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