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

This is a Phase 2 Study of PD-0332991 in the treatment of patients with Advanced Hepatocellular Carcinoma (HCC), a type of adenocarcinoma and the most common type of liver tumor. PD-0332991 is a compound that stops the tumor cell from entering the Synthesis phase of the cell cycle, therefore stopping DNA multiplication and decreased tumor cell copying.

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.

Eligibility Criteria:
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.