Clinical trial NCT03236636: The Phase III Study of Icaritin Versus HUACHANSU PIAN in Hepatocellular Carcinoma Subjects
Official title: Comparison of Efficacy and Safety of Icaritin Versus Cinobufotalin in First-line Treatment of Advanced Hepatocellular Carcinoma Subjects: a Multicenter, Randomized, Double-blind, Double-dummy Phase III Clinical Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Advanced HBV-Related Hepatocellular Carcinoma (HCC)
Lead sponsor: Beijing Shenogen Biomedical Co., Ltd
Sponsor class: INDUSTRY
Collaborators: name: Chinese Academy of Medical Sciences
name: NanJing PLA 81 Hospital
name: Peking University Cancer Hospital & Institute
name: Beijing Hospital
name: Guang'anmen Hospital of China Academy of Chinese Medical Sciences
name: Jinan Central Hospital
name: Linyi Tumour Hospital
name: The First Affiliated Hospital of Anhui Medical University
name: Anhui Provincial Hospital
name: The First Affiliated Hospital with Nanjing Medical University
name: The Affiliated Tumor Hospital of Nantong University, Nantong, Jiangsu Province, China
name: Nanfang Hospital, Southern Medical University
name: First People's Hospital of Foshan
name: Affiliated Cancer Hospital & Institute of Guangzhou Medical University
name: Hebei Medical University Fourth Hospital
name: The First Hospital of Jilin University
name: Haikou People's Hospital
name: Fudan University
name: West China Hospital
name: Chongqing Traditional Chinese Medicine Hospital
name: Chifeng Municipal Hospital
name: The Affiliated Hospital of Hangzhou Normal University
name: The First Affiliated Hospital of Zhengzhou University
name: Guilin Medical University, China
name: The Third Xiangya Hospital of Central South University
name: Yunnan Provincial Hospital of Traditional Chinese Medicine
name: The Sixth People's Hospital of Shenyang
First posted: 2017-08-02
Enrollment: 312
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: multicenter, randomized, double-blind, double-dummy, adaptive enrichment design
Primary purpose: TREATMENT

Brief summary: The enriched HBV-related advanced HCC patient population (composite biomarker score ≥ 2) and overall survival (OS) were compared between the two groups.

Detailed description: The basis of enrichment design adjustment ： The latest published literature shows that the heterogeneity and immune tolerance of patients with hepatitis B virus (HBV) - related HCC are significantly correlated with a number of cytokines, including helper T cell subgroup 1 / 2 (Th1 / Th2) related factors. Moreover, the accumulated data show that the immunomodulatory effect of flavonoids including Icaritin is related to Th1 / Th2 factors. At the same time, the recent REACH2 study published in Lancet Oncology has successfully used serum alpha fetoprotein (AFP≥400) to enrich patients with advanced HCC. Based on the updated published data and our phase II clinical trial data, considering that the ongoing clinical trials are still in a blind state and no statistical analysis has been conducted, with consulting of clinical experts, regulatory agency advice, the protocol was amended and approved into adaptive enrichment design. Before unblended and SAP, the amendment protocol was prospectively pre-defined including sample size, patient population (CBS score positive), and event number for interim and final analysis. combined with the latest FDA clinical trial enrichment design guidelines (2019), several experts recommended to use the composite biomarkers, including IFN-γ , TNF - α and AFP, which may demonstrate the clinical advantages of the immunomodulation therapy with Icaritin for HBV-related advanced HCC patients in China with poor prognosis, but currently lack of treatment options.

Definition of enriched HBV-related advanced HCC patient:

Patient with serum composite biomarker score (CBS)≥2

Enrichment design amendment:

Based on our previous phase II data of Icaritin collected from HBV-related advanced HCC patients and the related literature, we assume that the mOS of the enriched population (CBS≥2) is 420 days (14 months) in the experimental group and 240 days (8 months) in the HUACHASHU control group; the HR of the experimental group relative to the control group is 0.57. A total of 106 target death events and 130 evaluable subjects were required for the enrichment. Once the amendment protocol be effective, the enriched and non-enriched patients will be continuously randomized into the experimental and the control arms accordingly (1:1). When the number of enrolled cases reaches 280, or 60% of events (64) of 106 deaths has been observed in the enriched population, interim analysis will be performed.

Eligibility criteria: Inclusion Criteria:

* Only patients who meet all the following criteria are included in the study:

  1) Age≥18years, no gender restriction; 2) Advanced or metastatic HCC patients in strict compliance with the "Primary Liver Cancer Diagnosis and Treatment Standard" (2017 Edition) issued by the National Health and Family Planning Commission, clinical diagnostic criteria and/or diagnosed by pathology /cytology, patients who fail to undergo liver surgery and/or other local treatment (ablation or hepatic artery intervention), or patients who have recurrence and progression after surgery and/or other local treatment; 3) Not previously accepted first-line system therapy (systemic chemotherapy, molecular targeting, immunotherapy and research medication, etc.) for advanced or metastatic HCC, including but not limited to systematic chemotherapy with oxaliplatin, sorafenib, PD-1/PD-L1 antibody, Icaritin and cinobufotalin, etc.; 4) Liver surgery was performed more than 3 months ago, ablation or interventional treatment of hepatic artery was performed more than 4 weeks ago, and the adverse reactions returned to normal; After surgery or other local treatment, if patients have gone beyond the norm for systemic adjuvant chemotherapy, it will need more than 6 months after the chemotherapy, and disease progression and / or metastasis have occurred; 5) For patients who are not suitable for first-line treatment of advanced HCC which is recommended in "Primary Liver Cancer Diagnosis and Treatment Standard." issued by the National Health and Family Planning Commission, it's mainly due to partial blood test indicators (See the relaxed scope in 11th inclusion criteria ) or other indicators (Including mild ascites and so on) which are not suitable for the existing first-line standard treatment; Or in particular cases, the patients insist on refusing to accept the existing first-line standard treatment(For example, patients feel that their physical condition is weak and / or economic constraints, which must be strictly mastered and controlled); 6) 2 weeks before the first medication of the trial, there is no use of modern Chinese medicine preparation with liver cancer indication, including Delisheng injection, Kanglaite injection or soft capsule, Aidi injection or Considi injection, elemene injection/oral liquid, 1) 7) no use of blood transfusion or blood products, no use of hematopoietic stimulating factor, no transfusion of albumin or blood products 14 days before screening; 8) According to the evaluation criteria of solid tumor reaction (RECIST 1.1), it has at least one measurable target lesion, which defined as non-lymph node lesions with the longest diameter larger than 10mm, lymph node lesions with the short diameter larger than 15mm; the lesions previously received local treatment such as ablation or hepatic artery interventional therapy should be detected by computed tomography (CT) / magnetic resonance imaging (MRI) and according to RECIST1.1, It's sure that disease progression has occurred and the longest diameter is more than 1.0cm,it can be used as a measurable target lesions; 9) The Child-Pugh score of liver function is grade A or better grade B (score≤7); 10) The ECOG score of physical condition is 0-1; 11) Expected survival time≥12 weeks; 12) The function of the main organs is basically normal and meets the following requirements:

  ①Marrow: There is no blood transfusion and use of hematopoietic cell stimulating agent, including granulocyte colony stimulating factor (G-CSF)within 14 days before screening, platelet≥60×10E9/L, hemoglobin≥ 85g/L, white blood cell≥3.0×10E9/L; After a thorough measurement of the patient's condition, the above three items can be appropriately relaxed by the principal researchers at the research centre as: platelet 50 \~60×10E9/L, hemoglobin 80\~85g/L, white blood cell 2.5 \~3.0×10E9/L (contains critical values);

  ②Liver: Total bilirubin≤1.5 times of the upper limit of normal(ULN), Aspartate aminotransferase (AST) and alanine aminotransferase (ALT)≤5 × ULN; albumin≥ 28g/L;

  ④ Kidney: Serum creatinine≤ 1.5 x ULN, or creatinine clearance rate≥ 50ml/min; 13) If HBV-DNA≥104 copies/ml(2000IU/ml), antiviral therapy must be done first, the patient can be included in the group until HBV-DNA\<104 copies /ml(2000IU/ml); and continue to take antiviral drugs, monitor liver function and hepatitis B virus load; 14) Women of childbearing age must receive pregnancy tests 14 days before treatment and the results are negative; Men of childbearing age need effective contraception during treatment and within 3 months after treatment; 15) Patients are volunteered to join the study, sign the informed consent, have good compliance and cooperate with follow-up; 16) The subjects do not participate in other clinical trials within 4 weeks before screening; If the subject fails in other test screening, but meets the requirements of this test, then can be enrolled.

Exclusion Criteria:

* Patients who meet any of the following criteria are not allowed to enter the test:

  1. Imaging examination shows that HCC liver tumors are huge (≥60% of the liver volume), or cancer embolus of portal trunk (occupying ≥50% of the vascular diameter), or cancer embolus invading mesenteric vein or inferior vena cava;
  2. Middle or higher ascites which is clinically significant, it requires therapeutic abdominal paracentesis /drainage, or the Child-Pugh score \> 2;
  3. Local anticancer therapy (including surgery, ablation, hepatic arterial chemotherapy, embolization or radiotherapy) or major surgery was performed 28 days prior to randomization;
  4. Hepatocholangiocarcinoma and fibrolamellar cell carcinoma; In the past 5 years or at the same time, there were other malignancies, except cervical carcinoma in situ, previously treated basal cell carcinoma and superficial bladder tumor (Ta, Tis, T1);
  5. Pregnant or lactating women;
  6. The patient suffers from CTCAE classification type II or above myocardial ischemia or myocardial infarction, poorly controlled arrhythmia; and/or NYHA standard III to IV cardiac dysfunction.
  7. Allograft transplants including liver transplantation were performed previously, or a liver transplant was planned during the trial;
  8. Hepatic encephalopathy and / or hepatic nephropathy occurred within 6 months;
  9. Patient with active hepatitis C, that is, anti -HCV positive or HCV-RNA positive and abnormal liver function;
  10. Human immunodeficiency virus (HIV) tests are positive or severe infection requiring systemic treatment with antibiotics;
  11. Inability to swallow, chronic diarrhea or intestinal obstruction that significantly affecting medication intake and absorption;
  12. Having a history of digestive tract bleeding within 6 months, or with a clear gastrointestinal bleeding tendency, including local active ulcerative lesions, positive fecal occult blood;
  13. The patient has or is suspected to have known active autoimmune disease;
  14. If a central nervous system metastasis is known and a metastasis of the central nervous system is suspected, the cranial MRI examination should be performed to exclude it;
  15. Abnormal coagulation function: international normalized ratio (INR) \>1.5 or prothrombin time (PT) \>16S;
  16. There is a history of schizophrenia or psychotropic substance abuse;
  17. Known to be allergic or intolerant to Icaritin or cinobufotalin and excipients;
  18. Other conditions that researchers believe discourage patients from participating in trials.

Primary outcomes:
measure: Overall survival (OS)
timeFrame: 2-4 years
Secondary outcomes:
measure: Progression-free survival (PFS)
timeFrame: 2-3 years
measure: Time to progress（TTP）
timeFrame: 2-3 years
measure: Overall response rate (ORR)
timeFrame: 2-3 years
measure: Overall disease control rate (DCR)
timeFrame: 2-3 years
measure: Assessment on Quality of life 1
timeFrame: 2-4 years
measure: Assessment on Quality of life 2
timeFrame: 2-4 years
Other outcomes:
measure: Biomarker analysis of proteome level (Immunohistochemical method)
timeFrame: 2-4 years
measure: Genome level (DNA, mRNA, miRNA) biomarker analysis
timeFrame: 2-4 years
Locations:
city: Hefei
country: China
facility: Anhui Provincial Hospital
state: Anhui
city: Hefei
country: China
facility: The First Affiliated Hospital of Anhui Medical University
state: Anhui
city: Beijing
country: China
facility: Cancer Hospital Chinese Academy of Medical Sciences
state: Beijing
city: Beijing
country: China
facility: Beijing Hospital
state: Beijing
city: Beijing
country: China
facility: General Hospital of Chinese Armed Police Forces
state: Beijing
city: Beijing
country: China
facility: Guang'anmen Hospital of China Academy of Chinese Medical Sciences
state: Beijing
city: Beijing
country: China
facility: Peking University Cancer Hospital
state: Beijing
city: Chongqing
country: China
facility: Chongqing Traditional Chinese Medicine Hospital
state: Chongqing
city: Foshan
country: China
facility: The First People's Hospital of Foshan
state: Guangdong
city: Guilin
country: China
facility: Affiliated Hospital of Guilin Medical University
state: Guangxi
city: Nanning
country: China
facility: Guangxi Medical University Affiliated Tumor Hospital
state: Guangxi
city: Haikou
country: China
facility: Haikou People's Hospital
state: Hainan
city: Shijiazhuang
country: China
facility: The Fourth Hospital of Hebei Medical University
state: Hebei
city: Zhengzhou
country: China
facility: The First Affiliated Hospital of Zhengzhou University
state: Henan
city: Changsha
country: China
facility: The Third Xiangya Hospital of Central South University
state: Hunan
city: Nanjing
country: China
facility: Eastern Theater General Hospital,QinHuai District Medical Area
state: Jiangsu
city: Nanjing
country: China
facility: The First Affiliated Hospital with Nanjing Medical University
state: Jiangsu
city: Nantong
country: China
facility: The Affiliated Tumor Hospital of Nantong University
state: Jiangsu
city: Changchun
country: China
facility: First Hospital of Jilin University
state: Jilin
city: Shenyang
country: China
facility: The Sixth People's Hospital in Shenyang
state: Liaoning
city: Chifeng
country: China
facility: Chifeng Municipal Hospital
state: Neimenggu
city: Jinan
country: China
facility: Jinan Central Hospital
state: Shandong
city: Linyi
country: China
facility: Linyi Cancer Hospital
state: Shandong
city: Shanghai
country: China
facility: Fudan University Shanghai Cancer Center
state: Shanghai
city: Chengdu
country: China
facility: West China Hospital of Sichuan University
state: Sichuan
city: Kunming
country: China
facility: Yunnan Provincial Hospital of Traditional Chinese Medicine
state: Yunnan
city: Hangzhou
country: China
facility: The Affiliated Hospital of Hangzhou Normal University
state: Zhejiang
city: Guangzhou
country: China
facility: Nanfang Hospital of Southern Medical University
Study officials:
affiliation: Cancer Institute and Hospital, Chinese Academy of Medical Sciences
name: Yan Sun, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: NanJing PLA 81 Hospital
name: Shukui Qin
role: PRINCIPAL_INVESTIGATOR
References: