Durvalumab as Maintenance Following Chemoradiation for Unresectable Esophageal Squamous Cell Carcinoma

1. Study Title: Durvalumab (MEDI4736) as maintenance treatment following chemoradiation for locally advanced unresectable esophageal squamous cell carcinoma (DESC)
2. Protocol Number: ESR-17-12757
3. Clinical Phase: 2
4. Study Duration: 36 months
5. Investigational Product(s) and Reference Therapy: Durvalumab (MEDI4736)
6. Research Hypothesis: Is Durvalumab efficient in delay progression in patients with persistent disease after chemoradiation for locally advanced esophageal squamous cell carcinoma?
7. Objectives:

G1) Primary Objectives:

To assess the efficacy of durvalumab treatment in terms of 6-month progression-free survival.

G2) Secondary Objective(s):

To assess the incidence of grade 3 or higher toxicities; To further assess the efficacy of durvalumab in terms of overall survival, incidence of locoregional progression and incidence of distant progression.>>

G3) Exploratory Objective(s):

To investigate the relationship between immune biomarkers within the tumor microenvironment (immunohistochemistry) with efficacy outcomes with durvalumab

1. Study Design: Single arm phase II trial
2. Number of Centers: 1
3. Number of Patients:22
4. Study Population:

Patients with locally advanced unresectable or inoperable esophageal squamous cell carcinoma who had a persistent disease after completing definitive chemoradiotherapy, with no progressive disease.

1. Inclusion Criteria:

• Body weight >30kg and body mass index ≥ 16 kg / m2;
• Patients who are aphagic or able to ingest only liquids should also receive enteral nutritional support before inclusion in the study;
• Patients with histologically and/or cytologically confirmed esophageal or esophagogastric junction (Siewert I or II) squamous cell carcinoma, irrespective of PD-1/PD-L1 or any other biomarker expression;
• Patients who had a persistent disease 6-8 weeks after completing chemoradiotherapy with at least 50 Gy and platinum-based chemo and without clinical complete response or progressive disease;
• CT scans within 4 weeks revealing persistent disease;
• Must be included <12 weeks after completing chemoradiotherapy to ensure durvalumab begins no later than 16 weeks after completion of chemoradiotherapy;
• Patients unsuitable to salvage esophagectomy;
• All the tumor volume should have been treated with CRT (included in the radiation field); ECOG 0 - 1;
• Age 18 years or older;
• Life expectancy of higher than 3 months;
• Laboratory values must meet the following criteria: Absolute neutrophil count (ANC) > 1.5 (>1500 per mm3); Platelet count ≥ 100 x109/L. Hemoglobin >9.0 g/dL. Creatinine < 1.5 times institutional ULN or CrCl > 40 mL/min. AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal. Serum bilirubin ≤ 1.5 times institutional ULN (This will not apply to patients with confirmed Gilbert's syndrome - persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology, who will be allowed only in consultation with their physician)
• All toxicities attributed to prior chemoradiotherapy other than alopecia, fatigue, or peripheral neuropathy must have resolved to grade 2 or less.

1. Exclusion Criteria:

• Presence of any site of metastatic disease, including lymph node which has not been included in radiation field;
• Are currently receiving or have had prior use of immunosuppressive medication within 28 days before the first dose of study drug (10 milligrams/day of prednisone or an equivalent corticosteroid is allowed);
• Received any immunotherapy for esophageal cancer;
• Has known active hepatitis B, hepatitis C or human immunodeficiency virus (HIV1/2 antibodies);
• Has known active or prior autoimmune disease, except for:
• skin diseases (vitiligo, psoriasis, alopecia)
• diabetes mellitus type 1, with hormone replacement
• hypothyroidism, with hormone replacement
• Receipt of live attenuated vaccination within 30 days prior to study entry.
• Grade 3 or higher pulmonary toxicity of dyspnea, hypoxia, or pneumonitis experienced during chemoradiation;
• Presence of tracheoesophageal fistula that has not been treated with endoprosthesis>>

1. Investigational Product(s), Dose and Mode of Administration:

Patients in the durvalumab (MEDI4736) monotherapy treatment group will receive 1500 mg durvalumab (MEDI4736) via IV infusion Q4W <<for up to a maximum of 12 months (up to 13 doses/cycles) with the last administration on week 48 unless there is unacceptable toxicity, disease progression, withdrawal of consent, or another discontinuation criterion is met. If a patient's weight falls to 30 kg or below for 1 week or longer ( ≥ 7 days) durvalumab will be permanently discontinued.

1. Study Assessments and Criteria for Evaluation:

O.1) Safety Assessments:

Safety assessments will be performed in accordance with the National Cancer Institute Common Terminology Criteria, version 5.0.

At least every 4 weeks, during each visit, data on toxicity on treatment will be evaluated.

Laboratory analysis will also be performed at least every 4 weeks to assess toxicity.

O.2) Efficacy Assessments:

Patients will undergo tumor assessments with cross-sectional imaging at study site at start and then 8 ± 1w until complete 12 months after first dose; Patients who have disease control following completion of 12 months (13 cycles) of treatment will continue to have objective tumor assessment q12w ± 1w for more 12 months or until disease progression (whichever comes first); Patients who are withdrawn from durvalumab treatment for reasons other than confirmed PD (e.g toxicity) will continue to have objective tumor assessments q8w ± 1w until complete 12 months after first dose. Then, they will have objective tumor assessments q12w ± 1w for more 12 months (24 months after first dose) or until disease progression; Measurable target and nontarget lesions will be assessed according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1).

1. Statistical Methods and Data Analysis:

Safety analysis will be performed considering all enrolled patients who received at least one dose of durvalumab; Efficacy analysis will be performed using intention-to-treat approach; Will be used an alpha error of 0.05 (1-sided) and a power (1 - beta error) of 90%; Primary endpoint will be 6-month progression free survival rate; Secondary endpoints will be overall survival, incidence of locoregional progression and incidence of distant progression; Locoregional progression is defined when an in-field lesion (primary tumor or lymph nodes) is the first site of progression or in case of worsening dysphagia with an upper endoscopy revealing an unequivocal local progression; Distant progression is defined when an out-field lesion (lymph node, visceral, bone) is the first site of progression; We estimate 12 months of recruitment, with 2 patients per month; Overall survival will be estimated using Kaplan-Meier method.

1. Sample Size Determination:

Single arm phase II trial; Will be estimated p0 (null-hypothesis 6-month PFS) as 10%; Will be estimated p1 (alternative hypothesis 6-month PFS) as 35%; With an estimated dropout rate of 10%, our sample size will be 22 patients.