Einstein Montefiore

Eligibility

Eligible Ages

Over 18 Years

Eligible Genders

All

Accepts Healthy Volunteers

No

Criteria

Subjects to be included

1. ≥ 18 years old

2. Signed and dated written informed consent

3. Histologically or cytologically or radiologically confirmed unresectable locally
advanced or metastatic hepatocellular carcinoma. Measurable or evaluable disease by
RECIST 1.1 criteria. Patients can be either untreated or have progressed on both
bevacizumab and atezolizumab or both bevacizumab and atezolizumab in combination with
a second immune checkpoint inhibitor.

o Patients who may have progressed on bevacizumab and atezolizumab who have any
suggestion of pseudo-progression, should remain on bevacizumab and atezolizumab until
progression is confirmed.

4. Child-Pugh Class A.

5. ECOG performance status ≤ 1 (see Appendix A) and life expectancy ≥ 3 months.

6. Body weight > 30 kg

7. Measured creatinine clearance (crCL) >40 mL/min or calculated crCL >40 mL/min as
determined by Cockcroft-Gault (using actual body weight) Males CrCL = Weight (kg) ×
(140 - Age) 72 × serum creatinine (mg/dL) Females CrCL = Weight (kg) × (140 - Age) 85
× serum creatinine (mg/dL)

8. Sexually active pre-menopausal female subjects (and female partners of male subjects)
must use highly effective contraceptive measures, while on study and for at least 90
days after the last dose of study drug. Sexually active male subjects must use
adequate contraceptive measures, while on study and for at least 90 days after the
last dose of study drug. All fertile male and female subjects and their partners must
agree to use a highly effective method of contraception.

Note - COVID-19 testing is not required prior to enrollment into the protocol, however,
institutional guidelines on testing should be followed.

Subjects to be excluded

1. Subjects who have received prior systemic treatment for HCC except for both
bevacizumab and atezolizumab or both bevacizumab and atezolizumab in combination with
a second immune checkpoint inhibitor.

2. Female subjects who are pregnant or breastfeeding or male or female subjects of
reproductive potential who are not willing to employ effective birth control from
screening to 90 days after the last dose of study drug.

3. Brain metastases or spinal cord compression. Subjects with suspected brain metastases
at screening should have an MRI (preferred) or CT scan each preferable with IV
contrast of the brain prior to study entry. Brain metastases will not be recorded on
RECIST Target Lesions at baseline.

4. Any of the following hematologic abnormalities:

- Hemoglobin < 9.0 g/dL

- Absolute neutrophil count (ANC) < 1500 per mm3

- Platelet count < 75,000 per mm3

5. Any of the following serum chemistry or urinalysis abnormalities:

- Total bilirubin > 2 × ULN (>2.5 mg/dL in subjects with Gilbert's syndrome)

- AST or ALT > 5 × ULN

- Alkaline phosphatase > 2.5 × ULN (or > 5 × ULN for subjects with liver or bone
metastasis)

- Serum creatinine > 1.5 × ULN •> 2+ proteinuria

6. History of hepatic encephalopathy within past 12 months or requirement for medications
to prevent or control encephalopathy (eg, no lactulose, rifaximin, etc if used for
purposes of hepatic encephalopathy).

7. GI Bleeding (eg, esophageal varices or ulcer bleeding) within 12 months. (Note: For
patients with a history of GI bleeding for more than 12 months or assessed as high
risk for esophageal variceal bleed by the Investigator, adequate endoscopic therapy
according to institutional standards is required).

8. Clinically meaningful ascites defined as ascites requiring non-pharmacologic
intervention (eg, paracentesis) to maintain symptomatic control, within 6 months prior
to the first scheduled dose. Subjects on stable doses of diuretics for ascites for ≥ 2
months are eligible.

9. Main portal vein thrombosis (Vp4) as documented on imaging. (VP4 is defined as portal
vein thrombosis in the main trunk of the portal vein or a portal vein branch
contralateral to the primarily involved lobe (or both).

10. For subjects who require ongoing therapeutic anti-coagulation or anti-platelet
therapy; the subject must be off either therapy for at least 7 days prior to the first
dose of investigational product. Low-dose aspirin for cardiac prophylaxis/protection
is permitted per local institutional standards.

11. Patients co-infected with HBV and HCV. HBV positive [presence of hepatitis B surface
antigen (HBsAg) and/or hepatitis B core antibodies (anti-HBcAb) with detectable HBV
DNA (≥10IU/ml)]; HCV positive (presence of anti-HCV antibodies).

12. Major surgery (as defined by the investigator) within 28 days prior to first dose of
IP or still recovering from prior surgery. Local procedures (eg, core needle biopsy,
and prostate biopsy) are allowed if completed at least 3 days prior to the
administration of the first dose of study treatment.

13. Significant cardiovascular disease, including:

- Clinically symptomatic heart failure. Subjects with a history of heart failure
must have an ECHO or MUGA scan to document left ventricular ejection fraction
(LVEF) > 45% prior to start of protocol therapy

- Any New York Heart Association classification ≥ Class 2 (prefer Class 0 or 1)

- Any stenting procedure within the last 3 months

- Venous thromboembolism or arterial thromboembolism within the last 3 months

- Any IVC tumor thrombosis

- History of a hemorrhagic event (i.e., GI bleed within 6 months)

- Uncontrolled hypertension: blood pressure >150/95 mmHg on more than 2
antihypertensive medications, on two consecutive measurements obtained at least
24 hours apart. Subjects with a history of hypertension must have been on stable
doses of anti-hypertensive drugs for ≥ 2 weeks prior to start of protocol
therapy.

- Myocardial infarction within 3 months prior to start of protocol therapy

14. Subjects with delayed healing of wounds, ulcers, and/or bone fractures

15. Serious/active infection or infection requiring parenteral antibiotics

16. Inadequate recovery from any prior surgical procedure; major surgical procedure within
4 weeks prior to start of protocol therapy.

17. Inability to comply with protocol requirements

18. History of another primary malignancy except for:

- Malignancy treated with curative intent and with no known active disease ≥ 5
years before the first dose of study drug and low potential risk for recurrence

- Adequately treated non-melanoma skin cancer of lentigo maligna without evidence
of disease

19. Active infection including tuberculosis (clinical evaluation that includes clinical
history, physical examination and radiographic findings, and tuberculosis testing in
line with local practice), hepatitis C, or human immunodeficiency virus (positive HIV
1/2 antibodies). Subjects positive for hepatitis C (HCV) antibody are eligible only if
polymerase chain reaction is negative for HCV RNA.

20. Patients with a history or current HBV infection (detectable HBV DNA), should be
placed on anti-viral treatment and tested at every cycle for HBV DNA viral load.

21. Palliative radiotherapy with a limited field of radiation within 2 weeks or with wide
field of radiation or to more than 30% of the bone marrow within 4 weeks before the
first dose of study intervention.

22. Treatment with systemic hormonal therapy within 3 weeks prior to start of protocol
therapy, with the exception of:

- Hormonal therapy for appetite stimulation or contraception

- Nasal, ophthalmic, inhaled and topical steroid preparations

- Oral replacement therapy for adrenal insufficiency

- Low-dose maintenance steroid therapy (equivalent of prednisone 10mg/day) for
other conditions

- Hormone replacement therapy such as testosterone

23. Strong CYP3A4 inducers (see Appendix B) within 2 weeks prior to start of, or during,
protocol therapy.

24. Prior exposure to tivozanib or durvalumab. For subjects who have received prior
atezolizumab:

- Must not have experienced a toxicity that led to permanent discontinuation of
prior immunotherapy.

- All AEs while receiving prior immunotherapy must have completely resolved or
resolved to baseline prior to screening for this study.

- Must not have experienced a Grade ≥ 3 immune-related AE or an immune-related
neurologic or ocular AE of any grade while receiving prior immunotherapy. Note:
Participants with an endocrine AE of Grade ≤ 2 are permitted to enroll if they
are stably maintained on appropriate replacement therapy and are asymptomatic.

- Must not have required the use of additional immunosuppression other than
corticosteroids for the management of an AE, not have experienced recurrence of
an AE if re-challenged, and not currently require maintenance doses of > 10 mg
prednisone or equivalent per day.

25. History of allogeneic organ transplantation

26. Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with
the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome,
or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid
arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this
criterion:

- Subjects with vitiligo or alopecia

- Subjects with hypothyroidism (e.g., following Hashimoto syndrome) stable on
hormone replacement

- Any chronic skin condition that does not require systemic therapy

- Subjects without active disease in the last 5 years may be included but only
after consultation with Medical Monitor

- Subjects with celiac disease controlled by diet alone

27. Uncontrolled intercurrent illness, including but not limited to, ongoing or active
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
angina pectoris, uncontrolled cardiac arrhythmia, active interstitial lung disease,
serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric
illness/social situations that would limit compliance with study requirement,
substantially increase risk of incurring AEs or compromise the ability of the subject
to give written informed consent

28. History of leptomeningeal carcinomatosis

29. History of active primary immunodeficiency

30. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms
calculated from 3 ECGs (within 15 minutes at 5 minutes apart)

31. Known allergy or hypersensitivity to any of the study drugs or any of the study drug
excipients

32. Concurrent enrollment in another clinical study, unless it is an observational (non
interventional) clinical study or during the follow-up period of an interventional
study

33. Receipt of live attenuated vaccine within 30 days prior to the first dose of study
drug. Note: Subjects, if enrolled, should not receive live vaccine whilst receiving
study drug and up to 30 days after the last dose of study drug.

34. Current or prior use of immunosuppressive medication within 14 days before the first
dose of durvalumab. The following are exceptions to this criterion:

- Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra
articular injection)

- Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
prednisone or its equivalent

- Steroids as premedication for hypersensitivity reactions (e.g., CT scan
premedication)

35. Previous study drug assignment in the present study.