Lenvatinib in Combination With Camrelizumab as First-Line Therapy in Patients With Advanced HCC

Hepatocellular Carcinoma Clinical Trial

Official title:

A Single-arm, Non-randomized, Single-center Study to Evaluate Lenvatinib in Combination With Camrelizumab as First-Line Therapy in Patients With Advanced Hepatocellular Carcinoma

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04443309
• Other study ID #: JS-2286
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: September 11, 2020
• Est. completion date: August 2024

Study information

• Verified date: January 2023
• Source: Peking Union Medical College Hospital
• Contact: Xiaobo Yang
• Phone: 010-69156043
• Email: yangxulcyx[@]163.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a single arm, open-label, non-randomized and single-center phase I/II clinical study, to evaluate the the safety, tolerance and efficacy of Lenvatinib plus Camrelizumab as first-line therapy in patients with advanced Hepatocellular Carcinoma.

Description:

The purpose of this study is to evaluate the safety, tolerance and efficacy of Lenvatinib combined with Camrelizumab as first-line therapy for patients with advanced hepatocellular carcinoma.The target sample size is 53.In the first phase 6 panticipants was evaluated (N=3+3), If there was no obvious dose-limiting toxicity (DLT), then entered the extended phase (N=47).Treatment continually until disease progression or intolerable toxicity or patients withdrawal of consent.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 53
• Est. completion date: August 2024
• Est. primary completion date: August 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Voluntary agreement to provide written informed consent and the willingness and ability to comply with all aspects of the protocol;

2. Males or females, age = 18 years at the time of informed consent;

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

4. BCLC stage B or C, and not suitable for surgical or local therapy, or has progressed following surgical and/or local therapy;

5. No previous systematic treatment for HCC;

6. Have at least one measurable lesion (in accordance with RECIST v1.1); the measurable lesion has a long diameter = 10 mm or lymphadenopathy has a short diameter = 15 mm in spiral CT scan;

7. ECOG-PS score 0 or 1

8. Child-Pugh Class: Grade A

9. Life Expectancy of at least 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;

11. Hematology and organ functions 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 = 85 g/L; Neutrophils = 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; Adequate renal function: Cr=1.5×ULN, or CCr>50mL/min; Female: CrCl = ((140- year) x weight (kg) x 0.85)/72x Cr (mg/dL) Male: CrCl = ((140- year) x weight (kg) x 1.00)/72xCr (mg/dL)

12. 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:

1. Hepatocellular carcinoma patients with any of the following:

Suitable for radical surgery; without an assessment lesion after radical surgery; liver transplantation history or ready for liver transplantation;

2. History of hepatic encephalopathy;

3. Known hepatocholangiocarcinoma, sarcomatoid HCC, mixed cell carcinoma and lamellar cell carcinoma;

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

5. Known history of serious allergy to any monoclonal antibody or targeted anti-angiogenic drug (or any excipient);

6. 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;

7. Previous or existing CTCAE 5.0 standard grade 3 or above gastrointestinal fistula or non-gastrointestinal fistula (such as skin);

8. Factors to affect oral administration and absorption (such as inability to swallow, chronic diarrhea and intestinal obstruction);

9. Ascites with clinical symptoms (i.e. ascites with Child-Pugh rating > 2) or cancerous ascites require therapeutic abdominal puncture or drainage. Or uncontrolled malignant ascites (ascites that researchers believe diuretics or puncture cannot control);

10. Major surgical operations (except biopsy) were performed within 4 weeks prior to the first study of drug therapy or the surgical incision was not completely healed; Minor surgery (i.e. simple resection, biopsy, etc.) was performed within 7 days before the first round of research intervention.

11. Cardiovascular and cerebrovascular diseases with significant clinical significance, including but not limited to acute myocardial infarction, severe/unstable angina pectoris, cerebrovascular accident or transient ischemic attack, congestive heart failure occurred within 6 months prior to admission (New York Heart Association Grade =2, see Appendix 4); Arrhythmia requiring antiarrhythmic drugs (except ß receptor blocker or digoxin); Repeated ECG detection QTcF interval>480 milliseconds (ms).

12. Hepatic and renal insufficiency, such as jaundice, ascites, and/or bilirubin>3×ULN, creatinine ratio>3.5g/24h, or renal failure requiring blood or peritoneal dialysis, etc. And/or urine routine showed proteinuria =++or confirmed 24-hour proteinuria>1.0g.

13. Persistent>2 grade (CTC-AE5.0) infection.

14. History of thromboembolism (including stroke and/or transient ischemic attack) in the past 6 months.

15. Hypertension (systolic blood pressure>160mmHg, diastolic blood pressure>100 mmHg) that not be well controlled through antihypertensive drug treatment.

16. History of active autoimmune diseases or autoimmune diseases in the past two years.

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

18. Be ready for or previously received organ or allogenic bone marrow transplantation.

19. Known history of active tuberculosis (Mycobacterium tuberculosis).

20. History of gastrointestinal hemorrhage within 6 months prior to the start of study treatment or clear tendency of gastrointestinal hemorrhage.

21. History of human immunodeficiency virus (HIV)infection.

22. Active hepatitis B virus or C virus infection and not receive regular treatment;

23. Serious non-healing wound, ulcer or fracture.

24. Drug abuse exists; or any medical, psychological or social condition that may affect research, unstable patient compliance or even endanger patient safety.

25. Any>1 grade (CTC-AE 5.0) unresolved toxicity due to previous treatment or operation, except for hair loss, anemia, and hypothyroidism.

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

27. 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.

28. With other active malignant tumors except HCC within 5 years or simultaneously.

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

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

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Hepatocellular
• Hepatocellular Carcinoma

Intervention

Drug:
• Camrelizumab
Camrelizumab 200mg,iv,d1,q2w
• Lenvatinib
Lenvatinib 8mg (<60kg) or 12mg (=60kg),po,d2,qd

Locations

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

Sponsors (2)

Lead Sponsor	Collaborator
Peking Union Medical College Hospital	Jiangsu HengRui Medicine Co., Ltd.

Country where clinical trial is conducted

China, 

References & Publications (12)

8. Qin S OX, Bai Y, Cheng Y, Chen Z, Ren Z, Song T, Dutcus C, Saito K, Tamai T, Yau TCC, Rau K-M, Cheng A-L, Han G. Subgroup analysis of Chinese patients in a phase 3 study of lenvatinib vs sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma. Hepatol Int 2019;13:S170.

Boussiotis VA. Molecular and Biochemical Aspects of the PD-1 Checkpoint Pathway. N Engl J Med. 2016 Nov 3;375(18):1767-1778. doi: 10.1056/NEJMra1514296. No abstract available. — View Citation

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. — View Citation

Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015 Mar 1;136(5):E359-86. doi: 10.1002/ijc.29210. Epub 2014 Oct 9. — View Citation

Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, Kudo M, Breder V, Merle P, Kaseb AO, Li D, Verret W, Xu DZ, Hernandez S, Liu J, Huang C, Mulla S, Wang Y, Lim HY, Zhu AX, Cheng AL; IMbrave150 Investigators. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med. 2020 May 14;382(20):1894-1905. doi: 10.1056/NEJMoa1915745. — View Citation

Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet. 2012 Mar 31;379(9822):1245-55. doi: 10.1016/S0140-6736(11)61347-0. Epub 2012 Feb 20. — View Citation

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. — View Citation

Llovet JM, Montal R, Villanueva A. Randomized trials and endpoints in advanced HCC: Role of PFS as a surrogate of survival. J Hepatol. 2019 Jun;70(6):1262-1277. doi: 10.1016/j.jhep.2019.01.028. Epub 2019 Mar 31. — View Citation

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

Ma W, Gilligan BM, Yuan J, Li T. Current status and perspectives in translational biomarker research for PD-1/PD-L1 immune checkpoint blockade therapy. J Hematol Oncol. 2016 May 27;9(1):47. doi: 10.1186/s13045-016-0277-y. — View Citation

Qin S, Ren Z, Meng Z, Chen Z, Chai X, Xiong J, Bai Y, Yang L, Zhu H, Fang W, Lin X, Chen X, Li E, Wang L, Chen C, Zou J. Camrelizumab in patients with previously treated advanced hepatocellular carcinoma: a multicentre, open-label, parallel-group, randomised, phase 2 trial. Lancet Oncol. 2020 Apr;21(4):571-580. doi: 10.1016/S1470-2045(20)30011-5. Epub 2020 Feb 26. — View Citation

Villanueva A. Hepatocellular Carcinoma. N Engl J Med. 2019 Apr 11;380(15):1450-1462. doi: 10.1056/NEJMra1713263. No abstract available. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Biomarker	Biomarkers (such as AFP, PD-L1 expression, CD8 T cell immunohistochemistry, RNA-sequencing) related with efficacy	two years
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	one 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	one year
Secondary	Progression-free Survival (PFS)	A duration from the date of initial treatment to disease progression (defined by RECIST 1.1) or death of any cause	one year
Secondary	Overall Survival (OS)	Duration from the date of initial treatment to the date of death due to any cause.	one year
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	one year
Secondary	Clinical Benefit Rate (CBR)	Proportion of patients achieved complete response and partial response for more than 6 months	two years
Secondary	3-months and 6-months 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	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	one year
Secondary	Adverse Events (AE)	Any adverse events related with treatment drugs and details include adverse events type, frequency and severity	two years