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

March 27, 2023 updated by: Peking Union Medical College Hospital

Axitinib Plus Toripalimab as Second-line Treatment in Hepatobiliary Malignant Tumors: a Single-arm, Non-randomized, Single-center Phase II Trial

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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

Interventional

Enrollment (Anticipated)

60

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • China
    • Beijing
      • Beijing, Beijing, China, 100730
        • Recruiting
        • Peking Union Medical College Hospital
        • Contact:
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
one year
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.
six months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
one year
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.
two years
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.
one year
Stable Disease (SD)
Time Frame: one year
Proportion of patients with stable disease status more than 4 months.
one year
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.
six months
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.
one year

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Any adverse events related with treatment with axitinib plus toripalimab.
Time Frame: one year
Safety and tolerability of the treatment
one year
PD-L1 expression
Time Frame: six months
PD-L1 expression in tumor tissues.
six months
Tumor mutation burden
Time Frame: six months
Tumor mutation burden assessed by whole exome sequencing.
six months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Peking Union Medical College Hospital

Collaborators

Shanghai Junshi Bioscience Co., Ltd.

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

May 1, 2020

Primary Completion (Anticipated)

January 1, 2024

Study Completion (Anticipated)

June 30, 2024

Study Registration Dates

First Submitted

July 2, 2019

First Submitted That Met QC Criteria

July 5, 2019

First Posted (Actual)

July 8, 2019

Study Record Updates

Last Update Posted (Actual)

March 29, 2023

Last Update Submitted That Met QC Criteria

March 27, 2023

Last Verified

January 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • JS-1964

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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