LEE001 and Chemoembolization In Patients With Advanced Hepatocellular Carcinoma

Description

Single-arm, single-institution, non-randomized, open-label phase II study to determine the efficacy and safety of treatment with LEE011 and chemoembolization in patients with advanced HCC (Hepatocellular Carcinoma) not amenable to curative therapies. A total of 40 patients will be enrolled and undergo chemoembolization. Patients will receive LEE011 (600 mg PO once daily, 3 weeks on/1 week off) on Day 1 with chemoembolization. Patients can receive a total of 4 chemoembolization treatments within 6 month following first treatment as needed to treat initial HCC (Hepatocellular Carcinoma) lesion.

Progression free survival will be based on tumor assessment using RECIST 1.1 criteria (Response Evaluation Criteria in Solid Tumors) Patients will receive trial treatment until disease progression, unacceptable toxicity, death or discontinuation from the study treatment for any other reason. Patients will be followed for survival regardless of treatment discontinuation for any reason.

The study will include men and women with locally advanced HCC (Hepatocellular Carcinoma) not amenable to curative therapy who have received no prior therapy for advanced disease.

Investigational Therapy:

LEE011 oral (3 weeks on/1 week off) in combination with chemoembolization.

Efficacy Assessments:

1. Dynamic contrasted abdominal computed tomography or magnetic resonance imaging will be done at baseline, every 8 weeks, and every 3 months thereafter following initial chemoembolization.
2. Chest CT imaging as clinically indicated
3. Survival status every 12 months (or earlier if required) regardless of treatment discontinuation reason

Data Analysis:

The primary endpoint of the trial will be progression free survival (PFS) of HCC patients. PFS is defined to be the time from initiation of treatment to progression or death without evidence of progression. For cases without documentation of progression, follow-up will be censored at the date of last disease assessment without progression, unless death occurs within 4 months following the date of last progression-free, in which case death will be counted as an event. The historical median PFS for TACE (Transcatheter arterial chemoembolization) alone is 8-10 months. This study will target a hazard ratio of 0.69 with an 80% power and a one-sided significance level of 10%. Assuming a 24-month accrual and an 18-month follow-up period the study requires 38 patients initiating LEE011 treatment with the median PFS for TACE alone is 8 months, and 41 patients with the median PFS for TACE(Transcatheter arterial chemoembolization) alone is 10 months. PFS will be estimated using the Kaplan-Meier method, and Greenwood's formula will be used to calculate the standard error of the corresponding Kaplan-Meier estimate and 95% confidence interval. Survival curves will be estimated using Kaplan-Meier methodology.

Secondary endpoints of efficacy are to evaluate OS (Overall Survival). The statistical methods used for the analysis of PFS will be used for the analysis of OS.

Other secondary objectives will include description of toxicity of the therapy regimen. These data will be analyzed separately. The safety analyses will be performed on all patients who receive any dose of therapy. Adverse events will be described using the NCI CTCAE v 4.03 criteria (ctep.cancer.gov/forms.CTCAEv4.pdf). Frequency and severity of adverse events according to the NCI CTCAE ) v 4.03 (Common Terminology Criteria for Adverse Events) body system and severity criteria will be described. In addition, frequency of Grade 3 or 4 adverse events will be described separately. Causality will also be noted. Adverse events will be recorded for up to 1 year following discontinuation from study. Response rate and toxicity rate will be estimated using an exact binomial method along with the 95% confidence interval

Details