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

Prior treatment

• Prior liver transplant;
• Patient who has received previous systemic therapy for HCC;
• 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;
• Active or fungal infections requiring systemic treatment within 7 days prior to screening;
• Pre-existing thyroid abnormality with thyroid function that cannot be maintained in the normal range with medication;
• 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.);
• 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);
• Active gastrointestinal bleeding within previous 2 months;
• Prior immunotherapy including anti-PD-1, anti-PD-L1, or anti-PD-L2 agents;

Other illness

• Clinically significant, uncontrolled heart disease and/or recent events including any of the following:
• History of documented congestive heart failure (New York Heart Association functional classification III-IV);
• 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;
• 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;
• 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.
• Known history of active bacillus tuberculosis;
• Patient has a known hypersensitivity to any of the excipients of bavituximab or pembrolizumab or monoclonal antibody;
• Has dual active HBV infection (HBsAg (+) and /or detectable HBV DNA) and HCV infection (anti-HCV Ab(+) and detectable HCV RNA) at study entry.

Lab values

• Patient has a left ventricular ejection fraction \<40% as determined by MUGA scan or ECHO (MUGA and ECHO are not required prior to enrollment);
• History of any condition requiring anti-platelet therapy (aspirin \>300 mg/day, clopidogrel \>75 mg/day);
• 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;

Other

• Documented cardiomyopathy;
• Clinically apparent ascites on physical examination, ascites present on imaging studies is allowed;
• Prisoners or subjects who are involuntarily incarcerated;
• Symptomatic or clinically active brain metastases;

• 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:
  • Total bilirubin ≤ 2.0 mg/ml
  • INR ≤ 1.7
  • Hgb ≥ 8.5 g/dl
  • AST, ALT ≤5 times ULN
  • Platelet count ≥ 50,000/mm3
  • Serum creatinine ≤ 1.5 mg/dL or creatinine clearance ≥ 50 mL/min
  • Albumin ≥ 2.5 g/dl
  • 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.
• 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.