Oncolytic Virotherapy Plus PD-1 Inhibitor and Lenvatinib as Second-line or Later Therapy in Patients With Advanced Hepatocellular Carcinoma

A Phase 1b Dose-escalation and Cohort-expansion Study of the Safety/Tolerability, and Efficacy of Oncolytic Virotherapy Plus PD-1 Inhibitor and Lenvatinib for Patients With Advanced Hepatocellular Carcinoma

The objective of this study is to evaluate the safety/tolerability efficacy of oncolytic virotherapy combined with Tislelizumab plus lenvatinib as second-line or later therapy in patients with advanced hepatocellular carcinoma.

Study Overview

• Status: Recruiting
• Conditions: Hepatocellular Carcinoma
• Intervention / Treatment: Drug: Oncorine; Drug: Tislelizumab; Drug: Lenvatinib

Detailed Description

Recent studies have suggested that local destruction of tumor tissue by oncolytic virus induced activation and maturation of dendritic cells and tumor-specific T cells by cross-presentation of tumor antigens. While pd-1 blocking antibody interferes with PD-1 mediated T-cell regulatory signaling. And combination of pd-1 blocking antibody plus lenvatinib showed increased ORR in many types of human cancers. Therefore, the objective of this study is to evaluate the safety and efficacy of oncolytic virotherapy combined with Tislelizumab plus lenvatinib as second-line or later therapy in patients with advanced hepatocellular carcinoma.

• Study Type: Interventional
• Enrollment (Anticipated): 25
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Peng Wang, MD; Phone Number: 86-21-64175590; Email: wangp413@163.com

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China, 200032
      • Recruiting
      • Fudan University Shanghai Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Written informed consent obtained.
2. Age ≥ 18 years at time of study entry.
3. Participants must have unresectable or metastatic histologically or cytologically confirmed hepatocellular carcinoma.
4. Participants must have failed 1 line of systemic regimens for advanced hepatocellular carcinoma due to disease progression or toxicity.
5. Patients had been refractory or intolerant to previous systemic chemotherapy (oxaliplatin-based chemotherapy), targeted therapy (eg, sorafenib or lenvatinib), or anti-PD-1 or anti-PD-L1 based regimen.
6. At least one measurable site of disease as defined by RECIST criteria with spiral CT scan or MRI.
7. Performance status (PS) ≤ 2 (ECOG scale).
8. Life expectancy of at least 12 weeks.
9. Adequate blood count, liver-enzymes, and renal function: absolute neutrophil count ≥ 1,500/L, platelets ≥75 x103/L; Total bilirubin ≤ 3x upper normal limit; Aspartate Aminotransferase (SGOT), Alanine aminotransferase (SGPT) ≤ 5 x upper normal limit (ULN); International normalized ratio (INR) ≤1.25; Albumin ≥ 31 g/dL; Serum Creatinine ≤ 1.5 x institutional ULN or creatinine clearance (CrCl) ≥ 30 mL/min (if using the Cockcroft-Gault formula )
10. Female patients with reproductive potential must have a negative urine or serum pregnancy test within 7 days prior to start of trial.
11. Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment, adherence to contraceptive measures, scheduled visits and examinations including follow up.

Exclusion Criteria:

1. History of cardiac disease, including clinically significant gastrointestinal bleeding within 4 weeks prior to start of study treatment
2. Thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within the 6 months Prior to the first dose of study drug with the exception of thrombosis of a segmental portal vein.
3. RFA and resection administered less then 4 weeks prior to study treatment start.
4. Radiotherapy administered less then 4 weeks prior to study treatment start.
5. Major surgery within 4 weeks of starting the study treatment OR subjects who have not recovered from effects of major surgery.
6. Patients with second primary cancer, except adequately treated basal skin cancer or carcinoma in-situ of the cervix.
7. Immunocompromised patients, e.g. patients who are known to be serologically positive for human immunodeficiency virus (HIV).
8. Participation in another clinical study with an investigational product during the last 30 days before inclusion or 7 half-lifes of previously used trial medication, whichever is longer.

9. Any condition or comorbidity that, in the opinion of the investigator, would interfere with evaluation of study Treatment or interpretation of patient safety or study results, including but not limited to:

   1. history of interstitial lung disease
   2. Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) coinfection (i.e double infection)
   3. known acute or chronic pancreatitis
   4. active tuberculosis
   5. any other active infection (viral, fungal or bacterial) requiring systemic therapy
   6. history of allogeneic tissue/solid organ transplant
   7. diagnosis of immunodeficiency or patient is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of Tislelizumab treatment.
   8. Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Exceptions: Subjects with vitiligo, hypothyroidism, diabetes mellitus type I or resolved childhood asthma/atopy are an exception to this rule. Subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Subjects with Hashimoto thyroiditis, hypothyroidism stable on hormone replacement or psoriasis not requiring treatment are not excluded from the study.
   9. Live vaccine within 30 days prior to the first dose of Tislelizumab treatment or during study treatment.
   10. History or clinical evidence of Central Nervous System (CNS) metastases Exceptions are: Subjects who have completed local therapy and who meet both of the following criteria: I. are asymptomatic and II. have no requirement for steroids 6 weeks prior to start of Tislelizumab treatment. Screening with CNS imaging (CT or MRI) is required only if clinically indicated or if the subject has a history of CNS
10. Medication that is known to interfere with any of the agents applied in the trial.
11. Any other efficacious cancer treatment except protocol specified treatment at study start.
12. Patient has received any other investigational product within 28 days of study entry.
13. Female subjects who are pregnant, breast-feeding or male/female patients of reproductive potential who are not employing an effective method of birth control (failure rate of less than 1% per year). [Acceptable methods of contraception are: implants, injectable contraceptives, combined oral contraceptives, intrauterine pessars (only hormonal devices), sexual abstinence or vasectomy of the partner]. Women of childbearing potential must have a negative pregnancy test (serum β-HCG) at screening.

Patient with any significant history of non-compliance to medical regimens or with inability to grant reliable informed consent.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: H101 + Tislelizumab+ Lenvatinib; (Dose escalation and cohort expansion) H101 administered by intratumoral injection in combination with Tislelizumab administered intravenously (IV), and Lenvatinib administered orally. H101 intratumorally injection starts at day 0. Tislelizumab plus lenvatinib will be initiated on day 1. Tislelizumab will be administered at 200 mg i.v. every 3 weeks plus a lenvatinib (bodyweight ≥ 60 kg, 12 mg; < 60 kg, 8 mg) orally daily every 3 weeks until documented disease progression, development of unacceptable toxicity, participant request, or withdrawal of consent.

Drug: Oncorine; a modified human recombinant type 5 adenovirus with genetic modifications; Other Names: H101; Drug: Tislelizumab; PD-1inhibitor; Drug: Lenvatinib; TKI

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose Limiting Toxicities (DLT)	The DLT assessment period is defined as: Day of Injection through 28 days post injection (Safety Follow Up). A DLT will be defined as any Grade 3 or higher adverse event, as assessed by the National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE) version 5.0.	28 days
Maximum tolerated dose	A MTD is determined if any cohort experiences 2 subjects with DLT's. Safety	max 24 months
Adverse event (AE).		max 24 months
Treatment emergent adverse event(TEAE).		max 24 months
Serious adverse event (SAE).		max 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR)	ORR according to RECIST 1.1	max 24 months
DoR	Duration of Response	max 24 months
PFS	Progression Free Survival	max 24 months
OS	Overall survival	max 42 months
DCR	disdisease control rate	max 24 months
Detection of systemic and local immune activation in tumors and peripheral blood mononuclear cell will be assessed by single cell RNA seq and/or bulk RNA seq.		max 24 months

Collaborators and Investigators

• Sponsor: Fudan University

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2023
• Primary Completion (Anticipated): December 30, 2025
• Study Completion (Anticipated): December 30, 2025

Study Registration Dates

• First Submitted: December 29, 2022
• First Submitted That Met QC Criteria: December 29, 2022
• First Posted (Actual): January 9, 2023

Study Record Updates

• Last Update Posted (Estimate): March 6, 2023
• Last Update Submitted That Met QC Criteria: March 2, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms; Carcinoma; Carcinoma, Hepatocellular; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Lenvatinib
• Other Study ID Numbers: OPTIONS-04

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No