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

NCT ID: NCT05339581

Last Updated: 2022-04-27

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: NA
• Total Enrollment: 78 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-05-20
• Study Completion Date: 2024-05-31

Brief Summary

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.

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.

Conditions

Liver Cancer; Liver Transplant; Complications; Hepatocellular Carcinoma; Portal Vein Thrombosis; Radiotherapy; Complications

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

intensity-modulated radiotherapy

Intervention Type: RADIATION

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.

Pembrolizumab

Intervention Type: COMBINATION_PRODUCT

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.

Sintilimab

Intervention Type: DRUG

Sintilimab is a recombinant anti-human PD-1 monoclonal antibody.

Camrelizumab

Intervention Type: DRUG

Camrelizumab is a humanized anti-human PD-1 monoclonal antibody.

Tislelizumab

Intervention Type: DRUG

Tislelizumab is a recombinant anti-human PD-1 monoclonal antibody.

Lenvatinib Mesylate Capsule

Intervention Type: DRUG

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.

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.

Group Type: ACTIVE_COMPARATOR

Pembrolizumab

Intervention Type: COMBINATION_PRODUCT

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.

Sintilimab

Intervention Type: DRUG

Sintilimab is a recombinant anti-human PD-1 monoclonal antibody.

Camrelizumab

Intervention Type: DRUG

Camrelizumab is a humanized anti-human PD-1 monoclonal antibody.

Tislelizumab

Intervention Type: DRUG

Tislelizumab is a recombinant anti-human PD-1 monoclonal antibody.

Lenvatinib Mesylate Capsule

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: RADIATION

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.

Intervention Type: COMBINATION_PRODUCT

Sintilimab

Sintilimab is a recombinant anti-human PD-1 monoclonal antibody.

Intervention Type: DRUG

Camrelizumab

Camrelizumab is a humanized anti-human PD-1 monoclonal antibody.

Intervention Type: DRUG

Tislelizumab

Tislelizumab is a recombinant anti-human PD-1 monoclonal antibody.

Intervention Type: 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.

Intervention Type: DRUG

Other Intervention Names

IMRT; Keytruda; Tyvyt; AiRuiKa; LENVIMA

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

RenJi Hospital

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Qiang Xia, MD, Ph.D

Role: STUDY_CHAIR

Dept. Liver Surgery, Renji Hospital, School of Medicine, SJTU

Yong-rui Bai, MD

Role: STUDY_CHAIR

Dept. Radiotherapy, Renji Hospital, School of Medicine, SJTU

Xiu-mei Ma, MD

Role: PRINCIPAL_INVESTIGATOR

Dept. Radiotherapy, Renji Hospital, School of Medicine, SJTU

Xiao-hang Wang, MD

Role: PRINCIPAL_INVESTIGATOR

Dept. Radiotherapy, Renji Hospital, School of Medicine, SJTU

Hao Feng, MD, Ph.D

Role: PRINCIPAL_INVESTIGATOR

Dept. Liver Surgery, Renji Hospital, School of Medicine, SJTU

Locations

Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University

Shanghai, , China

Countries

China

Central Contacts

Hao Feng, MD, Ph.D

Role: CONTACT

surgeonfeng@live.com

008615000901110

Qiang Xia, MD, Ph.D

Role: CONTACT

Other Identifiers

Renji-IIT2022-011

Identifier Type: -

Identifier Source: org_study_id