Sorafenib Plus Toripalimab for Unresectable HCC With Portal Vein Tumor Thrombus

NCT04069949 | Unknown Phase 1 DMC

• 1 other identifier: LQ108
• Study Type: interventional
• Target: 39
• Locations: 0 countries
• Sites: N/A

Brief Summary

This study aims to evaluate the efficacy and safety of sorafenib plus toripalimab for unresectable hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT).

Conditions

Unresectable Hepatocellular Cancer; Portal Vein Tumor Thrombus

Keywords

Sorafenib; Toripalimab; Unresectable; Hepatocellular Cancer; Portal Vein Tumor Thrombus

Outcome Measures

Primary Outcomes (2)

• 6-month Progression Free Survival rate

  Proportion of patients with Progression Free Survival in 6-month

  up to 6 months

• Incidence of Treatment-Emergent Adverse Event

  Any adverse events related with treatment with Sorafenib Plus Toripalimab

  up to 6 months

Secondary Outcomes (5)

• Objective Response Rate

  up to 6 months

• Disease Control Rate

  up to 6 months

• Progression Free Survival

  up to 6 months

• Overall Survival

  up to 1 year

• Duration of response

  From the date of study enrollment to the time of death from any cause, assessed up to 1 year

Study Arms (1)

sorafenib plus toripalimab

EXPERIMENTAL

Stage I：Subjects (n=3) in cohort A received oral sorafenib (400 mg qd), in combination with intravenous toripalimab (240 mg d1, q3w). Subjects (n=3) in cohort B received oral sorafenib (400 mg bid) and the administration of toripalimab is consistent with cohort A. If dose-limiting toxicity (DLT) does not occur within 42 days of the first administration, the dose is escalated. Stage II: According to the expansion dose based on stage I, subjects are enlarged to 39.

Drug: sorafenib; toripalimab

Interventions

sorafenib; toripalimab DRUG

Stage I: cohort A: sorafenib 400 mg qd+ toripalimab 240 mg d1; q3w cohort B: sorafenib 400 mg bid, toripalimab 240 mg d1; q3w Stage II: According to the expansion dose based on stage I, subjects are enlarged to 39.

sorafenib plus toripalimab

Eligibility Criteria

• Age: 18 Years - 74 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologic or cytologic diagnosis of unresectable hepatocellular carcinoma, or confirmed clinically in accordance with Chinese Association for the Study of Liver Diseases criteria (v2017)
• Radiographically measurable disease by RECIST version 1.1 in at least one site
• Radiographic evidence of portal vein cancer thrombus
• Survival expectation ≥3 months
• Eastern Cooperative Oncology Group: 0 or 1
• Child-Pugh score A or B: score ≤7
• Not previously treated with any systemic anti-cancer treatment (i.e. chemotherapy, target drugs, immune checkpoint inhibitors); Subjects who have received local hepatic therapy such as surgery, ablation, radiotherapy or transcatheter arterial chemoembolization, progression of target lesions after local treatment is required to increase by 25%, or target lesions are untreated, and the end of local treatment is more than 4 weeks.
• All eligible patients have adequate organ function (ANC ≥1.5× 10⁹ / L, PLT ≥75 × 10⁹ /L, HGB≥90 g/L (no blood transfusion or EPO tolerance within 7 days), Cr≤1.5 times the ULN, TBN ≤1.5 times ULN, ALT and AST ≤3 times ULN, albumin ≥30g/L (albumin or branched chain amino acids supplementation is not allowed within 14 days), INR≤1.5 times the ULN, Urine protein≤1+).
• Signed and dated written informed consent

You may not qualify if:

• History of severe allergic reactions to chimeric, human or humanized antibodies, or fusion proteins. Hypersensitive to any component of the CHO cell-derived preparation or JS001 preparation
• Pregnant or lactating women, men and women of childbearing age who are unwilling or unable to take effective contraceptive measures
• History of other malignancy within the past 5 years
• Medium or more pleural and ascites with clinical symptoms
• Active hemorrhage or abnormal coagulation function (PT\>16s, APTT\>43s, INR\>1.5 x ULN), or having a tendency to bleed or undergoing thrombolysis, anticoagulation or anti-platelet therapy
• Central nervous system metastases
• Hepatic encephalopathy
• History of gastrointestinal bleeding or having a tendency to bleed within 6 months before enrollment, e.g. local active ulcer lesions; fecal occult blood (+ +) or above should not be included; if continuous fecal occult blood (+), gastroscopy should be performed.
• Gastric or esophageal varices requiring treatment
• Untreated active hepatitis B (i.e. subjects with hepatitis B undergoing antiviral therapy and HBV Load \< 100IU/mL before the first administration of Toripalimab , is allowed to be enrolled; for subjects with anti-HBc (+), HBsAg (-), anti-HBs (-) and HBV viral load (-) , prophylactic anti-HBV therapy is not required, but virus activation should be closely monitored)
• HCV and the anti-HCV treatment ended within 4 weeks of the first administration. Notably, subjects with untreated chronic HCV infection or untreated HCV are allowed.
• History of drug abuse or mental disorders
• History of organ or marrow transplants, or active autoimmune diseases requiring systemic treatment occurred within 2 years of the first administration
• Immunodeficiency disorders or HIV
• Pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonia, drug-related pneumonia and severe impairment of pulmonary function

Sponsors & Collaborators

• Sichuan University: lead

Related Publications (20)

• Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018 Nov;68(6):394-424. doi: 10.3322/caac.21492. Epub 2018 Sep 12.

  PMID: 30207593 BACKGROUND

• Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015 Mar;65(2):87-108. doi: 10.3322/caac.21262. Epub 2015 Feb 4.

  PMID: 25651787 BACKGROUND

• Zhang ZM, Lai EC, Zhang C, Yu HW, Liu Z, Wan BJ, Liu LM, Tian ZH, Deng H, Sun QH, Chen XP. The strategies for treating primary hepatocellular carcinoma with portal vein tumor thrombus. Int J Surg. 2015 Aug;20:8-16. doi: 10.1016/j.ijsu.2015.05.009. Epub 2015 May 27.

  PMID: 26026424 BACKGROUND

• Schoniger-Hekele M, Muller C, Kutilek M, Oesterreicher C, Ferenci P, Gangl A. Hepatocellular carcinoma in Central Europe: prognostic features and survival. Gut. 2001 Jan;48(1):103-9. doi: 10.1136/gut.48.1.103.

  PMID: 11115830 BACKGROUND

• Pawarode A, Voravud N, Sriuranpong V, Kullavanijaya P, Patt YZ. Natural history of untreated primary hepatocellular carcinoma: a retrospective study of 157 patients. Am J Clin Oncol. 1998 Aug;21(4):386-91. doi: 10.1097/00000421-199808000-00014.

  PMID: 9708639 BACKGROUND

• Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Haussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J; SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008 Jul 24;359(4):378-90. doi: 10.1056/NEJMoa0708857.

  PMID: 18650514 BACKGROUND

• Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, Luo R, Feng J, Ye S, Yang TS, Xu J, Sun Y, Liang H, Liu J, Wang J, Tak WY, Pan H, Burock K, Zou J, Voliotis D, Guan Z. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009 Jan;10(1):25-34. doi: 10.1016/S1470-2045(08)70285-7. Epub 2008 Dec 16.

  PMID: 19095497 BACKGROUND

• Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, Baron A, Park JW, Han G, Jassem J, Blanc JF, Vogel A, Komov D, Evans TRJ, Lopez C, Dutcus C, Guo M, Saito K, Kraljevic S, Tamai T, Ren M, Cheng AL. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018 Mar 24;391(10126):1163-1173. doi: 10.1016/S0140-6736(18)30207-1.

  PMID: 29433850 BACKGROUND

• Choi JH, Chung WJ, Bae SH, Song DS, Song MJ, Kim YS, Yim HJ, Jung YK, Suh SJ, Park JY, Kim DY, Kim SU, Cho SB. Randomized, prospective, comparative study on the effects and safety of sorafenib vs. hepatic arterial infusion chemotherapy in patients with advanced hepatocellular carcinoma with portal vein tumor thrombosis. Cancer Chemother Pharmacol. 2018 Sep;82(3):469-478. doi: 10.1007/s00280-018-3638-0. Epub 2018 Jul 7.

  PMID: 29982870 BACKGROUND

• Cheng AL, Guan Z, Chen Z, Tsao CJ, Qin S, Kim JS, Yang TS, Tak WY, Pan H, Yu S, Xu J, Fang F, Zou J, Lentini G, Voliotis D, Kang YK. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma according to baseline status: subset analyses of the phase III Sorafenib Asia-Pacific trial. Eur J Cancer. 2012 Jul;48(10):1452-65. doi: 10.1016/j.ejca.2011.12.006. Epub 2012 Jan 10.

  PMID: 22240282 BACKGROUND

• Jeong SW, Jang JY, Shim KY, Lee SH, Kim SG, Cha SW, Kim YS, Cho YD, Kim HS, Kim BS, Kim KH, Kim JH. Practical effect of sorafenib monotherapy on advanced hepatocellular carcinoma and portal vein tumor thrombosis. Gut Liver. 2013 Nov;7(6):696-703. doi: 10.5009/gnl.2013.7.6.696. Epub 2013 Aug 14.

  PMID: 24312711 BACKGROUND

• Song DS, Song MJ, Bae SH, Chung WJ, Jang JY, Kim YS, Lee SH, Park JY, Yim HJ, Cho SB, Park SY, Yang JM. A comparative study between sorafenib and hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma with portal vein tumor thrombosis. J Gastroenterol. 2015 Apr;50(4):445-54. doi: 10.1007/s00535-014-0978-3. Epub 2014 Jul 16.

  PMID: 25027973 BACKGROUND

• Lee IC, Chen YT, Chao Y, Huo TI, Li CP, Su CW, Lin HC, Lee FY, Huang YH. Determinants of survival after sorafenib failure in patients with BCLC-C hepatocellular carcinoma in real-world practice. Medicine (Baltimore). 2015 Apr;94(14):e688. doi: 10.1097/MD.0000000000000688.

  PMID: 25860213 BACKGROUND

• El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, Kim TY, Choo SP, Trojan J, Welling TH Rd, Meyer T, Kang YK, Yeo W, Chopra A, Anderson J, Dela Cruz C, Lang L, Neely J, Tang H, Dastani HB, Melero I. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017 Jun 24;389(10088):2492-2502. doi: 10.1016/S0140-6736(17)31046-2. Epub 2017 Apr 20.

  PMID: 28434648 BACKGROUND

• Zhu AX, Finn RS, Edeline J, Cattan S, Ogasawara S, Palmer D, Verslype C, Zagonel V, Fartoux L, Vogel A, Sarker D, Verset G, Chan SL, Knox J, Daniele B, Webber AL, Ebbinghaus SW, Ma J, Siegel AB, Cheng AL, Kudo M; KEYNOTE-224 investigators. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol. 2018 Jul;19(7):940-952. doi: 10.1016/S1470-2045(18)30351-6. Epub 2018 Jun 3.

  PMID: 29875066 BACKGROUND

• Xu J, Zhang Y, Jia R, Yue C, Chang L, Liu R, Zhang G, Zhao C, Zhang Y, Chen C, Wang Y, Yi X, Hu Z, Zou J, Wang Q. Anti-PD-1 Antibody SHR-1210 Combined with Apatinib for Advanced Hepatocellular Carcinoma, Gastric, or Esophagogastric Junction Cancer: An Open-label, Dose Escalation and Expansion Study. Clin Cancer Res. 2019 Jan 15;25(2):515-523. doi: 10.1158/1078-0432.CCR-18-2484. Epub 2018 Oct 22.

  PMID: 30348638 BACKGROUND

• Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, Hodi FS, Schachter J, Pavlick AC, Lewis KD, Cranmer LD, Blank CU, O'Day SJ, Ascierto PA, Salama AK, Margolin KA, Loquai C, Eigentler TK, Gangadhar TC, Carlino MS, Agarwala SS, Moschos SJ, Sosman JA, Goldinger SM, Shapira-Frommer R, Gonzalez R, Kirkwood JM, Wolchok JD, Eggermont A, Li XN, Zhou W, Zernhelt AM, Lis J, Ebbinghaus S, Kang SP, Daud A. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015 Aug;16(8):908-18. doi: 10.1016/S1470-2045(15)00083-2. Epub 2015 Jun 23.

  PMID: 26115796 BACKGROUND

• Robert C, Ribas A, Wolchok JD, Hodi FS, Hamid O, Kefford R, Weber JS, Joshua AM, Hwu WJ, Gangadhar TC, Patnaik A, Dronca R, Zarour H, Joseph RW, Boasberg P, Chmielowski B, Mateus C, Postow MA, Gergich K, Elassaiss-Schaap J, Li XN, Iannone R, Ebbinghaus SW, Kang SP, Daud A. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014 Sep 20;384(9948):1109-17. doi: 10.1016/S0140-6736(14)60958-2. Epub 2014 Jul 15.

  PMID: 25034862 BACKGROUND

• Tang B, Yan X, Sheng X, Si L, Cui C, Kong Y, Mao L, Lian B, Bai X, Wang X, Li S, Zhou L, Yu J, Dai J, Wang K, Hu J, Dong L, Song H, Wu H, Feng H, Yao S, Chi Z, Guo J. Safety and clinical activity with an anti-PD-1 antibody JS001 in advanced melanoma or urologic cancer patients. J Hematol Oncol. 2019 Jan 14;12(1):7. doi: 10.1186/s13045-018-0693-2.

  PMID: 30642373 BACKGROUND

• Shuqun C, Mengchao W, Han C, Feng S, Jiahe Y, Guanghui D, Wenming C, Peijun W, Yuxiang Z. Tumor thrombus types influence the prognosis of hepatocellular carcinoma with the tumor thrombi in the portal vein. Hepatogastroenterology. 2007 Mar;54(74):499-502.

  PMID: 17523307 BACKGROUND

Related Links

• PVTT classification refers to Cheng's classification

MeSH Terms

Conditions

Liver Neoplasms

Interventions

Sorafenib; toripalimab

Condition Hierarchy (Ancestors)

Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Liver Diseases

Intervention Hierarchy (Ancestors)

Phenylurea Compounds; Urea; Amides; Organic Chemicals; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Niacinamide; Nicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring

Study Officials

• Qiu Li, Professor

  West China Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Qiu Li, Professor

CONTACT

86-028-85423609; fbqiu9@163.com

Yu Yang, Associate Professor

CONTACT

86-18980606616; yangyuflying@hotmail.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: one-arm study

Study Record Dates

• First Submitted: August 24, 2019
• First Posted: August 28, 2019
• Study Start: December 1, 2019
• Primary Completion: October 1, 2020
• Study Completion: October 1, 2021
• Last Updated: October 25, 2019

Record last verified: 2019-10

Data Sharing

• IPD Sharing: Will not share