A Clinical Research Study to Determine Whether PD 0332991 May Be Effective in Treating Patients With Liver Cancer

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.

Inclusion Criteria:

1. Male or female, age > or = 18 years with HCC refractory to currently available
therapies.

2. Documented HCC by at least 2 out of 3 mentioned criteria and evidence of
non-resectability by a multidisciplinary team:

A. Radiological - MRI with arterial enhancement and rapid venous washout B. Biopsy C.
Serum alpha-fetoprotein level > or = 200

3. Positive staining for RB-function on tumor biopsy.

4. Subject must be able to give written informed consent and be able to follow protocol
requirements

5. Life expectancy greater than 3 months

6. Be Child's-Pugh class A or B

7. ECOG Performance status of < or = 2

8. If female of childbearing potential must have negative pregnancy test at screening and
may not be breast-feeding

9. Females of child-bearing potential (< one year post-menopausal with documented FSH
greater than 30 IU/L or surgically not sterile), must agree to practice an effective
method of avoiding pregnancy (including oral or implanted contraceptives, intrauterine
device, condom, diaphragm with spermicidal, cervical cap, abstinence or sterile sex
partner) from the time informed consent is signed through follow-up. Males must agree
to take appropriate precautions to avoid fathering a child from screening through
follow-up.

10. No other active malignancy requiring treatment in the last 3 years other than
adequately treated non-melanomatous skin cancer, adequately treated cervical carcinoma
in-situ, superficial adequately treated bladder cancer or prostatic intraepithelial
neoplasia without evidence of prostate cancer.

11. Adequate bone marrow, liver and renal function as assessed by the following:

A. Hemoglobin > or = 8 g/dL B. WBC > or = 4,000/uL C. Absolute neutrophil count > or =
1,500/uL D. Platelets > or = 75,000/uL E. Total bilirubin < or = 1.5 times ULN F. ALT
and AST < or = 5 times ULN G. Creatinine < or = 1.5 times ULN H. Albumin > or = 2.5
mg/dL

12. Subjects who have received previous radiotherapy, loco-regional, or systemic therapy
are eligible. A minimum interval of 4 weeks since the last anti-cancer treatment of
any kind is required.

13. Subjects with brain metastases or a history of previously treated brain metastasis are
eligible but must:

A. Have been treated by surgery or stereotactic radiosurgery (SRS) at least 4 weeks prior
to enrollment B. AND have a baseline MRI or CT that shows no evidence of active
intercranial disease C. AND be off steroids for at least 1 week prior to study enrollment

Exclusion Criteria:

1. Any concurrent active malignancy requiring treatment (other than basal or squamous
cell carcinoma of the skin, carcinoma in situ of the cervix, superficial bladder
tumors, or other malignancies curatively treated > 3 years prior to study entry)

2. History of severe cardiovascular disease within the last 12 months: symptomatic
congestive heart failure, myocardial infarction, coronary artery disease (CAD), life
threatening arrhythmias, uncontrolled hypertension

3. Renal failure requiring hemo- or peritoneal dialysis

4. Unstable systemic diseases or active uncontrolled infection

5. Known history of HIV infection

6. Clinically significant gastrointestinal bleeding within 30 days prior to study entry

7. Major surgery, open biopsy or significant traumatic injury within 4 weeks prior to
study entry

8. Child's-Pugh Class C

9. Any malabsorption problem that, in the investigator's opinion, would prevent adequate
absorption of the study drug

10. Presence of any other medical complications that in the investigator's opinion,
suggests a survival of < 3 months

11. Substance abuse, or medical, psychological or social conditions that may interfere
with the patient's participation in the study or evaluation of the study results

12. Patient inability to swallow oral medications

13. Any condition that is unstable or which could jeopardize the safety of the patient and
his/her compliance in the study

14. Pregnant or breast-feeding patients

15. Being of reproductive potential and unable or unwilling to practice an effective
contraceptive method

16. Lack of positive staining for RB-function on tumor biopsy.