IMRT Plus PD-1 Blockade and Lenvatinib for HCC With PVTT (Vp3) Before Liver Transplantation (iPLENTY-pvtt)

PILOT Study on the Safety and Efficacy of IMRT Combined With PD-1 Blockade and LEnvatinib as Neoadjuvant TherapY for Hepatocellular Carcinoma With Portal Vein Tumor Thrombus (Vp3) Before Liver Transplantation（iPLENTY-pvtt）

This is a parallel assigned, open-label, perspective trial studying the safety and efficacy of intensity-modulated radiotherapy (IMRT) combined with PD-1 Blockade and Lenvatinib for Hepatocellular Carcinoma (HCC) with Vp3 Portal Vein Tumor Thrombus (PVTT, Japanese Liver Cancer Study Group classification) before liver transplantation.

Study Overview

• Status: Not yet recruiting
• Conditions: Hepatocellular Carcinoma; Liver Transplant; Complications; Liver Cancer; Portal Vein Thrombosis; Radiotherapy; Complications
• Intervention / Treatment: Radiation: intensity-modulated radiotherapy; Combination product: Pembrolizumab; Drug: Sintilimab; Drug: Camrelizumab; Drug: Tislelizumab; Drug: Lenvatinib Mesylate Capsule

Detailed Description

In most criteria (e.g.Milan, UCSF, Up-to-seven), PVTT remains as an absolute contraindication for liver transplant due to the high rate of recurrence and poor prognosis. Neoadjuvant therapy has induced pathological responses in multiple tumor types and might decrease the risk of postoperative recurrence in HCC. The primary endpoint is the necrosis rate of PVTT and the primary tumor.

Participants receive PD-1 Blockade (Pembrolizumab，Sintilimab， Camrelizumab，Tislelizumab) 200 mg intravenously on day 1 of a regular treatment cycle and Lenvatinib Mesylate Capsule (Lenvima®) 8 mg orally once daily. Neoadjuvant IMRT will be initiated at the third treatment cycle, and the dose prescription of IMRT is for planning target volume (PTV). The prescription dose to 95%PTV should be ≥50 Gy and ≤60 Gy, and been given in daily dose fractions of 2 Gy, 5 days per week. And the final prescription dose is determined according to dose constraints for organs at risk.

• Study Type: Interventional
• Enrollment (Anticipated): 78
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Hao Feng, MD, Ph.D; Phone Number: 008615000901110; Email: surgeonfeng@live.com
• Study Contact Backup: Name: Qiang Xia, MD, Ph.D

Study Locations

• China
  • Shanghai, China, 200127
    • Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients must have pathologically or cytologically or by radiological criteria proven hepatocellular carcinoma（exceeding Milan criteria）; known mixed histology (e.g. hepatocellular carcinoma plus cholangiocarcinoma) or fibrolamellar variant is not allowed.
• The maximum diameter of a single tumor ≤9cm. Or the number of tumors ≤3 and the maximum diameter of the largest tumors ≤5cm, and the sum of the maximum diameters of all tumors ≤9cm.
• Vp3 PVTT according to Japanese Vp classification.
• Without lymph node metastasis or extrahepatic metastasis.
• Baseline AFP≥20ng/ mL
• Has an eligibility scan (CT of the chest, triphasic CT scan and MRI of the abdomen) <1 week before the treatment.
• Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 7 days prior to Cycle 1, Day 1.
• Has a Child-Pugh A-B7 liver score (5 to 7 points) within 7 days prior to Cycle 1, Day 1.
• Laboratory tests within 7 days prior to Cycle 1, Day 1:
• Neutrophils ≥1.5×109/L
• Hemoglobin ≥8.5g/dL
• Platelets ≥100×109/L,
• Creatinine ≤1.5× upper limit of normal (ULN) and endogenous creatinine clearance ≥50ml/min (standard Cockcroft Gaul formula)
• Total bilirubin ≤3×ULN, ALT≤5×ULN, AST≤5×ULN, INR≤1.7
• Has controlled hepatitis B (HBV-DNA<105IU/ml)
• The estimate time length between enrollment and liver transplantation should be at least 3 months.
• No prior systematic therapy such as immunotherapy, targeted therapy and chemotherapy for HCC.
• No prior local treatment such as TACE, HAIC, radiofrequency ablation or radiotherapy was received within 2 months before enrollment.
• If female, is not pregnant or breastfeeding, and at least one of the following conditions applies: 1) Is not a woman of childbearing potential (WOCBP); or 2) Is a WOCBP and using a contraceptive method that is highly effective or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (a WOCBP must have a negative pregnancy test within 72 hours before the first dose of study treatment).
• No obvious insufficiency of other organs.
• Patients with a history of hypertension should be well controlled (< 140/90 mmHg) on a regimen of anti-hypertensive therapy.
• Patients voluntarily joined the study and signed informed consent with good compliance and follow-up.

Exclusion Criteria:

• • Known mixed histology (e.g. hepatocellular carcinoma plus cholangiocarcinoma) or fibrolamellar variant.

  • Surgery within the past 6 months.
  • Has had esophageal or gastric variceal bleeding within the last 6 months.
  • Has clinically apparent ascites on physical examination.
  • Has received systematic therapy such as immunotherapy, targeted therapy and chemotherapy for HCC.
  • Has received TACE, HAIC, radiofrequency ablation and other local treatments in recent 2 months.
  • Has received liver radiotherapy.
  • Has received radiotherapy with grade 4 toxicity.
  • Significant history of cardiac disease is not allowed: Congestive heart failure > class II New York Heart Association (NYHA) Myocardial infarction within 6 months prior to registration Serious myocardial dysfunction, defined as scintigraphically (multigated acquisition scan [MUGA], myocardial scintigram) determined absolute left ventricular ejection fraction (LVEF) below 45% or an LVEF on echocardiogram (ECHO) below the normal limit at the individual institution.
  • Has severe hypersensitivity (≥Grade 3) to monoclonal antibody.
  • Has an active autoimmune disease that has required systemic treatment (skin diseases that do not require systemic treatment such as vitiligo, psoriasis; type I diabetes, and autoimmune hypothyroidism due to hormone replacement therapy are allowed).
  • Patients with other active malignant tumors within 5 years before the first use of the study drug (cured localized tumors such as basal cell carcinoma of skin, squamous cell carcinoma of skin, superficial bladder cancer, carcinoma in situ of prostate, carcinoma in situ of cervix and carcinoma in situ of breast are allowed).
  • Has an active infection requiring systemic therapy.
  • Has a known history of human immunodeficiency virus (HIV) infection.
  • Has known active tuberculosis within 5 years.
  • Has received a live vaccine within 30 days prior to the first dose of study treatment.
  • Has received bone-marrow allotransplantation or solid organ transplantation.
  • Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to Cycle 1, Day 1.
  • Dysphagia or known drug absorption disorder.
  • Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study treatment.
  • Conditions considered unsuitable for inclusion by other researchers.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: IMRT combined with PD-1 Blockade and Lenvatinib; Participants receive PD-1 Blockade (Pembrolizumab，Sintilimab， Camrelizumab，Tislelizumab) 200 mg intravenously on day 1 of a 21-day treatment cycle until >42 days before liver transplantation or unacceptable toxicity develops. Participants receive Lenvatinib Mesylate Capsule (Lenvima®) 8 mg orally once daily until >7 days before liver transplantation. Neoadjuvant IMRT will be initiated at the third treatment cycle, and the dose prescription of IMRT is for planning target volume (PTV). The prescription dose to 95%PTV should be ≥50 Gy and ≤60 Gy, and been given in daily dose fractions of 2 Gy, 5 days per week. And the final prescription dose is determined according to dose constraints for organs at risk.	Radiation: intensity-modulated radiotherapy; Neoadjuvant IMRT will be initiated at the third treatment cycle, and the dose prescription of IMRT is for planning target volume (PTV). The prescription dose to 95%PTV should be ≥50 Gy and ≤60 Gy, and been given in daily dose fractions of 2 Gy, 5 days per week. And the final prescription dose is determined according to dose constraints for organs at risk.; Other Names: IMRT; Combination product: Pembrolizumab; Participants receive PD-1 Blockade (Pembrolizumab 200mg，Sintilimab 200mg， Camrelizumab 200mg，Tislelizumab 200mg) 100-200 mg intravenously on day 1 of a regular treatment cycle until >42 days before liver transplantation or unacceptable toxicity develops. Participants receive Lenvatinib Mesylate Capsule (Lenvima®) 8 mg orally once daily until >7 days before liver transplantation.; Other Names: Keytruda; Drug: Sintilimab; Sintilimab is a recombinant anti-human PD-1 monoclonal antibody.; Other Names: Tyvyt; Drug: Camrelizumab; Camrelizumab is a humanized anti-human PD-1 monoclonal antibody.; Other Names: AiRuiKa; Drug: Tislelizumab; Tislelizumab is a recombinant anti-human PD-1 monoclonal antibody.; Drug: Lenvatinib Mesylate Capsule; Lenvatinib (Lenvima®, Eisai China) is a novel angiogenesis inhibitor which targets vascular endothelial growth factor 1-3, fibroblast growth factor receptor 1-4, platelet-derived growth factor receptor β, RET and KIT.; Other Names: LENVIMA
Active Comparator: PD-1 Blockade and Lenvatinib; Participants receive PD-1 Blockade (Pembrolizumab，Sintilimab， Camrelizumab，Tislelizumab) 200 mg intravenously on day 1 of a 21-day treatment cycle until >42 days before liver transplantation or unacceptable toxicity develops. Participants receive Lenvatinib Mesylate Capsule (Lenvima®) 8 mg orally once daily until >7 days before liver transplantation.	Combination product: Pembrolizumab; Participants receive PD-1 Blockade (Pembrolizumab 200mg，Sintilimab 200mg， Camrelizumab 200mg，Tislelizumab 200mg) 100-200 mg intravenously on day 1 of a regular treatment cycle until >42 days before liver transplantation or unacceptable toxicity develops. Participants receive Lenvatinib Mesylate Capsule (Lenvima®) 8 mg orally once daily until >7 days before liver transplantation.; Other Names: Keytruda; Drug: Sintilimab; Sintilimab is a recombinant anti-human PD-1 monoclonal antibody.; Other Names: Tyvyt; Drug: Camrelizumab; Camrelizumab is a humanized anti-human PD-1 monoclonal antibody.; Other Names: AiRuiKa; Drug: Tislelizumab; Tislelizumab is a recombinant anti-human PD-1 monoclonal antibody.; Drug: Lenvatinib Mesylate Capsule; Lenvatinib (Lenvima®, Eisai China) is a novel angiogenesis inhibitor which targets vascular endothelial growth factor 1-3, fibroblast growth factor receptor 1-4, platelet-derived growth factor receptor β, RET and KIT.; Other Names: LENVIMA

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PVTT RR/NR	Portal vein tumor thrombus related Response and Necrosis Rate	up to 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Alpha Fetoprotein Response (AFP-R)	AFP-R is defined as a >20% decrease in AFP serum level from baseline to the time of liver transplant, if liver transplant is not possible, the final AFP level would be measured as the AFP level at 12 months.	up to 12 months
Progression-free survival (PFS)	PFS is defined as the time from the date of treatment initiation to the date of the first observation of progressive disease (PD) by independent radiologic review according to mRECIST criteria or death from any cause.	up to 12 months
Objective Response Rate (ORR)	RR is defined as the proportion of patients whose tumor volume has reached a predetermined value and can maintain a minimum time limit, including complete response(CR) and partial response(PR) by independent radiologic review according to mRECIST criteria.	up to 12 months
Time to Progression (TTP)	TTP is defined as the duration from the date of patient recruited to the first progress at any site or the date of death from any cause.	up to 12 months
Duration of response (DOR)	DOR is defined as the duration from the date that measurement criteria are met for CR or PR to the first progress at any site or the date of death from any cause.	up to 12 months

Collaborators and Investigators

• Sponsor: RenJi Hospital
• Investigators: Study Chair: Qiang Xia, MD, Ph.D, Dept. Liver Surgery, Renji Hospital, School of Medicine, SJTU; Study Chair: Yong-rui Bai, MD, Dept. Radiotherapy, Renji Hospital, School of Medicine, SJTU; Principal Investigator: Xiu-mei Ma, MD, Dept. Radiotherapy, Renji Hospital, School of Medicine, SJTU; Principal Investigator: Xiao-hang Wang, MD, Dept. Radiotherapy, Renji Hospital, School of Medicine, SJTU; Principal Investigator: Hao Feng, MD, Ph.D, Dept. Liver Surgery, Renji Hospital, School of Medicine, SJTU

Study record dates

Study Major Dates

• Study Start (Anticipated): May 20, 2022
• Primary Completion (Anticipated): December 31, 2023
• Study Completion (Anticipated): May 31, 2024

Study Registration Dates

• First Submitted: April 15, 2022
• First Submitted That Met QC Criteria: April 15, 2022
• First Posted (Actual): April 21, 2022

Study Record Updates

• Last Update Posted (Actual): April 27, 2022
• Last Update Submitted That Met QC Criteria: April 20, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Cardiovascular Diseases; Vascular Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Embolism and Thrombosis; Liver Neoplasms; Carcinoma; Carcinoma, Hepatocellular; Thrombosis; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Immunological; Protein Kinase Inhibitors; Pembrolizumab; Lenvatinib
• Other Study ID Numbers: Renji-IIT2022-011

Drug and device information, study documents

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