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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether combining chemotherapy with immunotherapy controls esophageal or gastroesophageal cancer more effectively than chemotherapy alone. Specifically, it examines the use of atezolizumab (an immunotherapy drug also known as Tecentriq) with chemotherapy drugs oxaliplatin and 5-fluorouracil (5-FU) before surgery to assess cancer management. Another group will test if adding tiragolumab to this combination improves outcomes. Suitable candidates have esophageal or gastroesophageal adenocarcinoma that hasn't been treated yet and are medically cleared for surgery. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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.

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

Research has shown that combining atezolizumab with oxaliplatin and 5-fluorouracil (5-FU) is generally safe. In studies, only a few patients experienced severe side effects. Specifically, two patients encountered serious treatment-related issues, known as grade 4 adverse events, but these are rare. This indicates that most people tolerate the combination well.

The safety of combining atezolizumab and tiragolumab with oxaliplatin and 5-FU appears similar. Research is ongoing, but early results suggest this combination might also be safe for most people. In some trials, patients have taken these drugs without major safety concerns.

These treatments are still under investigation to ensure they are safe and effective for people with esophageal cancer. Those considering joining a trial should discuss potential risks with their doctor to make an informed decision. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard chemotherapy treatments for esophageal cancer, which typically involve drugs like cisplatin or carboplatin, the investigational treatment combines chemotherapy with immunotherapy using drugs like Atezolizumab and Tiragolumab. Researchers are excited because this combination not only attacks the cancer cells directly but also stimulates the immune system to recognize and fight the cancer more effectively. Atezolizumab is a PD-L1 inhibitor, and Tiragolumab is a novel TIGIT inhibitor, together offering a dual mechanism of action that enhances the immune response against cancer cells. This innovative approach has the potential to improve patient outcomes by providing a more comprehensive attack on the tumor.

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

This trial will evaluate two different treatment combinations for esophageal cancer. In one arm, participants will receive a combination of atezolizumab, oxaliplatin, and 5-fluorouracil (5-FU). Studies have shown that this combination can help manage esophageal and gastroesophageal cancer by enabling the immune system to find and attack cancer cells. In the other arm, participants will receive the same combination with the addition of tiragolumab, which targets a protein called TIGIT, potentially enhancing the treatment's effectiveness. Research suggests that these combinations have worked well in treating similar cancers, indicating possible benefits for this condition. Early trials found that these treatments can shrink tumors and may help patients live longer. ^{1 2 6 7 8}

Who Is on the Research Team?

Mariela Blum

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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 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]

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]

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 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]

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 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 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]

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]

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 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]

Citations

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Chemotherapy Plus Atezolizumab Pre- and Post-Resection in ... Two patients had grade 4 treatment-related adverse events. These findings suggest that atezolizumab with oxaliplatin and 5-fluorouracil for the ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37963317/

Perioperative Atezolizumab Plus Fluorouracil, Leucovorin, ... This trial evaluates the addition of the PD-L1 antibody atezolizumab (ATZ) to standard-of-care fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) as a ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT03784326

NCT03784326 | Phase I/II Study of Perioperative ... To learn if atezolizumab in combination with oxaliplatin and 5-fluorouracil (5-FU), when given before surgery, can help to control esophageal and/or ...

4. ascopubs.org ascopubs.org/doi/abs/10.1200/JCO.23.00975

Interim Results From the Randomized, Multicenter, Phase II ... This trial evaluates the addition of the PD-L1 antibody atezolizumab (ATZ) to standard-of-care fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) as a ...

5. gioncologynow.com gioncologynow.com/post/atomic-atezolizumab-plus-chemotherapy-as-new-soc-in-stage-iii-dmmr-colon-cancer

ATOMIC: Atezolizumab Plus Chemotherapy in dMMR ... The phase 3 ATOMIC trial has demonstrated that adding atezolizumab to standard adjuvant mFOLFOX6 chemotherapy significantly improves disease-free survival (DFS)

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04933227

NCT04933227 | A Study to Explore the Efficacy and Safety ... This study is designed to evaluate the efficacy and safety of atezolizumab plus tiragolumab in combination with capecitabine plus oxaliplatin (XELOX) for ...

7. anzctr.org.au anzctr.org.au/Trial/Registration/TrialReview.aspx?id=19310&isClinicalTrial=True

ANZCTR - Registration Participants who progressed on treatment had the option of receiving Atezolizumab + Cobimetinib treatment, provided they met the eligibility criteria.

8. surgoncinsight.org surgoncinsight.org/article/S2950-2470(25)00087-8/fulltext

An overview of current immunotherapy approaches for ... For esophageal cancer, trials like CheckMate 577, KEYNOTE 590, 811, and MATTERHORN have demonstrated improved benefit with ICIs. Pancreatic cancer, ...