Short Course Neoadjuvant Chemo-radiotherapy Plus Toripalimab for Locally Advanced Resectble Squamous Cell Carcinoma of Esophagus (SCALE-2)

Short Course Neoadjuvant Chemo-radiotherapy Plus Anti-PD-1 Antibody (Toripalimab) for Locally Advanced Resectble Squamous Cell Carcinoma of Esophagus (SCALE-2）

Adding PD-1 inhibitors to neoadjuvant chemoradiotherapy has shown promising results in locally advanced resectable esophageal squamous cell carcinoma (ESCC). However, there is a need to explore safer and more effective treatment doses and schedules. This is an open labeled, prospective, single-arm phase II trial to evaluate the safety and efficacy of the short course neoadjuvant chemo-radiotherapy plus Toripalimab for locally advanced resectble ESCC.

Study Overview

• Status: Recruiting
• Conditions: Locally Advanced Esophageal Carcinoma
• Intervention / Treatment: Drug: Neoadjuvant Chemotherapy; Drug: Neoadjuvant Toripalimab; Radiation: Short Course Neoadjuvant Radiotherapy

Detailed Description

Although neoadjuvant chemoradiotherapy (CRT) followed by surgery has become the standard treatment option for locally advanced ESCC, prognosis of these patients is still poor. Adding PD-1/PD-L1 checkpoints inhibitor to neoadjuvant chemoradiotherapy (CRT) have shown potential benefit in locally advanced resectble ESCC. However, the conventional radiation dose may lead to irreversible toxicity. There is need to explore more effective and safer treatment doses and schedules for this combination.

The investigators proposed a novel strategy (short course neoadjuvant radiotherapy plus preoperative chemotherapy and toripalimab, the SCALE strategy) for the treatment of locally advanced resectble ESCC. In the phase Ib SCALE-1 (ChCTR2100045104) study, 23 patients were enrolled and 20 patients had undergone surgery after the preoperative treatment. The preliminary results showed that the SCALE strategy was safe and induced a pCR and MPR in 55% and 80% of resected tumors, respectively. In this prospective, phase II study, the investigators will further evaluate the safety and efficacy of the SCALE strategy in locally advanced resectble ESCC. This study will provide valuable information for further clinical use of SCALE strategy in locally advanced resectble ESCC.

• Study Type: Interventional
• Enrollment (Anticipated): 63
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Xiangzhi Zhu, M.D.; Phone Number: +86 25 83283535; Email: 13182948068@163.com
• Study Contact Backup: Name: Ning Jiang, M.D.; Phone Number: +86 25 83283535; Email: njiang117@njmu.edu.cn

Study Locations

• China
  • Jiangsu
    • Nanjing, Jiangsu, China, 210000
      • Recruiting
      • Jiangsu Cancer Hospital /Jiangsu Institute of Cancer Research
      • Contact: Xiangzhi Zhu, M.D.; Phone Number: +86 25 83283535; Email: 13182948068@163.com
      • Contact: Ning Jiang, M.D.; Phone Number: +86 25 83283535; Email: njiang117@njmu.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Be able to provide written informed consent and understand and agree to follow the research requirements and evaluation schedule.
2. Endoscopic biopsy of thoracic esophageal primary lesion histologically diagnosed as squamous cell carcinoma.
3. Clinical stage T1-4aN+M0 or T3-4aN0M0 in the UICC-TNM classification 8th edition.
4. The age is over 20 years old and under 75 on the enrollment date (including 20 and 75), including both female and male.
5. PS 0-1.
6. According to RECIST version 1.1, there were measurable or evaluable lesions.
7. No medical history of treatment for cancer (No medical history of chemotherapy, radiotherapy and endocrine therapy, immune-therapy or other study drugs including treatment for other types of cancer).

8. The results of laboratory tests within 14 days before enrollment meet the inclusion criteria：（patients should not receive blood transfusion or growth factor support because neutrophil count, platelet or hemoglobin are lower than the research requirements within 14 days before blood sample collection）.

   • Bone marrow function: hemoglobin (Hb) >=90g/L; white blood cell count (WBC) >= lower limit of normal value; absolute neutrophil value (ANC) >= 1.5x10^9 /L; platelet count >= 100x10^9 / L;
   • Renal function: Cr <= 1.5 UNL, endogenous creatinine clearance rate (Ccr) >= 60 ml/min（Cockcroft-Gault）;
   • Liver function: total bilirubin <= 1.5 ULN; ALT and AST <= 2.5 ULN (patients with liver metastases can be relaxed to <=5 ULN);
   • Blood coagulation function: the international standardized ratio of prothrombin time <= 1.5 ULN, and the partial thromboplastin time is within the normal range.
9. Patients with hepatitis B virus (HBV) infection, inactive / asymptomatic HBV carriers, or patients with chronic or active HBV will be allowed to be enrolled if HBV DNA < 500 IU / ml (or 2500 copies / ml) at screening. Patients with positive hepatitis C antibody will be allowed to be enrolled if HCV-RNA is negative during screening.Note: patients who can detect hepatitis B surface antigen (HBsAg) or HBV DNA should be treated with antiviral drugs for more than 2 weeks before enrollment, and the treatment should be continued for 6 months after the study drug treatment.
10. Women of childbearing age (wocbp) should take the urine or serum pregnancy test, and the result of which should be negtive within ≤ 72 hours before treatment. For females, who have agreed with contraception from start of investigational drug administration to 5 months after last dose of investigational drug. For males who have agreed with contraception from start of investigational drug administration to 7 months after last dose of investigational drug.

Exclusion Criteria:

1. Have received any treatment for esophageal squamous cell carcinoma in the past;
2. Patients with evidence or high risk of gastrointestinal hemorrhage or fistula (esophagus / bronchus or esophagus / aorta);
3. Patients with severe malnutrition, with body mass index lower than 18.5kg/m2, or PG-SGA score ≥9；
4. Any active autoimmune disease or history of autoimmune disease (as follows, but not limited to: interstitial pneumonia, uveitis, enteritis, autoimmune hepatitis, pituitritis, vasculitis, nephritis, hyperthyroidism, thyroid dysfunction); Subjects with vitiligo or who have had complete remission from childhood asthma without any intervention after adulthood may be included; Asthma requiring medical intervention with bronchodilators was not included.
5. Has a previous radiotherapy, chemotherapy, hormone therapy, surgery, molecular targeted therapy or immune therapy for this malignancy or for any other past malignancy;
6. Any condition requiring systemic corticosteroid therapy (prednisone with a dose higher than 10 mg / day or equivalent dose of similar drugs) or other immunosuppressants within 14 days before treatment. （Excluding the following steroid regimens：Local, ophthalmic, intra-articular, nasal and inhaled corticosteroids with minimal systemic absorption；Prophylactic short-term (≤ 7 days) use of corticosteroids (e.g., prevention of contrast media allergy) or for the treatment of non-autoimmune disorders (e.g., delayed hypersensitivity caused by exposure to allergens).
7. Live vaccine injection was received in ≤ 4 weeks before treatment.
8. A history of immunodeficiency, including HIV infection, other acquired or congenital immunodeficiency, or a history of organ or bone marrow implantation that need immunosuppressive medications.
9. There are clinical symptoms or diseases of the heart that are not well controlled, such as: 1). heart failure above grade 2 by the Criteria of NYHA; 2). unstable angina pectoris; 3). myocardial infarction occurred within 1 year; 4). Clinically meaningful supraventricular or ventricular arrhythmias require treatment or intervention;
10. Has severe infections （CTCAE>2 grade）within 4 weeks before treatment; basal thoracic imaging indicating active pneumonia, or other infectious situation that need oral or intravenous antibiotic treatment (excluding Prophylactic medication for antibiotics).
11. A history of interstitial lung disease, non-infectious pneumonia or uncontrolled disease, including pulmonary fibrosis, acute lung disease, etc.
12. Has active pulmonary tuberculosis found by CT imaging; or has active pulmonary tuberculosis less than 1 year before inclusion; or has active pulmonary tuberculosis but without standard treatment over 1 year before inclusion;
13. Allergic to any drug used in this study.
14. Pregnant or lactating women；participants who unwilling to take contraception.
15. Other factors that could lead to the termination of this study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: short course neoadjuvant chemoradiotherapy plus toripalimab; Paclitaxel, carboplatin and toripalimab every 3 weeks for two cycles. Concurrent short course neoadjuvant radiotherapy (30 Gy in 12 fractions, 5 days per week, D3-D18). Surgery will be performed within 8-10 weeks after the completion of preoperative therapy described above.	Drug: Neoadjuvant Chemotherapy; Paclitaxel (135 mg /m2) and carboplatin (AUC=5) every 3 weeks for two cycles (D1,D22); Drug: Neoadjuvant Toripalimab; Toripalimab 240mg every 3 weeks for two cycles (D2,D23); Radiation: Short Course Neoadjuvant Radiotherapy; 30 Gy in 12 fractions, 1 fraction per day, 5 days per week, D3-D18

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathologic complete response	Pathologic complete response was defined as pT0N0M0 or pTisN0M0	1 month after resection

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease free survival	Disease free survival defined as the time from enrollment to the first documented disease progression of local recurrence or distant metastasis or death due to any cause.	3 years after resection
3-year overall survival	Defined as from date of enrollment until the date of death from any cause or the date of last follow-up, whichever came first.	3 years after enrollment
Incidence of Treatment-related Adverse Events	The neoadjuvant treatment-related adverse events as assessed by CTCAE v5.0	From the date of enrollment until surgery was applied during study period or up to at least 90 days after last dose
Perioperative complication rate	The perioperative complication rate of esophagectomy using clavien-Dindo classification	From date of surgery to 30 days later
Health related quality of Life	To compare change in Quality of Life, as defined by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ-C30 (Version 3)) during the neoadjuvant therapy and perioperative period. The EORTC QLQ-C30 (Version 3) uses for the questions 1 to 28 a 4-point scale. The scale scores from 1 to 4: 1 ("Not at all"), 2 ("A little"), 3 ("Quite a bit") and 4 ("Very much"). Half points are not allowed. The range is 3. For the raw score, less points are considered to have a better outcome. The EORTC QLQ-C30 (Version 3) uses for the questions 29 and 30 a 7-points scale. The scale scores from 1 to 7: 1 ("very poor") to 7 ("excellent"). Half points are not allowed. The range is 6. First of all, raw score has to be calculated with mean values. Afterwards linear transformation is performed to be comparable. More points are considered to have a better outcome.	Measured before and after neoadjuvant therapy, before and 1, 3, 6, 9, 12 months after surgery.
Health related quality of Life related to esophageal carcinoma	To compare change in Quality of Life in esophageal carcinoma patients, the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire for Esophageal Cancer (EORTC QLQ-QES18) was used. The EORTC QLQ-QES18 uses for the questions 1 to 18 a 4-point scale. The scale scores from 1 to 4: 1 ("Not at all"), 2 ("A little"), 3 ("Quite a bit") and 4 ("Very much"). Half points are not allowed. The range is 3. For the raw score, less points are considered to have a better outcome.	Measured before and after neoadjuvant therapy, before and 1, 3, 6, 9, 12 months after surgery.

Collaborators and Investigators

• Sponsor: Jiangsu Cancer Institute & Hospital
• Investigators: Study Director: Xiangzhi Zhu, M.D., Jiangsu Cancer Institute & Hospital; Study Director: Ming Jiang, M.D., Jiangsu Cancer Institute & Hospital; Study Director: Feng Jiang, M.D., Jiangsu Cancer Institute & Hospital

Study record dates

Study Major Dates

• Study Start (Actual): April 29, 2022
• Primary Completion (Anticipated): December 31, 2023
• Study Completion (Anticipated): December 31, 2024

Study Registration Dates

• First Submitted: June 10, 2022
• First Submitted That Met QC Criteria: June 15, 2022
• First Posted (Actual): June 21, 2022

Study Record Updates

• Last Update Posted (Actual): June 27, 2022
• Last Update Submitted That Met QC Criteria: June 21, 2022
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Keywords: Toripalimab; neoadjuvant chemoradiotherapy; esophageal carcinoma; short course neoadjuvant radiotherapy
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Head and Neck Neoplasms; Esophageal Diseases; Neoplasms, Squamous Cell; Carcinoma; Carcinoma, Squamous Cell; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma
• Other Study ID Numbers: SCALE-2

Drug and device information, study documents

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