Study of Bavituximab, Axitinib, and Avelumab in Advanced Hepatocellular Carcinoma
Condition: Hepatocellular Carcinoma
MeSH terms: Carcinoma; Carcinoma, Hepatocellular
Intervention: Axitinib; Avelumab; Bavituximab
Intervention description: Axitinib to be administered orally BID; Avelumab to be administered as a 1-hour IV infusion on Day 1 and Day 15 of each 28-day cycle.; Bavituximab to be administered weekly on Days 1, 8, 15 and 22 of the 28-day cycle.
Intervention MeSH terms: Avelumab; Bavituximab; Axitinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 1.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      Across cancer types, immune checkpoint inhibitors have been shown to induce complete
      response, partial response, and stable disease after initial evidence of radiographic
      increase in tumor burden. Treatment beyond progression should be considered when the patient
      is stable (or improving) symptomatically and if tumor reassessment can be performed within a
      short period.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Patient must have a histologically confirmed diagnosis consistent with HCC; known
             fibrolamellar HCC, or combined HCC-cholangiocarcinoma will be excluded.

          2. Locally advanced or metastatic disease

               1. 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.

               2. 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).

          3. Availability of recent formalin-fixed, paraffin-embedded (FFPE) tumor tissue block or
             slides (biopsied tumor lesion should not be a RECIST target lesion): 1) the biopsy or
             resection was performed within 2 years of AND 2) the patient has not received any
             intervening systemic anti-cancer treatment from the time the tissue was obtained.

          4. Prior therapy is allowed provided the following are met: at least 4 weeks since prior
             locoregional therapy including surgical resection, chemoembolization, definitive
             radiotherapy with intent of disease control, 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 as long as the target lesion is not the treated lesion and radiotherapy
             will be completed at least 2 weeks prior to study drug administration.

          5. Age ≥ 18 years

          6. Child-Pugh Score A

          7. ECOG Performance score of 0-1

          8. Adequate organ and marrow function as defined below:

               1. Platelet count ≥ 50,000/mm3

               2. Hgb ≥ 8.5 g/dl

               3. Absolute neutrophil ≥ 1,500 cells/mm3

               4. Total bilirubin ≤ 2.0 mg/ml

               5. INR ≤ 1.7

               6. AST, ALT ≤5 times ULN

               7. Serum creatinine ≤ 1.5 mg/dL or creatinine clearance ≥ 50 mL/min

               8. albumin ≥ 2.5 g/dl

          9. All men, as well as women of child-bearing potential must agree to use adequate
             contraception (hormonal or barrier method of birth control; abstinence) 4 weeks prior
             to study entry, for the duration of study participation, and for 90 days following
             completion of therapy. Should a woman become pregnant or suspect she is pregnant while
             participating in this study, she should inform her treating physician immediately.

             a. A female of child-bearing potential is any woman (regardless of sexual orientation,
             marital status, having undergone a tubal ligation, or remaining celibate by choice)
             who meets the following criteria:

               -  Has not undergone a hysterectomy or bilateral oophorectomy; or

               -  Has not been naturally postmenopausal for at least 12 consecutive months (i.e.,
                  has had menses at any time in the preceding 12 consecutive months).

         10. Women of childbearing potential must have a negative serum pregnancy test within 72
             hours prior to receiving the first dose of study medication.

         11. Subjects are eligible to enroll if they have non-viral-HCC, or if they have HBV-HCC,
             or HCV-HCC defined as follows:

               1. 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.

               2. 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.

         12. Ability to understand and the willingness to sign a written informed consent.

         13. Patients who have received the vector, protein subunit, or nucleic acid COVID-19
             vaccines are eligible to enroll.

        Exclusion Criteria:

          1. Prior liver transplant.

          2. Prior systemic therapy directed at advanced or metastatic HCC.

          3. Prior immunotherapy with IL-2, or anti-PD-1, anti-PD-L1, or anti-cytotoxic
             T-lymphocyte-associated antigen-4 (CTLA-4) antibody, or any other antibody or drug
             specifically targeting T-cell co-stimulation or immune checkpoint pathways.

          4. Prior therapy with axitinib or any prior therapies with other VEGF pathway inhibitors.

          5. Clinically significant, uncontrolled heart disease and/or recent events including any
             of the following:

               1. 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).

               2. History of documented congestive heart failure (New York Heart Association
                  functional classification III-IV).

               3. History of cerebrovascular accident, transient ischemic attack, deep vein
                  thrombosis, or pulmonary embolism within 6 months of screening.

               4. Patient has a left ventricular ejection fraction <40% as determined by MUGA scan
                  or ECHO (MUGA and ECHO are not required prior to enrollment).

          6. Known human immunodeficiency virus (HIV) positive (testing not required).

          7. History of cerebrovascular accident, transient ischemic attack, or thromboembolic
             events (including both pulmonary embolism and deep venous thrombus but not including
             tumor thrombus) within the last 6 months.

          8. Hypersensitivity to IV contrast; not suitable for pre-medication.

          9. Active or fungal infections requiring systemic treatment within 7 days prior to
             screening.

         10. Known history of, or any evidence of, interstitial lung disease or active
             noninfectious pneumonitis.

         11. Evidence of poorly controlled hypertension which is defined as systolic blood pressure
             >159 mmHg or diastolic pressure >99 mmHg despite optimal medical management.

         12. Pre-existing thyroid abnormality with thyroid function that cannot be maintained in
             the normal range with medication.

         13. Active, known, or suspected autoimmune disease with the exception of subjects with
             vitiligo, type I diabetes mellitus, resolved childhood asthma or atopy. Subjects with
             suspected autoimmune thyroid disorders may be enrolled if they are currently euthyroid
             or with residual hypothyroidism requiring only hormone replacement. Subjects with
             psoriasis requiring systemic therapy must be excluded from enrollment.

         14. 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.).

         15. Known history of active bacillus tuberculosis.

         16. 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.

         17. Patient who has received definitive radiotherapy with the sole intent of disease
             control ≤ 4 weeks prior to study entry. Palliative radiotherapy for symptomatic
             control (such as to bone metastases) is acceptable (if completed at least 2 weeks
             prior to study drug administration and no additional radiotherapy for the same lesion
             is planned).

         18. 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).

         19. Clinically apparent ascites on physical examination, ascites present on imaging
             studies is allowed.

         20. Known severe hypersensitivity reactions to monoclonal antibodies (Grade 3).

         21. Active gastrointestinal bleeding within previous 2 months.

         22. History of any condition requiring anti-platelet therapy (aspirin >300 mg/day,
             clopidogrel >75 mg/day).

         23. Diagnosis of any other malignancy within 5 years prior to screening visit, except for
             adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of
             the breast or of the cervix, or low-grade (Gleason 6 or below) prostate cancer on
             surveillance with no plans for treatment intervention (eg, surgery, radiation, or
             castration).

         24. Prisoners or subjects who are involuntarily incarcerated.

         25. History of leptomeningeal disease.

         26. Symptomatic or clinically active brain metastases.

         27. 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.

         28. Has dual active HBV infection (HBsAg (+) and /or detectable HBV DNA) and HCV infection
             (anti-HCV Ab(+) and detectable HCV RNA) at study entry.

         29. Known prior or suspected hypersensitivity to study drugs or any component in their
             formulations.

         30. Current use or anticipated need for drugs that are known strong CYP3A4/5 inducers,
             including their administration within 10 days prior to patient receiving the first
             study treatment, eg, phenobarbital, rifampin, phenytoin, carbamazepine, rifabutin,
             rifapentin, clevidipine, St John's wort.

         31. Patients with 2+ proteinuria on urine dipstick analysis and confirmed to have ≥2 grams
             of protein in a 24-hour urine collection.

         32. Current use or anticipated need for treatment with drugs or foods that are known
             strong CYP3A4/5 inhibitors, including their administration within 10 days prior to
             patient receiving the first study treatment, (eg, grapefruit juice or
             grapefruit/grapefruit-related citrus fruits, ketoconazole, miconazole, itraconazole,
             voriconazole, posaconazole, clarithromycin, telithromycin, indinavir, saquinavir,
             ritonavir, nelfinavir, amprenavir, fosamprenavir nefazodone, lopinavir,
             troleandomycin, mibefradil, and conivaptan). The topical use of these medications (if
             applicable), such as 2% ketoconazole cream, is allowed.