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出境医 / 临床实验 / Metronomic Chemotherapy With Capecitabine for Pancreatic Cancer

Metronomic Chemotherapy With Capecitabine for Pancreatic Cancer

Study Description
Brief Summary:
The latest guidelines recommend Gemcitabine plus Capecitabine as the first choice of adjuvant chemotherapy for pancreatic cancer patients in good physical condition. In order to prolong the survival of patients and improve the cure rate, metronomic chemotherapy with capecitabine is a safe, effective and economical treatment mode after adjuvant chemotherapy. This study is trying to determine that compared with observation group, if capecitabine metronomic medication is a better choice after adjuvant chemotherapy.

Condition or disease Intervention/treatment Phase
Pancreatic Cancer Drug: Capecitabine Phase 2 Phase 3

Detailed Description:
Capecitabine (Xeloda ®) is currently the most biologically active oral fluoropyrimidine drug, and is widely used in adjuvant therapy for pancreatic cancer. It is usually taken twice a day (in the morning and in the evening) for 2 weeks, followed by a 1 week break before repeating the next dosage cycle. In this study, capecitabine will be prescribed as dosage of 500mg/m2, and maintain for a whole year after the standard treatment in stage II/III pancreatic cancer patients. 1 year disease-free survival is set as the primary outcome, OS, RFS, AEs and exploratory biomarkers including effects of metronome chemotherapy on immune cells, such as NK cells, T cells, TAMs, B cells, etc are also observed as the secondary outcomes. Statistical analysis are made to see compared with observation group, whether this metronomic therapy of capecitabine ( 500mg/m2) will bring benefit to pancreatic cancer patients.
Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 231 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Investigator)
Primary Purpose: Treatment
Official Title: A Multi-center, II Phase，Randomized Controlled Clinical Study of Capecitabine Metronomic Chemotherapy After Gemcitabine Plus Capecitabine Standard Adjuvant Therapy for Stage II/III Pancreatic Cancer
Actual Study Start Date : January 5, 2020
Estimated Primary Completion Date : June 30, 2022
Estimated Study Completion Date : June 30, 2023
Arms and Interventions
Arm Intervention/treatment
Experimental: Capecitabine metronomic chemotherapy
Capecitabine 500mg/m2 po qd
 Drug: Capecitabine
Oral fluorouracil
Other Name: Xeloda
No Intervention: Observation
Observation
Outcome Measures
Primary Outcome Measures :
  1. One year disease-free survival [ Time Frame: 1 year ]
    was defined as the rate of disease recurrence, metastasis or death due to disease progression within 1 year after the surgery


Secondary Outcome Measures :
  1. Overall Survival (OS) [ Time Frame: 5 year ]
    was defined as the time from the date of surgery until the date of any death occurred

  2. Recurrence-free Survival (RFS) [ Time Frame: 1 year ]
    was defined as the time from the date of surgery until the date of local recurrence of the tumor

  3. AEs [ Time Frame: 5 year ]
    Hand and foot syndrome and other treatment related AE

  4. Exploratory biomarkers [ Time Frame: 1 yaer ]
    including effects of metronome chemotherapy on immune cells, such as NK cells, T cells, TAMs, B cells, etc


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Histologically confirmed pancreatic invasive ductal adenocarcinoma.
  2. The patient underwent surgery for pancreatic tumor resection, and no gross residual lesions were found postoperatively (R2).
  3. Stage II/III pancreatic cancer was determined according to AJCC/UICC TNM stage eighth.
  4. At least 6 cycles of gemcitabine plus capecitabine chemotherapy have been completed.
  5. Age 18-70 years old, gender not limited.
  6. ECOG performance score is 0 or 1.
  7. Without dysphagia, able to tolerate oral administration.
  8. No relevant clinical or imaging evidence of recurrence or metastasis showing within the 28 days before random.
  9. Chemotherapy with capecitabine combined with gemcitabine regimen was given within 12 weeks after surgery, and last chemotherapy to random time ≤ 6 weeks.
  10. Adequate bone marrow, liver, and kidney function in measurements taken within 7 days before registration ：

  11. Hemoglobin ≥ 90 g/L, Platelet count ≥ 100×109/L, Absolute granulocyte count ≥ 1.5×109/L.

    i. Note: patients should not receive blood transfusion or growth factor support within 14 days before collection of blood samples.

  12. Serum creatinine≤ 1.5 ULN, and calculated creatinine clearance of ≥ 60 mL/min/1.73m2.
  13. AST and ALT ≤ 2.5 X ULN, serum total bilirubin ≤ 1.5 X ULN (Patients with Gilbert syndrome with total bilirubin≤ 3 X ULN can be enrolled).
  14. INR or PT ≤ 1.5×ULN，unless the patient is receiving anticoagulant therapy and the PT value is within the expected therapeutic range of the anticoagulant.
  15. Electrocardiogram and cardiac function were not contraindicated in chemotherapy.
  16. Women should have a negative pregnancy test, and all the patients have no planning within 3 years and should take contraceptive measures during treatment.
  17. Informed consent form signed.

Exclusion Criteria:

  1. Other pathological types of pancreatic malignancies (e.g. neuroendocrine carcinoma, large cell carcinoma, signet ring cell carcinoma, etc.).
  2. With distant metastasis or malignant pleural effusion.
  3. Pregnant and breast-feeding women.
  4. Unable to oral medication.
  5. Previous or concurrent malignancies, excluding curatively treated in situ carcinoma of the cervix or non-melanoma skin cancer, unless at least 5 years have elapsed since last treatment and the patient is considered cured.
  6. A history of transient ischemic attack, cerebrovascular accident, thrombosis, or thromboembolism (pulmonary embolism or deep venous thrombosis) within 180 days before randomization.
  7. Any of the following uncontrolled or severe cardiovascular disease history:
  8. Myocardial infarction occurred 180 days before randomization.
  9. Uncontrolled angina occurred within 180 days before randomization.
  10. Heart failure of class III or IV (according to New York Heart Association functional classification).
  11. Uncontrolled hypertension after appropriate treatment (e.g. Systolic blood pressure ≥150mmHg or diastolic blood pressure ≥90mmHg for 24h or longer).
  12. Arrhythmias that require treatment, including pacemakers.
  13. Serious drug allergy.
  14. Uncontrolled diabetes or systemic infection.
  15. Known dihydro pyrimidine dehydrogenase (DPD) deficiency.
  16. Any other reasons the investigator considers the patient should not participate in the study.
  17. Without personal freedom and independent civil capacity.
  18. Already enrolled into other clinical trials.
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Jun Zhang, MD & Ph. D +86-13818332497 junzhang10977@sjtu.edu.cn
Contact: Jinling Jiang, MD & MS +86-21-13816423993 jiangjinling2000@163.com

Locations
Layout table for location information
China
Department of Oncology, Ruijin Hospital Recruiting
Shanghai, China, 200025
Contact: Jun Zhang, MD & Ph. D    +86-13818332497    junzhang10977@sjtu.edu.cn   
Contact: Jinling Jiang, MD & MS    +86-21-13816423993    jiangjinling2000@163.com   
Principal Investigator: Jun Zhang, MD & Ph. D         
Sponsors and Collaborators
Ruijin Hospital
Investigators
Layout table for investigator information
Principal Investigator: Jun Zhang, MD & Ph. D Ruijin Hospital
Tracking Information
First Submitted Date  ICMJE May 18, 2019
First Posted Date  ICMJE May 22, 2019
Last Update Posted Date April 30, 2021
Actual Study Start Date  ICMJE January 5, 2020
Estimated Primary Completion Date June 30, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 21, 2019) 		One year disease-free survival [ Time Frame: 1 year ]
was defined as the rate of disease recurrence, metastasis or death due to disease progression within 1 year after the surgery
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 21, 2019)
  • Overall Survival (OS) [ Time Frame: 5 year ]
    was defined as the time from the date of surgery until the date of any death occurred
  • Recurrence-free Survival (RFS) [ Time Frame: 1 year ]
    was defined as the time from the date of surgery until the date of local recurrence of the tumor
  • AEs [ Time Frame: 5 year ]
    Hand and foot syndrome and other treatment related AE
  • Exploratory biomarkers [ Time Frame: 1 yaer ]
    including effects of metronome chemotherapy on immune cells, such as NK cells, T cells, TAMs, B cells, etc
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Metronomic Chemotherapy With Capecitabine for Pancreatic Cancer
Official Title  ICMJE A Multi-center, II Phase，Randomized Controlled Clinical Study of Capecitabine Metronomic Chemotherapy After Gemcitabine Plus Capecitabine Standard Adjuvant Therapy for Stage II/III Pancreatic Cancer
Brief Summary The latest guidelines recommend Gemcitabine plus Capecitabine as the first choice of adjuvant chemotherapy for pancreatic cancer patients in good physical condition. In order to prolong the survival of patients and improve the cure rate, metronomic chemotherapy with capecitabine is a safe, effective and economical treatment mode after adjuvant chemotherapy. This study is trying to determine that compared with observation group, if capecitabine metronomic medication is a better choice after adjuvant chemotherapy.
Detailed Description Capecitabine (Xeloda ®) is currently the most biologically active oral fluoropyrimidine drug, and is widely used in adjuvant therapy for pancreatic cancer. It is usually taken twice a day (in the morning and in the evening) for 2 weeks, followed by a 1 week break before repeating the next dosage cycle. In this study, capecitabine will be prescribed as dosage of 500mg/m2, and maintain for a whole year after the standard treatment in stage II/III pancreatic cancer patients. 1 year disease-free survival is set as the primary outcome, OS, RFS, AEs and exploratory biomarkers including effects of metronome chemotherapy on immune cells, such as NK cells, T cells, TAMs, B cells, etc are also observed as the secondary outcomes. Statistical analysis are made to see compared with observation group, whether this metronomic therapy of capecitabine ( 500mg/m2) will bring benefit to pancreatic cancer patients.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Investigator)
Primary Purpose: Treatment
Condition  ICMJE Pancreatic Cancer
Intervention  ICMJE Drug: Capecitabine
Oral fluorouracil
Other Name: Xeloda
Study Arms  ICMJE
  • Experimental: Capecitabine metronomic chemotherapy
    Capecitabine 500mg/m2 po qd
    Intervention: Drug: Capecitabine
  • No Intervention: Observation
    Observation
Publications *
  • Siravegna G, Bardelli A. Blood circulating tumor DNA for non-invasive genotyping of colon cancer patients. Mol Oncol. 2016 Mar;10(3):475-80. doi: 10.1016/j.molonc.2015.12.005. Epub 2015 Dec 17. Review.
  • Witkowski ER, Smith JK, Tseng JF. Outcomes following resection of pancreatic cancer. J Surg Oncol. 2013 Jan;107(1):97-103. doi: 10.1002/jso.23267. Epub 2012 Sep 18. Review.
  • Ansari D, Gustafsson A, Andersson R. Update on the management of pancreatic cancer: surgery is not enough. World J Gastroenterol. 2015 Mar 21;21(11):3157-65. doi: 10.3748/wjg.v21.i11.3157. Review.
  • Liao WC, Chien KL, Lin YL, Wu MS, Lin JT, Wang HP, Tu YK. Adjuvant treatments for resected pancreatic adenocarcinoma: a systematic review and network meta-analysis. Lancet Oncol. 2013 Oct;14(11):1095-1103. doi: 10.1016/S1470-2045(13)70388-7. Epub 2013 Sep 12. Review.
  • Ferrone CR, Pieretti-Vanmarcke R, Bloom JP, Zheng H, Szymonifka J, Wargo JA, Thayer SP, Lauwers GY, Deshpande V, Mino-Kenudson M, Fernández-del Castillo C, Lillemoe KD, Warshaw AL. Pancreatic ductal adenocarcinoma: long-term survival does not equal cure. Surgery. 2012 Sep;152(3 Suppl 1):S43-9. doi: 10.1016/j.surg.2012.05.020. Epub 2012 Jul 3.
  • Narang AK, Miller RC, Hsu CC, Bhatia S, Pawlik TM, Laheru D, Hruban RH, Zhou J, Winter JM, Haddock MG, Donohue JH, Schulick RD, Wolfgang CL, Cameron JL, Herman JM. Evaluation of adjuvant chemoradiation therapy for ampullary adenocarcinoma: the Johns Hopkins Hospital-Mayo Clinic collaborative study. Radiat Oncol. 2011 Sep 28;6:126. doi: 10.1186/1748-717X-6-126.
  • Kalser MH, Ellenberg SS. Pancreatic cancer. Adjuvant combined radiation and chemotherapy following curative resection. Arch Surg. 1985 Aug;120(8):899-903. Erratum in: Arch Surg 1986 Sep;121(9):1045.
  • Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997 Jun;15(6):2403-13.
  • Javle M, Hsueh CT. Updates in Gastrointestinal Oncology - insights from the 2008 44th annual meeting of the American Society of Clinical Oncology. J Hematol Oncol. 2009 Feb 23;2:9. doi: 10.1186/1756-8722-2-9.
  • Oettle H, Neuhaus P, Hochhaus A, Hartmann JT, Gellert K, Ridwelski K, Niedergethmann M, Zülke C, Fahlke J, Arning MB, Sinn M, Hinke A, Riess H. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA. 2013 Oct 9;310(14):1473-81. doi: 10.1001/jama.2013.279201.
  • Uesaka K, Boku N, Fukutomi A, Okamura Y, Konishi M, Matsumoto I, Kaneoka Y, Shimizu Y, Nakamori S, Sakamoto H, Morinaga S, Kainuma O, Imai K, Sata N, Hishinuma S, Ojima H, Yamaguchi R, Hirano S, Sudo T, Ohashi Y; JASPAC 01 Study Group. Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: a phase 3, open-label, randomised, non-inferiority trial (JASPAC 01). Lancet. 2016 Jul 16;388(10041):248-57. doi: 10.1016/S0140-6736(16)30583-9. Epub 2016 Jun 2.
  • Neoptolemos JP, Moore MJ, Cox TF, Valle JW, Palmer DH, McDonald AC, Carter R, Tebbutt NC, Dervenis C, Smith D, Glimelius B, Charnley RM, Lacaine F, Scarfe AG, Middleton MR, Anthoney A, Ghaneh P, Halloran CM, Lerch MM, Oláh A, Rawcliffe CL, Verbeke CS, Campbell F, Büchler MW; European Study Group for Pancreatic Cancer. Effect of adjuvant chemotherapy with fluorouracil plus folinic acid or gemcitabine vs observation on survival in patients with resected periampullary adenocarcinoma: the ESPAC-3 periampullary cancer randomized trial. JAMA. 2012 Jul 11;308(2):147-56. doi: 10.1001/jama.2012.7352. Erratum in: JAMA. 2012 Nov 14;308(18):1861.
  • Neoptolemos JP, Palmer DH, Ghaneh P, Psarelli EE, Valle JW, Halloran CM, Faluyi O, O'Reilly DA, Cunningham D, Wadsley J, Darby S, Meyer T, Gillmore R, Anthoney A, Lind P, Glimelius B, Falk S, Izbicki JR, Middleton GW, Cummins S, Ross PJ, Wasan H, McDonald A, Crosby T, Ma YT, Patel K, Sherriff D, Soomal R, Borg D, Sothi S, Hammel P, Hackert T, Jackson R, Büchler MW; European Study Group for Pancreatic Cancer. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet. 2017 Mar 11;389(10073):1011-1024. doi: 10.1016/S0140-6736(16)32409-6. Epub 2017 Jan 25.
  • Khorana AA, Mangu PB, Berlin J, Engebretson A, Hong TS, Maitra A, Mohile SG, Mumber M, Schulick R, Shapiro M, Urba S, Zeh HJ, Katz MHG. Potentially Curable Pancreatic Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. 2017 Jul 10;35(20):2324-2328. doi: 10.1200/JCO.2017.72.4948. Epub 2017 Apr 11.

*   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: May 21, 2019) 		231
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 30, 2023
Estimated Primary Completion Date June 30, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Histologically confirmed pancreatic invasive ductal adenocarcinoma.
  2. The patient underwent surgery for pancreatic tumor resection, and no gross residual lesions were found postoperatively (R2).
  3. Stage II/III pancreatic cancer was determined according to AJCC/UICC TNM stage eighth.
  4. At least 6 cycles of gemcitabine plus capecitabine chemotherapy have been completed.
  5. Age 18-70 years old, gender not limited.
  6. ECOG performance score is 0 or 1.
  7. Without dysphagia, able to tolerate oral administration.
  8. No relevant clinical or imaging evidence of recurrence or metastasis showing within the 28 days before random.
  9. Chemotherapy with capecitabine combined with gemcitabine regimen was given within 12 weeks after surgery, and last chemotherapy to random time ≤ 6 weeks.
  10. Adequate bone marrow, liver, and kidney function in measurements taken within 7 days before registration ：

  11. Hemoglobin ≥ 90 g/L, Platelet count ≥ 100×109/L, Absolute granulocyte count ≥ 1.5×109/L.

    i. Note: patients should not receive blood transfusion or growth factor support within 14 days before collection of blood samples.

  12. Serum creatinine≤ 1.5 ULN, and calculated creatinine clearance of ≥ 60 mL/min/1.73m2.
  13. AST and ALT ≤ 2.5 X ULN, serum total bilirubin ≤ 1.5 X ULN (Patients with Gilbert syndrome with total bilirubin≤ 3 X ULN can be enrolled).
  14. INR or PT ≤ 1.5×ULN，unless the patient is receiving anticoagulant therapy and the PT value is within the expected therapeutic range of the anticoagulant.
  15. Electrocardiogram and cardiac function were not contraindicated in chemotherapy.
  16. Women should have a negative pregnancy test, and all the patients have no planning within 3 years and should take contraceptive measures during treatment.
  17. Informed consent form signed.

Exclusion Criteria:

  1. Other pathological types of pancreatic malignancies (e.g. neuroendocrine carcinoma, large cell carcinoma, signet ring cell carcinoma, etc.).
  2. With distant metastasis or malignant pleural effusion.
  3. Pregnant and breast-feeding women.
  4. Unable to oral medication.
  5. Previous or concurrent malignancies, excluding curatively treated in situ carcinoma of the cervix or non-melanoma skin cancer, unless at least 5 years have elapsed since last treatment and the patient is considered cured.
  6. A history of transient ischemic attack, cerebrovascular accident, thrombosis, or thromboembolism (pulmonary embolism or deep venous thrombosis) within 180 days before randomization.
  7. Any of the following uncontrolled or severe cardiovascular disease history:
  8. Myocardial infarction occurred 180 days before randomization.
  9. Uncontrolled angina occurred within 180 days before randomization.
  10. Heart failure of class III or IV (according to New York Heart Association functional classification).
  11. Uncontrolled hypertension after appropriate treatment (e.g. Systolic blood pressure ≥150mmHg or diastolic blood pressure ≥90mmHg for 24h or longer).
  12. Arrhythmias that require treatment, including pacemakers.
  13. Serious drug allergy.
  14. Uncontrolled diabetes or systemic infection.
  15. Known dihydro pyrimidine dehydrogenase (DPD) deficiency.
  16. Any other reasons the investigator considers the patient should not participate in the study.
  17. Without personal freedom and independent civil capacity.
  18. Already enrolled into other clinical trials.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Jun Zhang, MD & Ph. D +86-13818332497 junzhang10977@sjtu.edu.cn
Contact: Jinling Jiang, MD & MS +86-21-13816423993 jiangjinling2000@163.com
Listed Location Countries  ICMJE China
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03959150
Other Study ID Numbers  ICMJE Metro-PC
Has Data Monitoring Committee Yes
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
Plan to Share IPD: No
Responsible Party Jun Zhang, Ruijin Hospital
Study Sponsor  ICMJE Ruijin Hospital
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Jun Zhang, MD & Ph. D Ruijin Hospital
PRS Account Ruijin Hospital
Verification Date April 2021

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

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