Penpulimab Plus Chemotherapy With/Without Anlotinib for Patients With Advanced Esophageal Squamous Cell Carcinoma (ANSWER)

Penpulimab Plus Chemotherapy With or Without Anlotinib as First-line Therapy for Patients With Advanced Esophageal Squamous Cell Carcinoma (Answer): A Randomized Two-arm Clinical Study

Penpulimab plus chemotherapy with or without Anlotinib as first-line therapy for patients with advanced esophageal squamous cell carcinoma (Answer): A randomized two-arm clinical study.

Study Overview

• Status: Recruiting
• Conditions: Essential Tremor
• Intervention / Treatment: Drug: Anlotinib/Penpulimab/Chemotherapy; Drug: Penpulimab/Chemotherapy

Detailed Description

This is a open-label, phase II study of Penpulimab plus chemotherapy with or without Anlotinib as first-line therapy in subjects With resectable advanced esophageal squamous cell carcinoma. The patients will be divided into two groups. In group A, Penpulimab plus chemotherapy with Anlotinib will be given every 3 weeks for 4-6 cycles in initial stage, then in maintenance treatment, Anlotinib and Penpulimab will be used every 3 weeks until disease progression or intolerance; In group B, Penpulimab plus chemotherapy will be given every 3 weeks for 4-6 cycles in initial stage, then in maintenance treatment, Penpulimab will be used every 3 weeks until disease progression or intolerance;

• Study Type: Interventional
• Enrollment (Anticipated): 100
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: wei wang; Phone Number: 020-61642136; Email: wwei9500@smu.edu.cn

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China
      • Recruiting
      • Nanfang Hospital, Southern Medical University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Patients with advanced metastatic esophageal squamous cell carcinoma who cannot receive radical treatment (excluding mixed adenosquamous carcinoma);
2. Those who have not received systemic treatment in the past, or (new) adjuvant treatment/radical surgery/radical radiotherapy and chemotherapy have relapsed for more than 6 months; Note: Including patients with advanced or recurring non-target lesions who have progressed again after radiotherapy alone. For local lesions (non-target lesions), the time from the end of palliative treatment to the enrollment time> 2 weeks;
3. According to the RECIST 1.1 version of the curative effect evaluation standard for solid tumors, there is at least one measurable lesion; the measurable lesion should not have received local treatment such as radiotherapy (the lesion located in the previous radiotherapy area, if it is confirmed that it has progressed, and meets RECIST1.1 Standard, target lesions can also be selected);
4. Patients between 18 and 75 years old;
5. ECOGPS score: 0~1 points; the expected survival period is more than 3 months;
6. Tumor specimens can be provided to determine gene detection and PD-L1 expression, at least 15 white sheets (assessed by the company); provide two oral swabs; within 7 days before the medication, the first, third, and sixth at the end of the cycle, one tube of 6ml EDTA anticoagulant blood will be provided.
7. It has sufficient organ and bone marrow function, that is, it meets the following standards:

(1) The standard of routine blood examination must meet: Hemoglobin content (HB) ≥90g/L (no blood transfusion within 28 days); Absolute neutrophil count (ANC) ≥1.5×109/L; Platelet count (PLT) ≥100×109/L. (2) The biochemical inspection shall meet the following standards: Serum total bilirubin (TBIL) ≤ 1.5 times the upper limit of normal (ULN); ALT and AST≤2.5´ULN; if there is liver metastasis, ALT and AST≤5´ULN; Cr≤1.5´ULN or creatinine clearance (CCr)≥60ml/min; (Cockcroft-Gault formula) (3) The coagulation function is adequate, which is defined as the international normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 times ULN; 8) Women of childbearing age must take appropriate contraceptive measures from screening to 3 months after stopping the treatment, and they must be non-lactating patients. Before starting the administration, the pregnancy test is negative, or meeting one of the following criteria proves that there is no risk of pregnancy:

1. Post-menopausal is defined as amenorrhea at least 12 months after the age is greater than 50 years and all exogenous hormone replacement therapy is stopped;
2. For women younger than 50 years old, if the amenorrhea is 12 months or more after stopping all exogenous hormone treatments, and the levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH) are within the laboratory postmenopausal reference value range, also Can be considered post-menopausal;
3. Have received irreversible sterilization, including hysterectomy, bilateral ovariectomy or bilateral fallopian tube resection, except for bilateral tubal ligation.

For men, they must agree to use appropriate methods of contraception or have been surgically sterilized during the trial period and 8 weeks after the last trial drug administration; 9) The patient voluntarily joined the study, signed an informed consent form, had good compliance, and cooperated with the follow-up.

Exclusion Criteria:

1. It is known that esophageal squamous cell carcinoma tends to be completely obstructed under endoscopy and requires interventional treatment to relieve the obstruction;
2. Patients with ulcerative esophageal squamous cell carcinoma;
3. Patients who have a higher risk of bleeding or perforation due to the tumor's obvious invasion of the adjacent organs (aorta or trachea) of the esophageal lesion, or patients who have formed a fistula;
4. Patients with esophageal squamous cell carcinoma whose esophageal lesions have not been reduced after radiotherapy without surgical resection of the primary lesion;
5. Allergy to paclitaxel and cisplatin preparations or excipient ingredients;
6. Patients who have used paclitaxel or cisplatin in adjuvant chemotherapy and have relapsed or metastasized within six months; Note: Those who have relapsed or metastasized for more than six months can be included in the study;
7. Previously received anti-tumor immunotherapy (including immune checkpoint inhibitors, immune cell therapy, etc.) or anti-angiogenesis targeted therapy drugs (including antibodies and small molecule tyrosine kinase inhibitors);
8. There are many factors that affect oral medications (such as inability to swallow, chronic diarrhea, intestinal obstruction, etc.), but patients who have difficulty swallowing and can drink, can take Anlotinib after dissolving the granules;
9. The burden of liver metastases accounts for more than 50% of the entire liver volume;

10. Patients with any severe and/uncontrolled diseases, including:

    1. Patients with unsatisfactory blood pressure control using antihypertensive drugs (systolic blood pressure ≥150mmHg or diastolic blood pressure ≥100mmHg); patients with grade II or higher myocardial ischemia or myocardial infarction, arrhythmia (including QT interval ≥480ms); according to NYHA standards , Grade III-IV cardiac insufficiency, or cardiac color Doppler ultrasound examination reveals that the left ventricular ejection fraction (LVEF) is less than 50%;
    2. Active or uncontrolled serious infection;
    3. Liver diseases such as cirrhosis, decompensated liver disease, chronic active hepatitis;
    4. Poor control of diabetes (fasting blood glucose (FBG)> 10mmol/L);
    5. Urine routines suggest that urine protein is ≥++, and the 24-hour urine protein content is confirmed to be greater than 1.0g;
11. Long-term unhealed wounds or fractures;
12. Patients with esophageal squamous cell carcinoma with active bleeding within 2 months of the primary lesion; pulmonary hemorrhage with NCICTCAE grade> grade 1 occurred within 4 weeks before enrollment; other sites with NCICTCAE grade> grade 2 occurred within 4 weeks before enrollment Bleeding; patients with bleeding tendency (such as active peptic ulcer) or who are receiving thrombolytic or anticoagulant therapy such as warfarin, heparin or their analogues;
13. Major surgery (craniotomy, thoracotomy, or laparotomy) within 4 weeks before the first dose of the study or expected major surgery during the study treatment period.
14. A history of gastrointestinal perforation and/or fistula in the 6 months before the enrollment treatment; or arteriovenous thrombotic events, such as cerebrovascular accidents (including temporary ischemic attacks), deep vein thrombosis and lungs Embolizer
15. There are known symptomatic central nervous system metastases and/or cancerous meningitis;
16. Ascites with clinical significance, including any ascites that can be found on physical examination, ascites that has been treated in the past or still needs to be treated at present, only those with a small amount of ascites but asymptomatic on imaging can be selected;
17. Patients with moderate pleural effusion on both sides, or large pleural effusion on one side, or patients who have caused respiratory dysfunction and require drainage;
18. Known to have active tuberculosis;
19. Suffer from interstitial lung disease that requires steroid therapy;
20. Uncontrolled metabolic disorders or other non-malignant tumor organs or systemic diseases or cancer secondary reactions, which may lead to higher medical risks and/or uncertainty in survival evaluation;
21. Patients with significant malnutrition, BMI<13.6kg/m2;
22. People who have a history of psychotropic drug abuse and cannot be quit or have mental disorders;
23. Have a history of immunodeficiency, including those who have tested positive for HIV or have other acquired or congenital immunodeficiency diseases, or have a history of organ transplantation;
24. History of other primary malignant tumors, except for the following: 1) Malignant tumors that have been completely remitted for at least 2 years before enrollment and no other treatment is required during the study period; 2) Non-melanoma skin that has been adequately treated and has no evidence of disease recurrence Carcinoma or malignant freckle-like nevus; 3) Carcinoma in situ that has been adequately treated and has no evidence of disease recurrence;
25. Female patients who are pregnant or breastfeeding;
26. According to the judgment of the investigator, those with concomitant diseases that seriously endanger the safety of the patient or affect the patient's completion of the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: group A; Penpulimab plus chemotherapy with Anlotinib	Drug: Anlotinib/Penpulimab/Chemotherapy; Initial treatment (4-6 cycles): Anlotinib, Penpulimab, Paclitaxel or Albumin Paclitaxel,Cisplatin; Anlotinib: once a day, 1 capsule each time (10mg for body weight <60KG, 12mg for body weight ≥60KG), d1-d14, 3 weeks as a treatment cycle.; Penpulimab: 200 mg, d1 per cycle, once every 3 weeks.; Paclitaxel: According to 135-175mg/m2, intravenous infusion> 2h, d1, 3 weeks as a treatment cycle; Albumin paclitaxel: According to 200-260mg/m2, intravenous infusion for 30 minutes, d1, 3 weeks as a treatment cycle.; Cisplatin: 60-75mg/m2, intravenous infusion, divided into d1-d3 medication per cycle; 3 weeks is a treatment cycle. Maintenance treatment: Anlotinib, Penpulimab; Anlotinib: once a day, 1 capsule each time (the same as the initial treatment dose), take the drug every cycle d1-d14, 3 weeks as a treatment cycle.; Penpulimab: 200mg, d1 per cycle, once every 3 weeks; Other Names: Anlotinib, Penpulimab, Paclitaxel or Albumin Paclitaxel,Cisplatin
Experimental: group B; Penpulimab plus chemotherapy	Drug: Penpulimab/Chemotherapy; Initial treatment (4-6 cycles): Penpulimab, Paclitaxel or Albumin Paclitaxel,Cisplatin; Penpulimab: 200 mg, d1 per cycle, once every 3 weeks.; Paclitaxel: According to 135-175mg/m2, intravenous infusion> 2h, d1, 3 weeks as a treatment cycle; Albumin paclitaxel: According to 200-260mg/m2, intravenous infusion for 30 minutes, d1, 3 weeks as a treatment cycle.; Cisplatin: 60-75mg/m2, intravenous infusion, divided into d1-d3 medication per cycle; 3 weeks is a treatment cycle. Maintenance treatment: Penpulimab • Penpulimab: 200mg, d1 per cycle, once every 3 weeks; Other Names: Penpulimab, Paclitaxel or Albumin Paclitaxel,Cisplatin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR)	ORR was defined as the percentage of participants who have a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1	up to approximately 2 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease Control Rate (DCR)	DCR was defined as the percentage of participants who have a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) or a Stable Response per RECIST 1.1	up to approximately 2 year
Progression Free Survival (PFS) include PFS1,PFS2	PFS was defined as the time from first day of study treatment to the first documented PD or death due to any cause during the specific treatment period, whichever occurred first	up to approximately 2 year
Overall Survival (OS)	OS was defined as the time from first day of study treatment to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up	up to approximately 3 year
Safety: AE	Safety was defined as the Number of Participants With an Adverse Event	up to approximately 2 year
Change From Baseline in Health-related Quality of life (HRQoL) Score Using European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30)	The EORTC QLQ-C30 is a questionnaire to assess the overall HRQoL. Participant responses to the question " How would you rate your overall quality of life (QoL) during the past week?" are scored on a 7-point scale (1=Very Poor to 7=Excellent). A higher score indicates a better overall QoL. Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. The change from baseline in HRQoL EORTC QLQ-C30 score in participants will be presented.	up to approximately 2 year
Change From Baseline in HRQoL Score Using EORTC Quality of Life Questionnaire-Oesophageal Module (QLQ-OES18)	The EORTC QLQ-OES18 is a disease-specific questionnaire to assess measurements specific to esophageal cancer. It contains 18 items and is based on four subscales-dysphagia, eating, reflux and pain. All items are scored using a four-point scale that offers these response choices: 1=not at all, 2=a little, 3=quite a bit, 4=very much. A higher score indicates worse level of symptoms. Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. The change from baseline in HRQoL QLQ-OES18 score in participants will be presented.	up to approximately 2 year
The 1-year OS rate	OS was defined as the time from first day of study treatment to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up	1 year
The 2-year OS rate	OS was defined as the time from first day of study treatment to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up	2 years
The 3-year OS rate	OS was defined as the time from first day of study treatment to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up	3 years

Collaborators and Investigators

• Sponsor: Nanfang Hospital of Southern Medical University
• Investigators: Principal Investigator: wei wang, Nanfang Hospital of Southern Medical University

Study record dates

Study Major Dates

• Study Start (Actual): September 2, 2022
• Primary Completion (Anticipated): March 1, 2023
• Study Completion (Anticipated): July 1, 2024

Study Registration Dates

• First Submitted: January 3, 2022
• First Submitted That Met QC Criteria: January 14, 2022
• First Posted (Actual): January 28, 2022

Study Record Updates

• Last Update Posted (Actual): September 29, 2022
• Last Update Submitted That Met QC Criteria: September 27, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: PD-1 inhibitor/anlotinib
• Additional Relevant MeSH Terms: Digestive System Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Head and Neck Neoplasms; Movement Disorders; Esophageal Diseases; Neoplasms, Squamous Cell; Esophageal Neoplasms; Carcinoma, Squamous Cell; Esophageal Squamous Cell Carcinoma; Essential Tremor; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Paclitaxel; Cisplatin; Albumin-Bound Paclitaxel
• Other Study ID Numbers: NFEC-202111-K4

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No