RICE: Radio-Immuno-Chemotherapy of Cancer of the EsophagusA 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
- Conditions
- C15Malignant neoplasm of oesophagus
- Registration Number
- DRKS00015218
- Lead Sponsor
- niversität zu Köln
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Complete
- Sex
- All
- Target Recruitment
- 56
1. Study participants must have signed and dated an IRB/IEC approved written informed consent form
2. Study participants must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests and other requirements of the study.
3. Histologically confirmed, resectable adenocarcinoma of the esophagus (uT3, cNx, cM0), with the following specifications:
• Medical and technical operability
• No preceding cytotoxic or targeted therapy
• No prior partial or complete tumor resection
4. Male or female patients = 18 years of age at time of consent
5. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1
6. Study participants must be willing to undergo at least 2 biopsies (baseline, after neoadjuvant treatment)
7. Life expectancy of = 12 months
8. Body weight = 30kg
9. Adequate normal blood and marrow function as defined below
• WBC = 1500/µL
• Neutrophils = 1000/µL
• Platelets = 75 x103/µL
• Hemoglobin > 9.0 g/dL
• Serum creatinine = 1.5 x ULN or creatinine clearance (CrCl) = 40 mL/min (Cockcroft-Gault) measured creatinine clearance(CL) > 40 mL/min or calculated creatinine clearance CL > 40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance
• AST/ALT (SGOT/SGPT) = 2,5x ULN
• Total Bilirubin = 1.5 x ULN (except study participants with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL)
10. Reproductive Status
• Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception and must agree to use adequate method to avoid pregnancy for 7 month after the last dose of study drug.
• Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of ß-HCG) within one until two weeks prior to the start of durvalumab at time of neoadjuvant treatment and after surgery before starting adjuvant treatment.
• Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. Men receiving durvalumab and who are sexually active with WOCBP must be willing to adhere to contraception for a period of 7 month post treatment completion.
• Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:
• Women < 50 years of age would be considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
• Women = 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses > 1 year ago, had chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
1. Study participants with squamous cell carcinoma of the esophagus
2. Prior treatment with chemotherapy, targeted therapy or radiotherapy for treatment of advanced disease
3. Patients are excluded if they are not resectable because of tumor infiltrating any other organs (cM1), except the stomach, or if they are not resectable in case of other serious or uncontrolled medical disease.
4. Patients with tumor stadium less than uT3 or confirmed metastatic diseases
5. 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
6. Presence or history of any other primary malignancy other than adenocarcinoma of the esophagus within 5 years prior to enrolment into the trial, except for adequately treated basal or squamous cell carcinoma of the skin or any adequately treated in situ carcinoma.
7. 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 disease in the last 5 years may be included but only after consultation with the study physician
• Patients with celiac disease controlled by diet alone.
• Patients with a condition requiring systemic treatment with either corticosteroids (> 10mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of first dose of study drug administration. Inhaled or topical steroids and adrenal replacement steroid doses > 10mg daily prednisone equivalent are permitted in the absence of active autoimmune disease.
8. History of active primary immunodeficiency
9. History of any allogenic organ transplantation with currently intake of immune suppressive treatment
10. Positive test for hepatitis B or hepatitis C or E indicating acute or chronic infection
11. Patients are excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
12. History of another primary malignancy except for
• Malignancy treated with curative intent and with no known active disease = 5 years before the first dose of IP and of low potential risk for recurrence
• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
• Adequately treated carcinoma in situ without evidence of disease
13. Patients with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity.
14. Patients has known current symptomatic congestive heart failure (NYHA III and IV), unstable angina pectoris, or cardiac arrhythmia
15. Prisoners or study participants who are involuntarily incarcerated
16. Allergies and Advers
Study & Design
- Study Type
- interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method The primary endpoint for efficacy is the pathological complete response rate (pCR, ypT0, ypN0, M0), measured by standardized pathological examination of the resection specimens. <br>The primary endpoint for safety is incidence, severity and grading of treatment emergent AEs and SAEs.<br>The resection specimens will be taken during each patient's surgery.
- Secondary Outcome Measures
Name Time Method 1. To determine the Best Objective Response (BOR) as defined by RECIST 1.1 and iRECIST criteria after neoadjuvant treatment<br>2. To determine Progression free survival (PFS), Disease free survival (DFS) and Overall Survival (OS) in durvalumab vs. durvalumab + tremelimumab adjuvant treatment<br>3. To assess the subject’s esophageal-cancer-related quality of life using the Functional Assessment of Cancer Therapy-Esophageal (FACT-E) questionnaire<br><br>The results of the secondary endpoints will be determined after last patients last visit (LPLV).