Clinical Trial 23065

• Overview

  Study Title:

  A Phase 2, Open-label, Multicenter Study Investigating RP2 Oncolytic Immunotherapy in Combination with Second-line Therapy in Patients with Locally Advanced Unresectable, Recurrent and/or Metastatic Hepatocellular Carcinoma

  Objective:

  Primary: To assess the efficacy of RP2 treatment in combination with atezolizumab and bevacizumab as 2L systemic treatment in patients with locally advanced unresectable, recurrent, and/or metastatic HCC. Secondary: To assess the safety of RP2 treatment in combination with atezolizumab and bevacizumab. To assess additional measures of antitumor activity of RP2 treatment in combination with atezolizumab and bevacizumab.

• Treatments

  Therapies:

  Immunotherapy; Oncolytic Virotherapy; PD-L1 Inhibitor

  Medications:

  AMP-514 (Durvalumab); Atezolizumab (Tecentriq); Avastin (Bevacizumab); Bevacizumab (); Durvalumab (); MEDI4736 (Durvalumab); RP2 ()

• Inclusion Criteria

  Key Inclusion Criteria:
  • Male or female who is 18 years of age or older at the time of signed informed consent.
  • Has locally advanced unresectable, recurrent, and/or metastatic HCC, with the diagnosis confirmed by histologic or cytologic analysis or clinical features or imaging criteria (using LI-RADS v2018; [Chernyak 2018]) according to the American Association for the Study of Liver Diseases criteria for patients with cirrhosis (Marrero 2018). Sites should select lesions that are either "probable HCC - LIRADS 4" or "definite HCC – LIRADS 5".
  • Must have progressed while on their first and only prior systemic therapy, which must have included anti-PD-1 or anti-PD-L1 therapy (eg, atezolizumab plus bevacizumab combination, durvalumab plus tremelimumab combination, durvalumab, pembrolizumab, or nivolumab monotherapy, or nivolumab in combination with ipilimumab) as their immediate prior treatment regimen.
  • Child-Pugh A, determined within 14 days before first study treatment.
  • Has at least 1 measurable tumor of ≥ 1 cm in longest diameter (or ≥ 1.5 cm shortest diameter for lymph nodes) as defined by RECIST 1.1.
  • Has injectable tumor(s), which alone or in aggregate, total at least 1 cm in diameter.
  • Must be willing to consent to provide fresh tumor biopsy sample or archival tumor biopsy sample obtained within 90 days before the first dose of study treatment.
  • Has adequate hematologic function, including: White blood cell (WBC) count ≥ 2.0 × 10^9 /L, Absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L (without granulocyte-colony stimulating factor support), Platelet count ≥ 50 × 10^9/L (without transfusion), Hemoglobin ≥ 8.5 g/dL (may have received transfusions; however, patient must not be transfusion-dependent).
  • Has adequate hepatic function, including: Total bilirubin > Has adequate renal function, defined as serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 30 mL/minute (measured using Cockcroft-Gault formula).
  • Serum albumin ≥ 2.8 g/dL.
  • Prothrombin time (PT) ≤ 1.5 × ULN (or international normalization ratio [INR] ≤ 1.7) and partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN.
  • Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
  • Women of childbearing potential (as defined in Appendix A) and men of reproductive potential must agree to avoid becoming pregnant or impregnating a partner, respectively, and adhere to highly effective contraception requirements after signing informed consent, during the treatment period, and for at least (a) 90 days after the last dose of RP2 or (b) 5 months after the last dose of atezolizumab or (c) 6 months after the last dose of bevacizumab, whichever is longer. Men must also agree to refrain from donating sperm during the treatment period and for at least 90 days after the last dose of RP2.
  • Women of childbearing potential (as defined in Appendix A) must have a negative serum beta-human chorionic gonadotropin (β-hCG) test with a minimum sensitivity of 25 IU/L or equivalent units of β-hCG within 72 hours before the first dose and a negative urine pregnancy test on Dose 1 Day 1.
  • Capable of giving signed informed consent which includes willingness to comply with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
  • Other inclusion criteria may apply.

• Exclusion Criteria

  Key Exclusion Criteria:
  • Child-Pugh B or C.
  • Patients with untreated or incompletely treated esophageal or gastric varices with bleeding or high-risk for bleeding.
  • Significant bleeding event within the last 12 months that places the patient at unjustifiable risk for bleeding from intratumoral injection procedure, based on Investigator or interventional radiologist assessment.
  • Macroscopic intravascular invasion into the hepatic and/or segmental portal vein(s), hepatic vein, vena cava, or other major blood vessel, or into the hepatic and/or common bile duct(s).
  • Histologic evidence of fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma with HCC, or other rare HCC variants.
  • History of medically refractory hepatic encephalopathy and/or hepato-renal syndrome.
  • Disease that is amenable to curative surgical and/or locoregional therapies.
  • Presence of liver tumors that are estimated to invade more than one-third of the liver.
  • Uncontrollable pleural effusion, pericardial effusion, or ascites requiring drainage within 7 days before enrollment.
  • Known acute or chronic hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or acute or chronic hepatitis C virus (defined as HCV RNA [qualitative] is detected).
  • Known human immunodeficiency virus (HIV) infection.
  • Active significant herpetic infections or prior complications of HSV-1 infection (eg, herpetic keratitis or encephalitis) or requires intermittent or chronic use of systemic (oral or intravenous [IV]) antivirals with known antiherpetic activity (eg, acyclovir).
  • Systemic infection requiring IV antibiotics or other serious infection within 14 days before dosing.
  • Received a live vaccine within 28 days before the first dose of study treatment.
  • Known central nervous system (CNS) metastases and/or carcinomatous meningitis.
  • Prior malignancy, other than HCC, active within the previous 3 years, except for localized cancers that have been cured including basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.
  • Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks before the first dose of study treatment.
  • Systemic anticancer therapies within 4 weeks of the first dose of study drug. The prior anti-PD-1 or anti-PD-L1 containing regimen is excluded from this requirement.
  • Received radiotherapy within 2 weeks of start of study treatment. Patients must have recovered from all radiation-related toxicities (except for radiation-induced xerostomia), not require corticosteroids, and not have had radiation pneumonitis. A 1week washout is permitted for palliative radiation (≤ 2 weeks of radiotherapy) to non-CNS disease.
  • Received prior treatment with an oncolytic virus therapy.
  • History of significant cardiac disease including myocarditis or congestive heart failure (defined as New York Heart Association Functional Classification III or IV), or unstable angina, serious uncontrolled cardiac arrhythmia, or myocardial infarction within 6 months of enrollment.
  • Uncontrolled infection.
  • History of interstitial lung disease, idiopathic pulmonary fibrosis, organizing pneumonia (eg, bronchiolitis obliterans), non-infectious pneumonitis that required steroids, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan.
  • Active tuberculosis.
  • Other exclusion criteria may apply.

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