang, B., Xin, D., et al.[2023]

In a study of 22 patients with advanced esophageal squamous cell cancer, a chemotherapy regimen combining continuous infusional paclitaxel and 5-FU resulted in a promising overall response rate of 68.2%, with 2 complete responses and 9 partial responses.

The treatment was well-tolerated, with manageable side effects such as marrow depression, alopecia, and fatigue, indicating that this low-dose continuous infusion approach could be a safe option for patients who are not candidates for surgery or radiation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study on continuous infusional paclitaxel and 5-Fu as first-line chemotherapy for patients with advanced esophageal cancer. Gu, M., Li, SY., Huang, XE., et al.[2022]

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]

Nimotuzumab (h-R3) showed a weak inhibitory effect on the proliferation of human esophageal squamous cell carcinoma (ESCC) EC1 cells, with a maximum inhibition rate of only 10.10% after 48 hours, indicating limited efficacy as a standalone treatment.

Combining h-R3 with chemotherapeutic agents like cisplatin or fluorouracil did not significantly enhance the inhibition of cell growth or increase apoptosis rates compared to the chemotherapeutic agents alone, suggesting that h-R3 may not provide additional benefits in treating ESCC in vitro.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nimotuzumab with cisplatin or fluorouracil on human esophageal squamous cell carcinoma EC1 cells. Ji, YH., Yang, XY., Wu, JQ., et al.[2019]

The study established a 5-Fluorouracil (5-FU) and cisplatin-resistant xenograft model in SCID mice to investigate the mechanisms behind acquired resistance in esophageal cancer treatment.

Gene expression analysis revealed that resistance to FP chemotherapy is linked to the activation of specific genes related to 5-FU and cisplatin, as well as the PI3K/AKT signaling pathway, suggesting potential targets for overcoming resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene expression changes in a chemoresistant model with human esophageal cancer xenografts using cDNA microarray. Yoshida, T., Miyoshi, T., Seike, J., et al.[2015]

References

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

Interferon alfa-2a and fluorouracil in the treatment of patients with advanced esophageal cancer. [2018]

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

Phase II trial of oxaliplatin, leucovorin and fluorouracil in patients with advanced carcinoma of the esophagus. [2020]

3. 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]

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

Pembrolizumab versus paclitaxel for previously treated, advanced gastro-esophageal junction cancer: A systematic review and meta-analysis of randomized clinical trials. [2022]

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

Cetuximab plus cisplatin-5-fluorouracil versus cisplatin-5-fluorouracil alone in first-line metastatic squamous cell carcinoma of the esophagus: a randomized phase II study of the Arbeitsgemeinschaft Internistische Onkologie. [2022]

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

Phase I clinical and pharmacokinetic study of oral S-1 in patients with advanced solid tumors. [2022]

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

A Phase II Study with Lead-In Safety Cohort of 5-Fluorouracil, Oxaliplatin, and Lapatinib in Combination with Radiation Therapy as Neoadjuvant Treatment for Patients with Localized HER2-Positive Esophagogastric Adenocarcinomas. [2018]

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

First-line serplulimab or placebo plus chemotherapy in PD-L1-positive esophageal squamous cell carcinoma: a randomized, double-blind phase 3 trial. [2023]

9. Thailand pubmed.ncbi.nlm.nih.gov

A phase II study on continuous infusional paclitaxel and 5-Fu as first-line chemotherapy for patients with advanced esophageal cancer. [2022]

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. Italy pubmed.ncbi.nlm.nih.gov

Nimotuzumab with cisplatin or fluorouracil on human esophageal squamous cell carcinoma EC1 cells. [2019]

12. Greece pubmed.ncbi.nlm.nih.gov

Gene expression changes in a chemoresistant model with human esophageal cancer xenografts using cDNA microarray. [2015]