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Adjuvant Pembrolizumab for Patients With Locally Advanced Esophageal Squamous Cell Carcinoma at High Risk of Recurrence

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ClinicalTrials.gov Identifier: NCT03322267
Recruitment Status : Recruiting
First Posted : October 26, 2017
Last Update Posted : November 6, 2018
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
National Taiwan University Hospital

Tracking Information
First Submitted Date  ICMJE October 16, 2017
First Posted Date  ICMJE October 26, 2017
Last Update Posted Date November 6, 2018
Actual Study Start Date  ICMJE October 27, 2018
Estimated Primary Completion Date January 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 24, 2017)
1-year relapse-free survival (RFS) rate. [ Time Frame: 1 year ]
Recurrence-free survival is the time from enrollment to disease recurrence or the last follow-up (censored). Recurrence will be detected by regular image study (computed scan and esophagoscopy) every 3 months during the 1st to 3rd years then every 6 months during 4th and 5th years after esophagectomy. Response Evaluation Criteria in Solid Tumors 1.1 will be used for assessment.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03322267 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: October 24, 2017)
  • The median RFS [ Time Frame: 3 years ]
    Recurrence-free survival is the time from enrollment to disease recurrence or the last follow-up (censored). Recurrence will be detected by regular image study (computed scan and esophagoscopy) every 3 months during the 1st to 3rd years then every 6 months during 4th and 5th years after esophagectomy. Response Evaluation Criteria in Solid Tumors 1.1 will be used for assessment.
  • The median overall survival (OS) [ Time Frame: 5 years ]
    OS is the time from enrollment to death of any cause or the last follow-up (censored).
  • The 3-year RFS rate [ Time Frame: 3 years ]
    Recurrence-free survival is the time from enrollment to disease recurrence or the last follow-up (censored). Recurrence will be detected by regular image study (computed scan and esophagoscopy) every 3 months during the 1st to 3rd years then every 6 months during 4th and 5th years after esophagectomy. Response Evaluation Criteria in Solid Tumors 1.1 will be used for assessment.
  • The 3-year OS rate. [ Time Frame: 3 years ]
    OS is the time from enrollment to death of any cause or the last follow-up (censored).
  • Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) [ Time Frame: 3 years ]
    Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: October 24, 2017)
  • Tissue-based biomarkers [ Time Frame: 3 years ]
    To explore the tumor tissue-based biomarkers associated with tumor recurrence.
  • Blood-based biomarkers [ Time Frame: 3 years ]
    To explore the blood-based biomarkers associated with tumor recurrence.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Adjuvant Pembrolizumab for Patients With Locally Advanced Esophageal Squamous Cell Carcinoma at High Risk of Recurrence
Official Title  ICMJE A Single-arm Phase II Study of Chemoradiotherapy Plus Pembrolizumab as Adjuvant Therapy for Locally Advanced Esophageal Squamous Cell Carcinoma Patients at High Risk of Recurrence Following Preoperative Chemoradiotherapy Plus Surgery
Brief Summary In this study, participants with histologically diagnosed locally advanced esophageal squamous cell carcinoma who have received preoperative cisplatin-based chemoradiotherapy followed by surgery harbouring high risk of tumor recurrence will receive adjuvant cisplatin-based chemoradiotherapy followed by pembrolizumab. The primary study hypothesis is that adjuvant pembrolizumab will improve the 1-year recurrence-free survival rate compared to historical control.
Detailed Description It is a single-arm phase II trial. The target population is patients with histologically diagnosed locally advanced ESCC patients (clinically staged at least T3 and/or any N and M0 by endoscopic ultrasonography [EUS] and fludeoxyglucose-positron emission tomography [FDG-PET]) who have received preoperative cisplatin-based chemoradiotherapy (CRT) followed by surgery, and exhibit high risk (closed or involved resection margin or extranodal invasion of involved lymph nodes) of tumor recurrence. Eligible patients will receive adjuvant cisplatin-based CRT followed by pembrolizumab for 18 cycles.The study will enroll 46 patients in Taiwan. The estimated enrollment period is 2 years.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Intervention Model Description:
Adjuvant cisplatin-chemoradiotherapy followed by pembrolizumab
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Esophageal Squamous Cell Carcinoma
Intervention  ICMJE Drug: Pembrolizumab
Cisplatin (30 mg/m2, QW, 2 cycles) and radiotherapy (18 Gy/10 fractions) as adjuvant chemoradiotherapy, followed by pembrolizumab (200mg, Q3W, 18 cycles)
Study Arms  ICMJE Experimental: Pembrolizumab
Adjuvant cisplatin-chemoradiotherapy followed by pembrolizumab
Intervention: Drug: Pembrolizumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: October 24, 2017)
46
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 2025
Estimated Primary Completion Date January 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Be willing and able to provide written informed consent/assent for the trial.
  2. Be ≥ 20 years of age on day of signing informed consent.
  3. Be a diagnosed by pathology or cytology with a locally advanced ESCC, which is clinically stage according to the TNM system of the American Joint Committee on Cancer (AJCC) Cancer Staging System (7th edition), fulfilling one of the following criteria as determined by endoscopic ultrasound, computed tomography, bronchoscopy and positron emission tomography:

    1. T3, N0, M0;
    2. T4a, N0, M0;
    3. T1-4a, N1-3, M0.
  4. Have been treated with preoperative cisplatin-based CRT followed by esophagectomy with lymph node dissection for the locally advanced ESCC (defined by above criteria).
  5. Have a performance status of 0 or 1 on the ECOG Performance Scale.
  6. Exhibit at least one risk factor of tumor recurrence in the post-CRT surgical tissues:

    1. Close (≤1mm) or involved margin;
    2. Residual tumor cells in lymph nodes with extranodal invasion.
  7. Adequate hemogram and organ function:

    1. Absolute neutrophil count ≥1,500 /mcL; platelets ≥100,000 / mcL; hemoglobin ≥9 g/dL without transfusion or EPO dependency (within 7 days of assessment)
    2. Serum creatinine ≤1.5 X upper limit of normal or measured or calculated creatinine clearance ≥60 mL/min; serum total bilirubin ≤ 1.5 X ULN; AST and ALT ≤ 2.5 X ULN; albumin >2.5 mg/dL; international normalized ratio or prothrombin time and activated partial thromboplastin time ≤1.5 X ULN unless subject is receiving anticoagulant therapy
  8. Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
  9. Female subjects of childbearing potential must be willing to use an adequate method of contraception. Contraception, for the course of the study through 120 days after the last dose of study medication.
  10. Male subjects of childbearing potential must agree to use an adequate method of contraception. Contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy.

Exclusion Criteria:

  1. Is diagnosed with adenocarcinoma of esophagus or gastroesophageal junction.
  2. Has synchronously diagnosed with a squamous cell carcinoma of aero-digestive way, other than esophageal cancer.
  3. Has prior malignancy, except for: (a) adequately treated basal cell or squamous cell skin cancer; (b) in-situ cervical cancer; (c) previously diagnosed malignancy which have been adequately treated and shown no evidence of recurrence for more than 5 years.
  4. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
  5. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
  6. Has a known history of active TB (Bacillus Tuberculosis)
  7. Hypersensitivity to pembrolizumab or any of its excipients.
  8. Has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent. Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study. If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
  9. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
  10. Has known history of, or any evidence of active, non-infectious pneumonitis.
  11. Has an active infection requiring systemic therapy.
  12. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
  13. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  14. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
  15. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
  16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
  17. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., anti-HCV reactive or HCV RNA [qualitative] is detected).
  18. Has received a live vaccine within 30 days of planned start of study therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.
  19. Has received organ transplantation.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 20 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Chih-Hung Hsu, MD, PhD +886-2-23123456 ext 67680 chihhunghsu@ntu.edu.tw
Listed Location Countries  ICMJE Taiwan
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03322267
Other Study ID Numbers  ICMJE 201708042MIPD
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party National Taiwan University Hospital
Study Sponsor  ICMJE National Taiwan University Hospital
Collaborators  ICMJE Merck Sharp & Dohme Corp.
Investigators  ICMJE
Principal Investigator: Chih-Hung Hsu, MD, PhD National Taiwan University Hospital
PRS Account National Taiwan University Hospital
Verification Date October 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP