Efficacy of Neoadjuvant PD-1 Blockade Plus Chemotherapy for Esophageal Squamous Cell Carcinoma

Esophageal Squamous Cell Carcinoma Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04225364
• Other study ID #: NIC-ESCC2019
• Status: Completed
• Phase: Phase 2
• Start date: January 17, 2020
• Est. completion date: January 31, 2021

Study information

• Verified date: January 2021
• Source: Guangzhou Institute of Respiratory Disease
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 56
• Est. completion date: January 31, 2021
• Est. primary completion date: January 15, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 17 Years to 70 Years

Eligibility

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 ?, 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.

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Squamous Cell
• Esophageal Squamous Cell Carcinoma
• Immunotherapy

Intervention

Drug:
• camrelizumab
Participants will receive camrelizumab, 200mg, intravenously over 30 - 60 minutes, day 1 of every 3 weeks for 6 weeks. Discontinuation will be considered due to toxicity, withdrawal of consent, or end of study. Every 3-week treatment period was considered to be a cycle.
• Paclitaxel for injection (albumin-bound)
Paclitaxel for injection (albumin-bound): 260mg/m2(in total), ivgtt d1, d8, q3w,for 2 cycle
• Cisplatin
75mg/m2(in total), ivgtt d1-d3, q3w, for 2 cycles

Locations

Country	Name	City	State
China	Jingpei Li	Guangzhou	Guangdong

Sponsors (3)

Lead Sponsor	Collaborator
Guangzhou Institute of Respiratory Disease	BGI-Shenzhen, Jiangsu HengRui Medicine Co., Ltd.

Country where clinical trial is conducted

China, 

References & Publications (3)

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. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	safety of neoadjuvant PD-1 Blockade Plus Chemotherapy	Incidence of grade 3-5 adverse events [Safety and Tolerability]	Every 3 weeks (up to 3 months after surgery)
Other	Evaluation of molecular features and ctDNA changing in pre, per and post-treatment plasma	All DNA samples were tested to calculate single nucleotide variants (SNV's), small insertions or deletions (Indels), copy number variations (CNV's), splice variations (SV's), gene fusions (GF's), tumor mutation burden (TMB) and micro-satellite instability (MSI) and others value by all enrolled. NGS (Next generation sequencing)-panel (688 genes) for monitoring on post-treatment residual disease in order to identify mechanisms of response. Measurement of different baseline ctDNA for their prognostic value.	every 2 months (up to 12 months)
Other	Evaluation of Immunomicroenvironment changing in pre, per and post-treatment plasma	the tumor immune microenvironment evaluated with multiplexed immunohistochemistry (mIHC), The evaluation of immune microenvironment uses the method of multiple immunofluorescence, through the detection of CD8, CD163, CD68, PD-1 and PD-L1 four bio-markers, determine the situation of related immune cells in the process and efficacy.	every 2 months (up to 12 months)
Other	perioperative adverse events	The participants were followed up daily and perioperative adverse events as defined by the American College of Surgeons National Quality Improvement Program. The participants were followed up until discharge or 30 days of in hospital stay and the secondary outcome measures entered into a questionnaire.	Time to discharge or 30 days of in hospital stay whichever came first
Primary	Pathologic complete remission (PCR)	Primary tumor or lymph node surgery specimen pathological examination without residual tumor cell	4 weeks after surgery
Secondary	Objective Response Rate (ORR)	Objective Response Rate Determine the tumor shrinkage rate, tumor boundary and the adhesion of tumor	At the end of Cycle 2 (each cycle is 21 days)
Secondary	2-year progression-free survival (PFS)	From date of surgery until the date of first documented progression or date of death from any cause	every 2 months (up to 24 months)
Secondary	Progression-free survival (PFS)	From date of surgery until the date of first documented progression or date of death from any cause	every 2 months (up to 24 months)
Secondary	Overall survival (OS)	Defined from date of Signing ICF to date of first documentation of death from any cause or censored at the date of the last follow-up.	every 2 months (up to 24 months)