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Pembrolizumab in Hepatocellular Carcinoma

Primary Purpose

HCC

Status
Recruiting
Phase
Phase 2
Locations
Hong Kong
Study Type
Interventional
Intervention
pembrolizumab
Sponsored by
CCTU
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for HCC

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Confirmed diagnosis of advanced hepatocellular carcinoma (in accordance with the AASLD guidelines)
  2. Confirmed chronic infection with hepatitis B virus as defined by positivity for HBsAg
  3. For patients who are positive for HBsAg, antiviral therapy for HBV must be given for at least 12 weeks and HBV viral load must be less than 100 IU/mL prior to first dose of study drug. Subjects on active HBV therapy with viral loads under 100 IU/ml should stay on the same therapy throughout study treatment.
  4. Disease extent is not amenable to curative surgery or loco-ablation
  5. Patients who are fit and agreeable with baseline and post-treatment biopsy of tumor Subject Inclusion Criteria

    In order to be eligible for participation in this trial, the subject must:

  6. Be willing and able to provide written informed consent/assent for the trial.
  7. Be ≥ 18 years of age on day of signing informed consent.
  8. Have measurable disease based on RECIST 1.1.
  9. Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion. Newly-obtained is defined as a specimen obtained up to 6 weeks (42 days) prior to initiation of treatment on Day 1. Subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible or subject safety concern) may submit an archived specimen only upon agreement from the Sponsor.
  10. Have a performance status of 0 or 1 on the ECOG Performance Scale.
  11. Demonstrate adequate organ function as defined, all screening labs should be performed within 10 days of treatment initiation.

    Adequate Organ Function Laboratory Values:

    Hematological Absolute neutrophil count (ANC) ≥1,200 /mcL Platelets ≥75,000 / mcL Hemoglobin ≥8g/dL without transfusion or EPO dependency (within 7 days of assessment) Renal Serum creatinine OR Measured or calculateda creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≤1.5 X upper limit of normal (ULN) OR ≥60 mL/min for subject with creatinine levels > 1.5 X institutional ULN Hepatic Serum total bilirubin ≤ 2mg/dL, or direct bilirubin≤ULN for those with total bilirubin > 2mg/dL or Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN AST (SGOT) and ALT (SGPT) ≤ 5 X ULN Albumin >3.0 mg/dL Coagulation International Normalized Ratio (INR) or Prothrombin Time (PT) orActivated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN Creatinine clearance should be calculated per institutional standard.

  12. Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
  13. Female subjects of childbearing potential (Section 5.7.2) must be willing to use an adequate method of contraception as outlined in Section 5.7.2 - Contraception, for the course of the study through 120 days after the last dose of study medication.

    Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.

  14. Male subjects of childbearing potential (Section 5.7.1) must agree to use an adequate method of contraception as outlined in Section 5.7.1- Contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy.

Exclusion Criteria:

  1. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapyor used an investigational device within 4 weeks of the first dose of treatment.
  2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
  3. Has a known history of active TB (Bacillus Tuberculosis)
  4. Hypersensitivity to pembrolizumab or any of its excipients.
  5. Had a solid organ or hematologic transplant
  6. Has had esophageal or gastric variceal bleeding within the last 6 months. All subjects will be screened for esophageal varices, unless such screening has been performed in the past 12 months before first dose of treatment. If varices are present, they should be treated according to institutional standards before starting trial treatment
  7. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
  8. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.

    • Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.
    • Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
  9. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include cancer-insitu with curative treatment or malignancy more than 3 years prior to enrollment.
  10. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
  11. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
  12. Has known history of, or any evidence of active, non-infectious pneumonitis.
  13. Has an active infection requiring systemic therapy.
  14. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
  15. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  16. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
  17. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
  18. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
  19. Has untreated active Hepatitis B Note: To qualify for enrollment, antiviral therapy for HBV must be given for at least 3 months, and HBV viral load must be less than 100 IU/mL prior to first dose of study drug. Those on active HBV therapy with viral loads under 100 IU/mL should stay on the same therapy throughout trial treatment. Those subjects who are anti-HBc (+), and negative for HBsAg, and negative for anti-HBs, and have an HBV viral load under 100 IU/mL do not require HBV anti-viral prophylaxis, but need close monitoring.
  20. Baseline HBV DNA level > 100 IU/ml
  21. Patients with concomitant HCV infection (as evidenced by Anti-HCV positivity)
  22. Has received a live vaccine within 30 days of planned start of study therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.

Sites / Locations

  • Department of Clinical Oncology, Prince of Wales HospitalRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

pembrolizumab

Arm Description

Outcomes

Primary Outcome Measures

Response rate (RR) according to RECIST1.1

Secondary Outcome Measures

1-year survival rate
Response rate according to irRECIST
Assessment of response duration
Progression-free survival (PFS)
Time-to-progression (TTP)
Overall survival (OS)

Full Information

First Posted
January 10, 2018
Last Updated
September 28, 2022
Sponsor
CCTU
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1. Study Identification

Unique Protocol Identification Number
NCT03419481
Brief Title
Pembrolizumab in Hepatocellular Carcinoma
Official Title
A Clinical Trial of Pembrolizumab in Patients With Hepatitis B Virus-related Hepatocellular Carcinoma, With Parallel Study on Baseline and Serial Change in the Immune Environment
Study Type
Interventional

2. Study Status

Record Verification Date
September 2022
Overall Recruitment Status
Recruiting
Study Start Date
April 30, 2018 (Actual)
Primary Completion Date
December 30, 2023 (Anticipated)
Study Completion Date
December 30, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
CCTU

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
This is a single-arm Phase II trial of pembrolizumab in patients with hepatitis B virus-related hepatocellular carcinoma with parallel study on baseline and serial change in the immune environment. Subjects should have a confirmed diagnosis of HCC (in accordance with the AASLD guideline) and confirmed chronic infection with hepatitis B virus as defined by positivity for HBsAg. Antiviral therapy for HBV must be given for at least 12 weeks and HBV viral load must be less than 100 IU/mL prior to first dose of study drug. They must have disease not amenable to a curative treatment approach or loco-ablation. Subject must be fit and agreeable with baseline and post-treatment biopsy of tumor. Subjects must have at least one measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, an Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1 and adequate organ functions. 30 subjects will be enrolled to receive pembrolizumab 200 mg IV every 3 weeks(Q3W). Pre-treatment and on-treatment biopsy after 2 cycles of Pembrolizumab will be preformed. Treatment will be stopped when progression of disease or intolerable toxicity occurs. The primary objectives of this trial are to study the efficacy and safety of pembrolizumab in patients with HBV-related HCC and to study the serial change in RNA expression of immune-related gene panel in post-treatment biopsy tissue. The secondary objectives of this trial are to study the serial change in cytokine profile between pre-treatment and post-treatment samples, to study the PD-L1 immunohistochemical (IHC) expression in tumor sample at baseline and post-treatment tissue samples and to study the presence of tumor infiltrating lymphocytes in the baseline and post-treatment tumor samples. The exploratory objective of this trial is to evaluate the possibility of using baseline and the serial change in RNA expression of immune-related gene panel or PD-L1/2 IHC to predict treatment response.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
HCC

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
30 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
pembrolizumab
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
pembrolizumab
Intervention Description
200mg every 3 weeks infusion
Primary Outcome Measure Information:
Title
Response rate (RR) according to RECIST1.1
Time Frame
2 years
Secondary Outcome Measure Information:
Title
1-year survival rate
Time Frame
2 years
Title
Response rate according to irRECIST
Time Frame
2 years
Title
Assessment of response duration
Time Frame
2 years
Title
Progression-free survival (PFS)
Time Frame
2 years
Title
Time-to-progression (TTP)
Time Frame
2 years
Title
Overall survival (OS)
Time Frame
2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Confirmed diagnosis of advanced hepatocellular carcinoma (in accordance with the AASLD guidelines) Confirmed chronic infection with hepatitis B virus as defined by positivity for HBsAg For patients who are positive for HBsAg, antiviral therapy for HBV must be given for at least 12 weeks and HBV viral load must be less than 100 IU/mL prior to first dose of study drug. Subjects on active HBV therapy with viral loads under 100 IU/ml should stay on the same therapy throughout study treatment. Disease extent is not amenable to curative surgery or loco-ablation Patients who are fit and agreeable with baseline and post-treatment biopsy of tumor Subject Inclusion Criteria In order to be eligible for participation in this trial, the subject must: Be willing and able to provide written informed consent/assent for the trial. Be ≥ 18 years of age on day of signing informed consent. Have measurable disease based on RECIST 1.1. Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion. Newly-obtained is defined as a specimen obtained up to 6 weeks (42 days) prior to initiation of treatment on Day 1. Subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible or subject safety concern) may submit an archived specimen only upon agreement from the Sponsor. Have a performance status of 0 or 1 on the ECOG Performance Scale. Demonstrate adequate organ function as defined, all screening labs should be performed within 10 days of treatment initiation. Adequate Organ Function Laboratory Values: Hematological Absolute neutrophil count (ANC) ≥1,200 /mcL Platelets ≥75,000 / mcL Hemoglobin ≥8g/dL without transfusion or EPO dependency (within 7 days of assessment) Renal Serum creatinine OR Measured or calculateda creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≤1.5 X upper limit of normal (ULN) OR ≥60 mL/min for subject with creatinine levels > 1.5 X institutional ULN Hepatic Serum total bilirubin ≤ 2mg/dL, or direct bilirubin≤ULN for those with total bilirubin > 2mg/dL or Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN AST (SGOT) and ALT (SGPT) ≤ 5 X ULN Albumin >3.0 mg/dL Coagulation International Normalized Ratio (INR) or Prothrombin Time (PT) orActivated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN Creatinine clearance should be calculated per institutional standard. Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Female subjects of childbearing potential (Section 5.7.2) must be willing to use an adequate method of contraception as outlined in Section 5.7.2 - Contraception, for the course of the study through 120 days after the last dose of study medication. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject. Male subjects of childbearing potential (Section 5.7.1) must agree to use an adequate method of contraception as outlined in Section 5.7.1- Contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy. Exclusion Criteria: Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapyor used an investigational device within 4 weeks of the first dose of treatment. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. Has a known history of active TB (Bacillus Tuberculosis) Hypersensitivity to pembrolizumab or any of its excipients. Had a solid organ or hematologic transplant Has had esophageal or gastric variceal bleeding within the last 6 months. All subjects will be screened for esophageal varices, unless such screening has been performed in the past 12 months before first dose of treatment. If varices are present, they should be treated according to institutional standards before starting trial treatment Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent. Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study. Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include cancer-insitu with curative treatment or malignancy more than 3 years prior to enrollment. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Has known history of, or any evidence of active, non-infectious pneumonitis. Has an active infection requiring systemic therapy. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). Has untreated active Hepatitis B Note: To qualify for enrollment, antiviral therapy for HBV must be given for at least 3 months, and HBV viral load must be less than 100 IU/mL prior to first dose of study drug. Those on active HBV therapy with viral loads under 100 IU/mL should stay on the same therapy throughout trial treatment. Those subjects who are anti-HBc (+), and negative for HBsAg, and negative for anti-HBs, and have an HBV viral load under 100 IU/mL do not require HBV anti-viral prophylaxis, but need close monitoring. Baseline HBV DNA level > 100 IU/ml Patients with concomitant HCV infection (as evidenced by Anti-HCV positivity) Has received a live vaccine within 30 days of planned start of study therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Stephen Chan, MD, FRCP
Phone
3505 2166
Email
l_chan@clo.cuhk.edu.hk
First Name & Middle Initial & Last Name or Official Title & Degree
Nicole Yim, RN
Phone
3505 1046
Email
nicole@clo.cuhk.edu.hk
Facility Information:
Facility Name
Department of Clinical Oncology, Prince of Wales Hospital
City
Hong Kong
Country
Hong Kong
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Stephen Lam Chan, FHKCP
Phone
3505 1042
Email
l_chan@clo.cuhk.edu.hk
First Name & Middle Initial & Last Name & Degree
Nicole Yim, RN
Phone
3505 1046
Email
nicole@clo.cuhk.edu.hk
First Name & Middle Initial & Last Name & Degree
Stephen Lam Chan, FHKCP

12. IPD Sharing Statement

Plan to Share IPD
Undecided

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Pembrolizumab in Hepatocellular Carcinoma

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