Clinical trial NCT04225364: Efficacy of Neoadjuvant PD-1 Blockade Plus Chemotherapy for Esophageal Squamous Cell Carcinoma
Official title: The Efficacy of Neoadjuvant PD-1 Plus Concurrent Chemotherapy for Stage II-IVA Operable Esophageal Squamous Cell Carcinoma：A Single Armed, Open-label, Multicentre, Clinical Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Esophageal Squamous Cell Carcinoma
Immunotherapy
Keywords: neoadjuvant immunotherapy
Stage II-IVA
esophageal squamous cell carcinoma
ctDNA
neoadjuvant chemotherapy
Lead sponsor: Guangzhou Institute of Respiratory Disease
Sponsor class: OTHER
Collaborators: name: BGI-Shenzhen
name: Jiangsu HengRui Medicine Co., Ltd.
First posted: 2020-01-13
Enrollment: 56
Sex: ALL
Minimum age (years): 17
Maximum age (years): 70
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Patients with II-IVA stage with pathologically diagnosed squamous cell lung carcinoma will be enrolled in this study. Camrelizumab plus chemotherapy will be administrated intravenously per 3 weeks at the dosage of 200mg. Contrast-CT evaluation and peripheral blood collected will be performed at pre-neoadjuvant therapy and pre-operation. 6 weeks after neoadjuvant therapy, participants who meet the indication will be assigned to operation. Another peripheral blood sample will be harvested 3-4 weeks after operation.
Primary purpose: TREATMENT

Brief summary: This study aims to evaluate the efficacy of Camrelizumab plus concurrent chemotherapy as neoadjuvant approach for patients with opearble esophageal squamous cell carcinoma. In addition, potential clinical utility of ctDNA in monitoring tumor burden and dynamics of tumor clonality during neoadjuvant immunotherapy will be assessed as well. At the same time, CD8 and PD-L1 will also be used as monitoring indicators.

Detailed description: Immunotherapy improves clinical outcome of patients with advanced stage or metastatic esophageal squamous cell carcinoma (ESCC). In addition, superior effect of immunotherapy for esophageal squamous cell carcinoma was also reported recently. While, clinical application of ctDNA, PD-L1 and CD8 T cell monitoring in neoadjuvant immunotherapy for patients with esophageal squamous cell carcinoma is largely unknown. This trial will evaluate firstly the efficacy and the safety of Camrelizumab plus chemotherapy （albumin-bound paclitaxel plus cisplatin）as neoadjuvant approach. The evaluation indicators include pathological complete response rate (pCR) and objective imaging response rate after neoadjuvant therapy (ORR). ), 2-year progression-free survival (2y-PFS), postoperative progression-free survival (PFS), and overall survival (OS) after treatment. Objective response rate (ORR) based upon immune-Response Evaluation Criteria in Solid Tumors Version (RECIST v1.1). Major pathological response assessed by post-operational pathological review ctDNA efficacy will also be evaluated along with clinical management. Monitoring tumor burden, clonality as well as tumor heterogeneity evaluation will be correlated to radiological assessment and pathological findings.

Eligibility criteria: Inclusion Criteria:

* Male and female patients aged ≥18 years, ≤70 years.
* Gastroscope/ultrasound gastroscopy biopsy, Histologically or cytologically confirmed esophageal squamous cell carcinoma. Clinically diagnosed as II-IVA esophageal squamous cell carcinoma (cT2N1-3M0/cT3N0-3M0/cT4N0-3M0).
* Non-Cervical Esophageal Cancer
* Previously received no systemic or topical treatment for esophageal cancer, at least one measurable lesion for neoadjuvant treatment imaging evaluation according to RECIST 1.1;
* Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
* Estimated survival time ≥ 12 months;
* Subjects had no major organ dysfunction, and the investigators assessed thyroid, lung, liver, kidney function, and cardiac function as normal.
* Women of childbearing age must have taken reliable Contraception or have the negative predictive value of urine/ serum pregnancy test within 7 days prior to enrollment. They are also willing to use appropriate methods of contraception during the trial and 8 weeks after the last administration of the test drugs. For men, They must agree to use contraception or surgical sterilization during the trial and 8 weeks after the last administration of the test drug.
* Subjects voluntarily joined the study and signed informed consent. patients who accept blood sample collection at multiple time points. Able to comply with the required protocol and follow-up procedures, and able to receive oral medications.

Exclusion Criteria:

* Have a history of gastrectomy or have surgical contraindications
* The investigator assessed that the patient had other serious illnesses that may affect follow-up and short-term survival;
* There are any active autoimmune diseases or a medical history of autoimmune (including, but not limited to: autoimmune hepatitis, interstitial pneumonia, uveitis, enteritis, hepatitis, pituitary inflammation, vasculitis, nephritis, hyperthyroidism, thyroid function Decreased. Subjects with vitiligo or adults who have had childhood asthma but have fully relieved without any intervention may be included. However, subjects who require bronchodilators for medical intervention cannot be included.)
* Cardiac clinical symptoms or diseases that are not well controlled, such as: a. Heart Failure NYHA \> Class Ⅱ, b. unstable angina, c. myocardial infarction within 1 year; d. Clinically significant supraventricular or ventricular arrhythmia requiring treatment or intervention.
* Subjects with congenital or acquired immunodeficiency (such as HIV-infected), or active hepatitis (hepatitis B reference: HBsAg-positive, HBV DNA ≥ 2000 IU/ml or copy number ≥ 104/ml; hepatitis C reference: HCV antibody-positive.)
* Uncontrollable history of diabetes;
* Patients who have used other clinical trial study drugs within 4 weeks prior to the first dose.
* Severe allergic reactions to monoclonal antibodies or allergy to paclitaxel or human albumin.
* Peripheral blood neutrophil count is less than 1500/mm3
* Patients who have received or are undergoing other chemotherapy, radiation therapy or targeted therapy.
* According to the investigator's assessment, there are other factors that may lead to the termination of the study, such as other serious diseases (including mental illness) requiring combined treatment. Any other condition and social/psychological problems, etc., the investigator judged that the patient was not suitable for participation in the study.

Primary outcomes:
measure: Pathologic complete remission (PCR)
timeFrame: 4 weeks after surgery
Secondary outcomes:
measure: Objective Response Rate (ORR)
timeFrame: At the end of Cycle 2 (each cycle is 21 days)
measure: 2-year progression-free survival (PFS)
timeFrame: every 2 months (up to 24 months)
measure: Progression-free survival (PFS)
timeFrame: every 2 months (up to 24 months)
measure: Overall survival (OS)
timeFrame: every 2 months (up to 24 months)
Other outcomes:
measure: safety of neoadjuvant PD-1 Blockade Plus Chemotherapy
timeFrame: Every 3 weeks (up to 3 months after surgery)
measure: Evaluation of molecular features and ctDNA changing in pre, per and post-treatment plasma
timeFrame: every 2 months (up to 12 months)
measure: Evaluation of Immunomicroenvironment changing in pre, per and post-treatment plasma
timeFrame: every 2 months (up to 12 months)
measure: perioperative adverse events
timeFrame: Time to discharge or 30 days of in hospital stay whichever came first
Locations:
city: Guangzhou
country: China
facility: Jingpei Li
state: Guangdong
Study officials:
affiliation: The First Affiliated Hospital of Guangzhou Medical University
name: Jun liu, Ph.D, M.D
role: STUDY_CHAIR
References:
citation: Kang YK, Boku N, Satoh T, Ryu MH, Chao Y, Kato K, Chung HC, Chen JS, Muro K, Kang WK, Yeh KH, Yoshikawa T, Oh SC, Bai LY, Tamura T, Lee KW, Hamamoto Y, Kim JG, Chin K, Oh DY, Minashi K, Cho JY, Tsuda M, Chen LT. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017 Dec 2;390(10111):2461-2471. doi: 10.1016/S0140-6736(17)31827-5. Epub 2017 Oct 6.
citation: Shapiro J, van Lanschot JJB, Hulshof MCCM, van Hagen P, van Berge Henegouwen MI, Wijnhoven BPL, van Laarhoven HWM, Nieuwenhuijzen GAP, Hospers GAP, Bonenkamp JJ, Cuesta MA, Blaisse RJB, Busch ORC, Ten Kate FJW, Creemers GM, Punt CJA, Plukker JTM, Verheul HMW, Bilgen EJS, van Dekken H, van der Sangen MJC, Rozema T, Biermann K, Beukema JC, Piet AHM, van Rij CM, Reinders JG, Tilanus HW, Steyerberg EW, van der Gaast A; CROSS study group. Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial. Lancet Oncol. 2015 Sep;16(9):1090-1098. doi: 10.1016/S1470-2045(15)00040-6. Epub 2015 Aug 5.
citation: Yang H, Liu H, Chen Y, Zhu C, Fang W, Yu Z, Mao W, Xiang J, Han Y, Chen Z, Yang H, Wang J, Pang Q, Zheng X, Yang H, Li T, Lordick F, D'Journo XB, Cerfolio RJ, Korst RJ, Novoa NM, Swanson SJ, Brunelli A, Ismail M, Fernando HC, Zhang X, Li Q, Wang G, Chen B, Mao T, Kong M, Guo X, Lin T, Liu M, Fu J; AME Thoracic Surgery Collaborative Group. Neoadjuvant Chemoradiotherapy Followed by Surgery Versus Surgery Alone for Locally Advanced Squamous Cell Carcinoma of the Esophagus (NEOCRTEC5010): A Phase III Multicenter, Randomized, Open-Label Clinical Trial. J Clin Oncol. 2018 Sep 20;36(27):2796-2803. doi: 10.1200/JCO.2018.79.1483. Epub 2018 Aug 8.