Study of RP2 in Combination With Second-line Therapy in Patients With Locally Advanced or Metastatic HCC

NCT05733598 | Recruiting Phase 2 FDA Drug

• 1 other identifier: RP2-003
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 12

Brief Summary

The purpose of this study is to assess the efficacy and safety of RP2 in combination with atezolizumab plus bevacizumab (Cohorts 1a and 1b) and RP2 monotherapy (Cohort 2) in the as second line treatment in patients with locally advanced unresectable, recurrent, and/or metastatic HCC and in combination with durvalumab as treatment in patients with unresectable locally advanced or metastatic BTC.

Conditions

Hepatocellular Carcinoma; Biliary Tract Cancer

Keywords

Oncolytic virus; Hepatocellular Carcinoma; HCC; Biliary Tract Cancer; BTC

Outcome Measures

Primary Outcomes (1)

• Overall Response Rate per modified RECIST 1.1

  The proportion of patients achieving a BOR of CR or PR per RECIST 1.1 among those that are evaluable for response.

  From Day 1 up to 3 years after first RP2 dose of last patient.

Secondary Outcomes (3)

• Number of patients with treatment-emergent adverse events (TEAEs)

  From Day 1 up to 135 days after last dose.

• ORR per RECIST modified for HCC (HCC mRECIST) for HCC cohort only

  From Day 1 up to 3 years after first RP2 dose of last patient

• Duration of response (DOR)

  From Day 1 up to 3 years after first RP2 dose of last patient.

Study Arms (3)

RP2+Bevacizumab and Atezolizumab

EXPERIMENTAL

HCC Cohort 1a and 1b: Patients with locally advanced unresectable, recurrent and/or metastatic HCC who have progressed on 1 prior systemic treatment, which must have included anti-programmed cell death 1 (PD-1)/anti-PD-L1 therapy. Patients will receive atezolizumab plus bevacizumab therapy combined with RP2. In cohort 1a, patients will receive RP2 intratumorally every 2 weeks (Q2W) for 4 doses, then every 3 weeks (Q3W) for 4 doses combined with atezolizumab plus bevacizumab. In cohort 1b, patients will receive RP2 intratumorally every 2 weeks (Q2W) for 8 doses combined with atezolizumab plus bevacizumab.

Biological: RP2; Biological: Bevacizumab; Biological: Atezolizumab

RP2 Monotherapy

EXPERIMENTAL

HCC Cohort 2: Patients with locally advanced unresectable, recurrent and/or metastatic HCC who have progressed on 1 prior systemic treatment, which must have included anti-programmed cell death 1 (PD-1)/anti-PD-L1 therapy. Patients will receive RP2 monotherapy every 2 weeks (Q2W).

Biological: RP2 Monotherapy

RP2+Durvalumab

EXPERIMENTAL

BTC Cohort (Cohort 3): Patients with locally advanced or metastatic BTC (intrahepatic or extrahepatic cholangiocarcinoma or gall bladder carcinoma), who have received treatment with combination gemcitabine, platinum-containing chemotherapy, and checkpoint inhibitor for a minimum of 12 weeks (4 to 8 cycles) and maximum of 24 weeks, and who have had stable disease or partial response on 2 on treatment scans and no progressive disease. After the last combination chemotherapy treatment, checkpoint inhibitor treatment must be limited to 2 doses (8 weeks). Patients will receive durvalumab combined with RP2.

Biological: RP2; Biological: Durvalumab

Interventions

RP2 BIOLOGICAL

Genetically modified herpes simplex type 1 virus for tumor lysis and immune stimulation.

RP2+Bevacizumab and Atezolizumab; RP2+Durvalumab

Bevacizumab BIOLOGICAL

Anti-VEGF therapy.

Also known as: Avastin

RP2+Bevacizumab and Atezolizumab

Atezolizumab BIOLOGICAL

Anti-PD-L1 monoclonal antibody.

Also known as: Tecentriq

RP2+Bevacizumab and Atezolizumab

Durvalumab BIOLOGICAL

Anti-PD-L1 monoclonal antibody

Also known as: Imfinzi

RP2+Durvalumab

RP2 Monotherapy BIOLOGICAL

Genetically modified herpes simplex type 1 virus for tumor lysis and immune stimulation.

Also known as: RP2

RP2 Monotherapy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• I 1. Male or female ≥ 18 years of age. I 2. (HCC only) 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".
• I 3. (HCC only) Must have progressed while on first and only 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.
• I 4. (HCC only) Child-Pugh A, determined within 14 days before first study treatment.
• I 5. 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.
• I 6. Has injectable tumor(s), which alone or in aggregate, total at least 1 cm in diameter.
• I 7. 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.
• I 8. Has adequate hematologic function, including: White blood cell (WBC) count ≥ 2.0 × 109/L; absolute neutrophil count (ANC) ≥ 1.5 × 109/L (without granulocyte-colony stimulating factor support); platelet count ≥ 75 × 109/L (without transfusion); hemoglobin ≥ 8.5 g/dL (may have received transfusions; however, patient must not be transfusion-dependent).
• I 9. Has adequate hepatic function including: total bilirubin ≤ 3.0 × upper limit of normal (ULN); aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤ 5.0 × ULN.
• I 10. Has adequate renal function, defined as serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 30 mL/minute (measured using Cockcroft-Gault formula).
• I 11. Serum albumin ≥ 2.8 g/dL. I 12. 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.
• I 13. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
• I 14. Female and male patients who meet the following criteria:
• Female patients are eligible if not pregnant (see IC #15) or breastfeeding and if one of the following applies 1) is a woman of non-childbearing potential (WNCBP) OR 2) is a woman of childbearing potential and must agree to use a highly effective contraception method 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, or (d) 90 days after the last dose of durvalumab, whichever is longer.
• Male patients are eligible to participate if they agree to the following during the study treatment period, and for at least 90 days after the last dose of RP2: refrain from donating fresh unwashed sperm plus either be abstinent from intercourse where pregnancy can occur (abstinent on a long term and persistent basis) OR must agree to use an external condom and also should advise their partner to use a highly effective method of contraception as a condom may break or leak.
• I 15. Women of childbearing potential 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.

You may not qualify if:

• E 1. (HCC only) Child-Pugh B or C. E 2. (HCC only) Patients with untreated or incompletely treated esophageal and/or gastric varices with bleeding or high-risk for bleeding.
• Note: Note: All patients in Cohort 1a and 1b must undergo an esophagogastroduodenoscopy (EGD), and all varices (irrespective of size) must be assessed and treated regardless of grade before enrollment. Patients who have undergone endoscopic treatment of all known varices 90 days before initiation of study treatment do not need to repeat the procedure.
• Note: EGD is not required for patients in Cohort 2 (RP2 monotherapy). E 3. Significant bleeding event within the last 12 months that places the patient at unjustifiable risk for bleeding from intratumoral injection procedures, based on Investigator or interventional radiologist assessment.
• E 4. (HCC only) Macroscopic intravascular invasion into the hepatic and/or portal vein(s) (ie, no Vp4), , vena cava, and/or other major blood vessel, or into the common bile duct(s).
• E 5. (HCC only) Histologic evidence of fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma with HCC, or other rare HCC variants.
• E 6. History of medically refractory hepatic encephalopathy and/or hepato-renal syndrome.
• E 7. Disease that is amenable to curative surgical and/or locoregional therapies.
• E 8. Presence of liver tumors that are estimated to invade more than one-third of the liver.
• E 9. Uncontrollable pleural effusion, pericardial effusion, or ascites requiring drainage within 7 days before enrollment.
• E 10. Hepatitis B virus (HBV) DNA \> 500 IU/mL obtained within 28 days prior to initiation of study treatment. Co-infection of HBV and hepatitis C virus (HCV) is not allowed.
• Note: Patients with HBV DNA ≤ 500 U/mL are eligible to enroll in the study. Patients must be on anti-HBV treatment (per local standard care that do not have activity with HSV. Entecavir, tenofovir, telbivudine, lamivudine can be used. Anti-HBV treatment must be given for a minimum of 14 days prior to Week 1 Day 1 and must continue antiviral treatment for the length of the study.
• E 11. Known human immunodeficiency virus (HIV) infection. Note: Testing for HIV is not required unless mandated by local health authority or clinically indicated.
• E 12. 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 IV) antivirals with known antiherpetic activity (eg, acyclovir).
• Note: Patients with sporadic cold sores may be enrolled if no active cold sores are present at the time of Dose 1 Day 1.
• E 13. Systemic infection requiring IV antibiotics or other serious infection within 14 days before dosing.

Sponsors & Collaborators

• Replimune Inc.: lead

Study Sites (12)

Beverly Hills Cancer Center

Beverly Hills, California, 90211, United States

RECRUITING

UC San Diego Moores Cancer Center

La Jolla, California, 92037, United States

RECRUITING

Sylvester Comprehensive Cancer Center (University of Miami Hospital and Clinics)

Miami, Florida, 33136, United States

RECRUITING

Moffitt Cancer Center

Tampa, Florida, 33612, United States

RECRUITING

University of Maryland Medical Center

Baltimore, Maryland, 21201, United States

RECRUITING

Roswell Park Comprehensive Cancer Center

Buffalo, New York, 14236, United States

RECRUITING

Montefiore Medical CenterMontefiore Medical Park

The Bronx, New York, 10461, United States

RECRUITING

University of Pennsylvania, Abramson Cancer Center

Philadelphia, Pennsylvania, 19104, United States

RECRUITING

UPMC Hillman Cancer Center

Pittsburgh, Pennsylvania, 15232, United States

RECRUITING

The West Clinic

Germantown, Tennessee, 38138, United States

RECRUITING

University of Tennessee Medical Center

Knoxville, Tennessee, 37920, United States

RECRUITING

Houston Methodist Hospital Cancer Center

Houston, Texas, 77030, United States

RECRUITING

MeSH Terms

Conditions

Carcinoma, Hepatocellular; Biliary Tract Neoplasms

Interventions

Bevacizumab; atezolizumab; durvalumab

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases; Biliary Tract Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Gary Vanasse, MD

  Replimune Inc.

  STUDY DIRECTOR

Central Study Contacts

Clinical Trials at Replimune

CONTACT

1-781-222-9570; hccstudy@replimune.com

Clinical Trials at Replimune

CONTACT

+44 1235 242 488; hccstudy@replimune.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: This study will enroll patients with locally advanced unresectable, recurrent, and/or metastatic HCC (second line) and patients with unresectable locally advanced or metastatic BTC (first line after chemotherapy discontinuation). Study periods include Screening (28 days), Treatment, and Follow-Up. HCC Cohorts 1a/1b/2: First tumor assessment at Week 10 (±3 days) from first dose; second: 9 (±3 days) weeks later; then every 8 weeks (Q8W). BTC Cohort 3: First assessment at Week 8 (±3 days); then Q8W. Safety Follow-Up: 30 and 60 days after last RP2 dose; 135 days after last atezolizumab, bevacizumab, or durvalumab dose. Efficacy Follow-Up: Imaging every 12 weeks. Survival Follow-Up: Collected by phone every 3 months for up to 3 years from first RP2 dose or until death.

Study Record Dates

• First Submitted: February 8, 2023
• First Posted: February 17, 2023
• Study Start: August 1, 2024
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): July 1, 2028
• Last Updated: April 2, 2026

Record last verified: 2026-03

Locations

US (12)