NCT03490292

Avelumab With Chemoradiation for Stage II/III Resectable Esophageal and Gastroesophageal Cancer

Completed Phase 1, PHASE2 Results posted Last updated 26 July 2024

What this trial tests

Phase 1, PHASE2 trial testing Avelumab combined with Chemoradiation in Resectable Esophageal Cancer in 22 participants. Completed in 12 July 2023.

Timeline

29 May 2018

Primary endpoint
19 January 2022

12 July 2023

Quick facts

Lead sponsor	University of Wisconsin, Madison
Phase	Phase 1, PHASE2
Status	Completed
Study type	INTERVENTIONAL
Allocation	non randomized
Design	parallel
Masking	none
Primary purpose	treatment
Enrollment	22
Start date	29 May 2018
Primary completion	19 January 2022
Estimated completion	12 July 2023
Sites	1 location across United States

Drugs / interventions tested

• Avelumab combined with Chemoradiation
• Carboplatin (Carboplatin) — full drug profile →
• Paclitaxel — full drug profile →
• Radiation

Conditions studied

• Resectable Esophageal Cancer — all drugs for Resectable Esophageal Cancer →
• GastroEsophageal Cancer — all drugs for GastroEsophageal Cancer →

Sponsor

University of Wisconsin, Madison

Who can join

18 and older, any sex, with Resectable Esophageal Cancer or GastroEsophageal Cancer. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Number of Participants With Dose Limiting Toxicity Primary · Up to 4 weeks post-resection (up to approximately 4 months on study) of all Run-In Phase participants

A total number of 6 subjects will be enrolled during the run-in phase of the trial. A sample size of 6 is sufficient to estimate the true dose limiting toxicity rate of the proposed avelumab/chemoradiation therapy with adequate accuracy.The proposed treatment combination will be considered as safe if dose limiting toxicities are observed in at most 1 patient.

Group	Value	95% CI
Run-In Phase	0

Number of Participants With Pathological Complete Response Primary · Post-resection (80-100 days) pathology review for all participants (up to approximately 4 months on study)

Pathologic compete response (pCR) is defined as an absence of any viable tumor at microscopic examination of the primary tumor and any lymph nodes sampled after surgery following neoadjuvant therapy. Participants with invalid/missing pCR assessments will be defined as non-responders. The number and frequency of patients with a pCR will be summarized in tabular format.

Group	Value	95% CI
Run In Phase	2
Expansion Cohort	3

Number of Participants With Treatment Related Adverse Events Greater Than or Equal to Grade 3 Secondary · Up to 30 days post-avelumab of all (up to 4 months on study)

Part 2 will further evaluate the safety of the studied drug combination, building on the observations from Part 1. All patients who receive at least one dose of avelumab will be evaluated for toxicity. Toxicities observed will be summarized in terms of types and severities by Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 (see Adverse Events section).

Lymphopenia

Group	Value	95% CI
Run In Phase	5
Expansion Cohort	16

White Blood Cell Decrease

Group	Value	95% CI
Run In Phase	4
Expansion Cohort	9

Neutropenia

Group	Value	95% CI
Run In Phase	2
Expansion Cohort	4

Diarrhea

Group	Value	95% CI
Run In Phase	0
Expansion Cohort	1

Acute Kidney Injury

Group	Value	95% CI
Run In Phase	0
Expansion Cohort	1

Hypotension

Group	Value	95% CI
Run In Phase	0
Expansion Cohort	1

Dehydration

Group	Value	95% CI
Run In Phase	1
Expansion Cohort	0

Infusion Reaction

Group	Value	95% CI
Run In Phase	0
Expansion Cohort	1

Number of Participants Who Did or Did Not Complete Planned Treatment Secondary · Up to 30 days post-avelumab of all participants (up to 4 months on study)

Part 2 will further evaluate the tolerability of the studied drug combination, building on the observations from Part 1. Tolerability will be reported as the number of subjects who did or did not complete the planned treatment, including the reason they ended treatment early.

Completed All Protocol Treatment

Group	Value	95% CI
Run In Phase	6
Expansion Cohort	13

Completed Neoadjuvant Therapy and Planned Surgical Resection

Group	Value	95% CI
Run In Phase	6
Expansion Cohort	10

Did not complete all planned Neoadjuvant Treatment

Group	Value	95% CI
Run In Phase	0
Expansion Cohort	3

Number of Participants With Unexpected Surgical Complications Secondary · Following resection (80 -100 days) for all participants (up to approximately 5 months on study)

Group	Value	95% CI
Run In Phase	0
Expansion Cohort	0

Rate of R0 Resection Secondary · Following pathology review post-resection (80 -100 days) for all participants (up to approximately 4 months on study)

R0 resection corresponds to resection for cure or complete remission.

Group	Value	95% CI
Run In Phase	5
Expansion Cohort	10

Disease Free Survival Secondary · Up to 4 years post-resection for all participants

Disease free survival (DFS) will be defined as the number of days from the day of resection to the day a subject experiences an event of disease recurrence or death, whichever comes first. If a subject has not experienced an event of disease recurrence progression or death at the time of analysis, then the subject's data will be censored at the date of the last available evaluation. DFS will be summarized using point estimates of the median time to progression and the associated 95% confidence interval. The data will be presented graphically using Kaplan-Meier plots.

Group	Value	95% CI
Carboplatin, Paclitaxel, Radiation & Avelumab Combined With Chemoradiation	NA	NA – NA

Estimated 1-year Recurrence Free Survival Secondary · up to 1 year

Group	Value	95% CI
Carboplatin, Paclitaxel, Radiation & Avelumab Combined With Chemoradiation	71	43 – 87

Adverse events — posted to ClinicalTrials.gov

Time frame: up to 4 weeks post resection (up to 4 months on study), survival data collected up to 4 years. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Run In Phase

Serious: 3/6 (50%)

Deaths: 1/6

Expansion Cohort

Serious: 10/16 (63%)

Deaths: 6/16

Serious adverse events (24 terms)

Reaction	System	Run In Phase	Expansion Cohort
Fever	General disorders	—	—
Wound infection	Infections and infestations	—	—
Aspiration	Respiratory, thoracic and mediastinal disorders	—	—
Esophageal leak	Gastrointestinal disorders	—	—
Constipation	Gastrointestinal disorders	—	—
Diarrhea	Gastrointestinal disorders	—	—
Esophageal fistula	Gastrointestinal disorders	—	—
Nausea	Gastrointestinal disorders	—	—
Enterocolitis infectious	Infections and infestations	—	—
Sepsis	Infections and infestations	—	—
Urinary tract infection	Infections and infestations	—	—
Fall	Injury, poisoning and procedural complications	—	—
Weight loss	Investigations	—	—
Dehydration	Metabolism and nutrition disorders	—	—
Hyperglycemia	Metabolism and nutrition disorders	—	—
Hypoglycemia	Metabolism and nutrition disorders	—	—
Confusion	Psychiatric disorders	—	—
Acute kidney injury	Renal and urinary disorders	—	—
Tachypnea	Respiratory, thoracic and mediastinal disorders	—	—
Jejunal obstruction	Gastrointestinal disorders	—	—
Hypotension	Vascular disorders	—	—
Accidental J-tube removal	Injury, poisoning and procedural complications	—	—
Colonic Ischemia	Gastrointestinal disorders	—	—
Infusion Related Reaction	Injury, poisoning and procedural complications	—	—

Other adverse events (100 terms — click to expand)

Reaction	System	Run In Phase	Expansion Cohort
Lymphocyte count decreased	Investigations	—	—
White blood cell decreased	Investigations	—	—
Fatigue	General disorders	—	—
Neutrophil count decreased	Investigations	—	—
Platelet count decreased	Investigations	—	—
Hyperglycemia	Metabolism and nutrition disorders	—	—
Hypoalbuminemia	Metabolism and nutrition disorders	—	—
Hyponatremia	Metabolism and nutrition disorders	—	—
Esophagitis	Gastrointestinal disorders	—	—
Anemia	Blood and lymphatic system disorders	—	—
Weight loss	Investigations	—	—
Nausea	Gastrointestinal disorders	—	—
Diarrhea	Gastrointestinal disorders	—	—
Constipation	Gastrointestinal disorders	—	—
Vomiting	Gastrointestinal disorders	—	—
Hypertension	Vascular disorders	—	—
Infusion related reaction	Injury, poisoning and procedural complications	—	—
Dehydration	Metabolism and nutrition disorders	—	—
Dizziness	Nervous system disorders	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—
Dysphagia	Gastrointestinal disorders	—	—
Hypotension	Vascular disorders	—	—
Aspartate aminotransferase increased	Investigations	—	—
Blood bicarbonate decreased	Investigations	—	—
Anorexia	Metabolism and nutrition disorders	—	—
Hypokalemia	Metabolism and nutrition disorders	—	—
Headache	Nervous system disorders	—	—
Gastroesophageal reflux disease	Gastrointestinal disorders	—	—
Dyspepsia	Gastrointestinal disorders	—	—
Hyperkalemia	Metabolism and nutrition disorders	—	—
Dyspnea	Respiratory, thoracic and mediastinal disorders	—	—
Rash maculo-papular	Skin and subcutaneous tissue disorders	—	—
Rash acneiform	Skin and subcutaneous tissue disorders	—	—
Dysuria	Renal and urinary disorders	—	—
Abdominal pain	Gastrointestinal disorders	—	—
Creatinine increased	Investigations	—	—
Hypercalcemia	Metabolism and nutrition disorders	—	—
Pain	General disorders	—	—
Dysgeusia	Nervous system disorders	—	—
Akathisia	Nervous system disorders	—	—

Most-reported serious reactions: Fever, Wound infection, Aspiration, Esophageal leak, Constipation, Diarrhea, Esophageal fistula, Nausea.

Data from ClinicalTrials.gov NCT03490292 adverse events section.

Sponsor's own description

This is a 2 part Phase I/II clinical trial evaluating the safety, tolerability and efficacy of avelumab in combination with chemoradiation in patients with resectable esophageal and gastroesophageal cancer.

Part 1: This is the run-in phase of the trial. This portion will determine the safety and tolerability of avelumab in combination with chemoradiotherapy in 6 patients. The proposed combination will be considered as safe if dose limiting toxicities are observed in at most 1 patient.

Part 2: This is a Phase 2 portion of the trial, which will evaluate the efficacy of the proposed treatment regimen in patients with stage II/III resectable esophageal and gastroesophageal cancer

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Product review: avelumab, an anti-PD-L1 antibody.
   Collins JM, Gulley JL. · · 2019 · cited 62× · PMID 30481100 · DOI 10.1080/21645515.2018.1551671
2. Neoadjuvant immunotherapy for resectable esophageal cancer: A review.
   Li Q, Liu T, Ding Z. · · 2022 · cited 43× · PMID 36569908 · DOI 10.3389/fimmu.2022.1051841
3. Recent Advances in Combination of Immunotherapy and Chemoradiotherapy for Locally Advanced Esophageal Squamous Cell Carcinoma.
   Wang R, Liu S, Chen B, Xi M. · · 2022 · cited 35× · PMID 36291954 · DOI 10.3390/cancers14205168
4. The Combination Options and Predictive Biomarkers of PD-1/PD-L1 Inhibitors in Esophageal Cancer.
   Yang H, Wang K, Wang T, Li M, et al · · 2020 · cited 35× · PMID 32195194 · DOI 10.3389/fonc.2020.00300
5. Immunotherapy for Esophageal Cancer: State-of-the Art in 2021.
   Teixeira Farinha H, Digklia A, Schizas D, Demartines N, et al · · 2022 · cited 33× · PMID 35158822 · DOI 10.3390/cancers14030554
6. Efficacy and safety of neoadjuvant immunotherapy combined with chemoradiotherapy or chemotherapy in esophageal cancer: A systematic review and meta-analysis.
   Liu Y, Bao Y, Yang X, Sun S, et al · · 2023 · cited 24× · PMID 36761760 · DOI 10.3389/fimmu.2023.1117448
7. Neoadjuvant chemoradiotherapy combined with sequential perioperative toripalimab in locally advanced esophageal squamous cell cancer.
   Xu X, Sun Z, Liu Q, Zhang Y, et al · · 2024 · cited 22× · PMID 38458635 · DOI 10.1136/jitc-2023-008631
8. A phase II, single-centre trial of neoadjuvant toripalimab plus chemotherapy in locally advanced esophageal squamous cell carcinoma.
   Xing W, Zhao L, Fu X, Liang G, et al · · 2020 · cited 20× · PMID 33282388 · DOI 10.21037/jtd-20-2198