A Phase II Trial to Evaluate Safety and Efficacy of Adding Durvalumab (MEDI4736) to Standard Neoadjuvant Radiochemotherapy and of Adjuvant Durvalumab +/- Tremelimumab in Locally Advanced Esophageal Adenocarcinoma and to Evaluate Biomarkers Predictive for Response to Immune Checkpoint Inhibition
Overview
- Phase
- Phase 2
- Intervention
- Durvalumab 50 MG/ML
- Conditions
- Esophageal Adenocarcinoma
- Sponsor
- University of Cologne
- Enrollment
- 56
- Locations
- 2
- Primary Endpoint
- Evaluation of Safety and efficacy (measured by an increase of pathological complete response rate)
- Status
- Active, not recruiting
- Last Updated
- last year
Overview
Brief Summary
A phase II trial to evaluate safety and efficacy of adding durvalumab (MEDI4736) to standard neoadjuvant radiochemotherapy and of adjuvant durvalumab +/- tremelimumab in locally advanced esophageal adenocarcinoma and to evaluate biomarkers predictive for response to immune checkpoint inhibition
Detailed Description
Short Study Title: RICE - Radio-Immuno-Chemotherapy of Cancer of the Esophagus Study Phase: Phase II Research hypothesis: The investigators aim at evaluating if (I) esophageal cancer is susceptible to immunotherapeutic approaches based on interference with the PD1 / PDL1 axis, if (II) treatment of locally advanced tumors by immunotherapeutic approaches increases cure rate and if (III) combination with radiotherapy is feasible and increases anti-tumor immunity. Primary Objectives: The primary objective is to evaluate safety and efficacy (measured by an increase of pathological complete response rate from 20% to 35%) of the fully human monoclonal IgG1 antibody durvalumab targeting the programmed death-ligand 1 (PD-L1) in combination with neoadjuvant radiochemotherapy, followed by surgery for locally advanced esophageal cancer and cancer of the gastric esophageal junction (GEJ).
Investigators
Thomas Zander
Principal Investigator
University of Cologne
Eligibility Criteria
Inclusion Criteria
- •Signed Written Informed Consent
- •Study participants must have signed and dated an IEC approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol-related procedures that are not part of normal study participant care.
- •Study participants must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests and other requirements of the study.
- •Target Population
- •Histologically confirmed, resectable adenocarcinoma of the esophagus or cardia/gastric esophageal junction (uT3, cNx, cM0), with the following specifications:
- •Medical and technical operability, according to the techniques described in Section 2.1.3.
- •No preceding cytotoxic or targeted therapy
- •No prior partial or complete tumor resection
- •Male or female patients ≥ 18 years of age at time of study entry
- •Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1
Exclusion Criteria
- •Study participants with squamous cell carcinoma of the esophagus
- •Prior treatment with chemotherapy, targeted therapy or radiotherapy for treatment of advanced cancer disease less than 5 years
- •Enrollment is possible for patients with:
- •Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
- •Adequately treated carcinoma in situ without evidence of disease
- •Any other serious or uncontrolled medical disorder, active infections, physical exam findings, laboratory finding, altered mental status, or psychiatric condition that, in the opinion of the investigator, would limit a study participant's ability to comply with the study requirements, substantially increase risk to the study participant, or impact the interpretability or study results
- •Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease \[e.g., colitis or Crohn's disease\], diverticulitis \[with the exception of diverticulosis\], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome \[granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc\]). The following are exceptions to this criterion:
- •Patients with vitiligo or alopecia Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement Any chronic skin condition that does not require systemic therapy Patients without active autoimmune or inflammatory disease in the last 5 years may be included but only after consultation with study physician Patients with celiac disease controlled by diet alone. Inhaled or topical steroids and adrenal replacement steroid doses \> 10mg daily prednisone equivalent are permitted in the absence of active autoimmune disease.
- •History of active primary immunodeficiency
- •History of any allogenic organ transplantation with currently intake of immune suppressive treatment
Arms & Interventions
Durvalumab
Treatment arm A will receive durvalumab IV in a dosage of 1500mg every four weeks for 12 months as mono therapy.
Intervention: Durvalumab 50 MG/ML
Durvalumab + Tremelimumab
Treatment arm B receives durvalumab in a dosage of 1500mg every 4 weeks (-3/+7 days) for 12 months post-surgery. In addition these patients receive tremelimumab IV in a fixed dose of 75mg for the first four months on day 1; 29; 57; 85 (-3/+7).
Intervention: Durvalumab 50 MG/ML
Durvalumab + Tremelimumab
Treatment arm B receives durvalumab in a dosage of 1500mg every 4 weeks (-3/+7 days) for 12 months post-surgery. In addition these patients receive tremelimumab IV in a fixed dose of 75mg for the first four months on day 1; 29; 57; 85 (-3/+7).
Intervention: Tremelimumab
Outcomes
Primary Outcomes
Evaluation of Safety and efficacy (measured by an increase of pathological complete response rate)
Time Frame: Calculated once at the end of study (24 months after the end of treatment)
The primary objective is to evaluate safety and efficacy (measured by an increase of pathological complete response rate from 20% to 35%) of the fully human monoclonal IgG1 antibody durvalumab targeting the programmed death-ligand 1 (PD-L1) in combination with neoadjuvant radiochemotherapy, followed by surgery for locally advanced esophageal cancer and cancer of the gastric esophageal junction (GEJ).
Secondary Outcomes
- Determination of Progression Free Survival (PFS) in durvalumab vs. durvalumab + tremelimumab adjuvant treatment(Until 24 months after the end of treatment)
- Determination of Overall Survival (OS) in durvalumab vs. durvalumab + tremelimumab adjuvant treatment(From the study start until the date of death, assessed up to 240 months)
- Assessment of the subject's esophageal-cancer-related quality of life using the Functional Assessment of Cancer Therapy-Esophageal (FACT-E) questionnaire(Until 24 months after the end of treatment)
- Determination of Disease Free Survival (DFS) in durvalumab vs. durvalumab + tremelimumab adjuvant treatment(Until 24 months after the end of treatment)
- Determination of Best Objective Response (BOR) as defined by RECIST 1.1 and iRECIST criteria after neoadjuvant treatment(Determined once after neoadjuvant treatment (up to 12 weeks after study start))