Study of Neoadjuvant Nivolumab or Placebo Plus Chemotherapy Followed by Surgery and Adjuvant Treatment in Subjects With Resectable ESCC

A Randomized, Multicenter, Double Blind, Phase II Study of Neoadjuvant Nivolumab or Placebo Plus Chemotherapy Followed by Surgery and Adjuvant Treatment in Subjects With Resectable Esophageal Squamous Cell Carcinoma

Esophageal cancer, the 7th most common cancer globally, accounts for more than half a million deaths each year. The incidence of ESCC, the most common histologic type, has been stable, whereas the incidences of esophageal and gastroesophageal junction adenocarcinomas continue to increase in Western countries.

Neoadjuvant chemoradiotherapy followed by surgery has become a standard of care for patients with locally advanced resectable esophageal or junctional cancer, especially in western countries. In Asia, nCT is considered as the standard of care for Stage II/III ESCC based on JCOG9204 and JCOG9907 trials. The superiority of nCRT/nCT, in terms of long-term survival, remains to be elucidated. For Stage II/III ESCC patients with multiple stations of lymph nodes involvement, nCT might be more appropriate for the inaccessibility of radiotherapy.

There are only limited studies on preoperative immune checkpoint inhibitor in combination with chemotherapy followed by surgery for the locally advanced ESCC. Therefore, this study intends to use Nivolumab 360 mg Q3W combined with standard chemotherapy as the neoadjuvant therapy regimen.

1. Background Esophageal cancer, the 7th most common cancer globally, accounts for more than half a million deaths each year. The incidence of ESCC, the most common histologic type, has been stable, whereas the incidences of esophageal and gastroesophageal junction adenocarcinomas continue to increase in Western countries.

   Neoadjuvant chemoradiotherapy followed by surgery has become a standard of care for patients with locally advanced resectable esophageal or junctional cancer, especially in western countries. In Asia (especially Japan), nCT is considered as the standard of care for Stage II/III ESCC based on JCOG9204 and JCOG9907 trials. The superiority of nCRT/nCT, in terms of long-term survival, remains to be elucidated. For Stage II/III ESCC patients with multiple stations of lymph nodes involvement, nCT might be more appropriate for the inaccessibility of radiotherapy.

   There are only limited studies on preoperative immune checkpoint inhibitor in combination with chemotherapy followed by surgery for the locally advanced ESCC. Therefore, this study intends to use Nivolumab 360 mg Q3W combined with standard chemotherapy as the neoadjuvant therapy regimen.

2. Sample Size The planned sample size is approximately 81 subjects. The sample size calculations are based on the results of neoadjuvant therapy clinical research in our center (Department of Thoracic Surgery, Zhongshan Hospital Affiliated to Fudan University).

   In the past two years, about 85% of patients can undergo surgery and complete the entire treatment plan, combining with the results of neoadjuvant immunotherapy in lung cancer. As calculated based on an asymptotic method, 81 patients will be 2:1 randomized to Nivolumab/Chemo and Chemo group, with 80% power to detect a 21% difference in the proportion of patients achieving a pCR at a one-sided α of 0.05, assuming a pCR rate of 25% in the Nivolumab/Chemo group and 4% in the Chemo group. Considering a 10% drop rate, 90 patients will be enrolled.

   10-20 more subjects may be added to each group after the evaluation of feasibility and safety as the justification.

3. Research Process 3.1 Screening period 1) Tumor evaluation, including CT/MRI, PET/CT, endoscopy and pathological evaluation should be performed within 14 days before enrollment.

2) The following assessments should be performed within 14 days before enrollment: demographic data, concomitant diseases/treatment, full physical examination (including vital signs, KPS score, height, weight, and physical examination of the nervous system ), laboratory tests (blood routine / biochemical, fecal routine + occult blood, urine routine, coagulation function, tumor markers, thyroid function, hepatitis B and C markers, myocardial enzyme spectrum, T-SPOT, HIV antibodies), electrocardiogram (ECG), echocardiography, and pregnancy tests (for all women with menopause less than 12 months).

3) Pulmonary function tests will be performed on patients suspected or known to have severe respiratory disease or have significant respiratory symptoms unrelated to underlying cancer, including but not limited to spirometry tests and assessment of lung dispersion during the screening period to help determine if it is appropriate to participate in this study.

4) After the completion of all screening items, the researcher must review the results/data, and the subjects can only be enrolled after passing the review.

5) Subjects are required to obtain written informed consent to participate in any specific research steps. (See table below) 3.2 Treatment period Baseline assessment

1. The baseline check is performed within 7 days after signing the informed consent, and treatment must be performed within 7 days after enrollment.
2. Make the following assessments within 1 week before treatment: vital signs (temperature, blood pressure, heart rate), physical examination (including PS score, height, weight, physical examination of each system), blood routine / biochemical examination (including creatinine clearance Calculation), coagulation function, fecal routine and occult blood, urine routine and pregnancy test, tumor markers, thyroid function, hepatitis B and C markers, myocardial enzyme spectrum, T-SPOT, HIV antibodies, ECG, cardiac ultrasound, lung function.
3. When performing routine blood / biochemical examination, take 10ml blood samples for ctDNA, TCR-Seq and other analysis, and if necessary, take tissue samples for further experiments.
4. According to the above schedule, if there are already laboratory tests in the screening period, the auxiliary tests can be used as a baseline within 7 days before the start of neoadjuvant therapy, and there is no need to repeat the tests.
5. Take the chest CT, PET/CT and endoscopy as the baseline for tumor evaluation during the screening period.

After completing all screening activities and baseline assessments, eligible patients identified by the sponsor will be treated with medications, and treatment options will not be allowed to change during the study. After the investigator's first evaluation of disease progression based on RECIST, treatment can be continued if there is evidence of "pseudoprogression" and the consent of the sponsor and the patient's signing of the consent form again.

Safety will be assessed throughout the study by monitoring AE / SAE (toxicity grades are assigned according to the National Cancer Institute's Common Criteria for Adverse Events Terminology [NCI-CTCAE] version 5.0) and laboratory results. Vital signs, physical examination, changes in ECOG score, ECG results, and other tests will also be used for safety assessment.

3.3 Follow-up period after study treatment

1. Follow up at the prescribed time (recommended physical examination, tumor markers, chest CT and PET/CT). If the patient has signs of recurrence (such as related clinical manifestations), additional tumor evaluations are performed during the treatment; possible reoperations and/or further cancer treatments are also documented.
2. During the follow-up period without tumor recurrence, other cytotoxic agents are not allowed.
3. Inspection can be performed within ± 4 weeks of the specified date.
4. Patient recurrence and survival will be followed up to the patient's death, the last date on which the patient is known to survive, or 1 year after the primary effectiveness analysis.

4.Adverse Effect 4.1SERIOUS ADVERSE EVENT COLLECTION AND REPORTING All Serious Adverse Events (SAEs) that occur following the subject's written consent to participate in the study through 100 days of discontinuation of dosing must be reported to BMS Worldwide Safety, whether related or not related to study drug. If applicable, SAEs must be collected that relate to any follow-up protocol-specified procedure (eg, a follow-up skin biopsy).

4.2 NON-SERIOUS ADVERSE EVENT COLLECTION AND REPORTING The collection of non-serious AE information should begin following the subject's written consent to participate in the study. All non serious adverse events (not only those deemed to be treatment-related) should be collected continuously during the treatment period and for a minimum of 100 days following the last dose of study treatment.

Non-serious AEs should be followed to resolution or stabilization, or reported as SAEs if they become serious. Follow-up is also required for non-serious AEs that cause interruption or discontinuation of study drug and for those present at the end of study treatment as appropriate.

Non-serious Adverse Events (AE) are to be provided to BMS in aggregate via interim or final study reports as specified in the agreement or, if a regulatory requirement [eg, IND US trial] as part of an annual reporting requirement.

4.3 LABORATORY TEST ABNORMALITIES All laboratory test results captured as part of the study should be recorded following institutional procedures. Test results that constitute SAEs should be documented and reported to BMS as such.

The following laboratory abnormalities should be documented and reported appropriately:

any laboratory test result that is clinically significant or meets the definition of an SAE any laboratory abnormality that required the participant to have study drug discontinued or interrupted any laboratory abnormality that required the subject to receive specific corrective therapy.

4.4 OTHER SAFETY CONSIDERATIONS Any significant worsening noted during interim or final physical examinations, electrocardiograms, X-rays, and any other potential safety assessments, whether or not these procedures are required by the protocol, should also be recorded as a non-serious or serious AE, as appropriate, and reported accordingly.

5. Statistical analysis of research data 5.1 Statistical software All statistical analysis will be calculated using SPSS 24.0 statistical analysis software programming.

5.2 Descriptive statistics Continuous data: number of cases (number of missing cases), mean, median, standard deviation, P25, P75, minimum and maximum; Categorical data: frequency and the corresponding percentages. For primary safety endpoint, calculate the 95% CI in addition to the percentage.

5.3 Statistic inference All statistical tests are two-sided. P values less than 0.05 will be considered statistically significant. The confidence interval (CI) is 95%.

Statistical analysis for primary endpoint: pCR rates will be calculated as the proportions of the subjects in the analysis population who have a complete response in postoperative pathology.

Statistical analysis for baseline variables and secondary endpoints: the 3-year OS rates in the two treatment arms will be calculated by the Kaplan-Meier method and compared by the log rank test. The Cox proportional hazard model will be used to evaluate the survival-independent factors. Continuous variables were examined by independent sample t-test or Wilcoxon rank-sum test, and categorical variables were compared by Pearson chi-square test, Fisher's exact test or CMH chi-square test as appropriate.

5.4 Analysis of withdraw patients The number of patients who are enrolled, withdrawn, removed, completed, and number of every analysis set will be listed.

6. Research-Related Ethics 6.1 Local regulations / Helsinki Declaration Researchers should ensure that the implementation of this research is in full compliance with the principles of the Helsinki Declaration or the law of the country in the country, regardless of the country's provisions on the protection of human rights. The research must strictly follow the "ICH guideline for Good Clinical Practice" ICH Tripartite Guideline (January 1997), or local law, whichever is more stringent.

6.2 Review by Ethics Committee This protocol, written informed consent, and data directly related to the subject must be submitted to the ethics committee, and formal research can only be conducted after obtaining written approval from the ethics committee. The researcher must submit an annual research report to the Ethics Committee at least annually (if applicable). When the study is suspended and / or completed, the researcher must notify the ethics committee in writing; the researcher must promptly report all changes to the ethics committee (such as amendments to the protocol and / or informed consent) to the ethics committee, and These changes shall not be implemented until approved by the Commission, except for changes made to eliminate obvious and immediate risks to the subject. In such cases, the Ethics Committee will be notified.

6.3 Informed consent The investigator must provide the subject or his or her legal representative with an easy-to-understand, informed consent form approved by the ethics committee, and give the subject or his or her legal representative sufficient time to consider the study. Subjects shall not be enrolled until a signed written informed consent is obtained. During the participant's participation, the subject will be provided with all updated versions of informed consent and written information. The informed consent form should be kept as an important document of the clinical trial for future reference.

7. Drug and specimen management 7.1 Management of trial drugs 7.1.1 Storage Nivolumab injection is clear to opalescent, colorless to pale yellow liquid, and there may be small (rare) particles. Divided into 40mg / 4mL and 100mg / 10mL two specifications. Store and transport at 2 to 8℃ protected from light, do not freeze.

7.1.2 Inventory Nivolumab will be provided by the sponsor. The research center will confirm the receipt of nivolumab through interactive feedback technology (IRT), and confirm the transportation conditions and contents. Any medicines that are damaged or lost during transportation will be replaced. Nivolumab will be processed at the research center in accordance with the standard operating procedures of the research center or returned to the sponsor with appropriate records. The research center's method of destroying the drug must be approved by the sponsor. The research center must obtain written authorization from the sponsor before the drug is destroyed, and the drug destruction must be recorded on the appropriate form. Accurate records of all drugs received, distributed, returned, and disposed of should be recorded in the research center's drug inventory log.

7.2 Specimen management Baseline pathological specimens and blood samples of patients, surgical pathological specimens will be uniformly numbered and properly stored in the pathology laboratory of our hospital.

8. Confidentiality measures The results of research through this project may be published in medical journals, but we will keep patient information confidential as required by law, and patients 'personal information will not be leaked unless required by relevant laws. When necessary, government management departments and hospital ethics committees and their related personnel may consult patient data as required.

Inclusion Criteria:

• Patients enrolled in the study must meet all of the following conditions:

  1. The patient volunteers to participate in the study, signs a consent form, has good compliance, and obeys the follow-up, and is willing and able to follow the protocol during the study.
  2. Male or female, aged ≥18 years and ≤75 years.
  3. The ECOG PS score is 0-1.
  4. Histologically-confirmed squamous cell carcinoma of the esophagus. Tumors of the esophagus are located in the thoracic cavity.
  5. Pre-treatment stage as Stage II-III (cT2N0-1M0, cT3N0-1M0, cT1-3N2M0, AJCC/UICC 8th Edition);
  6. Expected lifetime > 1 year.
  7. Adequate cardiac function. All patients should perform ECG, and those with a cardiac history or ECG abnormality should perform echocardiography with the left ventricular ejection fraction > 50 %.
  8. Adequate respiratory function with FEV1≥1.2L, FEV1%≥50% and DLCO≥50% shown in pulmonary function tests.
  9. Adequate bone marrow function (White Blood Cells >4x10^9 /L; Neutrophil >2.0×10^9 /L; Hemoglobin > 90 g/L; platelets>100x10^9 /L). AST, ALT ≤ 3 x ULN (If liver metastases exist, AST and ALT allow ≤ 5 x ULN).
  10. Adequate liver function (Total bilirubin <1.5x Upper Level of Normal (ULN); Aspartate transaminase (AST) and Alanine transaminase (ALT) <1.5x ULN).
  11. Adequate renal function (Glomerular filtration rate (CCr) >60 ml/min; serum creatinine (SCr) ≤120 μmol/L).
  12. All acute toxic effects of previous anti-cancer treatment or surgery were all relieved by NCI-CTCAE version 5.0 ≤ 1 (except for hair loss or other toxic effects that the investigator judges to have no risk to the patient's safety).
  13. Have the ability to act autonomously, have the ability to swallow pills, and have no gastrointestinal diseases that affect oral drug absorption.
  14. Agree to provide hematology and histology samples.

Exclusion Criteria:

• Patients who meet any of the following conditions will be excluded:

Patients have previously received an anti-PD-1, PD-L1 or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.

Related to cancer:

1. Patients with non-squamous cell carcinoma histology.
2. Patients with advanced inoperable or metastatic esophageal cancer (M1).
3. Patients without qualified Pre-treatment stage.
4. Patients with another previous or current malignant disease.

Others:

1. Any patient with a significant medical condition which is thought unlikely to tolerate the therapies. Such as cardiac disease (e.g. symptomatic coronary artery disease or myocardial infarction within last 12 months), clinically-significant lung disease, clinically-significant bone marrow, liver, renal function disorder.
2. Patients who have autoimmune diseases.
3. Pregnant or lactating women and fertile women who will not be using contraception during the trial.
4. Allergy to any drugs.
5. Patients who have received or are receiving other chemotherapy, radiotherapy or targeted therapy.
6. Patients who recently or currently taking hormones or immunosuppressive agents.
7. Immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV) active infection or known HIV seropositivity; including HBV or HCV surface antigen positive (RNA).