Lenalidomide to Reverse Drug Resistance After First-line Treatment of Advanced HCC

NCT05831969 | Unknown Phase 2

• 1 other identifier: Dream-004
• Study Type: interventional
• Target: 23
• Locations: 0 countries
• Sites: N/A

Brief Summary

The ORR of the lenvatinib combination (lenvatinib combined with PD-1 inhibitor) was largely similar to that of the "A+T" combination (bevacizumab and atelelizumab). The disease control rate (DCR) for the combination of lenvatinib was 88%, demonstrating the efficacy of lenvatinib in combination with immunotherapy. However, progression to second-line therapy after first-line treatment for advanced HCC still faces many challenges. In our clinical practice and review of the literature, we focused on lenalidomide showing some efficacy in second-line treatment of advanced HCC. Lenalidomide is a new generation derivative of thalidomide, which has dual anti-angiogenic and immunomodulatory anti-tumor effects. Lenalidomide may have the potential to reverse drug resistance and increase the efficacy of synergistic immune-targeted therapy. Based on the preliminary data of its effectiveness in the second-line treatment of advanced HCC alone or in combination with TKI, we propose to conduct a prospective, exploratory, single-arm, open, multicenter phase II clinical study of advanced HCC PD-1 inhibitor in combination with lenvatinib after progression of first-line treatment, to initially evaluate the efficacy and safety of this regimen.

Conditions

Advanced HCC

Keywords

lenalidomide; Drug resistance

Outcome Measures

Primary Outcomes (1)

• ORR

  Defines the proportion of patients whose tumor volume shrinks to a prespecified value and is maintained for a minimum period of time. The RECIST 1.1 standard was adopted, including complete remission of CR and partial remission of PR.

  up to approximately 24 months

Secondary Outcomes (4)

• PFS

  Randomization to the first occurrence of disease progression or death from any cause up to the clinical cut off date of June 5,2024

• OS

  up to approximately 24 months

• DOR

  up to approximately 18 months

• Percentage of Participants With Adverse Events

  Up to end of study (up to approximately 24 months

Study Arms (1)

Lenalidomide

EXPERIMENTAL

lenalidomide be used after Lenvatinib combined with PD-1 inhibitors in the first-line treatment

Drug: Lenalidomide

Interventions

Lenalidomide DRUG

Lenalidomide: 10mg/d, 1-21d/28d orally; until disease progression or intolerable adverse reactions.

Lenalidomide

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Willing and able to sign a written informed consent;
• Age ≥ 18 and ≤ 75 years old on the day of signing the informed consent form;
• Locally advanced hepatocellular carcinoma, clinical diagnosis of hepatocellular carcinoma by histology/cytology, imaging (enhanced MRI or enhanced CT or PET-CT);
• Advanced metastatic and/or unresectable HCC progresses after combination therapy with lenvatinib combined with PD-1 inhibitors (must be domestically approved for use in liver cancer);
• Eastern Cooperative Oncology Group (ECOG) physical status score is 0 or 1;
• Liver function in line with Child-Pugh A grade (score 5-6 points);
• Hepatitis B surface antigen detection is required before enrollment. For patients who are confirmed to have hepatitis B, antiviral drugs should be started 1 week before treatment;
• During the study screening period, patients must be tested for hepatitis C virus (HCV) RNA status. This study allowed for the study of patients with untreated chronic HCV infection. In addition, patients who have been cured of hepatitis C can be included in this study, but the hepatitis C treatment should be completed for more than 4 weeks at the time of enrollment;
• The main organ functions are basically normal and meet the following requirements:
• Bone marrow: absolute neutrophil count ≥1.5×109/L, platelet ≥50×109/L, hemoglobin ≥90g/L.
• Liver: total bilirubin ≤ 2 times the upper limit of normal (ULN), aspartate aminotransferase and alanine aminotransferase ≤ 5 × ULN, albumin ≥ 29 g/L.
• Kidney: serum creatinine ≤1.5×ULN, or creatinine clearance ≥50mL/min. Coagulation function: international normalized ratio (INR) ≤ 2, and activated partial thromboplastin time (APTT) ≤ 1.5 times ULN.
• The expected survival time is more than 3 months;
• Patients with other malignant tumors have lived disease-free for more than 2 years after initial treatment (such as non-melanoma skin cancer or cervical cancer in situ);
• Women of childbearing age must agree to use effective contraception for at least 4 weeks before enrollment in the study, during the study and within 4 weeks after the withdrawal of the study drug. Women of childbearing potential require a serum pregnancy test within 72 hours of starting treatment. Male subjects must also use effective contraception during treatment and within 4 weeks of drug withdrawal. The spouse of the subject also needs to do a good job of contraception during the subject's participation in the study;

You may not qualify if:

• Hypersensitivity to iridamine drugs;
• Fibrolamellar or sarcomatoid HCC;
• Mixed HCC-ICC;
• Currently participating in and receiving other experimental treatments, or participating in a study of immune checkpoint inhibitors and receiving study treatment;
• Previous solid organ transplantation, diagnosed as immunodeficiency, or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days before the first trial treatment;
• Esophageal or gastric variceal bleeding within 3 months before enrollment;
• Hepatic encephalopathy in the past 6 months, or obvious ascites at the time of enrollment;
• Have a known history of active tuberculosis;
• Hypersensitivity to PD-1 inhibitors;
• The subject has other known aggressive malignant tumors at the same time (except for those who have no evidence of tumor recurrence after treatment and the duration is more than 2 years). Exceptions include: basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, low-risk prostate cancer, or cervical cancer in situ;
• Patients with previous active autoimmune diseases requiring systemic treatment;
• History or any evidence of known active non-infectious pneumonia;
• Active infection requires systemic treatment;
• People with known mental illness or substance abuse disorder;
• Pregnant or lactating women;

Sponsors & Collaborators

• Shenyang Tenth People's Hospital: lead
• Beijing Tsinghua Changgeng Hospital: collaborator

Related Publications (13)

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  PMID: 32716739 BACKGROUND

• IMbrave150: Exploratory Efficacy and Safety Results in Patients With Hepatocellular Carcinoma Without Macrovascular Invasion or Extrahepatic Spread Treated With Atezolizumab + Bevacizumab or Sorafenib. Gastroenterol Hepatol (N Y). 2021 Nov;17(11 Suppl 6):14-15. No abstract available.

  PMID: 35611267 BACKGROUND

• Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, Pracht M, Yokosuka O, Rosmorduc O, Breder V, Gerolami R, Masi G, Ross PJ, Song T, Bronowicki JP, Ollivier-Hourmand I, Kudo M, Cheng AL, Llovet JM, Finn RS, LeBerre MA, Baumhauer A, Meinhardt G, Han G; RESORCE Investigators. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017 Jan 7;389(10064):56-66. doi: 10.1016/S0140-6736(16)32453-9. Epub 2016 Dec 6.

  PMID: 27932229 BACKGROUND

• Abou-Alfa GK, Meyer T, Cheng AL, El-Khoueiry AB, Rimassa L, Ryoo BY, Cicin I, Merle P, Chen Y, Park JW, Blanc JF, Bolondi L, Klumpen HJ, Chan SL, Zagonel V, Pressiani T, Ryu MH, Venook AP, Hessel C, Borgman-Hagey AE, Schwab G, Kelley RK. Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma. N Engl J Med. 2018 Jul 5;379(1):54-63. doi: 10.1056/NEJMoa1717002.

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• Zhu AX, Kang YK, Yen CJ, Finn RS, Galle PR, Llovet JM, Assenat E, Brandi G, Pracht M, Lim HY, Rau KM, Motomura K, Ohno I, Merle P, Daniele B, Shin DB, Gerken G, Borg C, Hiriart JB, Okusaka T, Morimoto M, Hsu Y, Abada PB, Kudo M; REACH-2 study investigators. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased alpha-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019 Feb;20(2):282-296. doi: 10.1016/S1470-2045(18)30937-9. Epub 2019 Jan 18.

  PMID: 30665869 BACKGROUND

• Yau T, Kang YK, Kim TY, El-Khoueiry AB, Santoro A, Sangro B, Melero I, Kudo M, Hou MM, Matilla A, Tovoli F, Knox JJ, Ruth He A, El-Rayes BF, Acosta-Rivera M, Lim HY, Neely J, Shen Y, Wisniewski T, Anderson J, Hsu C. Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients With Advanced Hepatocellular Carcinoma Previously Treated With Sorafenib: The CheckMate 040 Randomized Clinical Trial. JAMA Oncol. 2020 Nov 1;6(11):e204564. doi: 10.1001/jamaoncol.2020.4564. Epub 2020 Nov 12.

  PMID: 33001135 BACKGROUND

• Safran H, Charpentier KP, Kaubisch A, Mantripragada K, Dubel G, Perez K, Faricy-Anderson K, Miner T, Eng Y, Victor J, Plette A, Espat J, Bakalarski P, Wingate P, Berz D, Luppe D, Martel D, Rosati K, Aparo S. Lenalidomide for second-line treatment of advanced hepatocellular cancer: a Brown University oncology group phase II study. Am J Clin Oncol. 2015 Feb;38(1):1-4. doi: 10.1097/COC.0b013e3182868c66.

  PMID: 23648434 BACKGROUND

• Shao YY, Chen BB, Ou DL, Lin ZZ, Hsu CH, Wang MJ, Cheng AL, Hsu C. Lenalidomide as second-line therapy for advanced hepatocellular carcinoma: exploration of biomarkers for treatment efficacy. Aliment Pharmacol Ther. 2017 Oct;46(8):722-730. doi: 10.1111/apt.14270. Epub 2017 Aug 17.

  PMID: 28815645 BACKGROUND

• Richardson P, Anderson K. Immunomodulatory analogs of thalidomide: an emerging new therapy in myeloma. J Clin Oncol. 2004 Aug 15;22(16):3212-4. doi: 10.1200/JCO.2004.05.984. Epub 2004 Jul 12. No abstract available.

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• Guirguis AA, Ebert BL. Lenalidomide: deciphering mechanisms of action in myeloma, myelodysplastic syndrome and beyond. Curr Opin Cell Biol. 2015 Dec;37:61-7. doi: 10.1016/j.ceb.2015.10.004. Epub 2015 Nov 11.

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• Nicholas NS, Apollonio B, Ramsay AG. Tumor microenvironment (TME)-driven immune suppression in B cell malignancy. Biochim Biophys Acta. 2016 Mar;1863(3):471-482. doi: 10.1016/j.bbamcr.2015.11.003. Epub 2015 Nov 7.

  PMID: 26554850 BACKGROUND

• Chong EA, Ahmadi T, Aqui NA, Svoboda J, Nasta SD, Mato AR, Walsh KM, Schuster SJ. Combination of Lenalidomide and Rituximab Overcomes Rituximab Resistance in Patients with Indolent B-cell and Mantle Cell Lymphomas. Clin Cancer Res. 2015 Apr 15;21(8):1835-42. doi: 10.1158/1078-0432.CCR-14-2221. Epub 2015 Jan 28.

  PMID: 25632047 BACKGROUND

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MeSH Terms

Interventions

Lenalidomide

Intervention Hierarchy (Ancestors)

Phthalimides; Phthalic Acids; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals; Piperidones; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Isoindoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Jianhui Jia, M.B

  Shenyang Tenth People's Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Jianhui Jia, M.B

CONTACT

18900917100; xbl007jjh@163.com

Gong Li, M.M

CONTACT

13366061906; lga02375@btch.edu.cn

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 16, 2023
• First Posted: April 26, 2023
• Study Start: June 5, 2023
• Primary Completion: June 5, 2025
• Study Completion: October 5, 2025
• Last Updated: April 26, 2023

Record last verified: 2023-03

Data Sharing

• IPD Sharing: Will not share