(A) STUDY HYPOTHESIS
- Mebendazole augments response of lenvatinib by synergistic response.
- Addition of anti angiogenic drugs (lenvatinib and mebendazole) to hypoxic environment
generated post locoregional therapy like TACE leads to more effective control of
advanced HCC resulting in improvement in overall survival.
(B) AIM: To compare the efficacy of combination of mebendazole with lenvatinib in cirrhotics
with advanced Hepatocellular Carcinoma.
(C) OBJECTIVE:
Primary objective:
To compare the efficacy of combination of mebendazole with lenvatinib in improving the
overall survival at 15 months in cirrhotics with advanced HCC.
Secondary objective:
1. To compare the progression free survival with combination therapy of mebendazole and
lenvatinib in advanced Hepatocellular Carcinoma (HCC).
2. To compare the objective response rate (ORR), disease control rate (DCR) and clinical
benefit rate (CBR) with combinative therapy of mebendazole and lenvatinib in advanced
HCC.
3. To study therapy related adverse effects of mebendazole in cirrhotics.
4. To develop pre-clinical HCC animal model to prove the added efficacy of combination
therapy.
(D)STUDY DESIGN Type of study - Single center, prospective, open label, randomized control
study Study population - cirrhosis of liver of any etiology with advanced HCC undergoing at
ILBS Study duration - 22 months from the date of approval of IEC Sample size - Considering
mebendazole adds 2 months more to lenvatinib which offers 13 months overall survival, power
of the study as 80 %, attrition rate as 30 %, alpha error of 5%, sample size will be 85
patients in each arm ( totally 170 patients).
(F) Methodology: Cirrhotics with advanced HCC proven by imaging and or biopsy or cytology,
fulfilling the eligibility criteria will be enrolled in the study. They may undergo 1 or 2
sessions of locoregional therapy (TACE/ SBRT/RFA) if feasible. All patients will undergo
complete physical examination, CBC, LFT, KFT, INR, AFP, PIVKAII, CEMRI/ CECT upper abdomen
(Triple phase ), UGI endoscopy at baseline before randomization.
Randomization:
Those patients who are not feasible for locoregional therapy will be randomized at baseline.
Those patients undergoing locoregional therapy will be randomized after 1 month of last
locoregional therapy (patient may undergo maximum of two sessions of locoregional therapy
before randomization). The response will be determined by m RECIST criteria before
randomization. Those patients requiring further sessions of locoregional therapy beyond two
sessions will not be randomized into study.
Patient will be then randomized to one of the two groups Arm I :Lenvatinib +Placebo(
Lenvatinib will be given once a day(OD) orally at dose of 8 mg if body weight is < 60 kg and
12 mg if body weight is > 60 kg ) with placebo (Tab Mecovit) orally twice a day (BD) daily
Arm II : Lenvatinib and mebendazole ( Lenvatinib will be given orally once a day (OD) at dose
of 8 mg if body weight is < 60 kg and 12 mg if body weight is > 60 kg) and mebendazole will
be given at dose of 100 mg orally twice a day (BD) daily
Follow-up Patients will be followed up with clinical events, CBC, LFT, KFT, INR, AFP,
PIVKAII, CEMRI/ CECT upper abdomen (Triple phase ) at the end of 1 month, 3 months, 6 months,
9 months, 12 months and 15 months.
INVESTIGATIONS AND FOLLOW UP At Baseline (before therapy) and during follow up
- Hematology- repeated at the end of 1, 3, 6, 9, 12, 15 months.
- CBC
- Biochemistry - repeated at the end of 1, 3, 6, 9, 12, 15 months.
- Serum Electrolytes, Kidney function test
- Liver function test, INR
- CTP and MELD scores
- AFP, PIVKA II - repeated at the end of 1, 3, 6, 9, 12, 15 months.
- UGIE at baseline
- CEMRI / CECT upper abdomen - Triple phase - repeated at the end of 1, 3, 6, 9, 12, 15
months.
- PET CT - if systemic spread suspected or else at the end of 6 and 15 months
- Liver Biopsy/FNAC will be done in cases where its clinically indicated.
The pre-clinical model will be developed in mice, for which separate application will be
submitted to the animal ethics committee of the institute.
Timeline of follow up
- At the end of first month
- Then every 3 months until 15 months after starting therapy
STATISTICAL ANALYSIS
- Data will be reported as mean + SD
- Categorical variables will be compared using the chi-square test or Fisher exact test
- Normal continuous variables will be compared using the Student t test
- Non normal continuous variables will be compared using the Mann-Whitney rank-sum test
(unpaired data) or the Wilcoxon test (paired data).
- Comparison between groups on quantitative variables will be analyzed by ANOVA
- The actuarial probability of survival will be calculated by the Kaplan-Meier method and
compared using the log-rank test
- A Cox regression analysis will be performed to identify independent prognostic factors
for survival.
Intervention: This Randomized Controlled trial will be conducted at Institute of Liver &
Biliary SciencesLBS New Delhi between June 2020 and March 2022
Salvage therapy
- TACE or TARE if progressive disease
- Nivolilumab if the patient had a progressive disease at 6 months of therapy
Inclusion Criteria:
- Cirrhosis of Liver with HCC on imaging and/or biopsy or cytology
- Child Pugh A, Child Pugh B < 8
- Advanced HCC - as defined by BCLC - C
- ECOG Performance Status 1-2
- Adequately controlled blood pressure (BP) with up to 3 antihypertensive agents,
defined as BP ≤150/90 millimeters of mercury (mmHg) at screening and no change in
antihypertensive therapy within 1 week prior to commencement of intervention.
- Valid Consent
- Age 18-70 years
Exclusion Criteria:
- Decompensated Cirrhosis
- Child Pugh C, Child Pugh B > 7
- HCC patients with a curative therapy (RFA/MWA or LT)
- Prior systemic therapies (or) immunotherapy for HCC
- ECOG Performance Status 3-4
- Post Liver transplant HCC recurrence
- Pregnancy
