Clinical Trials /

A Study of Pembrolizumab and Bavituximab in Patients With Advanced Hepatocellular Carcinoma

NCT03519997

Description:

This is a non-randomized, open-label, multi-site phase II therapeutic trial of pembrolizumab and bavituximab in patients with locally advanced HCC. Locally advanced or metastatic HCC is defined as disease that is not amenable to surgical and/or locoregional therapies. Subjects must not have received prior systemic therapy for advanced HCC in keeping with the first-line setting of this study.

Related Conditions:
  • Hepatocellular Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study of Pembrolizumab and Bavituximab in Patients With Advanced Hepatocellular Carcinoma
  • Official Title: A Phase II Study of Pembrolizumab and Bavituximab in Patients With Advanced Hepatocellular Carcinoma

Clinical Trial IDs

  • ORG STUDY ID: STU 102017-015
  • NCT ID: NCT03519997

Conditions

  • Hepatocellular Carcinoma

Interventions

DrugSynonymsArms
PembrolizumabPembro + Bavi
BavituximabPembro + Bavi

Purpose

This is a non-randomized, open-label, multi-site phase II therapeutic trial of pembrolizumab and bavituximab in patients with locally advanced HCC. Locally advanced or metastatic HCC is defined as disease that is not amenable to surgical and/or locoregional therapies. Subjects must not have received prior systemic therapy for advanced HCC in keeping with the first-line setting of this study.

Detailed Description

      This is a non-randomized, open-label, multi-site phase II therapeutic trial of pembrolizumab
      and bavituximab in patients with locally advanced HCC. Locally advanced or metastatic HCC is
      defined as disease that is not amenable to surgical and/or locoregional therapies. Subjects
      must not have received prior systemic therapy for advanced HCC in keeping with the first-line
      setting of this study. Overall response rate (ORR) as assessed by the investigators and using
      RECIST 1.1 criteria, will be the primary endpoint.

      Prior to initiation on treatment, all patients will sign an informed consent form. Only
      patients with histological proved HCC will be eligible for treatment. Tissue, either from
      archival formalin fixed paraffin embedded samples or a new biopsy of a target lesion will be
      needed.

      Study therapy is defined as treatment with both pembrolizumab and bavituximab. Patients will
      receive trial treatment until disease progression, unacceptable toxicity, death or
      discontinuation from the study treatment for any other reason. Subjects will be allowed to
      continue study therapy after an initial investigator-assessed RECIST 1.1 defined progression
      as long as they meet the following criteria: 1) investigator assessed clinical benefit and 2)
      subject is tolerating study therapy. Subjects will be discontinued from study therapy upon
      the evidence of further progression, defined as an additional 10% or greater increase in
      tumor burden from time of initial progression (including all target lesions and new
      measurable lesions). New lesions are considered measurable if the longest diameter is at
      least 10 mm (except for pathological lymph nodes, which must have a short axis of at least 15
      mm). Any new lesion considered non-measurable may become measurable and therefore included in
      the tumor burden measurement if the longest diameter increases to at least 10 mm (except for
      pathological lymph nodes, which must have an increase in short axis to at least 15 mm. For
      statistical analyses that include the investigator-assessed progression date, subjects who
      continue treatment beyond initial investigator-assessed, RECIST 1.1-defined progression will
      be considered to have investigator-assessed progressive disease at the time of the initial
      progressive event irrespective of confirmation on subsequent imaging. Patients will be
      followed for survival regardless of treatment discontinuation for any reason, unless they
      withdraw their consent to be followed for survival.

      Treatment Phase

      The treatment phase for each patient will begin on the initiation of study drug on Cycle 1
      Day 1 (C1D1). Patients will continue study treatment until disease progression (or until
      discontinuation of study therapy in patient receiving pembrolizumab and bavituximab beyond
      progression), discontinuation due to toxicity, withdrawal of consent, or the study ends. A
      safety follow-up is mandatory at 30 days post the last dose.

      Efficacy, safety, and correlative assessments will be performed as outlined in the Schedule
      of Visits and Procedures (section 6.0). Safety assessments will include hematology,
      biochemistry, and thyroid tests as well as ongoing evaluations of adverse events. Tumor
      response will be assessed radiographically every 9 weeks for the first 54 weeks, then every
      12 weeks thereafter until disease progression (or until discontinuation of study therapy in
      patients receiving pembrolizumab or bavituximab beyond progression), loss to follow-up, or
      withdrawal of consent. Patients with radiological progression using RECIST may continue on
      study treatment if in the investigator's assessment the patient is experiencing clinical
      benefit and tolerating the treatment.

      Dose Limiting Toxicity:

      Initially, enrollment will be limited to 10 patients with no more than two patients enrolled
      per week. A safety committee comprised of the investigators and institutional GI Disease
      Orientated Team will monitor the occurrence of dose limiting toxicities (DLTs) for the first
      10 patients prior to enrolling the remainder of the trial. The period for evaluating DLTs
      will be from the time of the first administration of study treatment through Study Day 28.
      DLTs will follow the guidelines provided in the Common Terminology Criteria for Adverse
      Events (CTCAE) version 4.03.

      If three or more DLTs occur during this period, enrollment will be suspended and the safety
      committee will make a determination of whether to reduce the bavituximab dose to 1 mg/kg.
      After the DLT safety assessment period for the initial 10 patients, enrollment may proceed
      for the remainder of the trial provided at least one patient has either a complete or partial
      response by RECIST 1.1 and patient safety will be evaluated on a regular basis by the
      institutional data safety monitoring committee (DSMC). A DLT will be defined as any treatment
      related toxicity in the list below that occurs during the DLT evaluation period. Toxicity
      that is clearly and directly related to the primary disease or to another etiology is
      excluded from this definition. The following will be considered DLTs:

        -  Any grade 4 immune-related adverse events (irAE)

        -  Any ≥ grade 3 colitis

        -  Any grade 3 or 4 noninfectious pneumonitis irrespective of duration

        -  Any grade 2 pneumonitis that does not resolve to grade 1 within 5 days of the initiation
           of maximum supportive care

        -  Any grade 3 irAE, excluding colitis or pneumonitis, that does not downgrade to grade 2
           within 5 days of the event despite optimal medical management including systemic
           corticosteroids or does not downgrade to grade 1 or baseline within 14 days

        -  Liver transaminase elevation >8 x ULN or total bilirubin > 5 x ULN

        -  Any ≥ grade 3 non-irAE, except for the exclusions listed below

      The definition excludes the following conditions:

        -  Grade 3 fatigue ≤ 7days

        -  Grade 3 endocrine disorder (thyroid, pituitary, and/or adrenal insufficiency) that is
           managed with or without systemic corticosteroid therapy and/or hormone replacement
           therapy and the patient is asymptomatic

        -  Grade 3 inflammatory reaction attributed to a local antitumor response

        -  Concurrent vitiligo or alopecia of any grade

        -  Grade 3 infusion-related reaction (first occurrence and in the absence of steroid
           prophylaxis) that resolves within 6 hours with appropriate clinical management

        -  Grade 3 or 4 neutropenia that is not associated with fever or systemic infection that
           improves by at least 1 grade within 3 days. Grade 3 or 4 febrile neutropenia will be
           considered a DLT regardless of duration or reversibility

        -  Grade 3 or 4 lymphopenia

        -  Grade 3 thrombocytopenia that is not associated with clinically significant bleeding
           that requires medical intervention, and improves by at least 1 grade within 3 days

        -  Isolated grade 3 electrolyte abnormalities that are not associated with clinical signs
           or symptoms and are reversed with appropriate maximal medical intervention within 3 days

        -  Isolated grade 3 amylase or lipase abnormalities that are not associated with clinical
           signs/symptoms or findings on imaging consistent with pancreatitis.

      Survival follow-up phase

      Patients who are no longer receiving any study treatments and have experienced disease
      progression will enter survival follow-up, regardless of whether they have initiated
      subsequent anticancer therapy. Survival follow-up information (by chart review, phone call or
      clinic visits) will be collected approximately every 3 months until death, loss to follow-up,
      withdrawal of consent or study termination.
    

Trial Arms

NameTypeDescriptionInterventions
Pembro + BaviExperimentalPembrolizumab 200 mg IV every 3 weeks plus, Bavituximab 3mg/kg IV weekly
  • Pembrolizumab
  • Bavituximab

Eligibility Criteria

        Inclusion Criteria:

          -  Patient must have a histologically confirmed diagnosis hepatocellular carcinoma; known
             fibrolamellar HCC, sarcomatoid HCC or mixed cholangiocarcinoma and HCC will be
             excluded

          -  Locally advanced or metastatic disease

          -  Patients with locally advanced or metastatic disease must have disease deemed not
             amenable to surgical and/or locoregional therapies or patients who have progressed
             following surgical and/or locoregional therapies.

          -  Measurable disease, as defined as lesions that can accurately be measured in at least
             one dimension according to RECIST version 1.1 at least 1 cm with contrast enhanced
             dynamic imaging (magnetic resonance imaging or computed tomography).

          -  Child-Pugh Score A

          -  Age ≥ 18 years

          -  ECOG Performance score of 0-1

          -  Life expectancy greater than 6 months

          -  Following baseline laboratory values:

               1. Total bilirubin ≤ 2.0 mg/ml

               2. INR ≤ 1.7

               3. Hgb ≥ 8.5 g/dl

               4. AST, ALT ≤5 times ULN

               5. Platelet count ≥ 50,000/mm3

               6. Serum creatinine ≤ 1.5 mg/dL or creatinine clearance ≥ 50 mL/min

               7. Albumin ≥ 2.5 g/dl

               8. Absolute neutrophil ≥ 1,500 cells/mm3

          -  Male and female subjects of child bearing potential must agree to use an adequate
             method of contraception for the course of the study through 120 days after the last
             dose of study medication

          -  Women of childbearing potential must have a negative pregnancy test within 72 hours
             prior to receiving the first dose of study medication

          -  Subjects are eligible to enroll if they have non-viral-HCC, or if they have HBV-HCC,
             or HCV-HCC defined as follows:

        HBV-HCC: Controlled (treated) hepatitis B subjects will be allowed if they meet the
        following criteria:

        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.

        Subjects who are anti-HBc (+), negative for HBsAg, negative for anti-HBs, and have an HBV
        viral load under 100 IU/mL do not require HBV anti-viral prophylaxis.

        HCV-HCC: active or resolved HCV infection as evidenced by detectable HCV RNA or antibody.
        Patients who have failed HCV therapy as evidenced by detectable HCV RNA will be eligible.
        Subjects with chronic infection by HCV who are treated (successfully or treatment failure)
        or untreated are allowed on study. In addition, subjects with successful HCV treatment are
        allowed as long as there are ≥4 weeks between completion of HCV therapy and start of study
        drug.

        Successful HCV treatment definition: SVR12.

        - Prior therapy is allowed provided the following are met: at least 4 weeks since prior
        locoregional therapy including surgical resection, chemoembolization, radiotherapy, or
        ablation. Provided target lesion has increased in size by 25% or more or the target lesion
        was not treated with locoregional therapy. Patients treated with palliative radiotherapy
        for symptoms will be eligible 1 week after treatment as long as the target lesion is not
        the treated lesion.

        Exclusion Criteria:

          -  Prior liver transplant;

          -  Patient who has received previous systemic therapy for HCC;

          -  Clinically significant, uncontrolled heart disease and/or recent events including any
             of the following:

          -  History of acute coronary syndromes (including myocardial infarction, unstable angina,
             coronary artery bypass grafting, coronary angioplasty, or stenting) or symptomatic
             pericarditis within 12 months prior to screening;

          -  History of documented congestive heart failure (New York Heart Association functional
             classification III-IV);

          -  Documented cardiomyopathy;

          -  Patient has a left ventricular ejection fraction <40% as determined by MUGA scan or
             ECHO (MUGA and ECHO are not required prior to enrollment);

          -  Known human immunodeficiency virus (HIV) positive (testing not required);

          -  History of thromboembolic events (including both pulmonary embolism and deep venous
             thrombus but not including tumor thrombus) within the last 6 months;

          -  Hypersensitivity to IV contrast; not suitable for pre-medication;

          -  Active or fungal infections requiring systemic treatment within 7 days prior to
             screening;

          -  Known history of, or any evidence of, interstitial lung disease or active
             non-infectious pneumonitis;

          -  Evidence of poorly controlled hypertension which is defined as systolic blood pressure
             >150 mmHg or diastolic pressure >90 mmHg despite optimal medical management;

          -  Pre-existing thyroid abnormality with thyroid function that cannot be maintained in
             the normal range with medication;

          -  Active, known, or suspected autoimmune disease with the following exceptions i)
             Subjects with vitiligo, type I diabetes mellitus, resolved childhood asthma or atopy
             are permitted to enroll; ii) Subjects with suspected autoimmune thyroid disorders may
             be enrolled if they are currently euthyroid or with residual hypothyroidism requiring
             only hormone replacement.

        iii) Subjects with psoriasis requiring systemic therapy must be excluded from enrollment

          -  Patient has any other concurrent severe and/or uncontrolled medical condition that
             would, in the investigator's judgment, cause unacceptable safety risks, contraindicate
             patient participation in the study or compromise compliance with the protocol (e.g.
             chronic pancreatitis, active untreated or uncontrolled fungal, bacterial, or viral
             infections, etc.);

          -  Patient has any other concurrent severe and/or uncontrolled medical condition that
             would, in the investigator's judgment, cause unacceptable safety risks, contraindicate
             patient participation in the study or compromise compliance with the protocol (e.g.
             chronic pancreatitis, active untreated or uncontrolled fungal, bacterial, or viral
             infections, etc.);

          -  Known history of active bacillus tuberculosis;

          -  Subjects with a condition requiring systemic treatment with either corticosteroids (>
             10 mg/day prednisone equivalent) or other immunosuppressive medications within 14 days
             of study administration. Inhaled or topical steroids and adrenal replacement doses >10
             mg/day prednisone equivalents are permitted in the absence of autoimmune disease;

          -  Patient who has received radiotherapy ≤ 4 weeks prior to study entry. Palliative
             radiotherapy for symptomatic control is acceptable (if completed at least 2 weeks
             prior to study drug administration and no additional radiotherapy for the same lesion
             is planned);

          -  Patient has had major surgery within 14 days prior to starting study drug or has not
             recovered from major side effects (tumor biopsy is not considered as major surgery);

          -  Clinically apparent ascites on physical examination, ascites present on imaging
             studies is allowed;

          -  Patient has a known hypersensitivity to any of the excipients of bavituximab or
             pembrolizumab or monoclonal antibody;

          -  Active gastrointestinal bleeding within previous 2 months;

          -  History of any condition requiring anti-platelet therapy (aspirin >300 mg/day,
             clopidogrel >75 mg/day);

          -  Prisoners or subjects who are involuntarily incarcerated;

          -  Symptomatic or clinically active brain metastases;

          -  Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a
             female after contraception and until the termination of gestation, confirmed by a
             positive hCG laboratory test;

          -  Prior immunotherapy including anti-PD-1, anti-PD-L1, or anti-PD-L2 agents;

          -  Has dual active HBV infection (HBsAg (+) and /or detectable HBV DNA) and HCV infection
             (anti-HCV Ab(+) and detectable HCV RNA) at study entry.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Response Rate
Time Frame:36 months
Safety Issue:
Description:To determine the overall response rate (ORR) of combination pembrolizumab and bavituximab in patients with advanced HCC.

Secondary Outcome Measures

Measure:Overall Survival
Time Frame:36 months
Safety Issue:
Description:To determine overall survival, 6-month progression free survival, and duration of response of combination pembrolizumab and bavituximab compared to historical controls
Measure:Safety and Tolerability: rates of adverse events according to the CTCAE
Time Frame:36 months
Safety Issue:
Description:To determine the safety and tolerability of combination pembrolizumab and bavituximab as measured by rates of adverse events according to the CTCAE

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Texas Southwestern Medical Center

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