Immunotherapy + Chemoradiation Before Surgery for Esophageal Cancer

Recruiting at 6 trial locations

Overseen By Geoffrey Y. Ku

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: Immunosuppressants, PD-1/PD-L1 inhibitors

Disqualifiers: Metastatic disease, Autoimmune disorders, HIV, others

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

Compensation: Varies

Number of Visits: 7

79 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to test the safety of adding a new drug, durvalumab (also called MEDI4736), to chemoradiation with either FOLFOX/Capeox or carboplatin and paclitaxel, following initial chemotherapy with FOLFOX. The investigators want to find out what effects, good and/or bad, this combination has on the patient and cancer.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot use immunosuppressive medications within 28 days before starting the trial, except for certain types like low-dose corticosteroids or local steroid injections.

What data supports the effectiveness of this treatment for esophageal cancer?

Research shows that combining immune checkpoint inhibitors like durvalumab and tremelimumab with chemoradiotherapy can be effective for esophageal cancer. These drugs have shown promising results in treating various cancers, including esophageal cancer, by helping the immune system attack cancer cells more effectively. ^{1 2 3 4 5}

Is the combination of immunotherapy and chemoradiation generally safe for humans?

The combination of immunotherapy drugs like durvalumab and tremelimumab with chemotherapy has been studied in various cancers, showing that most side effects are mild to moderate, such as diarrhea and skin issues. However, some serious side effects like pneumonitis (lung inflammation) and myocarditis (heart inflammation) have been reported, and there were two treatment-related deaths in one study. ^{5 6 7 8 9}

How is the treatment of Immunotherapy + Chemoradiation Before Surgery for Esophageal Cancer different from other treatments?

This treatment is unique because it combines immunotherapy drugs like Durvalumab and Tremelimumab with chemoradiation (a mix of chemotherapy and radiation therapy) before surgery, aiming to enhance the body's immune response against cancer cells and improve surgical outcomes. This approach is different from traditional treatments that may not include the use of immunotherapy before surgery. ^{1 3 10 11 12}

Research Team

Geoffrey Y. Ku

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

This trial is for adults with confirmed adenocarcinoma of the esophagus or gastroesophageal junction, who have not had prior chemotherapy and whose disease is limited to those areas. Participants must be in good health with adequate organ function and no history of certain autoimmune diseases or other cancers within the last three years. Women must be non-reproductive or have a negative pregnancy test, and all participants should agree to use effective contraception.

Inclusion Criteria

I am 18 years old or older.

Able to provide written informed consent

I have stored tumor tissue available for research.

Exclusion Criteria

History of primary immunodeficiency

History of hypersensitivity to durvalumab or tremelimumab or any excipient

I do not have any uncontrolled illnesses.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Chemotherapy

Patients receive mFOLFOX6 chemotherapy followed by a PET/CT scan to assess response

4 weeks

2 visits (in-person)

Immunotherapy and Chemoradiation

Patients receive durvalumab and tremelimumab followed by radiation and concurrent chemotherapy based on PET response

6 weeks

5 visits (in-person) per week for radiation

Surgery

Surgical resection is performed 6-10 weeks after the completion of chemoradiation

1 week

Adjuvant Immunotherapy

Patients with R0 resections receive tremelimumab and durvalumab every 4 weeks for 6 doses

24 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

Treatment Details

Interventions

• Carboplatin
• Durvalumab
• External beam radiation (EBRT)
• Paclitaxel
• Tremelimumab

Trial Overview The study tests the safety of adding durvalumab (an anti-PDL1 antibody) to chemoradiation therapy before surgery for esophageal cancer patients. It examines how well this combination works compared to standard treatments. The treatment includes FOLFOX/Capeox or carboplatin and paclitaxel after initial chemotherapy, followed by an esophagogastrectomy.

Participant Groups

Group I: Esophageal Cancer Experimental Treatment 5 Interventions

This is a phase Ib/II trial of durvalumab (MEDI4736), a monoclonal antibody against programmed death ligand-1 (PD-L1)), and tremelimumab, an anti-CTLA-4 antibody, in combination with chemoradiation for patients with locally advanced (TanyN+M0 or T3-4NanyM0) esophageal or gastroesophageal (GE) junction adenocarcinoma.

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

Approved in United States as Paraplatin for:

• Ovarian cancer
• Testicular cancer
• Lung cancer
• Head and neck cancer
• Brain cancer

Approved in European Union as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer

Approved in Canada as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer
• Testicular cancer

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

AstraZeneca

Industry Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Findings from Research

Preoperative treatment with pembrolizumab combined with chemoradiotherapy was found to be safe for 20 patients with resectable esophageal squamous cell carcinoma, with a high pathologic complete response (pCR) rate of 55.6%.

Despite some patients experiencing significant adverse events, including grade III lymphopenia in 65% of cases, the treatment did not delay surgery, indicating its feasibility for clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preoperative pembrolizumab combined with chemoradiotherapy for oesophageal squamous cell carcinoma (PALACE-1). Li, C., Zhao, S., Zheng, Y., et al.[2021]

In a study of 45 patients with esophageal squamous cell carcinoma, simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) demonstrated promising overall survival rates of 42.2% and progression-free survival rates of 40.7% at 3 years, indicating its efficacy as a treatment option.

The treatment was associated with a low toxicity profile, as no patients experienced severe (grade 4-5) side effects, and the most common side effect, radiation esophagitis, was manageable, affecting 64% of patients but only 13% at grade 3 severity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Simultaneous integrated boost intensity-modulated radiotherapy in esophageal carcinoma: early results of a phase II study. Yu, WW., Zhu, ZF., Fu, XL., et al.[2021]

The ARION trial is investigating the efficacy of the anti-PD-L1 drug durvalumab combined with standard chemoradiotherapy (CRT) in patients with locally advanced unresectable esophageal cancer, aiming to improve progression-free survival from 50% to 68% at 12 months.

This multicenter phase II trial will also explore potential biomarkers, such as PD-L1 expression and gut microbiota, to better understand the immune response and treatment outcomes, highlighting the importance of combining immunotherapy with traditional treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of Radiochemotherapy to Immunotherapy in unresectable locally advanced Oesophageal carciNoma-randomized phase 2 trial ARION UCGI 33/PRODIGE 67: the study protocol. Modesto, A., Tougeron, D., Tremolières, P., et al.[2023]

A patient with advanced esophageal squamous cell carcinoma (ESCC) showed a significant response to the combination of durvalumab and tremelimumab for over 6 months, despite the primary esophageal tumor being resistant.

The study found that the esophageal tumor had a unique immune profile with higher levels of regulatory T cells and neutrophils, suggesting that these immune characteristics may influence the varied responses to immune checkpoint inhibitors in different tumor sites.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Different immune contextures underlie tumor site-specific responses to immune checkpoint blockade in esophageal cancer. Guo, JC., Hsu, CL., Hsieh, MS., et al.[2023]

Durvalumab monotherapy and the combination of durvalumab with tremelimumab showed acceptable safety profiles, with grade ≥3 treatment-related adverse events occurring in 19.0% of patients with biliary tract cancer (BTC) and 25.0% with head and neck squamous cell carcinoma (HNSCC).

The combination therapy demonstrated a higher objective response rate (ORR) of 10.8% in BTC and 20.3% in esophageal squamous cell carcinoma (ESCC), indicating potential clinical benefit for patients with advanced cancers who had disease progression after prior treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tolerability and efficacy of durvalumab, either as monotherapy or in combination with tremelimumab, in patients from Asia with advanced biliary tract, esophageal, or head-and-neck cancer. Doki, Y., Ueno, M., Hsu, CH., et al.[2022]

In a safety run-in phase of the DURIGAST PRODIGE 59 study involving 11 patients with advanced gastric or gastro-oesophageal junction adenocarcinoma, 63.6% experienced significant adverse events, primarily neutropenia, indicating a notable safety concern with the treatment combination.

The combination of FOLFIRI with Durvalumab and/or Tremelimumab showed an expected safety profile, allowing progression to the randomized phase II study, although careful monitoring for serious adverse events is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of FOLFIRI + Durvalumab +/- Tremelimumab in Second Line of Patients with Advanced Gastric Cancer: A Safety Run-In from the Randomized Phase II Study DURIGAST PRODIGE 59. Evrard, C., Aparicio, T., Soularue, E., et al.[2022]

In a phase Ib study involving 136 patients, durvalumab (Du) combined with tremelimumab (Tr) and standard platinum-doublet chemotherapy was found to be safe, with most drug-related adverse events being mild (≤ grade 2) and primarily due to chemotherapy.

Among 73 patients with non-small cell lung cancer (NSCLC), the treatment achieved a 51% objective response rate, with a median progression-free survival of 6.5 months and overall survival of 19.8 months, indicating promising efficacy comparable to other immunotherapy and chemotherapy combinations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase IB study of durvalumab with or without tremelimumab and platinum-doublet chemotherapy in advanced solid tumours: Canadian Cancer Trials Group Study IND226. Juergens, RA., Hao, D., Ellis, PM., et al.[2021]

In the CASPIAN study involving 805 patients with extensive-stage small-cell lung cancer (ES-SCLC), the combination of durvalumab and platinum-etoposide significantly improved overall survival compared to platinum-etoposide alone, with a median survival of 12.9 months versus 10.5 months.

However, adding tremelimumab to durvalumab and platinum-etoposide did not provide a significant survival benefit, indicating that durvalumab plus platinum-etoposide should be considered the new standard of care for first-line treatment of ES-SCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab, with or without tremelimumab, plus platinum-etoposide versus platinum-etoposide alone in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): updated results from a randomised, controlled, open-label, phase 3 trial. Goldman, JW., Dvorkin, M., Chen, Y., et al.[2021]

In a study of 107 patients with stage III non-small cell lung cancer (NSCLC) treated with concurrent chemoradiotherapy (CCRT) and intensity-modulated radiotherapy (IMRT), the median progression-free survival (PFS) was 20.7 months, indicating effective treatment outcomes.

Factors associated with longer PFS included a favorable response to CCRT, a radiation dose of 62 Gy or more, and having stage IIIA NSCLC, while shorter durations of durvalumab treatment and lower radiation doses were linked to increased mortality risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy profiles of concurrent chemoradiotherapy with intensity-modulated radiotherapy followed by durvalumab in patients with unresectable stage III non-small cell lung cancer: A multicenter retrospective cohort study. Takeda, Y., Kusaba, Y., Tsukita, Y., et al.[2022]

Pre-operative chemotherapy with Paclitaxel-Carboplatin followed by adjuvant immunotherapy using Nivolumab has significantly improved the management of locally advanced esophageal cancer, which historically has a poor prognosis.

Current trials are exploring the effectiveness of immunotherapy for non-operable esophageal cancers, while strategies like dose escalation and combining pre-operative chemo-radiotherapy with trastuzumab have not shown benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[News in gastrointestinal radiotherapy: The esophageal cancer]. Quéro, L., Besnard, C., Guillerm, S., et al.[2022]

The NICE-2 study is a phase II clinical trial involving 204 patients that aims to compare the effectiveness of camrelizumab combined with chemotherapy or chemoradiotherapy against standard chemoradiotherapy for treating locally advanced esophageal squamous cell carcinoma (ESCC).

The primary goal of the study is to determine the rate of pathological complete response (pCR), which will help establish the best preoperative treatment approach for patients with this type of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Three-arm phase II trial comparing camrelizumab plus chemotherapy versus camrelizumab plus chemoradiation versus chemoradiation as preoperative treatment for locally advanced esophageal squamous cell carcinoma (NICE-2 Study). Yang, Y., Zhu, L., Cheng, Y., et al.[2022]

In a phase II study involving 86 patients with esophageal squamous cell carcinoma, adjuvant durvalumab did not show a significant improvement in disease-free survival or overall survival compared to placebo after neoadjuvant chemoradiotherapy.

However, in patients with positive PD-L1 expression, durvalumab was associated with a higher overall survival rate, suggesting that PD-L1 status may help predict the effectiveness of durvalumab in this treatment context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjuvant durvalumab for esophageal squamous cell carcinoma after neoadjuvant chemoradiotherapy: a placebo-controlled, randomized, double-blind, phase II study. Park, S., Sun, JM., Choi, YL., et al.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

Preoperative pembrolizumab combined with chemoradiotherapy for oesophageal squamous cell carcinoma (PALACE-1). [2021]

2. Germany pubmed.ncbi.nlm.nih.gov

Simultaneous integrated boost intensity-modulated radiotherapy in esophageal carcinoma: early results of a phase II study. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Association of Radiochemotherapy to Immunotherapy in unresectable locally advanced Oesophageal carciNoma-randomized phase 2 trial ARION UCGI 33/PRODIGE 67: the study protocol. [2023]

4. Singapore pubmed.ncbi.nlm.nih.gov

Different immune contextures underlie tumor site-specific responses to immune checkpoint blockade in esophageal cancer. [2023]

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

Tolerability and efficacy of durvalumab, either as monotherapy or in combination with tremelimumab, in patients from Asia with advanced biliary tract, esophageal, or head-and-neck cancer. [2022]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Safety of FOLFIRI + Durvalumab +/- Tremelimumab in Second Line of Patients with Advanced Gastric Cancer: A Safety Run-In from the Randomized Phase II Study DURIGAST PRODIGE 59. [2022]

7. Ireland pubmed.ncbi.nlm.nih.gov

A phase IB study of durvalumab with or without tremelimumab and platinum-doublet chemotherapy in advanced solid tumours: Canadian Cancer Trials Group Study IND226. [2021]

8. England pubmed.ncbi.nlm.nih.gov

Durvalumab, with or without tremelimumab, plus platinum-etoposide versus platinum-etoposide alone in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): updated results from a randomised, controlled, open-label, phase 3 trial. [2021]

9. Ireland pubmed.ncbi.nlm.nih.gov

The efficacy profiles of concurrent chemoradiotherapy with intensity-modulated radiotherapy followed by durvalumab in patients with unresectable stage III non-small cell lung cancer: A multicenter retrospective cohort study. [2022]

10. France pubmed.ncbi.nlm.nih.gov

[News in gastrointestinal radiotherapy: The esophageal cancer]. [2022]

11. England pubmed.ncbi.nlm.nih.gov

Three-arm phase II trial comparing camrelizumab plus chemotherapy versus camrelizumab plus chemoradiation versus chemoradiation as preoperative treatment for locally advanced esophageal squamous cell carcinoma (NICE-2 Study). [2022]

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

Adjuvant durvalumab for esophageal squamous cell carcinoma after neoadjuvant chemoradiotherapy: a placebo-controlled, randomized, double-blind, phase II study. [2023]