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出境医 / 临床实验 / SOX-based CRT for Esophageal Cancer.

SOX-based CRT for Esophageal Cancer.

Study Description
Brief Summary:

Patients with esophageal cancer that had locally advanced diseases or with unresectable diseases are being asked to participate in this phase I/II study.

This phase I/II study is being conducted to determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), and efficacy of IMRT combined with S-1 and Oxaliplatin (SOX) based chemotherapy for unresectable locally advanced esophageal cancer.


Condition or disease Intervention/treatment Phase
Esophageal Cancer Drug: Oxaliplatin Drug: S-1 capsule Radiation: Intensity modulated radiotherapy (IMRT) Phase 1 Phase 2

Detailed Description:

Esophageal carcinoma (EC) remains difficult to cure with overall 5-year survival rates for locally advanced stages being poor. Definitive concurrent chemoradiotherapy (dCRT) remains the mainstay of treatment for locally advanced and unresectable EC. Oxaliplatin is a new generation platinum with a more preferable toxicity profile compared to cisplatin. Furthermore, S-1 combines 5-Fu prodrug (tegafur) and two modulators of 5-Fu metabolism, gimeracil (CDHP) and oteracil. Basic studies showed that S-1 has superior anti-cancer effects than 5-Fu and enhances the sensitivity of cancer cells to the effects of radiotherapy. Herein, we designed a prospective phase I/II study, which is combined S-1 and oxaliplatin with IMRT for the patients with locally advanced and unresectable esophageal cancer, and evaluated the tolerability and efficacy of this combination.

<Phase I>

Primary Objective:

To establish the safety of combination chemotherapy comprising oxaliplatin (escalating doses: 110, 120, 130 mg/m2, day 1 and day 29), fixed dose of S-1 (80 mg/m2, day1-14 and day 29-42) and IMRT (5040cGy/28fx/5W+) in unresectable locally advanced esophageal cancer.

Secondary Objective:

To observe the efficacy of this regimen in these patients.

<Phase II>

Primary Objective:

To assess the response rate of combination chemotherapy comprising oxaliplatin (recommended dose determined in phase I study, day1 and day29), fixed dose of S-1 (80 mg/m2, day1-14 and day 29-42), and IMRT (5040cGy/28fx/5W+) in unresectable locally advanced esophageal cancer.

Secondary Objectives:

To determine the adverse reactions of this regimen in these patients. To determine PFS(Progression free survival) of patients treated with this regimen.

To determine OS (overall survival) of patients treated with this regimen. To explore the Health-related Quality of life using EORTC QLQ-C30 and EORTC QLQ-OES18 in these patients.

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 45 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Study of S-1 and Oxaliplatin Based Definitive Concurrent Chemoradiotherapy (SOX-CRT-01) for Unresectable Locally Advanced Esophageal Cancer.
Actual Study Start Date : May 1, 2019
Estimated Primary Completion Date : December 31, 2021
Estimated Study Completion Date : December 31, 2023
Arms and Interventions
Arm Intervention/treatment
Experimental: SOX-based Chemoradiotherapy
IMRT is delivered with a daily fraction of 1.8 Gy to a total dose of 50.4 Gy over 5 weeks. Concurrent Oxaliplatin (3 levels for phase I: 110mg/m², 120 mg/m² and 130 mg/m², d1) and fixed dose of S-1 (80mg/ m², d1-14) are administered concurrently with IMRT, every 4 weeks. The recommended dose of Oxaliplatin are then further evaluated in the Phase II setting.
Drug: Oxaliplatin
Oxaliplatin (3 levels for phase I: 110 mg/m², 120 mg/m² and 130 mg/m²) is administered as a 2 h intravenous infusion in 500 mL of 5% glucose on day 1 and day 29 during the treatment course.

Drug: S-1 capsule
Patients received a fixed dose of S-1 with a dose of 80 mg/m2/d twice daily for 2 weeks, every 4 weeks.

Radiation: Intensity modulated radiotherapy (IMRT)
The total radiation dose was set to 50.4 Gy, which was given in 28 fractions of 1.8 Gy once-daily fractions for over 5 weeks.

Outcome Measures
Primary Outcome Measures :
  1. Incidence of Treatment-Emergent Adverse Events [ Time Frame: 1 month ]
    Phase I: toxicities will be assessed based on the common toxicity criteria for adverse events version 4.0 (CTCAE v4.0).

  2. Response rate [ Time Frame: 1 month ]
    Phase II: Response rate will be done after 4 weeks following the last radiotherapy session as evaluated by RECIST 1.1.


Secondary Outcome Measures :
  1. Recommended dose of Oxaliplatin for phase II trial. [ Time Frame: 1 month ]
    To determine the recommended phase II dose (RD) of Oxaliplatin with fixed dose of S-1 in combination with IMRT for esophageal cancer (Phase I).

  2. Number of Participants with Adverse Events (Phase II). [ Time Frame: 6 months ]
    Both the number of subjects with adverse events and the degree of the adverse events of each participant according to NCI CTCAE version 4.0 will be recorded. And the outcome of each adverse event will be followed.

  3. Overall survival time [ Time Frame: 0-2 years ]
    Overall survival (OS) is determined as the time (in months) between the first day of therapy and the last follow-up or the date of death.

  4. Progression-free survival time [ Time Frame: 0-2 years ]
    Progression-free survival (PFS) is calculated from the date of CRT initiation to the date of documented failure (local recurrence or metastasis occurrence) or the date of the last follow-up for those remaining.


Other Outcome Measures:
  1. Health-related Quality of life (HR-QoL, Phase II) [ Time Frame: 0-2 years ]
    In phase II trial, HR-QoL would be measured by standardized EORTC questionaires (EORTC QLQ-C30).

  2. Health-related Quality of life (HR-QoL, Phase II) [ Time Frame: 0-2 years ]
    In phase II trial, HR-QoL would be measured by standardized EORTC questionaires (EORTC QLQ-OES18).


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Cytopathological confirmed esophageal cancer with unresectable locally advanced diseases;
  2. Age of 18-70;
  3. ECOG performance status: 0-1;
  4. No treatments prior to enrollment;
  5. Patients must have measurable or evaluable disease with at least one tumor mass maximum diameter ≥10mm by multi-slice spiral CT or MR scan. Imaging exam must be performed within 15 days from enrollment.
  6. Normal marrow function and the blood tests must be collected within 7 days from enrollment with a hemoglobin of ≥90g/L, an white blood cell (WBC) counts of ≥4.0×109/L,a neutrophil count of ≥2.0×109/L, , a platelet count of ≥100×109/L, a total bilirubin (TBil) of ≤1.0 upper normal limitation (UNL), a creatinine (Cr) of ≤ 1.0 UNL, alanine aminotransferase (ALAT) and aspartate aminotransferase (ASAT) of ≤2.5 UNL, Alkaline phosphatase (AKP) ≤5.0 UNL. Pulmonary function (FEV1 >1L), and no major electrocardiogram abnormalities.
  7. Normal electrocardiogram results and no history of congestive heart failure;
  8. Patients must be with good compliance and agree to accept follow-up of disease progression and adverse events;
  9. Informed consent signed.

Exclusion Criteria:

  1. Prior treatments of chemotherapy or irradiation;
  2. Poor bone marrow, liver and kidney functions, which would make chemotherapy intolerable;
  3. Contraindication for irradiation: complete obstruction of esophagus, deep esophageal ulcer, fistula to mediastinum, or haematemesis;
  4. Participating in other clinical trials;
  5. Pregnancy, breast feeding, or not adopting birth control;
  6. Clinically significant and uncontrolled major medical conditions including but not limited to: active uncontrolled infection, symptomatic congestive heart failure, Unstable angina pectoris or cardiac arrhythmia, psychiatric illness/ social situation that would limit compliance with study requirements; any medical condition, which in the opinion of the study investigator places the subject at an unacceptably high risk for toxicities;
  7. Weight loss of 20% or more of normal body weight within 3 months.
  8. The subject has had another active malignancy within the past five years except for cervical cancer in site, in situ carcinoma of the bladder or non-melanoma carcinoma of the skin;
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Xiaodong Liang, MD +86-571-87666666 lxdctopone@sina.com
Contact: Tao Song, MD +86-571-87666666 songtao@hmc.edu.cn

Locations
Layout table for location information
China, Zhejiang
Zhejiang Provincial People's Hospital Recruiting
Hangzhou, Zhejiang, China, 310000
Contact: Yongshi Jia, MD    +86-571-87666666    jiayongshi@hmc.edu.cn   
Sponsors and Collaborators
Zhejiang Provincial People's Hospital
Tracking Information
First Submitted Date  ICMJE June 15, 2019
First Posted Date  ICMJE June 19, 2019
Last Update Posted Date June 19, 2019
Actual Study Start Date  ICMJE May 1, 2019
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 18, 2019)
  • Incidence of Treatment-Emergent Adverse Events [ Time Frame: 1 month ]
    Phase I: toxicities will be assessed based on the common toxicity criteria for adverse events version 4.0 (CTCAE v4.0).
  • Response rate [ Time Frame: 1 month ]
    Phase II: Response rate will be done after 4 weeks following the last radiotherapy session as evaluated by RECIST 1.1.
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: June 18, 2019)
  • Recommended dose of Oxaliplatin for phase II trial. [ Time Frame: 1 month ]
    To determine the recommended phase II dose (RD) of Oxaliplatin with fixed dose of S-1 in combination with IMRT for esophageal cancer (Phase I).
  • Number of Participants with Adverse Events (Phase II). [ Time Frame: 6 months ]
    Both the number of subjects with adverse events and the degree of the adverse events of each participant according to NCI CTCAE version 4.0 will be recorded. And the outcome of each adverse event will be followed.
  • Overall survival time [ Time Frame: 0-2 years ]
    Overall survival (OS) is determined as the time (in months) between the first day of therapy and the last follow-up or the date of death.
  • Progression-free survival time [ Time Frame: 0-2 years ]
    Progression-free survival (PFS) is calculated from the date of CRT initiation to the date of documented failure (local recurrence or metastasis occurrence) or the date of the last follow-up for those remaining.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: June 18, 2019)
  • Health-related Quality of life (HR-QoL, Phase II) [ Time Frame: 0-2 years ]
    In phase II trial, HR-QoL would be measured by standardized EORTC questionaires (EORTC QLQ-C30).
  • Health-related Quality of life (HR-QoL, Phase II) [ Time Frame: 0-2 years ]
    In phase II trial, HR-QoL would be measured by standardized EORTC questionaires (EORTC QLQ-OES18).
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE SOX-based CRT for Esophageal Cancer.
Official Title  ICMJE A Phase I/II Study of S-1 and Oxaliplatin Based Definitive Concurrent Chemoradiotherapy (SOX-CRT-01) for Unresectable Locally Advanced Esophageal Cancer.
Brief Summary

Patients with esophageal cancer that had locally advanced diseases or with unresectable diseases are being asked to participate in this phase I/II study.

This phase I/II study is being conducted to determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), and efficacy of IMRT combined with S-1 and Oxaliplatin (SOX) based chemotherapy for unresectable locally advanced esophageal cancer.

Detailed Description

Esophageal carcinoma (EC) remains difficult to cure with overall 5-year survival rates for locally advanced stages being poor. Definitive concurrent chemoradiotherapy (dCRT) remains the mainstay of treatment for locally advanced and unresectable EC. Oxaliplatin is a new generation platinum with a more preferable toxicity profile compared to cisplatin. Furthermore, S-1 combines 5-Fu prodrug (tegafur) and two modulators of 5-Fu metabolism, gimeracil (CDHP) and oteracil. Basic studies showed that S-1 has superior anti-cancer effects than 5-Fu and enhances the sensitivity of cancer cells to the effects of radiotherapy. Herein, we designed a prospective phase I/II study, which is combined S-1 and oxaliplatin with IMRT for the patients with locally advanced and unresectable esophageal cancer, and evaluated the tolerability and efficacy of this combination.

<Phase I>

Primary Objective:

To establish the safety of combination chemotherapy comprising oxaliplatin (escalating doses: 110, 120, 130 mg/m2, day 1 and day 29), fixed dose of S-1 (80 mg/m2, day1-14 and day 29-42) and IMRT (5040cGy/28fx/5W+) in unresectable locally advanced esophageal cancer.

Secondary Objective:

To observe the efficacy of this regimen in these patients.

<Phase II>

Primary Objective:

To assess the response rate of combination chemotherapy comprising oxaliplatin (recommended dose determined in phase I study, day1 and day29), fixed dose of S-1 (80 mg/m2, day1-14 and day 29-42), and IMRT (5040cGy/28fx/5W+) in unresectable locally advanced esophageal cancer.

Secondary Objectives:

To determine the adverse reactions of this regimen in these patients. To determine PFS(Progression free survival) of patients treated with this regimen.

To determine OS (overall survival) of patients treated with this regimen. To explore the Health-related Quality of life using EORTC QLQ-C30 and EORTC QLQ-OES18 in these patients.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Esophageal Cancer
Intervention  ICMJE
  • Drug: Oxaliplatin
    Oxaliplatin (3 levels for phase I: 110 mg/m², 120 mg/m² and 130 mg/m²) is administered as a 2 h intravenous infusion in 500 mL of 5% glucose on day 1 and day 29 during the treatment course.
  • Drug: S-1 capsule
    Patients received a fixed dose of S-1 with a dose of 80 mg/m2/d twice daily for 2 weeks, every 4 weeks.
  • Radiation: Intensity modulated radiotherapy (IMRT)
    The total radiation dose was set to 50.4 Gy, which was given in 28 fractions of 1.8 Gy once-daily fractions for over 5 weeks.
Study Arms  ICMJE Experimental: SOX-based Chemoradiotherapy
IMRT is delivered with a daily fraction of 1.8 Gy to a total dose of 50.4 Gy over 5 weeks. Concurrent Oxaliplatin (3 levels for phase I: 110mg/m², 120 mg/m² and 130 mg/m², d1) and fixed dose of S-1 (80mg/ m², d1-14) are administered concurrently with IMRT, every 4 weeks. The recommended dose of Oxaliplatin are then further evaluated in the Phase II setting.
Interventions:
  • Drug: Oxaliplatin
  • Drug: S-1 capsule
  • Radiation: Intensity modulated radiotherapy (IMRT)
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: June 18, 2019)
45
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 31, 2023
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Cytopathological confirmed esophageal cancer with unresectable locally advanced diseases;
  2. Age of 18-70;
  3. ECOG performance status: 0-1;
  4. No treatments prior to enrollment;
  5. Patients must have measurable or evaluable disease with at least one tumor mass maximum diameter ≥10mm by multi-slice spiral CT or MR scan. Imaging exam must be performed within 15 days from enrollment.
  6. Normal marrow function and the blood tests must be collected within 7 days from enrollment with a hemoglobin of ≥90g/L, an white blood cell (WBC) counts of ≥4.0×109/L,a neutrophil count of ≥2.0×109/L, , a platelet count of ≥100×109/L, a total bilirubin (TBil) of ≤1.0 upper normal limitation (UNL), a creatinine (Cr) of ≤ 1.0 UNL, alanine aminotransferase (ALAT) and aspartate aminotransferase (ASAT) of ≤2.5 UNL, Alkaline phosphatase (AKP) ≤5.0 UNL. Pulmonary function (FEV1 >1L), and no major electrocardiogram abnormalities.
  7. Normal electrocardiogram results and no history of congestive heart failure;
  8. Patients must be with good compliance and agree to accept follow-up of disease progression and adverse events;
  9. Informed consent signed.

Exclusion Criteria:

  1. Prior treatments of chemotherapy or irradiation;
  2. Poor bone marrow, liver and kidney functions, which would make chemotherapy intolerable;
  3. Contraindication for irradiation: complete obstruction of esophagus, deep esophageal ulcer, fistula to mediastinum, or haematemesis;
  4. Participating in other clinical trials;
  5. Pregnancy, breast feeding, or not adopting birth control;
  6. Clinically significant and uncontrolled major medical conditions including but not limited to: active uncontrolled infection, symptomatic congestive heart failure, Unstable angina pectoris or cardiac arrhythmia, psychiatric illness/ social situation that would limit compliance with study requirements; any medical condition, which in the opinion of the study investigator places the subject at an unacceptably high risk for toxicities;
  7. Weight loss of 20% or more of normal body weight within 3 months.
  8. The subject has had another active malignancy within the past five years except for cervical cancer in site, in situ carcinoma of the bladder or non-melanoma carcinoma of the skin;
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Xiaodong Liang, MD +86-571-87666666 lxdctopone@sina.com
Contact: Tao Song, MD +86-571-87666666 songtao@hmc.edu.cn
Listed Location Countries  ICMJE China
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03991104
Other Study ID Numbers  ICMJE Zhejiang Provincal PH006
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Yongshi Jia, Zhejiang Provincial People's Hospital
Study Sponsor  ICMJE Zhejiang Provincial People's Hospital
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Zhejiang Provincial People's Hospital
Verification Date June 2019

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

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