A Study of Durvalumab (MEDI4736) in Esophageal Cancer

Study Overview
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Brief Summary
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This is a phase II, open-label, single arm, single-stage study. A total of 23 evaluable patients will be enrolled. If total number of patients free of disease relapse at 1 year is less than or equal to 15, the drug would not be considered for further study in this setting. After six patients are treated with at least one dose of study drug, they will be observed for a minimum of 60 days. During the 60-day observation period, further accrual will be halted to evaluate unacceptable toxicities warranting early closure of the trial defined as: Any definitive durvalumab-related death. A durvalumab-related death will be continuously monitored throughout the trial and the trial will be suspended for re-evaluation whenever such an event is confirmed. Any unexpected and previously unreported grade 4 toxicities definitely related to durvalumab.

Detailed Description
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OUTLINE: This is a multi-center trial. INVESTIGATIONAL TREATMENT: Subjects will receive durvalumab 1500 mg IV every 4 weeks (1 cycle) for a maximum 13 doses (12 months), or until unacceptable toxicities or disease recurrence. The following baseline labs must be completed within 28 days prior to registration for protocol therapy: Hematopoietic: White blood cell count (WBC) > 3 K/mm^3 Hemoglobin (Hgb) > 9 g/dL. Transfusion is allowed, if needed, since patients are post esophagectomy. Platelets > 100 K/mm^3 Absolute neutrophil count (ANC) ≥ 1.5 K/mm^3 Renal: Calculated creatinine clearance of >/= 40 cc/min using the Cockcroft-Gault formula or by 24-hour urine collection. Hepatic: Bilirubin ≤ 1.5 x upper limit of normal (ULN) Aspartate aminotransferase (AST, SGOT) </= 2.5 x ULN Alanine aminotransferase (ALT, SGPT) </= 2.5 x ULN

Official Title
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A Phase II Study Evaluating Safety and Efficacy of Durvalumab (MEDI4736) Following Multi-modality Therapy in Esophageal Cancer: Big Ten Cancer Research Consortium BTCRC-ESO14-012

Conditions
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Esophageal Cancer

Intervention / Treatment
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* Drug: Durvalumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject must meet all of the following applicable inclusion criteria to participate in this study: Written informed consent and HIPAA authorization for release of protected health information obtained from the subject prior to performing any protocol-related procedures, including screening evaluations. NOTE: HIPAA authorization may be included in the informed consent or obtained separately. Age ≥ 18 years at the time of consent. ECOG Performance Status of 0-1 within 28 days prior to registration for protocol therapy. Females of childbearing potential and males must be willing to use two effective methods of contraception (see the protocol) from the time consent is signed until 3 months after treatment discontinuation. Females of childbearing potential must have a negative serum pregnancy test within 14 days prior to registration for protocol therapy. NOTE: Female subjects are considered of child bearing potential unless they are surgically sterile (they have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are ≥60 years old and naturally postmenopausal for at least 12 consecutive months. See the protocol. Histological evidence of persistent residual esophageal adenocarcinoma including gastroesophageal junction adenocarcinoma following definitive concurrent chemoradiotherapy (carboplatin and paclitaxel or cisplatin and 5-FU) in the surgical sample (esophagus or lymph node or both) obtained at the time of esophagectomy. NOTE: Persistent residual disease is defined as follows (modified from College of American Pathologists Guidelines): No residual tumor (Grade 0, complete response, 0% tumor). This group will not be included in this study. Marked response (Grade 1, 0-<10% residual tumor) Moderate response (Grade 2, 10-50% residual tumor) No definite response (Grade 3, >50% residual tumor) Minimum of 1 month and maximum of 3 months from surgical resection with no evidence of disease progression at the time of enrollment. Must have adequately recovered from surgery as judged by the treating investigator. Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up. Exclusion Criteria: Subjects meeting any of the criteria below may not participate in the study: Prior therapy with a PD-1, PD-L1, or CTLA-4 inhibitor or cancer-specific vaccine therapy. Evidence of active autoimmune disease requiring systemic treatment within preceding 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Exceptions to this rule include vitiligo, resolved childhood asthma/atopy, requirement of intermittent bronchodilators or local steroid injections, hypothyroidism stable on hormone replacement, psoriasis not requiring systemic treatment (within the past 2 years), Graves's disease and Sjogren's syndrome. Prior malignancy is not allowed except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, Gleason score ≤ 7 prostate cancers, or other cancer for which the subject has been disease-free for at least 3 years. Active or prior documented inflammatory bowel disease (e.g. Crohn's disease, ulcerative colitis). Presence of interstitial lung disease or history of pneumonitis requiring treatment with corticosteroids. Patients with diagnosis of primary immunodeficiency. Patients receiving chronic systemic corticosteroid therapy or other immunosuppressive therapy within 28 days prior to registration for protocol therapy. Exceptions include intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. History of allogeneic organ or stem cell transplant. Receipt of live attenuated vaccine within 30 days prior to registration for protocol therapy. Mean QT interval corrected for heart rate (QTc) > 470 msec calculated from 3 ECGs by Bazett's Correction. Ventricular arrhythmias requiring medication(s). Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, or active bleeding diatheses. History of psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent. Known HIV infection or chronic hepatitis B or C. Known history of previous clinical diagnosis of tuberculosis. Clinically significant infections as judged by the treating investigator. Clinically significant is defined as an active infection requiring IV antibiotics. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother, breastfeeding should be discontinued. In addition, breast milk cannot be stored for future use while the mother is being treated on study. Treatment with any investigational agent within 28 days prior to registration for protocol therapy. History of hypersensitivity to durvalumab or any excipient. Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results. Previous enrollment in the present study.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Investigational Treatment<br>Durvalumab 1500 mg IV every 4 weeks (1 cycle) for a maximum 13 doses (12 months), or until unacceptable toxicities or disease recurrence. | Drug: Durvalumab<br>* 1500 mg IV every 4 weeks (1 cycle) for a maximum 13 doses (12 months), or until unacceptable toxicities or disease recurrence.<br>* Other names: MEDI4736;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With One-Year Relapse Free Survival (RFS) With Post-Operative Durvalumab | Relapse free survival is defined as time from the date of surgery until the criteria for disease relapse is met, per Response Evaluation Criteria In Solid Tumors (RECIST 1.1), or death occurs. Complete Response (CR): Disappearance of all target lesions Partial Response (PR): At least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started The percentage of subjects who attained relapse free survival for 1 year and 95 % confidence interval has been reported here. | From the date of surgery until disease relapse or death up to a maximum of 40 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Adverse Events as a Measure of Safety and Tolerability | One of the secondary objective in this study is to assess toxicity and tolerability of durvalumab following trimodality therapy in patients with esophageal cancer. Adverse events were recorded from the time of consent for at least 90 days after treatment discontinuation, per Common Terminology Criteria for Adverse Events (CTCAE) v4. Events were assessed at every visit at an interval of 4 weeks. Adverse Event severity grades can be described as follows : Grade 1 indicates a mild event Grade 2 indicates a moderate event Grade 3 indicates a severe event Grade 4 indicates a potentially life-threatening event Grade 5 indicates death | From the time of consent until 90 days after last dose of durvalumab up to a maximum of 15 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Durvalumab, MEDI4736, PD-L1 inhibitor