Durvalumab as Maintenance Following Chemoradiation for Unresectable Esophageal Squamous Cell Carcinoma
Ключови думи
Резюме
Описание
A) Study Title: Durvalumab (MEDI4736) as maintenance treatment following chemoradiation for locally advanced unresectable esophageal squamous cell carcinoma (DESC)
B) Protocol Number: ESR-17-12757
C) Clinical Phase: 2
D) Study Duration: 36 months
E) Investigational Product(s) and Reference Therapy: Durvalumab (MEDI4736)
F) Research Hypothesis: Is Durvalumab efficient in delay progression in patients with persistent disease after chemoradiation for locally advanced esophageal squamous cell carcinoma?
G) 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
H) Study Design: Single arm phase II trial
I) Number of Centers: 1
J) Number of Patients:22
K) 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.
L) 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.
M) 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>>
N) 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 < O) 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). P) 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. Q) 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.
Дати
Последна проверка: | 07/31/2019 |
Първо изпратено: | 08/07/2019 |
Очаквано записване подадено: | 08/10/2019 |
Първо публикувано: | 08/12/2019 |
Изпратена последна актуализация: | 08/10/2019 |
Последна актуализация публикувана: | 08/12/2019 |
Действителна начална дата на проучването: | 09/30/2019 |
Приблизителна дата на първично завършване: | 09/30/2022 |
Очаквана дата на завършване на проучването: | 09/30/2022 |
Състояние или заболяване
Интервенция / лечение
Drug: Durvalumab
Фаза
Групи за ръце
Arm | Интервенция / лечение |
---|---|
Experimental: Durvalumab 1500 mg durvalumab (MEDI4736) via IV infusion Q4W < | Drug: Durvalumab Durvalumab (MEDI4736) will be supplied as a 500-mg vial solution for infusion after dilution. |
Критерии за допустимост
Възрасти, отговарящи на условията за проучване | 18 Years Да се 18 Years |
Полове, допустими за проучване | All |
Приема здрави доброволци | Да |
Критерии | Inclusion Criteria: 1. Body weight >30kg and body mass index ≥ 16 kg / m2; 2. Patients aphagic or able to ingest only liquids should also receive enteral nutritional sup-port before being included in the study; 3. Patients must have histologically confirmed esophageal or esophagogastric junction (Siewert I or II) squamous cell carcinoma, irrespective of PD-1/PD-L1 or other biomarkers expression; 4. Patients must have had a persistent disease 6-8 weeks after completing chemoradiotherapy with at least 50 Gy and platinum-based chemo and without complete response or progressive disease, based on upper endoscopy and/or CT scans; 5. Patients must have realized CT scans within 6-8 weeks after completion of chemoradiotherapy, revealing persistent disease; 6. Patients must be included <12 weeks after completing chemoradiotherapy; 7. Patients must be unsuitable to salvage esophagectomy, according multidisciplinary local board; 8. All the tumor volume should have been treated with CRT (included in the radiation field); 9. Eastern Cooperative Oncology Group (ECOG)>>< 10. Male or female aged 18 years or older at time of study entry; 11. Life expectancy of > 12 weeks; 12. Adequate normal organ and marrow function as defined below: - Haemoglobin ≥9.0 g/dL - Absolute neutrophil count (ANC) 1.5 x (> 1500 per mm3) - Platelet count ≥100 x 109/L - Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). < - AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be ≤5x ULN - Measured creatinine clearance (CL) >40 mL/min or Calculated creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance: CrCl, mL/min = (140 - age) × (weight, kg) × (0.85 if female) / (72 × Cr) 13. All toxicities attributed to prior chemoradiotherapy other than alopecia, fatigue, or peripheral neuropathy must have resolved to grade 2 or less; Exclusion Criteria: 1. Patients with metastases including lymph node not included in the radiation field; 2. Patients 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); 3. Received any immunotherapy for esophageal cancer; 4. Patients with active hepatitis B, hepatitis C or human immunodeficiency virus (HIV1/2 antibodies); 5. 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 6. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. 7. Grade 3 or higher pulmonary toxicity of dyspnea, hypoxia, or pneumonitis experienced during chemoradiation; 8. Presence of fistula between esophagus and trachea unless treated with endoscopic prosthesis. |
Резултат
Първични изходни мерки
1. Six-month progression-free survival [6 months]
Вторични изходни мерки
1. Incidence of Treatment-Related Adverse Events [Safety and Tolerability] [From time of informed consent through treatment period (12 months) or up to 12 months post last dose of study treatment.]
2. Overall survival [From time of informed consent until the date of death from any cause, assessed up to 60 months]
3. Incidence of locoregional progression [From time of informed consent through treatment period (12 months) or up to 12 months post last dose of study treatment.]
4. Incidence of distant progression [From time of informed consent through treatment period (12 months) or up to 12 months post last dose of study treatment.]
Други изходни мерки
1. Six-month progression-free survival according to immune biomarkers [6 months]