Lenalidomide to Reverse Drug Resistance After Lenvatinib Combined With PD-1 Inhibitors in the First-line Treatment of Advanced HCC ：a Prospective, Exploratory, Single-arm, Open-label, Multi-center Clinical Study
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 23
- 主要终点
- ORR
研究概览
简要总结
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.
详细描述
Advanced primary hepatocellular carcinoma (HCC) has entered a new phase of clinical research and patient outcomes with the continued availability of new targeted agents and immune checkpoint inhibitors. More notable are lenvatinib in combination with PD-1 inhibitor regimens and the data that continue to emerge from these studies.
The 2020 ASCO GI published the Study117, a phase Ib clinical study of lenvatinib in combination with Nivolumab for the first-line treatment of unresectable hepatocytes. The study was an open phase Ib study that enrolled 30 patients, 17 with BCLC- stage B and 13 with BCLC- stage C. In the ITT population, the median age of patients was 70 years (range: 36-81 years) and 24 (80%) were male. 28 patients with ECOG performance status of ECOG 0 and 1 patient with ECOG 2 were enrolled. Enrolled patients received lenvatinib 12 mg (weight ≥60 kg) or 8 mg (weight <60 kg) orally once daily and in combination with Nivolumab 240 mg intravenously once every 2 weeks. The study results were impressive, with an investigator-assessed overall complete remission rate of 10% CR, a partial remission rate of 66.7% PR, an objective remission rate of 76.7% ORR, and a disease control rate of 96.7% DCR.
The ORR of the lenvatinib combination (lenvatinib in combination with PD-1 inhibitor) was generally similar to that of the "A+T" combination (bevacizumab and atelelizumab). The disease control rate (DCR) for the lenvatinib combination was 88%, indicating the efficacy of lenvatinib in combination with immunotherapy.
However, there are still many challenges in progressing to second-line therapy after first-line treatment for advanced HCC. The first is the limited efficacy of second-line treatment options recommended by NCCN guidelines.
The RESORCE study showed that single-agent regorafenib after sorafenib failure treated patients with Child-Pugh class A liver function had a higher mOS (10.6 months vs. 7.8 months) and mPFS (3.1 months vs. 1.5 months) than the placebo group. the CELESTIAL study showed that single-agent cabozantinib for patients previously treated with sorafenib in patients with HCC who were eligible for progression after at least first-line systemic therapy, 707 patients were randomly assigned in a 2:1 ratio to receive either cabozantinib (60 mg, QD) or placebo. OS was significantly longer in the cabozantinib group (10.2 months vs. 8.0 months, P=0.005). mPFS was 5.2 months vs. 1.9 months, respectively (P<0.001); ORR was 4% and <1%, respectively (P=0.009). A randomized, double-blind, placebo-controlled, global phase III clinical study of advanced HCC patients with elevated AFP after first-line failure of sorafenib enrolled 292 HCC patients with failed sorafenib and baseline AFP ≥ 400ng/ml who were randomized to receive either Ramucirumab (8mg/kg) or placebo in a 2:1 ratio. Compared with placebo, ramolutumab improved patients' mOS (8.5 months vs. 7.3 months, P=0.019 9) and mPFS (2.8 months vs. 1.6 months, P<0.0001) and reduced the risk of death by 29%; while ORR was 4.6% and 1.1%, respectively (P=0.115 6).The CheckMate-040 study [ 7] opened a phase II study of a dual immune combination therapy strategy with Nivolumab in combination with Ipilimumab) for the second-line treatment of advanced HCC, enrolling patients with advanced HCC intolerant or progressing on sorafenib therapy, with 33% (16/49; 95% CI 20 to 48) responding to immune combination therapy; BICR was assessed according to RECIST v1.1 criteria, with 8% (4 /49) achieved CR and 24% (12/49) PR; DOR ranged from 4.6 months to 30.5 months, of which 88% lasted at least 6 months, 56% at least 12 months, and 31% at least 24 months. However, all of the above studies were done after failure of sorafenib alone, and there are no effective treatment options for progression beyond targeted combination immunotherapy.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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;
- •Did not participate in other clinical trials within 4 weeks before screening; those who failed to screen in other trials but met the requirements of this trial can be enrolled.
排除标准
- •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;
- •Known human immunodeficiency virus (HIV) medical history (HIV 1/2 antibody);
- •Have been vaccinated with live vaccines within 30 days before starting the study treatment;
- •Those who suffer from high blood pressure and cannot be well controlled by antihypertensive drug treatment (systolic blood pressure>140mmHg, diastolic blood pressure>100mmHg); suffer from myocardial ischemia or myocardial infarction above CTCAE grade II, poorly controlled arrhythmia, And/or New York Heart Association (NYHA) class III~IV cardiac insufficiency;
- •Other conditions that the investigator believes prevent patients from participating in this trial.
研究组 & 干预措施
Lenalidomide
lenalidomide be used after Lenvatinib combined with PD-1 inhibitors in the first-line treatment
干预措施: Lenalidomide (Drug)
结局指标
主要结局
ORR
时间窗: up to approximately 24 months
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.
次要结局
- OS(up to approximately 24 months)
- DOR(up to approximately 18 months)
- 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)
- Percentage of Participants With Adverse Events(Up to end of study (up to approximately 24 months)