Phase I/II Trial of Avelumab in Combination With Chemoradiation in the Treatment of Stage II/III Resectable Esophageal and Gastroesophageal Cancer
Overview
- Phase
- Phase 1
- Intervention
- Avelumab combined with Chemoradiation
- Conditions
- Resectable Esophageal Cancer
- Sponsor
- University of Wisconsin, Madison
- Enrollment
- 22
- Locations
- 1
- Primary Endpoint
- Number of Participants With Dose Limiting Toxicity
- Status
- Completed
- Last Updated
- last year
Overview
Brief Summary
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
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients with histologically confirmed, potentially curable squamous-cell carcinoma, adenocarcinoma, or large-cell undifferentiated carcinoma of the esophagus and gastroesophagus (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 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
- •Age 18 years or older
- •Eastern Cooperative Oncology Group (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
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
Arms & Interventions
Run-In Phase
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 dose-limiting toxicity (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.
Intervention: Avelumab combined with Chemoradiation
Run-In Phase
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 dose-limiting toxicity (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.
Intervention: Carboplatin
Run-In Phase
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 dose-limiting toxicity (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.
Intervention: Paclitaxel
Run-In Phase
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 dose-limiting toxicity (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.
Intervention: Radiation
Expansion Cohort
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).
Intervention: Avelumab combined with Chemoradiation
Expansion Cohort
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).
Intervention: Carboplatin
Expansion Cohort
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).
Intervention: Paclitaxel
Expansion Cohort
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).
Intervention: Radiation
Outcomes
Primary Outcomes
Number of Participants With Dose Limiting Toxicity
Time Frame: 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.
Number of Participants With Pathological Complete Response
Time Frame: 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.
Secondary Outcomes
- Disease Free Survival(Up to 4 years post-resection for all participants)
- Number of Participants With Treatment Related Adverse Events Greater Than or Equal to Grade 3(Up to 30 days post-avelumab of all (up to 4 months on study))
- Number of Participants With Unexpected Surgical Complications(Following resection (80 -100 days) for all participants (up to approximately 5 months on study))
- Rate of R0 Resection(Following pathology review post-resection (80 -100 days) for all participants (up to approximately 4 months on study))
- Estimated 1-year Recurrence Free Survival(up to 1 year)
- Number of Participants Who Did or Did Not Complete Planned Treatment(Up to 30 days post-avelumab of all participants (up to 4 months on study))