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

Study Overview
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Brief Summary
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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

Detailed Description
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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: 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. 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. 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: Safety and tolerability. Disease free survival. Incidence of surgical complications. 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.

Official Title
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Phase I/II Trial of Avelumab in Combination With Chemoradiation in the Treatment of Stage II/III Resectable Esophageal and Gastroesophageal Cancer

Conditions
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Resectable Esophageal Cancer, GastroEsophageal Cancer

Intervention / Treatment
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* Combination Product: Avelumab combined with Chemoradiation
* Drug: Carboplatin
* Drug: Paclitaxel
* Radiation: Radiation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with histologically confirmed, potentially curable squamous-cell carcinoma, adenocarcinoma, or large-cell undifferentiated carcinoma of the esophagus and gastroesopagus (Siewert type 1-3) Locoregional disease with clinical stage of T1N1 or T2-3N0-2 No clinical evidence of metastatic spread. Staging should include endoscopic ultrasound and PET/CT as recommended by NCCN guidelines. PET/CT should be performed within 3 weeks of signing informed consent Age 18 years or older ECOG performance status 0-2 Subjects must be deemed to be potential surgical candidates by an evaluating surgeon Adequate organ function: Absolute neutrophil count (ANC) ≥ 1.5 x 109/L Hemoglobin ≥ 9 g/dL (transfusions allowed) Platelets ≥ 100 x 109/L AST/ALT ≤ 2.5 x ULN Total serum bilirubin of ≤1.5 x institutional upper limit of normal (ULN) Estimated creatinine clearance ≥ 30 mL/min according to the Cockcroft-Gault formula 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 Male patients must agree to use adequate birth control during the study and up to 30 days after the last avelumab dose Women who are nursing must discontinue breast-feeding prior to the enrollment in the trial Patient must be able and willing to comply with study procedures as per protocol 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: Prior history of radiation to the mediastinum Diagnosis of cervical esophageal carcinoma 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) 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 Current use of immunosuppressive medication, except for the following: intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection) systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication) Active infection requiring systemic therapy at the time of study treatment initiation Prior organ transplantation including allogenic stem-cell transplantation Known history of testing positive for HIV or known immunodeficiency syndrome 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) Vaccination within 4 weeks of the first dose of avelumab and while on trials is prohibited except for administration of inactivated vaccines Major surgery within prior 4 weeks of treatment initiation (the surgical incision should be fully healed prior to all neoadjuvant treatment initiation) Any prior anticancer therapy for esophageal cancer 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) 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 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 Psychological, familial, or sociological condition potentially hampering compliance with the study protocol and follow-up schedule

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The study is a two-part phase 1/2 clinical trial conducted in one center. Part 1. Run-in phase to assess the safety and tolerability of avelumab in combination with chemoradiation. Will enroll 6 patients, after which accrual will be stopped temporarily while safety data is being obtained. Part 2. An open-label phase 2 study. Part 2 will obtain further safety data of the proposed drug combination and will evaluate the anti-tumor efficacy of perioperative avelumab and chemoradiation in this patient population. Will enroll 18 additional patients. Each phase of the study will have a 21-day screening period, treatment procedures (neoadjuvant therapy, resection and adjuvant therapy), and active surveillance for a year after the completion of adjuvant therapy. After active surveillance visit at 12 months post treatment completion, survival data and disease status will be collected via phone calls or medical record review every 6 months during the following 3 years.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Run-In Phase<br>6 patients enrolled will receive weekly carboplatin (AUC2) and paclitaxel (50 mg/m2) [intravenous infusion on days 1, 8, 15, 22, & 29] while undergoing radiation therapy [23 fractions, M-F, estimated completion day 35]. Avelumab combined with Chemoradiation - Avelumab (10 mg/kg IV) every 2 weeks starting on the day of the last chemotherapy infusion (day 29). A total of 3 doses administered during the pre-operative period and an additional 6 doses of avelumab post-operatively. Trial enrollment will resume after at least 5 patients do not have a DLT during the DLT evaluation period or until all 6 patients are seen for post-operative evaluation. If 2 or more patients experience dose limiting toxicities associated with the proposed treatments, further accrual of the subjects will be halted and trial will be suspended. Trial may be reopened in the future with appropriate schedule and dose modifications of the proposed treatment. | Combination Product: Avelumab combined with Chemoradiation<br>* Co-administration of avelumab with chemoradiation in pre-operative period.<br>Drug: Carboplatin<br>* Weekly Carboplatin (AUC2) [intravenous infusion on days 1, 8, 15, 22, & 29]<br>Drug: Paclitaxel<br>* Weekly paclitaxel [intravenous infusion on days 1, 8, 15, 22, & 29]<br>Radiation: Radiation<br>* Radiation therapy [23 fractions, M-F, estimated completion day 35]<br>|
| Experimental: Expansion Cohort<br>Following a determination of safe and tolerable treatment outcome of the Run-In Phase, Part 2 of the trial will enroll 18 additional patients to evaluate activity of the proposed treatment and to obtain further safety information (carboplatin, paclitaxel, radiation & Avelumab combined with Chemoradiation). | Combination Product: Avelumab combined with Chemoradiation<br>* Co-administration of avelumab with chemoradiation in pre-operative period.<br>Drug: Carboplatin<br>* Weekly Carboplatin (AUC2) [intravenous infusion on days 1, 8, 15, 22, & 29]<br>Drug: Paclitaxel<br>* Weekly paclitaxel [intravenous infusion on days 1, 8, 15, 22, & 29]<br>Radiation: Radiation<br>* Radiation therapy [23 fractions, M-F, estimated completion day 35]<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Dose Limiting Toxicity | 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. Specifically, the true dose limiting toxicity rate will be estimated with a standard error of 20%. The proposed treatment combination will be considered as safe if dose limiting toxicities are observed in at most 1 patient. | Up to 4 weeks post-resection of all 6 Part 1 subjects. | 
| Part 2: Pathological complete response rate. | 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. The pCR rate will be reported along with the corresponding 90% confidence interval which will be constructed using the Wilson score method. | Post-resection (80-100 days) pathology review for all 24 Part 2 subjects. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Adverse Events | 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. The number and severity of toxicity incidents will be analyzed descriptively in tabular format. The 90% confidence interval for the dose limiting toxicity rate (DLT) will be constructed using the Wilson score method. | Up to 30 days post-avelumab of all 24 Part 2 subjects. | 
| Number of Subjects who Complete Planned Treatment | 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. | Up to 30 days post-avelumab of all 24 Part 2 subjects. | 
| Disease free survival | 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. | Up to 4 years post-resection for all 24 subjects. | 
| Incidence of surgical complications | Incidence of surgical complications will be calculated and reported along with the corresponding 95% confidence intervals which will be constructed using the Wilson score method. | Following resection (80-100 days) for all 24 subjects. | 
| Rate of R0 resection | Rate of R0 resection will be calculated and reported along with the corresponding 95% confidence intervals which will be constructed using the Wilson score method. | Following pathology review post-resection (80-100 days) for all 24 subjects. |