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出境医 / 临床实验 / Axitinib Plus Toripalimab as Second-line Treatment in Hepatobiliary Malignant Tumors

Axitinib Plus Toripalimab as Second-line Treatment in Hepatobiliary Malignant Tumors

Study Description
Brief Summary:
The investigators design a phase II clinical study to explore the efficacy and safety of axitinib plus toripalimab as a second-line treatment in patients with hepatobiliary malignant tumors and to analyze potential biomarkers of therapeutic response.

Condition or disease Intervention/treatment Phase
Hepatobiliary Neoplasm Liver Neoplasm Biliary Tract Neoplasms Drug: axitinib plus toripalimab Phase 2

Detailed Description:

This phase II trial is a single-arm, non-randomized and single-center clinical study.

It is estimated that 60 patients who met the study criteria will be enrolled in PUMCH and treated with axitinib plus toripalimab. The investigators will follow up and collect subjects' data each month to evaluate the efficacy and safety of treatment, including overall survival and time to progression, until disease progression or death. Histopathology and multi-omics data analysis will be used to explore potential biomarkers of treatment response.

Study Type: Interventional. Masking: Open Label.

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: Patients were confirmed with advanced hepatobiliary malignancies by imaging and histological examination and meet with the inclusive criteria, including hepatocellular carcinoma, cholangiocarcinoma, ampullary carcinoma, gallbladder carcinoma, and mixed cancer).
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Axitinib Plus Toripalimab as Second-line Treatment in Hepatobiliary Malignant Tumors: a Single-arm, Non-randomized, Single-center Phase II Trial
Actual Study Start Date : May 1, 2020
Estimated Primary Completion Date : January 1, 2021
Estimated Study Completion Date : June 30, 2021
Arms and Interventions
Arm Intervention/treatment
Experimental: axitinib plus toripalimab

Axitinib (Inlyta, Pfizer Inc.) is a novel oral angiogenesis inhibitor that selectively targets vascular endothelial growth factor (VEGFR) 1, 2 and 3.

Toripalimab (Shanghai Junshi Biosciences Co., Ltd.) is a recombinant anti-human PD-1 IgG4 monoclonal antibody.

 Drug: axitinib plus toripalimab

Axitinib 5mg, twice a day, orally, 4 weeks a cycle. Dose reduction from 5mg twice a day to 3mg twice a day should be considered according to adverse events.

Toripalimab 240mg, every 3 weeks, intravenous infused, 6 weeks a cycle. Number of cycle: until disease progression or unacceptable toxicity events.
Outcome Measures
Primary Outcome Measures :
  1. objective response rate (ORR) [ Time Frame: one year ]
    Proportion of patients whose tumor volume has reached a predetermined value and can maintain a minimum time limit, including complete response and partial response patients.

  2. Progression-free Survival (PFS) [ Time Frame: six months ]
    A duration from the date of initial treatment with axitinib plus toripalimab to disease progression (defined by RECIST 1.1) or death of any cause.


Secondary Outcome Measures :
  1. Disease Control Rate (DCR) [ Time Frame: one year ]
    Proportion of patients whose tumor volume control (reduced or enlarged) reaches a predetermined value and can maintain a minimum time limit.

  2. Overall Survival (OS) [ Time Frame: two years ]
    Duration from the date of initial treatment with axitinib plus toripalimab to the date of death due to any cause.

  3. Duration of Response (DOR) [ Time Frame: one year ]
    Duration from the first time reported partial response or complete response to the first time of disease progression or death.

  4. Stable Disease (SD) [ Time Frame: one year ]
    Proportion of patients with stable disease status more than 4 months.

  5. Progression free survival rate [ Time Frame: six months ]
    Portion of patients who do not experience disease progression (defined by RECIST 1.1) or death of any cause after treated with axitinib plus toripalimab for 3 months and 6 months, respectively.

  6. Rate of 6-months and 1-year overall survival [ Time Frame: one year ]
    Portion of patients who die of any cause after treated with axitinib plus toripalimab for 6 months and 12 months, respectively.


Other Outcome Measures:
  1. Any adverse events related with treatment with axitinib plus toripalimab. [ Time Frame: one year ]
    Safety and tolerability of the treatment

  2. PD-L1 expression [ Time Frame: six months ]
    PD-L1 expression in tumor tissues.

  3. Tumor mutation burden [ Time Frame: six months ]
    Tumor mutation burden assessed by whole exome sequencing.


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria: Subjects must meet all of the following criteria

  • Subjects volunteer to participate in the study and agree to sign the informed consent with good compliance and follow-up.
  • Subjects are 18 years old or older when signing the informed consent and gender is not limited.
  • Subjects were diagnosed with advanced hepatobiliary malignant tumors (clinical stage IV) by imaging and histological examination, including hepatocellular carcinoma, cholangiocarcinoma, ampullary carcinoma, gallbladder carcinoma and mixed carcinoma.
  • The disease is not suitable for radical surgery and/or topical treatment, or disease progression occurs after surgery and/or local treatment.
  • At least one measurable lesion (according to RECIST version 1.1): the measurable lesion has a long diameter ≥ 10 mm or lymphadenopathy has a short diameter ≥ 15 mm in spiral CT scan.
  • Patients fail after at least one systemic failure, including surgery, intervention, radiotherapy, chemotherapy and targeted therapy and require palliative treatment.

Definition of treatment failure: Disease progression during treatment or relapse after treatment, such as after at least once radical or palliative resection surgery, revenue recurrence or progression after intervention therapy or radiotherapy. Intervention therapy or oxaliplatin treatment must be more than 1 cycle, and molecular targeted therapy must more than ≥14 days.

Definition of intolerance: Grade ≥IV hematologic toxicity, or grade ≥III non- hematologic toxicity, or grade ≥ II damage of heart, liver and kidney during treatment.

  • The ECOG score is 0-1 within 1 week before enrollment.
  • Liver function assessment: Child-Pugh Grade A or mild Grade B (score ≤ 7), BCLC stage B-C.
  • More than 2 weeks from first-line system treatment failure to sign informed consent for this study, and adverse events returned to normal (NCI-CTCAE ≤ I).
  • Estimated survival time ≥ 6 months.
  • HBV DNA <2000 IU/ml (10^4 copies/ml).
  • Hematology and organ function are sufficient based on the following laboratory results within 14 days prior to the treatment of this study:

Whole blood cell examination (no blood transfusion within 14 days, no G-CSF use and no drugs use): Hb≥100g/L, ANC≥1.5×10*9/L, PLT≥75×10*9/L.

Biochemical examination (no ALB infused within 14 days): ALB≥35g/L, ALT and AST<3×ULN, TBIL≤2×ULN, creatinine≤1.5×ULN, PT≤ULN+4S, INR≤2.2 (note: only one of albumin and bilirubin is permitted Child-Pugh score 2).

  • There are no active autoimmune diseases that require systemic therapy in the past 2 years (note: active state means requiring disease modulators, corticosteroids or immunosuppressive drugs use). Alternative therapies, such as thyroxine, insulin or a physiological corticosteroid replacement therapy are not considered as systemic therapy.
  • Women with fertility agree to abstinence during the treatment period and at least 6 months after the last dose (avoiding heterosexual intercourse) or using a contraceptive method with an annual contraceptive failure rate <1%.

If a female patient has menstruation and not reached the postmenopausal state (continuously no menstruation ≥ 12 months and no other causes), and has not undergone sterilization by removing the ovaries and/or uterus), then the patient has fertility.

Contraceptive methods with a contraceptive failure rate <1% include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices and copper intrauterine devices.

The reliability of sexual desire should be evaluated relative to the duration of the clinical trial and lifestyle of patient. Periodic abstinence (eg. calendar days, ovulation, symptomatic body temperature or post-ovulation methods) and in vitro ejaculation are unacceptable methods of contraception.

  • Male patients agree to abstinence (no heterosexual intercourse) or use of contraceptive measures and no sperm donation, as defined below:

When a female partner has fertility, male patients must abstinence from sex during treatment and at least 6 months after the last dose of treatment, or use condoms and other contraceptive methods with contraceptive failure rate <1%. At the same time, male patients must also agree not to donate sperm.

When a female partner is pregnant, the male patient must abstinence or using a condom during the treatment period and at least 6 months after the last dose of treatment to prevent the fetus from being affected by the study.

The reliability of sexual desire should be evaluated relative to the duration of the clinical trial and lifestyle of patient. Periodic abstinence (eg. calendar days, ovulation, symptomatic body temperature or post-ovulation methods) and in vitro ejaculation are unacceptable methods of contraception.

  • Tumor tissue must be available for biomarker analysis prior to the first dose of treatment, If not available, participants can consult the investigator for enrollment agreement. (Note: If an unstained section is submitted, the new section should be submitted to the laboratory within 14 days.)

Exclusion Criteria: Subjects with one or more than one of the following criteria should be excluded

  • Clinical stage I-III, and/or with any of the following: Suitable for radical surgery; Or, without an assessment lesion after radical surgery; Or, never receive any first line treatment; Or, liver transplantation history or ready for liver transplantation.
  • Already known to be allergic to recombinant humanized PD-1 monoclonal antibody drugs and components; known to be allergic to axitinib and components.
  • ECOG score ≥ 2 points.
  • Received any topical treatment within 4 weeks prior to the study, including but not limited to surgery, radiotherapy, hepatic artery embolization, TACE, hepatic artery perfusion, radiofrequency ablation, cryoablation or percutaneous ethanol injection.
  • Received any systemic anti-tumor treatment within 3 months prior to participation in the study, including but not limited to intravenous infused and/or oral chemotherapy, targeted drugs, antibody drugs, and traditional Chinese medicines known to have anticancer effects.
  • Ascites with clinical symptoms which requires abdominal puncture or drainage therapy, or Child-Pugh score >2 points.
  • With serious systemic diseases such as heart disease and cerebrovascular disease, and the condition is unstable or uncontrollable.
  • Already known active central nervous system metastasis and/or cancerous meningitis. Subjects with stable brain metastases after previous treatment may participate as long as no radiologic evidence of progression lasts for at least four weeks prior to this trial and any neurological symptoms have returned to baseline, and no new or enlarged metastatic evidence in brain and no steroids use for at least 7 days prior to trial treatment. Cancer meningitis should be excluded regardless of clinical stability.
  • Surgery was performed within 4 weeks prior to the trial and patients must be evaluated after wound healing.
  • Hepatic and renal dysfunction evidence: jaundice, ascites, and/or bilirubin ≥ 2 × ULN, and/or alkaline phosphatase ≥ 3 × ULN, and/or ≥ 3 grade (CTC-AE 5.0) proteinuria (> 3.5g /24 hours), or renal failure requiring blood dialysis or peritoneal dialysis.
  • Urine examination shows urinary protein ≥ ++ or 24 hours urine protein >1.0g.
  • Persistent >2 grade (CTC-AE5.0) infection.
  • History of allogeneic tissue transplantation or solid organ transplantation.
  • History of active tuberculosis, such as mycobacterium tuberculosis.
  • Intolerant of any drug (or any excipient) in this trial.
  • Female patients who are pregnant, breastfeeding or refuse contraception.
  • Known or untreated brain metastases, or patients with epilepsy who need medication treatment.
  • Patients with bone metastases received palliative radiotherapy (radiation area > 5% bone marrow area) within 4 weeks prior to this study, or there were wounds, ulcers or fractures that could not be healed, or patients have organ transplantation history.
  • Gastrointestinal bleeding history in the past 6 months or tendency to gastrointestinal bleeding, such as esophageal varices, local active ulceration lesions, fecal occult blood ≥ (++) (gastroscopy is required when fecal occult blood is (+)).
  • Evidence or history of ≥3 grade (CTC-AE5.0) bleeding events.
  • History of human immunodeficiency virus infection.
  • History of hepatitis B virus or hepatitis C virus infection, and not receive regular treatment.
  • Severe non-healing wounds, ulcers or fractures.
  • Prior treatment with either axitinib or any kind of anti-PD-1, anti-PD-L1 or anti-PD-L2 drugs.
  • Diagnosis of immunodeficiency or systemic steroid therapy or any form of immunosuppressants therapy within 7 days prior to this study. A physiological dose of corticosteroids (no more than 7.5 mg/d prednisone or equivalent) can be approved after clinical evaluation.
  • There exists drug abuse, or any medical, psychological or social condition which might affect the study, the compliance or even the safety of patients.
  • Variable factors which significantly affect drug use and absorption, such as inability to swallow, chronic diarrhea and intestinal obstruction.
  • Any >1 grade (CTC-AE5.0) unresolved toxicity due to previous treatment or operation, except for hair loss, anemia, and hypothyroidism.
  • Vaccination of any live virus vaccine within 30 days prior to this study, except for seasonal flu vaccines without live virus.
  • Previous and current evidence of pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonitis, drug-associated pneumonia and severe impairment of lung function.
  • Received a potent CYP3A4 inhibitor treatment within 7 days prior to the study, or received a potent CYP3A4 inducer within 12 days prior to the study.
  • Patients participate in another clinical study at the same time.
  • Patients are unsuitable for participation in this research after comprehensive assessment by the researchers.
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Jianzhen Lin, MD +86 18800158133 jzlin816@126.com
Contact: Haitao Haitao, Prof

Locations
Layout table for location information
China, Beijing
Peking Union Medical College Hospital Recruiting
Beijing, Beijing, China, 100730
Contact: Jianzhen Lin, MD    +86-18800158133    drlinjz@163.com   
Contact: Xiao-Bo Yang, MD    +86-138-1167-5126    yangxiaobo67@pumch.cn   
Principal Investigator: Hai-Tao Zhao, MD         
Sponsors and Collaborators
Peking Union Medical College Hospital
Shanghai Junshi Bioscience Co., Ltd.
Investigators
Layout table for investigator information
Study Chair: Haitao Haitao, Prof Peking Union Medical College Hospital (PUMCH)
Tracking Information
First Submitted Date  ICMJE July 2, 2019
First Posted Date  ICMJE July 8, 2019
Last Update Posted Date November 24, 2020
Actual Study Start Date  ICMJE May 1, 2020
Estimated Primary Completion Date January 1, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 5, 2019)
  • objective response rate (ORR) [ Time Frame: one year ]
    Proportion of patients whose tumor volume has reached a predetermined value and can maintain a minimum time limit, including complete response and partial response patients.
  • Progression-free Survival (PFS) [ Time Frame: six months ]
    A duration from the date of initial treatment with axitinib plus toripalimab to disease progression (defined by RECIST 1.1) or death of any cause.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 5, 2019)
  • Disease Control Rate (DCR) [ Time Frame: one year ]
    Proportion of patients whose tumor volume control (reduced or enlarged) reaches a predetermined value and can maintain a minimum time limit.
  • Overall Survival (OS) [ Time Frame: two years ]
    Duration from the date of initial treatment with axitinib plus toripalimab to the date of death due to any cause.
  • Duration of Response (DOR) [ Time Frame: one year ]
    Duration from the first time reported partial response or complete response to the first time of disease progression or death.
  • Stable Disease (SD) [ Time Frame: one year ]
    Proportion of patients with stable disease status more than 4 months.
  • Progression free survival rate [ Time Frame: six months ]
    Portion of patients who do not experience disease progression (defined by RECIST 1.1) or death of any cause after treated with axitinib plus toripalimab for 3 months and 6 months, respectively.
  • Rate of 6-months and 1-year overall survival [ Time Frame: one year ]
    Portion of patients who die of any cause after treated with axitinib plus toripalimab for 6 months and 12 months, respectively.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: July 5, 2019)
  • Any adverse events related with treatment with axitinib plus toripalimab. [ Time Frame: one year ]
    Safety and tolerability of the treatment
  • PD-L1 expression [ Time Frame: six months ]
    PD-L1 expression in tumor tissues.
  • Tumor mutation burden [ Time Frame: six months ]
    Tumor mutation burden assessed by whole exome sequencing.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Axitinib Plus Toripalimab as Second-line Treatment in Hepatobiliary Malignant Tumors
Official Title  ICMJE Axitinib Plus Toripalimab as Second-line Treatment in Hepatobiliary Malignant Tumors: a Single-arm, Non-randomized, Single-center Phase II Trial
Brief Summary The investigators design a phase II clinical study to explore the efficacy and safety of axitinib plus toripalimab as a second-line treatment in patients with hepatobiliary malignant tumors and to analyze potential biomarkers of therapeutic response.
Detailed Description

This phase II trial is a single-arm, non-randomized and single-center clinical study.

It is estimated that 60 patients who met the study criteria will be enrolled in PUMCH and treated with axitinib plus toripalimab. The investigators will follow up and collect subjects' data each month to evaluate the efficacy and safety of treatment, including overall survival and time to progression, until disease progression or death. Histopathology and multi-omics data analysis will be used to explore potential biomarkers of treatment response.

Study Type: Interventional. Masking: Open Label.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:
Patients were confirmed with advanced hepatobiliary malignancies by imaging and histological examination and meet with the inclusive criteria, including hepatocellular carcinoma, cholangiocarcinoma, ampullary carcinoma, gallbladder carcinoma, and mixed cancer).
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Hepatobiliary Neoplasm
  • Liver Neoplasm
  • Biliary Tract Neoplasms
Intervention  ICMJE Drug: axitinib plus toripalimab

Axitinib 5mg, twice a day, orally, 4 weeks a cycle. Dose reduction from 5mg twice a day to 3mg twice a day should be considered according to adverse events.

Toripalimab 240mg, every 3 weeks, intravenous infused, 6 weeks a cycle. Number of cycle: until disease progression or unacceptable toxicity events.
Study Arms  ICMJE Experimental: axitinib plus toripalimab

Axitinib (Inlyta, Pfizer Inc.) is a novel oral angiogenesis inhibitor that selectively targets vascular endothelial growth factor (VEGFR) 1, 2 and 3.

Toripalimab (Shanghai Junshi Biosciences Co., Ltd.) is a recombinant anti-human PD-1 IgG4 monoclonal antibody.

Intervention: Drug: axitinib plus toripalimab
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  • Gandara DR, Paul SM, Kowanetz M, Schleifman E, Zou W, Li Y, Rittmeyer A, Fehrenbacher L, Otto G, Malboeuf C, Lieber DS, Lipson D, Silterra J, Amler L, Riehl T, Cummings CA, Hegde PS, Sandler A, Ballinger M, Fabrizio D, Mok T, Shames DS. Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab. Nat Med. 2018 Sep;24(9):1441-1448. doi: 10.1038/s41591-018-0134-3. Epub 2018 Aug 6.
  • Gately MK, Warrier RR, Honasoge S, Carvajal DM, Faherty DA, Connaughton SE, Anderson TD, Sarmiento U, Hubbard BR, Murphy M. Administration of recombinant IL-12 to normal mice enhances cytolytic lymphocyte activity and induces production of IFN-gamma in vivo. Int Immunol. 1994 Jan;6(1):157-67.
  • Frucht DM, Fukao T, Bogdan C, Schindler H, O'Shea JJ, Koyasu S. IFN-gamma production by antigen-presenting cells: mechanisms emerge. Trends Immunol. 2001 Oct;22(10):556-60. Review.
  • Shin T, Nakayama T, Akutsu Y, Motohashi S, Shibata Y, Harada M, Kamada N, Shimizu C, Shimizu E, Saito T, Ochiai T, Taniguchi M. Inhibition of tumor metastasis by adoptive transfer of IL-12-activated Valpha14 NKT cells. Int J Cancer. 2001 Feb 15;91(4):523-8.
  • Schroder K, Hertzog PJ, Ravasi T, Hume DA. Interferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Biol. 2004 Feb;75(2):163-89. Epub 2003 Oct 2. Review.
  • Lee IC, Huang YH, Chau GY, Huo TI, Su CW, Wu JC, Lin HC. Serum interferon gamma level predicts recurrence in hepatocellular carcinoma patients after curative treatments. Int J Cancer. 2013 Dec 15;133(12):2895-902. doi: 10.1002/ijc.28311. Epub 2013 Jun 25.

*   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: July 5, 2019) 		60
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 30, 2021
Estimated Primary Completion Date January 1, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria: Subjects must meet all of the following criteria

  • Subjects volunteer to participate in the study and agree to sign the informed consent with good compliance and follow-up.
  • Subjects are 18 years old or older when signing the informed consent and gender is not limited.
  • Subjects were diagnosed with advanced hepatobiliary malignant tumors (clinical stage IV) by imaging and histological examination, including hepatocellular carcinoma, cholangiocarcinoma, ampullary carcinoma, gallbladder carcinoma and mixed carcinoma.
  • The disease is not suitable for radical surgery and/or topical treatment, or disease progression occurs after surgery and/or local treatment.
  • At least one measurable lesion (according to RECIST version 1.1): the measurable lesion has a long diameter ≥ 10 mm or lymphadenopathy has a short diameter ≥ 15 mm in spiral CT scan.
  • Patients fail after at least one systemic failure, including surgery, intervention, radiotherapy, chemotherapy and targeted therapy and require palliative treatment.

Definition of treatment failure: Disease progression during treatment or relapse after treatment, such as after at least once radical or palliative resection surgery, revenue recurrence or progression after intervention therapy or radiotherapy. Intervention therapy or oxaliplatin treatment must be more than 1 cycle, and molecular targeted therapy must more than ≥14 days.

Definition of intolerance: Grade ≥IV hematologic toxicity, or grade ≥III non- hematologic toxicity, or grade ≥ II damage of heart, liver and kidney during treatment.

  • The ECOG score is 0-1 within 1 week before enrollment.
  • Liver function assessment: Child-Pugh Grade A or mild Grade B (score ≤ 7), BCLC stage B-C.
  • More than 2 weeks from first-line system treatment failure to sign informed consent for this study, and adverse events returned to normal (NCI-CTCAE ≤ I).
  • Estimated survival time ≥ 6 months.
  • HBV DNA <2000 IU/ml (10^4 copies/ml).
  • Hematology and organ function are sufficient based on the following laboratory results within 14 days prior to the treatment of this study:

Whole blood cell examination (no blood transfusion within 14 days, no G-CSF use and no drugs use): Hb≥100g/L, ANC≥1.5×10*9/L, PLT≥75×10*9/L.

Biochemical examination (no ALB infused within 14 days): ALB≥35g/L, ALT and AST<3×ULN, TBIL≤2×ULN, creatinine≤1.5×ULN, PT≤ULN+4S, INR≤2.2 (note: only one of albumin and bilirubin is permitted Child-Pugh score 2).

  • There are no active autoimmune diseases that require systemic therapy in the past 2 years (note: active state means requiring disease modulators, corticosteroids or immunosuppressive drugs use). Alternative therapies, such as thyroxine, insulin or a physiological corticosteroid replacement therapy are not considered as systemic therapy.
  • Women with fertility agree to abstinence during the treatment period and at least 6 months after the last dose (avoiding heterosexual intercourse) or using a contraceptive method with an annual contraceptive failure rate <1%.

If a female patient has menstruation and not reached the postmenopausal state (continuously no menstruation ≥ 12 months and no other causes), and has not undergone sterilization by removing the ovaries and/or uterus), then the patient has fertility.

Contraceptive methods with a contraceptive failure rate <1% include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices and copper intrauterine devices.

The reliability of sexual desire should be evaluated relative to the duration of the clinical trial and lifestyle of patient. Periodic abstinence (eg. calendar days, ovulation, symptomatic body temperature or post-ovulation methods) and in vitro ejaculation are unacceptable methods of contraception.

  • Male patients agree to abstinence (no heterosexual intercourse) or use of contraceptive measures and no sperm donation, as defined below:

When a female partner has fertility, male patients must abstinence from sex during treatment and at least 6 months after the last dose of treatment, or use condoms and other contraceptive methods with contraceptive failure rate <1%. At the same time, male patients must also agree not to donate sperm.

When a female partner is pregnant, the male patient must abstinence or using a condom during the treatment period and at least 6 months after the last dose of treatment to prevent the fetus from being affected by the study.

The reliability of sexual desire should be evaluated relative to the duration of the clinical trial and lifestyle of patient. Periodic abstinence (eg. calendar days, ovulation, symptomatic body temperature or post-ovulation methods) and in vitro ejaculation are unacceptable methods of contraception.

  • Tumor tissue must be available for biomarker analysis prior to the first dose of treatment, If not available, participants can consult the investigator for enrollment agreement. (Note: If an unstained section is submitted, the new section should be submitted to the laboratory within 14 days.)

Exclusion Criteria: Subjects with one or more than one of the following criteria should be excluded

  • Clinical stage I-III, and/or with any of the following: Suitable for radical surgery; Or, without an assessment lesion after radical surgery; Or, never receive any first line treatment; Or, liver transplantation history or ready for liver transplantation.
  • Already known to be allergic to recombinant humanized PD-1 monoclonal antibody drugs and components; known to be allergic to axitinib and components.
  • ECOG score ≥ 2 points.
  • Received any topical treatment within 4 weeks prior to the study, including but not limited to surgery, radiotherapy, hepatic artery embolization, TACE, hepatic artery perfusion, radiofrequency ablation, cryoablation or percutaneous ethanol injection.
  • Received any systemic anti-tumor treatment within 3 months prior to participation in the study, including but not limited to intravenous infused and/or oral chemotherapy, targeted drugs, antibody drugs, and traditional Chinese medicines known to have anticancer effects.
  • Ascites with clinical symptoms which requires abdominal puncture or drainage therapy, or Child-Pugh score >2 points.
  • With serious systemic diseases such as heart disease and cerebrovascular disease, and the condition is unstable or uncontrollable.
  • Already known active central nervous system metastasis and/or cancerous meningitis. Subjects with stable brain metastases after previous treatment may participate as long as no radiologic evidence of progression lasts for at least four weeks prior to this trial and any neurological symptoms have returned to baseline, and no new or enlarged metastatic evidence in brain and no steroids use for at least 7 days prior to trial treatment. Cancer meningitis should be excluded regardless of clinical stability.
  • Surgery was performed within 4 weeks prior to the trial and patients must be evaluated after wound healing.
  • Hepatic and renal dysfunction evidence: jaundice, ascites, and/or bilirubin ≥ 2 × ULN, and/or alkaline phosphatase ≥ 3 × ULN, and/or ≥ 3 grade (CTC-AE 5.0) proteinuria (> 3.5g /24 hours), or renal failure requiring blood dialysis or peritoneal dialysis.
  • Urine examination shows urinary protein ≥ ++ or 24 hours urine protein >1.0g.
  • Persistent >2 grade (CTC-AE5.0) infection.
  • History of allogeneic tissue transplantation or solid organ transplantation.
  • History of active tuberculosis, such as mycobacterium tuberculosis.
  • Intolerant of any drug (or any excipient) in this trial.
  • Female patients who are pregnant, breastfeeding or refuse contraception.
  • Known or untreated brain metastases, or patients with epilepsy who need medication treatment.
  • Patients with bone metastases received palliative radiotherapy (radiation area > 5% bone marrow area) within 4 weeks prior to this study, or there were wounds, ulcers or fractures that could not be healed, or patients have organ transplantation history.
  • Gastrointestinal bleeding history in the past 6 months or tendency to gastrointestinal bleeding, such as esophageal varices, local active ulceration lesions, fecal occult blood ≥ (++) (gastroscopy is required when fecal occult blood is (+)).
  • Evidence or history of ≥3 grade (CTC-AE5.0) bleeding events.
  • History of human immunodeficiency virus infection.
  • History of hepatitis B virus or hepatitis C virus infection, and not receive regular treatment.
  • Severe non-healing wounds, ulcers or fractures.
  • Prior treatment with either axitinib or any kind of anti-PD-1, anti-PD-L1 or anti-PD-L2 drugs.
  • Diagnosis of immunodeficiency or systemic steroid therapy or any form of immunosuppressants therapy within 7 days prior to this study. A physiological dose of corticosteroids (no more than 7.5 mg/d prednisone or equivalent) can be approved after clinical evaluation.
  • There exists drug abuse, or any medical, psychological or social condition which might affect the study, the compliance or even the safety of patients.
  • Variable factors which significantly affect drug use and absorption, such as inability to swallow, chronic diarrhea and intestinal obstruction.
  • Any >1 grade (CTC-AE5.0) unresolved toxicity due to previous treatment or operation, except for hair loss, anemia, and hypothyroidism.
  • Vaccination of any live virus vaccine within 30 days prior to this study, except for seasonal flu vaccines without live virus.
  • Previous and current evidence of pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonitis, drug-associated pneumonia and severe impairment of lung function.
  • Received a potent CYP3A4 inhibitor treatment within 7 days prior to the study, or received a potent CYP3A4 inducer within 12 days prior to the study.
  • Patients participate in another clinical study at the same time.
  • Patients are unsuitable for participation in this research after comprehensive assessment by the researchers.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Jianzhen Lin, MD +86 18800158133 jzlin816@126.com
Contact: Haitao Haitao, Prof
Listed Location Countries  ICMJE China
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04010071
Other Study ID Numbers  ICMJE JS-1964
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 Peking Union Medical College Hospital
Study Sponsor  ICMJE Peking Union Medical College Hospital
Collaborators  ICMJE Shanghai Junshi Bioscience Co., Ltd.
Investigators  ICMJE
Study Chair: Haitao Haitao, Prof Peking Union Medical College Hospital (PUMCH)
PRS Account Peking Union Medical College Hospital
Verification Date November 2020

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

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