Clinical Trials /

BO-112 and Pembrolizumab for the Treatment of PD-1/PD-L1 Refractory Liver Cancer

NCT04777708

Description:

This early phase I trial evaluates the side effects of BO-112 and pembrolizumab and how well they work in treating patients with Barcelona Clinic Liver Cancer (BCLC) stage B or C liver cancer. Immunotherapy with BO-112, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the tumor, and may interfere with the ability of tumor cells to grow and spread. Giving BO-112 and pembrolizumab may help treat patients with liver cancer.

Related Conditions:
  • Hepatocellular Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Early Phase 1

Trial Eligibility

Document

Title

  • Brief Title: BO-112 and Pembrolizumab for the Treatment of PD-1/PD-L1 Refractory Liver Cancer
  • Official Title: Pilot Feasibility Study of Intratumoral BO-112 in Combination With Pembrolizumab for Advanced Hepatocellular Carcinoma

Clinical Trial IDs

  • ORG STUDY ID: 21-000276
  • SECONDARY ID: NCI-2021-00994
  • SECONDARY ID: 21-000276
  • NCT ID: NCT04777708

Conditions

  • Advanced Hepatocellular Carcinoma
  • BCLC Stage B Hepatocellular Carcinoma
  • BCLC Stage C Hepatocellular Carcinoma
  • Refractory Hepatocellular Carcinoma

Interventions

DrugSynonymsArms
Nanoplexed Poly I:C BO-112BO 112, BO-112, BO112, Nanoplexed Poly IC BO-112, Nanoplexed Polyinosinic:Polycytidylic Acid BO-112Treatment (pembrolizumab, BO-112)
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Treatment (pembrolizumab, BO-112)

Purpose

This early phase I trial evaluates the side effects of BO-112 and pembrolizumab and how well they work in treating patients with Barcelona Clinic Liver Cancer (BCLC) stage B or C liver cancer. Immunotherapy with BO-112, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the tumor, and may interfere with the ability of tumor cells to grow and spread. Giving BO-112 and pembrolizumab may help treat patients with liver cancer.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To determine the early efficacy and safety for the combination of intratumoral nanoplexed
      poly I:C BO-112 (BO-112) in combination with pembrolizumab in patients with advanced
      hepatocellular carcinoma (HCC) who have progressed on prior anti-PD-1/PD-L1 therapy.

      SECONDARY OBJECTIVES:

      I. To further elucidate efficacy endpoints of the combination the combination of BO-112 with
      pembrolizumab.

      II. To demonstrate the efficacy of BO-112 from its hypothesized mechanism of action.

      CORRELATIVE RESEARCH OBJECTIVES:

      I. Peripheral blood will be collected to assess changes in circulating cluster of
      differentiation 4 (CD4+), cluster of differentiation 8 (CD8+), natural killer (NK), and
      dendritic cells.

      II. Peripheral blood will be collected to assess leukocyte expression of interferon beta
      induced genes in conjunction with intratumoral studies to demonstrate increased intratumoral
      interferon beta and other hypothesized biomarkers.

      III. A baseline biopsy will be collected on cycle 1 day 1 and at cycle 2 day 15 (done at the
      same time as intratumoral injection).

      IIIa. From these biopsies, intratumoral CD4+, CD8+ expression and cluster of differentiation
      56 (CD56+) expression (NK cells) will be measured by immunohistochemistry on the baseline
      biopsy and the biopsy on cycle 2 day 15.

      IIIb. Myeloid dendritic cells will be assessed by flow cytometry, as their activity
      correlates with Toll-like receptor 3 (TLR3) activation.

      IIIc. Percentage of cells with apoptosis and necrosis will be assessed. IIId. The tumor
      microenvironment will be assessed by ribonucleic acid (RNA) expression profiling with
      nCounter Pancancer Immune Profiling Panel given its extensive validation to date.

      IV. To assess the potential of immune-related Response Evaluation Criteria in Solid Tumors
      (RECIST) (iRECIST) to determine disease control as compared to RECIST 1.1.

      OUTLINE:

      Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1 of odd number
      cycles. Patients also receive BO-112 by intratumoral injection on day 1, 8, and 15 of cycle
      1, and day 15 of subsequent cycles. Treatment repeats every 3 weeks for up to 17 cycles in
      the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 30 days, every 8 weeks for 1
      year, and then every 12 weeks thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (pembrolizumab, BO-112)ExperimentalPatients receive pembrolizumab IV over 30 minutes on day 1 of odd number cycles. Patients also receive BO-112 by intratumoral injection on day 1, 8, and 15 of cycle 1, and day 15 of subsequent cycles. Treatment repeats every 3 weeks for up to 17 cycles in the absence of disease progression or unacceptable toxicity.
  • Nanoplexed Poly I:C BO-112
  • Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

          -  Participants who are at least 18 years of age on the day of signing informed consent
             with confirmed diagnosis of hepatocellular carcinoma by radiology, histology, or
             cytology (fibrolamellar and mixed hepatocellular/cholangiocarcinoma subtypes are not
             eligible) will be enrolled in this study.

               -  Radiologic confirmation diagnosis is provided by the study site. Clinically
                  confirmed diagnosis of HCC as per the American Association for the Study of Liver
                  Diseases (AASLD) criteria, which requires:

                    -  Radiographically evident cirrhosis AND

                    -  A liver mass that shows arterial phase hyperenhancement on triphasic
                       computed tomography (CT) or magnetic resonance imaging (MRI), AND EITHER:

                         -  Is >= 20 mm with either non-peripheral portal washout or an enhancing
                            capsule OR

                         -  Is 10-19 mm with non-peripheral portal venous washout AND an enhancing
                            capsule

          -  Have Barcelona Clinic Liver Cancer (BCLC) stage C disease, or BCLC stage B disease not
             amenable to locoregional therapy or refractory to locoregional therapy, and not
             amenable to a curative treatment approach

          -  Have a Child-Pugh class A liver score within 14 days of first dose of study drug

          -  Have a predicted life expectancy of > 3 months

          -  A female participant is eligible to participate if she is not pregnant, not
             breastfeeding, and at least one of the following conditions applies:

               -  Not a woman of childbearing potential (WOCBP) OR

               -  A WOCBP who agrees to follow the contraceptive guidance during the treatment
                  period and for at least 120 days/weeks (corresponding to time needed to eliminate
                  any study treatment(s) after the last dose of study treatment.

               -  Note: a male participant is not required to use contraception during the
                  treatment period for pembrolizumab and BO-112. BO-112 does not have any evidence
                  of genotoxicity at any dose

          -  Participants must have progressed radiographically on treatment with an anti-PD-1/L1
             monoclonal antibody (mAb) administered either as monotherapy or in combination with
             other checkpoint inhibitors or other adjunct therapies. Participants must not have
             received BO-112 previously. PD-1/L1 treatment progression is defined by meeting all of
             the following criteria:

               -  Has received at least 2 doses of an approved anti-PD-1/L1 mAb

               -  Has demonstrated progressive disease after anti-PD-1/L1 as defined by RECIST
                  version (v)1.1

               -  Progressive disease has been documented within 12 weeks from the last dose of
                  anti-PD-1/L1 mAb

                    -  Progressive disease is determined according to RECIST 1.1

                    -  This determination is made by the investigator. Once disease progression is
                       confirmed, the initial date of disease progression documentation will be
                       considered the date of disease progression

          -  The participant (or legally acceptable representative if applicable) provides written
             informed consent for the trial

          -  Have measurable disease based on RECIST 1.1 and accessible for intratumoral injection
             and biopsy. (This lesion to be injected cannot infiltrate the main hepatic vessels.)
             Lesions situated in a previously irradiated area are considered measurable if
             progression has been demonstrated in such lesions after the administration of the
             radiotherapy

          -  Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
             Evaluation of ECOG is to be performed within 7 days prior to cycle 1 day 1 (C1D1)

          -  Subjects with chronic infection by hepatitis C virus (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 achieving sustained viral response (SVR12) and start of study drug.

               -  Successful HCV treatment definition: SVR12

          -  Has been treated with anti-hepatitis B therapy. Controlled (treated) hepatitis B
             subjects will be allowed if they meet the following criteria:

               -  Antiviral therapy for hepatitis B virus (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 hepatitis B core antibody (anti-HBc) (+), negative for hepatitis
                  B surface antigen (HBsAg), and negative or positive for hepatitis B surface
                  antibody (anti-HBs), and who have an HBV viral load under 100 IU/mL, do not
                  require HBV anti-viral prophylaxis

          -  Absolute neutrophil count (ANC) >= 1200/uL (microliters) (within 7 days prior to the
             start of study treatment)

          -  Platelets >= 60 000/uL (within 7 days prior to the start of study treatment)

          -  Hemoglobin >= 8.0 g/dL (within 7 days prior to the start of study treatment)

               -  Criteria must be met without erythropoietin dependency and without packed red
                  blood cell (pRBC) transfusion within last 2 weeks

          -  Creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine
             clearance (glomerular filtration rate [GFR] can be used in place of creatinine
             clearance [CrCl]) >= 30 mL/min for participant with creatinine levels > 1.5 x
             institutional ULN (within 7 days prior to the start of study treatment)

               -  Creatinine clearance (CrCl) should be calculated per institutional standard

          -  Total bilirubin =< 3 mg/dL, or direct bilirubin =< ULN for those with total bilirubin
             > 2 mg/dL (within 7 days prior to the start of study treatment)

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
             alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 5 x ULN
             (within 7 days prior to the start of study treatment)

          -  Albumin >= 2.8 g/dL (within 7 days prior to the start of study treatment)

               -  Note: No albumin supplement (or BCAA) allowed within the last 14 days

          -  International normalized ratio (INR) OR prothrombin time (PT) =< 1.7 unless
             participant is receiving anticoagulant therapy as long as PT or activated partial
             thromboplastin time (aPTT) is within therapeutic range of intended use of
             anticoagulants (within 7 days prior to the start of study treatment)

          -  Activated partial thromboplastin time (aPTT) =< 1.7 unless participant is receiving
             anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended
             use of anticoagulants (within 7 days prior to the start of study treatment)

        Exclusion Criteria:

          -  A WOCBP who has a positive urine pregnancy test within 72 hours prior to C1D1. If the
             urine test is positive or cannot be confirmed as negative, a serum pregnancy test will
             be required. Note: in the event that 72 hours have elapsed between the screening
             pregnancy test and the first dose of study treatment, another pregnancy test (urine or
             serum) must be performed and must be negative in order for subject to start receiving
             study medication

          -  Has received prior systemic anti-cancer therapy including investigational agents
             within 4 weeks prior to C1D1. Note: Participants must have recovered from all adverse
             events (AEs) due to previous therapies to=< grade 1 or baseline. Participants with =<
             grade 2 neuropathy may be eligible. Note: If participant received major surgery, they
             must have recovered adequately from the toxicity and/or complications from the
             intervention prior to starting study treatment

          -  Has had esophageal or gastric variceal bleeding within the last 6 months

          -  Has clinically apparent ascites on physical examination

               -  Note: ascites detectable on imaging studies only are allowed

          -  Has had clinically diagnosed hepatic encephalopathy in the last 3 months. Subjects on
             rifaximin or lactulose to control their hepatic encephalopathy are not allowed

          -  Has received locoregional therapy to liver (transcatheter chemoembolization [TACE],
             transcatheter embolization [TAE], hepatic arterial infusion [HAI], radiation,
             radioembolization, or ablation) within 4 weeks prior to the first dose of study drug.
             A 1-week washout is permitted for palliative radiation (=< 2 weeks of radiotherapy) to
             non-liver, non-central nervous system (CNS) disease

          -  Prior treatment with any Toll-like receptor (TLR) agonist

          -  Has liver lesions with macroscopic tumor infiltration into the main portal vein,
             hepatic vein, or inferior vena cava

          -  Has had major surgery to liver or other site within 4 weeks prior to the first dose of
             study drug

          -  Has had a minor surgery (i.e., simple excision, tooth extraction) =< 7 days prior to
             the first dose of study treatment (cycle 1, day 1)

          -  Contraindications to tumor biopsy and injections of the hepatic metastasis(es), such
             as coagulopathy, therapeutic dose anticoagulant treatment and/or treatment with
             long-acting agents such as clopidogrel which cannot be safely stopped

          -  Is currently participating in or has participated in a study of an investigational
             agent or has used an investigational device within 4 weeks prior to the first dose of
             study intervention. Note: Participants who have entered the follow-up phase of an
             investigational study may participate as long as it has been 4 weeks after the last
             dose of the previous investigational agent

          -  Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
             (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
             immunosuppressive therapy within 7 days prior to the first dose of study drug

          -  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 (e.g. thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
             form of systemic treatment and is allowed

          -  Has a history of a second malignancy, unless potentially curative treatment has been
             completed with no evidence of malignancy for 1 year. Note: The time requirement does
             not apply to participants who underwent successful definitive resection of basal cell
             carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder
             cancer, in situ cervical cancer, prostate cancer, or other in-situ cancers

          -  Has known active CNS metastases and/or carcinomatous meningitis. Participants with
             previously treated brain metastases may participate provided they are radiologically
             stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging
             (note that the repeat imaging should be performed during study screening and at each
             tumor assessment), clinically stable and without requirement of steroid treatment for
             at least 14 days prior to first dose of study intervention

          -  Has severe hypersensitivity (>= grade 3) to pembrolizumab/BO-112 and/or any of its
             excipients

          -  Has a history of (non-infectious) pneumonitis that required steroids or has current
             pneumonitis

          -  Has an active infection requiring systemic therapy

          -  Has a known history of human immunodeficiency virus (HIV) infection (HIV 1/2
             antibodies). Note: No HIV testing is required unless mandated by local health
             authority

          -  Has a known history of active TB (Bacillus tuberculosis)

          -  Has a history or current evidence of any condition, therapy, or laboratory abnormality
             that might confound the results of the study, interfere with the subject's
             participation for the full duration of the study, or is not in the best interest of
             the subject to participate, in the opinion of the treating investigator, including
             dialysis

          -  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 study, starting with the screening visit through 120 days
             after the last dose of trial treatment

          -  Has had an allogenic tissue/solid organ transplant

          -  Has received a live vaccine within 30 days prior to the first dose of study drug.
             Examples of live vaccines include, but are not limited to, the following: measles,
             mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus
             Calmette-Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection
             are generally killed virus vaccines and are allowed; however, intranasal influenza
             vaccines (e.g., FluMist) are live attenuated vaccines and are not allowed
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate (ORR)
Time Frame:Up to 4 years
Safety Issue:
Description:ORR is defined as the proportion of the subjects in the analysis population who have a complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. ORR will be estimated and 95% Clopper-Pearson exact confidence intervals (CIs) will be provided.

Secondary Outcome Measures

Measure:Progression-free survival (PFS)
Time Frame:From Cycle 1 day 1 (each cycle is 21 days) to the first documented disease progression or death due to any cause, whichever occurs first, assessed up to 4 years]
Safety Issue:
Description:Progression will be assessed per RECIST 1.1. PFS will be summarized using the Kaplan Meier method as well as descriptively (mean, standard deviation, median, first and third quartiles, minimum, maximum).
Measure:Time to progression (TTP)
Time Frame:From Cycle 1 day 1 (each cycle is 21 days) to the first documented disease progression, assessed up to 4 years]
Safety Issue:
Description:TTP will be summarized using the Kaplan Meier method as well as descriptively (mean, standard deviation, median, first and third quartiles, minimum, maximum).
Measure:Disease control rate (DCR)
Time Frame:Up to 4 years
Safety Issue:
Description:DCR is defined as the proportion of subjects who have achieved CR, PR, or stable disease after >= 5 weeks (the start of the window for the first scheduled scan) based on assessments by the site per RECIST 1.1.
Measure:Overall survival (OS)
Time Frame:From Cycle 1 day 1 (each cycle is 21 days) to death due to any cause, assessed up to 4 years]
Safety Issue:
Description:OS will be summarized using the Kaplan Meier method as well as descriptively (mean, standard deviation, median, first and third quartiles, minimum, maximum). Figures showing the Kaplan-Meier estimates will also be presented. 12-month survival rate will be recorded.
Measure:Incidence of adverse events
Time Frame:Up to 4 years
Safety Issue:
Description:

Details

Phase:Early Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Jonsson Comprehensive Cancer Center

Last Updated

March 2, 2021