Lenvatinib Combined Toripalimab in Advanced Hepatocellular Carcinoma

Hepatocellular Carcinoma Clinical Trial

Official title:

Lenvatinib Combined Toripalimab in Advanced Hepatocellular Carcinoma: a Single-center, Single-arm, Non-randomized Clinical Study

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04368078
• Other study ID #: JS-2295
• Status: Recruiting
• Phase: Phase 2
• Start date: July 11, 2020
• Est. completion date: April 2025

Study information

• Verified date: January 2023
• Source: Peking Union Medical College Hospital
• Contact: Xiaobo Yang, doctor
• Phone: 010-69156043
• Email: y110403606[@]126.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The investigators design a phase IIB clinical study to explore the efficacy and safety of Lenvatinib plus Toripalimab in patients with advanced hepatocellular carcinoma and to analyze potential biomarkers of therapeutic response.

Description:

This trial is a single-arm, non-randomized and single-center clinical study of targeted therapy combined immunotherapy in patients with hepatocellular carcinoma.

It is estimated that 76 patients who met the study criteria will be enrolled in Peking Union Medical College Hospital(PUMCH) and treated with Lenvatinib and Toripalimab. The investigators will follow up and collect subjects' data monthly to evaluate the efficacy and safety of treatment, including overall survival and time to progression. Multi-omics data analysis will be used to find potential biomarkers of treatment response.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 76
• Est. completion date: April 2025
• Est. primary completion date: April 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Subjects volunteer to participate in the study and agree to sign the informed consent with good compliance and follow-up.

• Subjects are 18 years old or older when signing the informed consent and gender is not limited.

• Imaging (by AASLD or Standard for the diagnosis and treatment of primary liver cancer 2017 in China) or histopathologically or cytologically confirmed advanced Hepatocellular carcinoma.

• BCLC stage B or C. The disease is not suitable for radical surgery and/or topical treatment, or disease progression occurs after surgery and/or local treatment.

• Subjects who have received first-line systemic treatment (targeted therapies other than Lenvatinib, chemotherapy, biological immunotherapy, etc.) except Toripalimab and Lenvatinib could be involved.

• At least one measurable lesion (according to RECIST version 1.1): the measurable lesion has a long diameter = 10 mm or lymphadenpathy has a short diameter = 15 mm in spiral CT scan.

• The ECOG score is 0-1 within 1 week before enrollment.

• Liver function assessment: Child-Pugh Grade A (5-6 points).

• Estimated survival time = 3 months.

• 10. Subjects with HBV infection: HBV DNA<2000 IU/ml or <10^4 copy/mL, and have received anti-HBV therapy for at least 14 days prior to enrollment in the study, subjects with HCV-RNA(+) must receive antiviral therapy;

• Hematology and organ function are sufficient based on the following laboratory results within 14 days prior to the treatment of this study:

• Whole blood cell examination (no blood transfusion within 14 days, no G-CSF use and no drugs use): WBC=3.0×10^9/L, Hb=85g/L, ANC=1.5×10^9/L, PLT=75×10^9/L.

• Biochemical examination (no ALB infused within 14 days): ALB=29 g/L, ALP and ALT and AST<5×ULN, TBIL=3×ULN, creatinine=1.5×ULN or CCr >50mL/min (standard Cockcroft-Gault formula): Female: CrCl=((140-age) × body weight (kg) × 0.85) / 72 × Serum creatinine (mg/dL); Male: CrCl=((140- age) × body weight (kg) × 1.00) / 72 × Serum creatinine (mg/dL)

• Agree to abstain from sex (avoid heterosexual intercourse) or use contraceptive methods with an annual contraceptive failure rate of less than 1% during treatment and for at least 6 months after the last administration.

Exclusion Criteria:

• Hepatocellular carcinoma patients with any of the following: Suitable for radical surgery; or without an assessment lesion after radical surgery; or liver transplantation history or ready for liver transplantation;

• ECOG score = 2 points.

• Previously received Lenvatinib or Toripalimab treatment.

• History of hepatic encephalopathy.

• Histopathological result show hepatobiliary carcinoma, sarcomatoid liver cancer, mixed cell carcinoma and layered cell carcinoma.

• Already known to be allergic or intolerant to recombinant humanized PD-1 monoclonal antibody drugs (or components) or Lenvatinib.

• Pregnant (positive pregnancy test before taking medicine) or lactating women.

• Received any topical treatment within 4 weeks prior to the study, including but not limited to surgery, radiotherapy, hepatic artery embolization, TACE, hepatic artery perfusion, radiofrequency ablation, cryoablation or percutaneous ethanol injection.

• Previous or existing grade 3 (CTCAE5.0 ) and above gastrointestinal fistula or non-gastrointestinal fistula (such as skin).

• Factors affect Lenvatinib use, such as inability to swallow, chronic diarrhea, intestinal obstruction, or other conditions that significantly affect drug intake and absorption.

• Ascites with clinical symptoms which requires abdominal puncture or drainage therapy, or Child-Pugh score >2.

• Surgery performed within 4 weeks or minor surgery (simple resection or biopsy) within 7 days prior to the trial and patients must be evaluated before the first medication.

• Severe cardiovascular and cerebrovascular diseases, including but not limited to acute myocardial infarction, severe/unstable angina pectoris, cerebrovascular accident or transient ischemic attack, congestive heart failure and arrhythmias within 6 months before enrollment.

• Hepatic and renal dysfunction evidence: jaundice, ascites, and/or bilirubin = 3× ULN, and/or = 3 grade (CTC-AE 5.0) proteinuria (> 3.5g /24 hours), or renal failure requiring blood dialysis or peritoneal dialysis, and / or urine examination shows urinary protein = ++ or 24 hours urine protein >1.0g.

• Persistent >2 grade (CTCAE 5.0) infection.

• Thromboembolism (including stroke and / or transient ischemic attack) within 12 months.

• Hypertension that cannot be controlled well with antihypertensive drugs (systolic blood pressure> 160mmHg, diastolic blood pressure> 100mmHg).

• Already known active central nervous system metastasis and/or cancerous meningitis.

• Active autoimmune disease or autoimmune disease within two years.

• Known central nervous system metastasis and/or cancerous meningitis.

• Prepared or previously received an organ or allogeneic bone marrow transplant

• History of active tuberculosis, such as mycobacterium tuberculosis.

• Gastrointestinal bleeding history in the past 6 months or tendency to gastrointestinal bleeding, such as esophageal varices, local active ulceration lesions, fecal occult blood = (++) (gastroscopy is required when fecal occult blood is (+)).

• History of human immunodeficiency virus infection.

• History of hepatitis B virus or hepatitis C virus infection, and not receive regular treatment.

• Severe non-healing wounds, ulcers or fractures.

• With other malignant tumors within 5 years.

• Previous and current evidence of pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonitis, drug-associated pneumonia and severe impairment of lung function.

• Received a potent CYP3A4 inhibitor treatment within 7 days prior to the study or received a potent CYP3A4 inducer within 12 days prior to the study.

• With other active malignant tumor except Hepatocellular carcinoma within 5 years or simultaneously.

• Patients are unsuitable for participation in this research after comprehensive assessment by the researchers.

• Patients participate in another clinical study at the same time.

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Hepatocellular
• Hepatocellular Carcinoma

Intervention

Drug:
• Toripalimab plus Lenvatinib
Toripalimab 240mg, every 3 weeks, intravenous infused, day 1, 6 weeks a cycle. Lenvatinib 8mg (weight<60kg) or 12mg (weight=60kg), once a day, oral at least 38 days of each 6 weeks cycle, day 2. Number of cycle: until progression or unacceptable toxicity events develop

Locations

Country	Name	City	State
China	Chinese Academy of Medical Sciences & Peking Union Medical College Hospital	Beijing	Beijing

Sponsors (2)

Lead Sponsor	Collaborator
Peking Union Medical College Hospital	Shanghai Junshi Bioscience Co., Ltd.

Country where clinical trial is conducted

China, 

References & Publications (16)

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Jia Y, Zeng Z, Li Y, Li Z, Jin L, Zhang Z, Wang L, Wang FS. Impaired function of CD4+ T follicular helper (Tfh) cells associated with hepatocellular carcinoma progression. PLoS One. 2015 Feb 17;10(2):e0117458. doi: 10.1371/journal.pone.0117458. eCollection 2015. — View Citation

Kato Y, Tabata K, Kimura T, Yachie-Kinoshita A, Ozawa Y, Yamada K, Ito J, Tachino S, Hori Y, Matsuki M, Matsuoka Y, Ghosh S, Kitano H, Nomoto K, Matsui J, Funahashi Y. Lenvatinib plus anti-PD-1 antibody combination treatment activates CD8+ T cells through reduction of tumor-associated macrophage and activation of the interferon pathway. PLoS One. 2019 Feb 27;14(2):e0212513. doi: 10.1371/journal.pone.0212513. eCollection 2019. — View Citation

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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. — View Citation

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Makker V, Rasco D, Vogelzang NJ, Brose MS, Cohn AL, Mier J, Di Simone C, Hyman DM, Stepan DE, Dutcus CE, Schmidt EV, Guo M, Sachdev P, Shumaker R, Aghajanian C, Taylor M. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer: an interim analysis of a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2019 May;20(5):711-718. doi: 10.1016/S1470-2045(19)30020-8. Epub 2019 Mar 25. — View Citation

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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. — View Citation

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* Note: There are 16 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Objective Response Rate (ORR)	Proportion of patients whose tumor volume has reached a predetermined value and can maintain a minimum time limit, including complete response and partial response patients.	Up to 1 year
Secondary	Disease Control Rate (DCR)	Proportion of patients whose tumor volume control (reduced or enlarged) reaches a predetermined value and can maintain a minimum time limit.	Up to 1 year
Secondary	Progression-free Survival (PFS)	A duration from the date of initial treatment with lenvatinib plus pembrolizumab to disease progression (defined by RECIST 1.1) or death of any cause.	Up to 1 years
Secondary	3-months and 6-month Progression free survival rate	Portion of patients who do not experience disease progression (defined by RECIST 1.1) or death of any cause after treated with toripalimab plus lenvatinib for 3 months and 6 months, respectively.	Up to 6 months
Secondary	6-months and 1-year mortality rate	Portion of patients who die of any cause after treated with toripalimab plus lenvatinib at 6 months and 1 year, respectively.	Up to 1 years
Secondary	Duration of Response (DOR)	Duration from the first time reported partial response or complete response to the first time of disease progression or death.	Up to 1 years
Secondary	Overall Survival (OS)	Duration from the date of initial treatment with lenvatinib plus pembrolizumab to the date of death due to any cause.	Up to 2 years
Secondary	clinical benefit rate (CBR)	Proportion of patients achieved complete response and partial response for more than 6 months.	up to 2 years
Secondary	Adverse events (AE)	Any adverse events related with treatment drugs and details include adverse events type, frequency and severity.	up to 2 years