Clinical trial NCT05733598: Study of RP2 in Combination With Second-line Therapy in Patients With Locally Advanced Unresectable or Metastatic HCC
Official 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Hepatocellular Carcinoma
Keywords: Oncolytic virus
Hepatocellular Carcinoma
Lead sponsor: Replimune Inc.
Sponsor class: INDUSTRY
First posted: 2023-02-17
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Patients will receive atezolizumab plus bevacizumab therapy combined with RP2.

Treatment Administration:

* RP2 administered intratumorally for a total of up to 8 doses as follows: Once every 2 weeks (Q2W) for the first 4 doses (Days 1, 15, 29, 43); Once every 3 weeks (Q3W) for up to 4 subsequent doses (Days 64, 85, 106, 127).
* The first 3 doses of bevacizumab will be administered intravenously (IV) at 10 mg/kg of body weight Q2W, starting with the fourth dose, bevacizumab will be given at 15 mg/kg of body weight Q3W. Starting with the second dose of RP2, atezolizumab will be administered IV at 840 mg for 2 doses Q2W. Starting with the fourth dose, atezolizumab will be administered IV at 1200 mg Q3W. When combination dosing with bevacizumab and atezolizumab starts, bevacizumab will be administered after atezolizumab on the same day, with a minimum of 10 minutes between dosing.
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate whether treatment with RP2 can provide efficacy as 2L treatment combined with atezolizumab plus bevacizumab in patients with locally advanced unresectable, recurrent, and/or metastatic HCC.


Eligibility criteria: Key Inclusion Criteria:

Patient Population For the purposes of this clinical study, "enrolled/enrollment" means that patients, or their legally acceptable representatives', agree to participate in the study following completion of the informed consent process, confirmation of eligibility, and attendance at a Week 1 Day 1 Visit.

Inclusion criteria:

I 1. Male or female ≥ 18 years of age. I 2. 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) according to the American Association for the Study of Liver Diseases criteria for patients with cirrhosis. Sites should select lesions that are either "probable HCC - LIRADS 4" or "definite HCC - LIRADS 5".

I 3. 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. 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:

1. Females who are not pregnant (see IC #15) or breast feeding. Women of childbearing potential (WOCBP ) must agree to avoid becoming pregnant, 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.
2. Male patients must agree to avoid impregnating a partner and adhere to highly effective contraception requirements after signing informed consent, during the RP2 treatment period, and for at least 90 days after the last does of RP2. Male patients must also agree to refrain from donating sperm during the RP2 treatment period and for at least 90 days after the last dose of RP2.

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.

I 16. Capable of giving signed informed consent which includes willingness to comply with the requirements and restrictions listed in the informed consent form and in this protocol.

Key Exclusion Criteria:

E 1. Child-Pugh B or C. E 2. Patients with untreated or incompletely treated esophageal and/or gastric varices with bleeding or high-risk for bleeding.

Note: All patients must undergo an esophagogastroduodenoscopy, and all varices (irrespective of size) must be assessed and treated per local standards of care before enrollment. Patients who have undergone endoscopic management of all known varices 120 days before initiation of study treatment do not need to repeat the procedure.

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. Macroscopic intravascular invasion into the hepatic and/or segmental vein(s) (ie, no Vp4), hepatic vein, vena cava, and/or other major blood vessel, or into the hepatic and/or common bile duct(s).

E 5. 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 provided that patients must be on anti-HBV treatment (per local standard care that do not have activity with HSV such as entecavir, tenofovir, telbivudine, lamivudine) for a minimum of 14 days prior to Cycle 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.

E 14. Received a live vaccine within 28 days before the first dose of study treatment.

E 15. Known central nervous system (CNS) metastases and/or carcinomatous meningitis.

E 16. Prior malignancy, other than HCC, active within the previous 3 years, except for localized cancers that have apparently been cured including basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.

E 17. 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.

Note: Patients who have entered the follow-up phase of an investigational study may participate if it has been 4 weeks after the last dose of the previous investigational agent.

E 18. 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.

Note: Patients must have recovered (to Grade ≤ 1 or baseline) from all AEs due to previous therapies. Patients with Grade ≤ 2 neuropathy may be eligible if approved by the Medical Monitor.

E 19. 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 1-week washout is permitted for palliative radiation (≤ 2 weeks of radiotherapy) to non-CNS disease.

E 20. Received prior treatment with an oncolytic virus therapy. E 21. 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.

E 22. Uncontrolled infection. E 23. 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 CT scan.

Note: History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

E 24. Active tuberculosis. E 25. History or evidence of psychiatric, substance abuse, or any other clinically significant disorder, condition, or disease (except for those outlined above) that, in the opinion of the Investigator or the Medical Monitor, would pose a risk to patient safety or interfere with the study evaluation, procedures, or completion.

E 26. History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study, or is not in the best interest of the patient to participate, in the opinion of the Investigator.

E 27. Active, known, or suspected autoimmune disease requiring systemic treatment.

Note: Patients with type 1 diabetes mellitus and/or hypothyroidism requiring only hormone replacement, and/or with autoimmune skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, and/or prior non-serious autoimmune conditions not expected to recur are permitted to enroll.

E 28. Conditions requiring treatment with immunosuppressive doses (\> 10 mg per day of prednisone or equivalent) of systemic corticosteroids within 14 days before Dose 1 Day 1.

Note: Patients who require a brief course (≤ 7 days) of corticosteroids (eg, as prophylaxis for imaging studies due to hypersensitivity to contrast agents) are not excluded. Physiologic replacement doses of systemic corticosteroids are permitted, only if the dose does not exceed 10 mg/day prednisone equivalent.

E 29. History of allergy or sensitivity to study drug components or prior monoclonal antibody treatment; known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab or bevacizumab formulation.

E 30. History of life-threatening toxicity related to prior immune therapy (eg, anti-cytotoxic T lymphocyte antigen 4 or anti-PD-1/anti-PD-L1 treatment or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways \[eg, CD40, 4 1BB\]) except those that are unlikely to recur or are expected to be manageable with standard countermeasures (eg, hormone replacement after adrenal crisis). Individual cases should be discussed with Medical Monitor if needed.

E 31. Current or recent (within 10 days of first dose of study treatment) use of aspirin or treatment with dipyridamole, ticlopidine, clopidogrel, or cilostazol. Current or recent (within 10 days prior to study treatment start) use of full-dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic (as opposed to prophylactic) purpose.

Note: Prophylactic anticoagulation for the patency of venous access devices is allowed.

E 32. Treatment with botanical preparations (eg, herbal supplements or traditional Chinese medicines) intended for general health support or to treat the disease under study within 2 weeks before treatment.

E 33. Prior organ transplantation including allogeneic stem-cell transplantation.

E 34. Major surgery within 28 days before starting bevacizumab or anticipated major surgery while on study.

Note: If a patient received major surgery, they must have recovered adequately from the intervention before starting study treatment and must have adequate wound healing, based on Investigator's assessment or surgeon's assessment, before starting bevacizumab.

Primary outcomes:
measure: Overall Response Rate per modified RECIST 1.1
timeFrame: From Day 1 up to 3 years after first RP2 dose of last patient.
Secondary outcomes:
measure: Number of patients with treatment-emergent adverse events (TEAEs).
timeFrame: From Day 1 up to 135 days after last dose.
measure: ORR per RECIST modified for HCC (HCC mRECIST)
timeFrame: From Day 1 up to 3 years after first RP2 dose of last patient
measure: Duration of response (DOR)
timeFrame: From Day 1 up to 3 years after first RP2 dose of last patient.
Other outcomes:
Locations:
city: Beverly Hills
country: United States
facility: Beverly Hills Cancer Center
state: California
city: La Jolla
country: United States
facility: UC San Diego Moores Cancer Center
state: California
city: Miami
country: United States
facility: Sylvester Comprehensive Cancer Center (University of Miami Hospital and Clinics)
state: Florida
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Louisville
country: United States
facility: University of Louisville
state: Kentucky
city: Baltimore
country: United States
facility: University of Maryland Medical Center
state: Maryland
city: Buffalo
country: United States
facility: Roswell Park Comprehensive Cancer Center
state: New York
city: Philadelphia
country: United States
facility: University of Pennsylvania, Abramson Cancer Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Hillman Cancer Center
state: Pennsylvania
city: Germantown
country: United States
facility: The West Clinic
state: Tennessee
city: Knoxville
country: United States
facility: University of Tennessee Medical Center
state: Tennessee
Study officials:
affiliation: Replimune Inc.
name: May Cho, MD
role: STUDY_DIRECTOR
References: