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

Not Applicable

• Conditions: Liver Transplant; Complications; Hepatocellular Carcinoma; Portal Vein Thrombosis; Liver Cancer; Radiotherapy; Complications
• Interventions: Combination Product: Pembrolizumab; Radiation: intensity-modulated radiotherapy; Drug: Sintilimab; Drug: Camrelizumab; Drug: Lenvatinib Mesylate Capsule; Drug: Tislelizumab

• Registration Number: NCT05339581
• Lead Sponsor: RenJi Hospital

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.

Study Timeline

• Status Verified: 2022-04
• Study First Submitted: 2022-04-15
• Study First Submitted QC: 2022-04-15
• Last Update Submitted: 2022-04-20
• Study First Posted: 2022-04-21
• Last Update Posted: 2022-04-27
• Study Start: 2022-05-20
• Primary Completion: 2023-12-31
• Study Completion: 2024-05-31

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 78

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
PD-1 Blockade and Lenvatinib	Lenvatinib Mesylate Capsule	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.
PD-1 Blockade and Lenvatinib	Pembrolizumab	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.
IMRT combined with PD-1 Blockade and Lenvatinib	intensity-modulated radiotherapy	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.
IMRT combined with PD-1 Blockade and Lenvatinib	Pembrolizumab	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.
IMRT combined with PD-1 Blockade and Lenvatinib	Lenvatinib Mesylate Capsule	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.
IMRT combined with PD-1 Blockade and Lenvatinib	Sintilimab	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.
IMRT combined with PD-1 Blockade and Lenvatinib	Camrelizumab	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.
IMRT combined with PD-1 Blockade and Lenvatinib	Tislelizumab	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.
PD-1 Blockade and Lenvatinib	Sintilimab	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.
PD-1 Blockade and Lenvatinib	Tislelizumab	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.
PD-1 Blockade and Lenvatinib	Camrelizumab	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.

Primary Outcome Measures

Name	Time	Method
PVTT RR/NR	up to 12 months	Portal vein tumor thrombus related Response and Necrosis Rate

Secondary Outcome Measures

Name	Time	Method
Objective Response Rate (ORR)	up to 12 months	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.
Progression-free survival (PFS)	up to 12 months	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.
Time to Progression (TTP)	up to 12 months	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.
Alpha Fetoprotein Response (AFP-R)	up to 12 months	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.
Duration of response (DOR)	up to 12 months	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.

Trial Locations

Locations (1)

Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University; 🇨🇳 Shanghai, China