A Clinical Research Study to Determine Whether PD 0332991 May Be Effective in Treating Patients With Liver Cancer
Advanced Hepatocellular Carcinoma
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase II Study of PD-0332991 in Adult Patients With Advanced Hepatocellular Carcinoma|
- Time to Disease Progression [ Time Frame: Every 8 weeks ] [ Designated as safety issue: No ]Time to progression (TTP) will be defined as the date of enrollment on trial to the first observation of disease progression, as classified by modified RECIST (Response Evaluation Criteria In Solid Tumors) or clinical progression. The date of last dose of treatment or death will be used as the date of this event in the case that recurrent disease was not assessable. An interim analysis for futility will be conducted after the first 10 events have occurred. The study will be stopped for futility if the conditional power is less than 60%.
- Number and Nature of Adverse Events [ Time Frame: Every 2 weeks during first 3 cycles, then monthly ] [ Designated as safety issue: Yes ]The number and nature of adverse events as a measure of safety and tolerability. Safety analysis will be conducted on all patients who receive at least one dose of PD-0332991 during the study period or follow-up. An adverse event is any unfavorable and unintended sign, symptom, syndrome or illness that develops during the period of observation in the clinical study, including a new illness or condition, worsening of a concomitant illnesses or condition, effect of the study medication or combination of 2 or more factors.
- Overall Survival (OS) [ Time Frame: Every 2 weeks during first 3 cycles, then monthly during treatment. Then Day 28, Day 56 and every 3 months from last administration of protocol directed therapy or death ] [ Designated as safety issue: No ]Overall survival (OS) is measured from the entry onto the trial until death of any cause. Date and cause of death will be recorded. The cause of death will be categorized as either cancer-related or cancer-unrelated.
- Response Rate (RR) [ Time Frame: Every 8 weeks ] [ Designated as safety issue: No ]The best overall response is the best response recorded from the start of treatment until disease progression or recurrence. The objective response rate is the proportion of subjects with either a confirmed complete response (CR) or a confirmed partial response (PR) as determined using modified RECIST (Response Evaluation Criteria In Solid Tumors) criteria. Subjects with the response of stable disease (SD) will be recorded and documented. Disease control rate defined as CR+PR+SD will be calculated for all subjects treated with PD-0332991.
|Study Start Date:||June 2011|
|Estimated Study Completion Date:||December 2015|
|Estimated Primary Completion Date:||December 2015 (Final data collection date for primary outcome measure)|
PD-0332991 in the Treatment in Patients with Advanced Hepatocellular Carcinoma
PD-0332991, 125mg, 3 cycles
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third most frequent cause of cancer-related mortality. To date, surgical resection and liver transplantation are considered the main curative treatment options for HCC (El-Serag et al. 2006). However, the majority (~75%) of patients present with advanced tumor stage and poor liver function, rendering the patient ineligible for surgical interventions. Until the multikinase inhibitor sorafenib (Nexavar) was approved for the treatment of HCC in patients with unresectable disease (disease that can't be removed by surgery), there were no standard systemic therapies, as classical cell killing drugs (administered singularly or in combination) had not led to reproducible response rates or survival benefit. Despite this, response rates to sorafenib are low with overall benefits modest, and moreover the toxicity profile of the drug limits treatment for many patients. There is still a critical need for additional effective drugs to treat advanced HCC.
PD-0332991 is an orally available, selective inhibitor of cyclin-dependent kinase 4/6 (CDK4/6), a key regulator of cell growth. Pre-clinical data with PD-0332991 demonstrated potent target-specificity. PD-0332991 demonstrated significant inhibition of tumor cell growth in hepatoma cell lines, as well as animal and xenograft model systems, and was more effective than the currently approved drug, sorafenib in these systems. Initial clinical trials have demonstrated and acceptable toxicity profile for the drug. Thus, PD-0332991 represents an ideal candidate for the treatment of patients with advanced HCC.
This trial is an open-label non-randomized single-institution study for subjects with inoperable, recurrent/refractory, advanced hepatocellular carcinoma (HCC). Subjects must have failed or be intolerant of standard first line therapy, sorafenib (Nexavar®). Eligible subjects will receive 125 mg PD-0332991 capsules orally once daily, administered on days 1-21 of a 28-day cycle, in repeated cycles. The primary objective of the study is to assess the time to disease progression (TTP). Secondary objectives include assessment of safety and tolerability, and determination of overall survival (OS) and response rate (RR).
Subjects will be permitted to receive protocol directed therapy until disease progression as determined by modified RECIST (Response Evaluation Criteria in Solid Tumors) guidelines or clinical progression, unacceptable toxicity, withdrawal of consent or death. Tumor response assessment will be performed by the Investigator and will consist of evaluation by CT or MRI every 8 weeks. Subjects who discontinue therapy will still be followed for safety on Day 28 (± 3 days), Day 56 (± 3 days) and every 3 months thereafter from the last administration of protocol-directed therapy or until death.
Subjects will be continuously assessed for evidence of acute and cumulative toxicity. Vital signs, physical examinations, performance status, laboratory safety tests will be obtained and assessed prior to drug administration at regular intervals throughout the study. Toxicity will be evaluated every 2 weeks during the first 3 cycles and thereafter monthly (once per cycle) by the Investigator according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01356628
|United States, Pennsylvania|
|Thomas Jefferson University|
|Philadelphia, Pennsylvania, United States, 19107|
|Principal Investigator:||Christina Brus, MD||Thomas Jefferson University|