Study of Anti-PD-1/PD-L1 Antibody Plus Apatinib as Second-Line Treatment of Advanced Esophageal Squamous Cell

Phase 2

Recruiting

• Conditions: Esophageal Cancer
• Interventions: Drug: Apatinib+ SHR-1210（Camrelizumab）; Drug: Apatinib+ SHR-1316（Adebrelimab）; Drug: SHR-1316（Adebrelimab）+SHR-A2009

• Registration Number: NCT03736863
• Lead Sponsor: The First Affiliated Hospital of Zhengzhou University

Brief Summary

The purpose of this study is to observe and evaluate the efficacy and safety of Anti-PD-1 antibody SHR-1210 or Anti-PD-L1 antibody SHR-1316 plus apatinib as second-line treatment of advanced esophageal squamous cell.

Detailed Description

The incidence of esophageal cancer is ranked seventh in the world, and the mortality rate ranks sixth in the world. At present, the first-line treatment of advanced esophageal cancer is mainly based on the combination of paclitaxel, cisplatin and fluorouracil. After the failure of first-line treatment, there is no standard second-line treatment. We designed a single-arm, open phase II clinical trial of anti-PD-1 antibody SHR-1210 or Anti-PD-L1 antibody SHR-1316 plus apatinib as second-line treatment of advanced esophageal squamous cell. The purpose of this study is to observe and evaluate the efficacy and safety of Anti-PD-1 antibody SHR-1210 or Anti-PD-L1 antibody SHR-1316 plus apatinib as second-line treatment of advanced esophageal squamous cell.

Study Timeline

• Study First Submitted: 2018-11-08
• Study First Submitted QC: 2018-11-08
• Study First Posted: 2018-11-09
• Study Start: 2019-12-05
• Primary Completion: 2021-06-20
• Status Verified: 2024-02
• Last Update Submitted: 2024-02-01
• Last Update Posted: 2024-02-05
• Study Completion: 2024-12-30

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 125

Inclusion Criteria

1. Aged 18-75 years, males or females;
2. Histologically or cytologically confirmed as ESCC, locally advanced and unresectable, with local recurrence (local lymph node metastases) or distant metastases;
3. Having progressed or being intolerant to first-line systemic chemotherapy (including chemotherapy based on cisplatin, taxol or fluorouracil) or chemotherapy combined with immunotherapy. Patients are also eligible if they progress after maintenance treatment following the first-line chemotherapy, or if patients with postoperative recurrence or metastasis progress after concurrent radiochemotherapy. As for the radical concurrent chemoradiotherapy, neoadjuvant/adjuvant treatment (chemotherapy or radiochemotherapy), if patients progress during the treatment or within six months after treatment, it is considered as a failure of first-line treatment;
4. The best overall response of first-line immunotherapy is CR, PR or SD, and PFS ≥ 3 months;
5. According to the Response Evaluation Criteria In Solid Tumour (RECIST 1.1), there is at least one measurable lesion, which has not received any local treatment, such as radiotherapy (if the lesion within the region of the previous radiotherapy is confirmed to progress and satisfies RECIST1.1, it can be also selected as the target lesion) ;
6. Tissue samples should be provided for biomarker analysis. The newly harvested tissues are preferred. If the newly harvested tissues are not available, 5-8 archival paraffin sections (5 um thick) can be provided;
7. ECOG: 0~1;
8. Expected survival time ≥ 12 weeks;
9. Adequate function of major organs defined as:(1) Routine blood test: a. HB ≥ 90 g/L; b. ANC ≥ 1.5 × 109/L; c. PLT ≥ 80 × 109/L;(2) Biochemical test: a. ALB ≥ 30 g/L; b. ALT and AST ≤ 2.5 ULN; if there is no liver metastasis, ALT and AST ≤ 5 ULN; c. TBIL ≤ 1.5ULN; d. Plasma Cr ≤ 1.5 ULN or creatinine clearance rate (CCr) ≥ 60 mL/min;
10. Doppler ultrasound evaluation: Left ventricular ejection fraction (LVEF) ≥ lower limit of normal (50%).
11. Women of childbearing age should consent to take contraception measures during the study period and within 6 months after the end of the study (eg., intrauterine device, oral contraceptive pills or condoms). The subjects must be negative for the serum or urine pregnancy test within 7 days before the recruitment. The female subjects must be non-lactating women. Males should consent to take contraception measures during the study period and within 6 months after the end of the study;
12. All subjects are recruited on a voluntary basis and sign the informed consent. They are required to be compliant with the study and cooperative with the follow-up.

Exclusion Criteria

1. Patients who have any active autoimmune diseases or a past history of autoimmune diseases (including but not limited to the following: autoimmune hepatitis, interstitial pneumonia, uveitis, enteritis, hepatitis, hypophysitis, vasculitis, nephritis, and hyperthyroidism; leukoderma. Subjects with fully remitted childhood asthma and no need for any intervention during adulthood can be included; those still having the need for bronchodilators for medical intervention cannot be included);
2. Patients who are currently on immunosuppressors or systemic hormone therapy for immunosuppressive purposes (dose > 10 mg/day, prednisone or other hormones with equivalent efficacy), and continue taking them within 2 weeks before recruitment;
3. ESCC patients with active bleeding in primary lesions;
4. ESCC patients in whom the primary lesions are not surgically resected and are not shrunken in size after radiotherapy;
5. Patients who have received treatment with VEGFR inhibitors, such as sorafenib, sunitinib, and apatinib;
6. Any of the following conditions that will interfere with oral medications: unable to swallow, having received gastroenterostomy, chronic diarrhea and intestinal obstruction;
7. Brain metastasis or brain metastases that have disappeared in less than 3 months;
8. Patients who have any severe and/or uncontrolled diseases, including: poor blood pressure control (systolic pressure ≥ 150 mmHg or diastolic pressure ≥ 100 mmHg); having myocardial ischemia or myocardial infarction and arrhythmia of Grade 1 and above (including QT interval ≥ 480 ms) and cardiac insufficiency of Grade 1; active or uncontrollable severe infection; liver diseases, such as decompensated liver failure, active hepatitis B (HBV-DNA ≥ 104 copy number/mL or 2000 IU/mL) or hepatitis C (positive for anti-HCV antibodies, and HCV-RNA higher than the lower limit of detection with the analytical method); routine urine test indicates urine protein ≥++ and confirms that the 24-hour urinary protein quantification>1.0 g;
9. Patients whose wounds or bone fractures remain unhealed for a long period of time;
10. Pneumorrhagia > NCI-CTC AE Grade1 within four weeks before recruitment; bleeding at other positions >NCI-CTC AE Grade 2 within four weeks before recruitment; having a bleeding tendency (eg., active peptic ulcer) or currently receiving thrombolytic or anticoagulant therapy, such as warfarin, heparin, or their analogs;
11. Patients who have experienced arterial/venous thrombotic events within six months, such as cerebrovascular accidents (including transient ischemic attack), deep venous thrombosis and pulmonary embolism;
12. The invasion of important blood vessels by the tumour or a high probability of the invasion of important blood vessels by the tumor that may lead to lethal hemorrhage in the study period ahead, as judged by the investigator according to the radiological examination;
13. Pregnancy or lactation;
14. Patients who have a history of other malignancies in the past five years (except for the cured basal cell carcinoma and cervical carcinoma in situ);
15. Patients who have a history of psychotropic drug abuse and unable to quit or having mental disorders;
16. Patients who have participated in other clinical trials of drugs in the past four weeks;
17. Patients who have concomitant diseases that may severely impair the safety of patients or make the patients unable to complete the study, as judged by the investigator;
18. Other patients who are considered inappropriate for participation by the investigator.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
CohortA：Apatinib+SHR-1210（Camrelizumab）	Apatinib+ SHR-1210（Camrelizumab）	Apatinib+SHR-1210（Camrelizumab）for ESCC who progressed or were intolerant to first-line systemic chemotherapy
CohortB：Apatinib+SHR-1210（Camrelizumab）	Apatinib+ SHR-1210（Camrelizumab）	Apatinib+SHR-1210（Camrelizumab）for ESCC who have failed prior immune checkpoint inhibitor therapies
CohortC：Apatinib+SHR-1316（Adebrelimab）	Apatinib+ SHR-1316（Adebrelimab）	Apatinib+SHR-1316（Adebrelimab）for ESCC who have failed prior immune checkpoint inhibitor therapies
CohortD：SHR-1316（Adebrelimab）+SHR-A2009	SHR-1316（Adebrelimab）+SHR-A2009	SHR-1316 was administered intravenously, 1200mg, Q3W; SHR-A2009 8mg/kg, iv, Q3W, for ESCC who have failed prior immune checkpoint inhibitor therapies.

Primary Outcome Measures

Name	Time	Method
Objective Response Rate (ORR)	up to 1 year	the proportion of patients with a confirmed complete response or partial response on two consecutive occasions≥4 weeks apart, as determined by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1

Secondary Outcome Measures

Name	Time	Method
6-, 9- and 12-month OS rates	up to 12 months	overall survival rates at 6-, 9- and 12-month
Disease Control Rate (DCR)	up to 1 year	the proportion of patients with a best overall response of confirmed complete or partial response, or stable disease (CR; + PR + SD)
Progression-free Survival (PFS)	up to 2 year	the time from treatment initiation to the first disease progression or death from any cause
Duration of response（DOR）	up to 2 year	the time from the first confirmed response date to the first disease progression or death date
Time to response（TTP）	up to 1 year	the time from treatment to first confirmed tumour response
Overall survival(OS)	up to 2 year	the time from treatment initiation until death from any reason
3- and 6-month PFS rates	up to 6 months	Progression-free survival rates at 3- and 6-month
adverse events(Safety)	up to 2 years	adverse events

Trial Locations

Locations (1)

The First Affiliated Hospital of Zhengzhou University; 🇨🇳 Zhengzhou, Henan, China