A Phase II Study of PD-0332991 in Adult Patients With Advanced Hepatocellular Carcinoma
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.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Time to Disease Progression
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%.
Every 8 weeks
Susan Littman, MD
Thomas Jefferson University
United States: Food and Drug Administration
|Thomas Jefferson University||Philadelphia, Pennsylvania 19107-6541|