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

Background:

Neoadjuvant chemoradiation is part of the standard of care for patients with stage II and III resectable esophageal and gastroesophageal cancer. This approach is based on the results of a large randomized clinical trial (CROSS) that demonstrated superior survival in patients receiving neoadjuvant chemoradiotherapy followed by surgical resection compared to patients treated with surgery alone. Pathological complete response at the time of resection is strongly linked to better survival. However, with current strategies pathological complete response is achieved only in a minority (29%) of patients. Remaining patients, especially those with positive lymph nodes at the time of the resection, are at significant risk for recurrences. Five-year survival rate for these patients is only 37%, and overall survival is as low as 9 months for those with persistent lymph node disease. Among patients who develop recurrent disease, most present with distant metastases outside of the radiation field. This is not surprising since the accepted treatment paradigm for this disease does not target possible disseminated microscopic systemic disease. Hence, novel strategies are needed to improve outcomes of these patients. We propose conducting a phase I/II clinical trial evaluating a role of immune checkpoint inhibitor in combination with chemoradiotherapy and post-operatively in the management of resectable esophageal cancer.

Study Rationale:

1. A number of preclinical and clinical studies demonstrated synergism between radiation and immunotherapy, suggesting that combining these approaches can enhance anti-tumor activity and increase treatment efficacy.
2. Immune checkpoint inhibitors have demonstrated promising activity in a subset of patients with metastatic esophageal and gastric cancers. Moving these agents into neoadjuvant setting may increase the cure rate of this disease compared to the standard approach.
3. Current neoadjuvant therapy does not target any potential microscopic disease outside of the radiation field since chemotherapy serves primarily as a radiation sensitizer. Immunotherapy treatment will target both local and systemic disease.

Hypothesis:

We hypothesize that co-administration of avelumab with chemoradiation will be well tolerated and will increase pathological complete response rate in resected tumor specimens. We hypothesize that avelumab treatment will also decrease the rates of disease recurrence.

Study Design:

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.

Objectives:

Primary: Evaluate the safety of avelumab in combination with chemoradiation in patients with resectable esophageal cancer and gastroesophageal receiving perioperative therapy.

Secondary: Obtain efficacy data and further safety data of the proposed drug combination in this patient population.

Exploratory objectives: The translational focus of the study will evaluate changes in tumor microenvironment that occur in response to radiation and immunotherapy.

Endpoints:

Part 1 - Primary endpoint: Establish safety and tolerability of the proposed treatment.

Part 2 - Primary Endpoint: Pathological complete response rate.

Part 2 - Secondary Endpoints:

1. Safety and tolerability.
2. Disease free survival.
3. Incidence of surgical complications.
4. Rate of R0 resection.

Number of centers & patients: One center.

Part 1: total of 6 eligible patients will be accrued to evaluate the safety and tolerability of the proposed combination.

Part 2: 18 patients will be enrolled in the phase 2 portion of the trial.

Population:

Patients with histologically confirmed, potentially curable squamous-cell carcinoma, adenocarcinoma, or large-cell undifferentiated carcinoma of the esophagus and gastroesophagus who are candidates for neoadjuvant therapy and surgical resection.

Investigational drugs:

Avelumab (Provided by EMD Serono). IND information to be added as needed.

Inclusion Criteria:

1. Patients with histologically confirmed, potentially curable squamous-cell carcinoma, adenocarcinoma, or large-cell undifferentiated carcinoma of the esophagus and gastroesophagus (Siewert type 1-3)

2. Locoregional disease with clinical stage of T1N1 or T2-3N0-2

3. No clinical evidence of metastatic spread. Staging should include endoscopic ultrasound and positron emission tomography/computed tomography (PET/CT) as recommended by National Comprehensive Cancer Network (NCCN) guidelines. PET/CT should be performed within 3 weeks of signing informed consent

4. Age 18 years or older

5. Eastern Cooperative Oncology Group (ECOG) performance status 0-2

6. Subjects must be deemed to be potential surgical candidates by an evaluating surgeon

7. Adequate organ function:

   1. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
   2. Hemoglobin ≥ 9 g/dL (transfusions allowed)
   3. Platelets ≥ 100 x 109/L
   4. Aspartate transaminase/Alanine transaminase (AST/ALT) ≤ 2.5 x ULN
   5. Total serum bilirubin of ≤1.5 x institutional upper limit of normal (ULN)
   6. Estimated creatinine clearance ≥ 30 mL/min according to the Cockcroft-Gault formula

8. Female patients of childbearing potential must have a negative pregnancy test (urine or serum) within 21 days prior to the start of the study drug treatment and must agree to use adequate birth control if conception is possible during the study and up to 30 days after the completion of adjuvant therapy

9. Male patients must agree to use adequate birth control during the study and up to 30 days after the last avelumab dose

10. Women who are nursing must discontinue breast-feeding prior to the enrollment in the trial

11. Patient must be able and willing to comply with study procedures as per protocol

12. Patient able to understand and willing to sign and date the written voluntary informed consent form (ICF) at screening visit prior to any protocol-specific procedures

Exclusion Criteria:

1. Prior history of radiation to the mediastinum

2. Diagnosis of cervical esophageal carcinoma

3. Other active malignancy within the last 3 years (except for non-melanoma skin cancer, a non-invasive/in situ cancer, or indolent non metastatic Gleason 6 prostate cancer)

4. Subjects with an active or known autoimmune disease. Subjects with type I diabetes mellitus, hypo- or hyperthyroidism only requiring hormone replacement/suppression, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic immunosuppressive treatment are eligible

5. Current use of immunosuppressive medication, except for the following:

   1. intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection)
   2. systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent
   3. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)

6. Active infection requiring systemic therapy at the time of study treatment initiation

7. Prior organ transplantation including allogenic stem-cell transplantation

8. Known history of testing positive for HIV or known immunodeficiency syndrome

9. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive)

10. Vaccination within 4 weeks of the first dose of avelumab and while on trials is prohibited except for administration of inactivated vaccines

11. Major surgery within prior 4 weeks of treatment initiation (the surgical incision should be fully healed prior to all neoadjuvant treatment initiation)

12. Any prior anticancer therapy for esophageal cancer

13. History of allergic reactions attributed to compounds of similar chemical or biologic composition to carboplatin, paclitaxel or avelumab, including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v5.0 Grade ≥ 3)

14. Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication. Patients with stable rate-controlled atrial fibrillation will be allowed to participate

15. Other severe acute or chronic medical conditions including immune colitis, inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study

16. Psychological, familial, or sociological condition potentially hampering compliance with the study protocol and follow-up schedule