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出境医 / 临床实验 / Combined Therapy Using Oxaliplatin and Gemcitabine Chemotherapy, Lenvatinib and PD1 Antibody (JS001) for Patients With Advanced and Unresectable Intrahepatic Cholangiocarcinoma

Combined Therapy Using Oxaliplatin and Gemcitabine Chemotherapy, Lenvatinib and PD1 Antibody (JS001) for Patients With Advanced and Unresectable Intrahepatic Cholangiocarcinoma

Study Description
Brief Summary:
In this phase 2 study, the investigators aim to evaluate the effects and safety of combined therapy using oxaliplatin and gemcitabine chemotherapy, Lenvatinib and immune checkpoint inhibitor PD-1 antibody (JS001) for patients with advanced and unresectable intrahepatic cholangiocarcinoma

Condition or disease Intervention/treatment Phase
Cholangiocarcinoma, Intrahepatic Drug: combined therapy using oxaliplatin and gemcitabine chemotherapy, Lenvatinib and PD1 antibody (JS001) Phase 2

Detailed Description:
Most intrahepatic cholangiocarcinoma (ICC) patients are often accompanied by local or distant metastases and lose the opportunity for surgical resection. For patients with unresectable ICC who have been in stages IIIb and IV (AJCC/UICC, V2, 2018), the survival time is less than 4 months, and there is currently no standard treatment. The Gemox chemotherapy (oxaliplatin + gemcitabine) has been used in the treatment of advanced intrahepatic cholangiocarcinoma, but the efficacy is still unsatisfactory. Lenvatinib is a small molecule multi-kinase inhibitor, the main targets including VEGFR1-3, fibroblast growth factor receptor 1-4, PDGFRα, RET(ret proto-oncogene ), KIT(KIT proto-oncogene, receptor tyrosine kinase), have anti-angiogenic effects, have been proven effective in hepatocellular carcinoma. In recent years, monoclonal antibodies against programmed cell death protein 1 (PD1) have shown remarkable therapeutic effects in the treatment of various solid tumors. Combined with other means such as chemotherapy and targeted drugs is an important direction to improve the therapeutic effect of immunological checkpoint inhibitors. In this study, the investigators aim to evaluate the effects and safety of Gemox chemotherapy combined with Lenvatinib and immune checkpoint inhibitor PD-1 antibody (JS001) for patients with advanced and unresectable intrahepatic cholangiocarcinoma.
Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: a Single-arm Study of Combined Therapy Using Oxaliplatin and Gemcitabine Chemotherapy, Lenvatinib and Programmed Cell Death Protein 1 Antibody (JS001) for Patients With Advanced and Unresectable Intrahepatic Cholangiocarcinoma
Actual Study Start Date : May 10, 2019
Actual Primary Completion Date : January 10, 2020
Estimated Study Completion Date : November 10, 2020
Arms and Interventions
Arm Intervention/treatment
Experimental: Combined therapy using Gemox, Lenvatinib and PD1
  1. Gemox chemotherapy Day1 oxaliplatin 85mg/m2+ gemcitabine 1g/m2, Day8 gemcitabine 1g/m2 Three weeks is a course of treatment with a total of 6 courses.
  2. Lenvatinib (8mg/d), continuous use for 1 year.
  3. PD-1 antibody (JS001) (240mg every 3 weeks), continuous use for 1 year.
 Drug: combined therapy using oxaliplatin and gemcitabine chemotherapy, Lenvatinib and PD1 antibody (JS001)
  1. Gemox chemotherapy Day1 oxaliplatin 85mg/m2+ gemcitabine 1g/m2, Day8 gemcitabine 1g/m2 Three weeks is a course of treatment with a total of 6 courses.
  2. Lenvatinib (8mg/d), continuous use for 1 year.
  3. PD-1 antibody (JS001) (240mg every 3 weeks), continuous use for 1 year.
Outcome Measures
Primary Outcome Measures :
  1. Objective response rate [ Time Frame: 12 months ]
    Objective response rate of advanced and unresectable intrahepatic cholangiocarcinoma in combination therapy


Secondary Outcome Measures :
  1. safety: the potential side effects [ Time Frame: 12 months ]
    the potential side effects

  2. overall survival [ Time Frame: 12 months ]
    From the beginning date of combined therapy to the date of death

  3. Progression free survival [ Time Frame: 12 months ]
    From the beginning date of combined therapy to the date of disease progression


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. The patient must be required to sign an informed consent form;
  2. age 18-75 years old, male or female;
  3. Eastern Cooperative Oncology Group (ECOG) fitness status score (PS score) 0;
  4. Child-Pugh score A;
  5. Histopathologically confirmed intrahepatic cholangiocarcinoma; consent to provide previously stored tumor tissue specimens or fresh biopsy tumor lesions;
  6. unresectable ICC patients;
  7. Functional indicators of vital organs meet the following requirements a Neutrophils ≥1.5*109/L; platelets≥100*109/L; hemoglobin≥9g/dl; serum albumin≥3g/dl; b Thyroid stimulating hormone (TSH) ≤ 1 times the upper limit of normal value(ULN), T3, T4 are in the normal range; c bilirubin ≤ 1.5 times ULN; Alanine aminotransferase （ALT） and Aspartate aminotransferase （AST） ≤ 1.5 times ULN; d serum creatinine ≤ 1.5 ULN, creatinine clearance rate ≥ 60ml / min;
  8. The subject has at least 1 measurable liver lesion or non-liver lesion (according to RECIST 1.1);
  9. Non-lactating or pregnant women, contraception during or after 3 months of treatment.

Exclusion Criteria:

  1. pathological diagnosis of hepatocellular carcinoma, mixed liver cancer and other non-cholangiocarcinoma malignant tumor components;
  2. patients who have received previous treatment with PD1 antibody, programmed death ligand -1 （PDL1） antibody or cytotoxic T lymphocyte-associated antigen-4 （CTLA4） antibody;
  3. with other malignant tumors, except for fully treated non-melanoma skin cancer, cervical carcinoma in situ, and papillary thyroid carcinoma;
  4. active tuberculosis infection. Patients with active tuberculosis infection within 1 year prior to enrollment; had a history of active tuberculosis infection more than 1 year before enrollment, did not receive formal anti-tuberculosis treatment or tuberculosis is still active;
  5. Have an active, known or suspected autoimmune disease. Subjects who require only hormone replacement therapy for hypothyroidism and skin diseases that do not require systemic therapy may be enrolled;
  6. previous interstitial lung disease, or (non-infectious) pneumonia and need oral or intravenous steroid therapy;
  7. Long-term systemic hormones (dose equivalent to >10 mg prednisone/day) or any other form of immunosuppressive therapy are required. Subjects using inhaled or topical corticosteroids may be enrolled;
  8. severe cardiopulmonary and renal dysfunction;
  9. suffering from high blood pressure, and can not be well controlled by antihypertensive drugs (systolic blood pressure ≥140mmHg or diastolic blood pressure ≥90mmHg);
  10. abnormal blood coagulation (PT>14s), with bleeding tendency or receiving thrombolytic or anticoagulant therapy;
  11. hepatitis B virus （HBV） DNA>2000 copies/ml, hepatitis C virus （HCV） RNA>1000;
  12. Significant clinically significant bleeding symptoms or a clear tendency to appear within 3 months prior to enrollment;
  13. active infections requiring systemic treatment;
  14. Human immunodeficiency virus (HIV) positive;
  15. History of psychotropic substance abuse, alcohol abuse or drug abuse;
  16. has a history of allergy to platinum;
  17. Other factors that may influence the safety of the subject or the compliance of the test by the investigator. Serious illnesses (including mental illness), severe laboratory tests, or other family or social factors that require combined treatment.
Contacts and Locations

Locations
Layout table for location information
China, Shanghai
Zhongshan Hospital
Shanghai, Shanghai, China, 200032
Sponsors and Collaborators
Shanghai Zhongshan Hospital
Investigators
Layout table for investigator information
Principal Investigator: Jian Zhou, MD&PhD Fudan University
Tracking Information
First Submitted Date  ICMJE May 14, 2019
First Posted Date  ICMJE May 15, 2019
Last Update Posted Date April 24, 2020
Actual Study Start Date  ICMJE May 10, 2019
Actual Primary Completion Date January 10, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 14, 2019) 		Objective response rate [ Time Frame: 12 months ]
Objective response rate of advanced and unresectable intrahepatic cholangiocarcinoma in combination therapy
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 14, 2019)
  • safety: the potential side effects [ Time Frame: 12 months ]
    the potential side effects
  • overall survival [ Time Frame: 12 months ]
    From the beginning date of combined therapy to the date of death
  • Progression free survival [ Time Frame: 12 months ]
    From the beginning date of combined therapy to the date of disease progression
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 Combined Therapy Using Oxaliplatin and Gemcitabine Chemotherapy, Lenvatinib and PD1 Antibody (JS001) for Patients With Advanced and Unresectable Intrahepatic Cholangiocarcinoma
Official Title  ICMJE a Single-arm Study of Combined Therapy Using Oxaliplatin and Gemcitabine Chemotherapy, Lenvatinib and Programmed Cell Death Protein 1 Antibody (JS001) for Patients With Advanced and Unresectable Intrahepatic Cholangiocarcinoma
Brief Summary In this phase 2 study, the investigators aim to evaluate the effects and safety of combined therapy using oxaliplatin and gemcitabine chemotherapy, Lenvatinib and immune checkpoint inhibitor PD-1 antibody (JS001) for patients with advanced and unresectable intrahepatic cholangiocarcinoma
Detailed Description Most intrahepatic cholangiocarcinoma (ICC) patients are often accompanied by local or distant metastases and lose the opportunity for surgical resection. For patients with unresectable ICC who have been in stages IIIb and IV (AJCC/UICC, V2, 2018), the survival time is less than 4 months, and there is currently no standard treatment. The Gemox chemotherapy (oxaliplatin + gemcitabine) has been used in the treatment of advanced intrahepatic cholangiocarcinoma, but the efficacy is still unsatisfactory. Lenvatinib is a small molecule multi-kinase inhibitor, the main targets including VEGFR1-3, fibroblast growth factor receptor 1-4, PDGFRα, RET(ret proto-oncogene ), KIT(KIT proto-oncogene, receptor tyrosine kinase), have anti-angiogenic effects, have been proven effective in hepatocellular carcinoma. In recent years, monoclonal antibodies against programmed cell death protein 1 (PD1) have shown remarkable therapeutic effects in the treatment of various solid tumors. Combined with other means such as chemotherapy and targeted drugs is an important direction to improve the therapeutic effect of immunological checkpoint inhibitors. In this study, the investigators aim to evaluate the effects and safety of Gemox chemotherapy combined with Lenvatinib and immune checkpoint inhibitor PD-1 antibody (JS001) for patients with advanced and unresectable intrahepatic cholangiocarcinoma.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Cholangiocarcinoma, Intrahepatic
Intervention  ICMJE Drug: combined therapy using oxaliplatin and gemcitabine chemotherapy, Lenvatinib and PD1 antibody (JS001)
  1. Gemox chemotherapy Day1 oxaliplatin 85mg/m2+ gemcitabine 1g/m2, Day8 gemcitabine 1g/m2 Three weeks is a course of treatment with a total of 6 courses.
  2. Lenvatinib (8mg/d), continuous use for 1 year.
  3. PD-1 antibody (JS001) (240mg every 3 weeks), continuous use for 1 year.
Study Arms  ICMJE Experimental: Combined therapy using Gemox, Lenvatinib and PD1
  1. Gemox chemotherapy Day1 oxaliplatin 85mg/m2+ gemcitabine 1g/m2, Day8 gemcitabine 1g/m2 Three weeks is a course of treatment with a total of 6 courses.
  2. Lenvatinib (8mg/d), continuous use for 1 year.
  3. PD-1 antibody (JS001) (240mg every 3 weeks), continuous use for 1 year.
Intervention: Drug: combined therapy using oxaliplatin and gemcitabine chemotherapy, Lenvatinib and PD1 antibody (JS001)
Publications *
  • André T, Tournigand C, Rosmorduc O, Provent S, Maindrault-Goebel F, Avenin D, Selle F, Paye F, Hannoun L, Houry S, Gayet B, Lotz JP, de Gramont A, Louvet C; GERCOR Group. Gemcitabine combined with oxaliplatin (GEMOX) in advanced biliary tract adenocarcinoma: a GERCOR study. Ann Oncol. 2004 Sep;15(9):1339-43.
  • Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, Baron A, Park JW, Han G, Jassem J, Blanc JF, Vogel A, Komov D, Evans TRJ, Lopez C, Dutcus C, Guo M, Saito K, Kraljevic S, Tamai T, Ren M, Cheng AL. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018 Mar 24;391(10126):1163-1173. doi: 10.1016/S0140-6736(18)30207-1.
  • El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, Kim TY, Choo SP, Trojan J, Welling TH Rd, Meyer T, Kang YK, Yeo W, Chopra A, Anderson J, Dela Cruz C, Lang L, Neely J, Tang H, Dastani HB, Melero I. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017 Jun 24;389(10088):2492-2502. doi: 10.1016/S0140-6736(17)31046-2. Epub 2017 Apr 20.

*   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 Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: May 14, 2019) 		30
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE November 10, 2020
Actual Primary Completion Date January 10, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. The patient must be required to sign an informed consent form;
  2. age 18-75 years old, male or female;
  3. Eastern Cooperative Oncology Group (ECOG) fitness status score (PS score) 0;
  4. Child-Pugh score A;
  5. Histopathologically confirmed intrahepatic cholangiocarcinoma; consent to provide previously stored tumor tissue specimens or fresh biopsy tumor lesions;
  6. unresectable ICC patients;
  7. Functional indicators of vital organs meet the following requirements a Neutrophils ≥1.5*109/L; platelets≥100*109/L; hemoglobin≥9g/dl; serum albumin≥3g/dl; b Thyroid stimulating hormone (TSH) ≤ 1 times the upper limit of normal value(ULN), T3, T4 are in the normal range; c bilirubin ≤ 1.5 times ULN; Alanine aminotransferase （ALT） and Aspartate aminotransferase （AST） ≤ 1.5 times ULN; d serum creatinine ≤ 1.5 ULN, creatinine clearance rate ≥ 60ml / min;
  8. The subject has at least 1 measurable liver lesion or non-liver lesion (according to RECIST 1.1);
  9. Non-lactating or pregnant women, contraception during or after 3 months of treatment.

Exclusion Criteria:

  1. pathological diagnosis of hepatocellular carcinoma, mixed liver cancer and other non-cholangiocarcinoma malignant tumor components;
  2. patients who have received previous treatment with PD1 antibody, programmed death ligand -1 （PDL1） antibody or cytotoxic T lymphocyte-associated antigen-4 （CTLA4） antibody;
  3. with other malignant tumors, except for fully treated non-melanoma skin cancer, cervical carcinoma in situ, and papillary thyroid carcinoma;
  4. active tuberculosis infection. Patients with active tuberculosis infection within 1 year prior to enrollment; had a history of active tuberculosis infection more than 1 year before enrollment, did not receive formal anti-tuberculosis treatment or tuberculosis is still active;
  5. Have an active, known or suspected autoimmune disease. Subjects who require only hormone replacement therapy for hypothyroidism and skin diseases that do not require systemic therapy may be enrolled;
  6. previous interstitial lung disease, or (non-infectious) pneumonia and need oral or intravenous steroid therapy;
  7. Long-term systemic hormones (dose equivalent to >10 mg prednisone/day) or any other form of immunosuppressive therapy are required. Subjects using inhaled or topical corticosteroids may be enrolled;
  8. severe cardiopulmonary and renal dysfunction;
  9. suffering from high blood pressure, and can not be well controlled by antihypertensive drugs (systolic blood pressure ≥140mmHg or diastolic blood pressure ≥90mmHg);
  10. abnormal blood coagulation (PT>14s), with bleeding tendency or receiving thrombolytic or anticoagulant therapy;
  11. hepatitis B virus （HBV） DNA>2000 copies/ml, hepatitis C virus （HCV） RNA>1000;
  12. Significant clinically significant bleeding symptoms or a clear tendency to appear within 3 months prior to enrollment;
  13. active infections requiring systemic treatment;
  14. Human immunodeficiency virus (HIV) positive;
  15. History of psychotropic substance abuse, alcohol abuse or drug abuse;
  16. has a history of allergy to platinum;
  17. Other factors that may influence the safety of the subject or the compliance of the test by the investigator. Serious illnesses (including mental illness), severe laboratory tests, or other family or social factors that require combined treatment.
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 information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE China
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03951597
Other Study ID Numbers  ICMJE zs-ICC-2019
Has Data Monitoring Committee No
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 Shanghai Zhongshan Hospital
Study Sponsor  ICMJE Shanghai Zhongshan Hospital
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Jian Zhou, MD&PhD Fudan University
PRS Account Shanghai Zhongshan Hospital
Verification Date December 2019

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

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