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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase II Study of PD-0332991 in Adult Patients With Advanced Hepatocellular Carcinoma

Conditions
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Advanced Hepatocellular Carcinoma, HCC, Liver Cancer

Intervention / Treatment
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* Drug: PD-0332991


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, age > or = 18 years with HCC refractory to currently available therapies. 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 Positive staining for RB-function on tumor biopsy. Subject must be able to give written informed consent and be able to follow protocol requirements Life expectancy greater than 3 months Be Child's-Pugh class A or B ECOG Performance status of < or = 2 If female of childbearing potential must have negative pregnancy test at screening and may not be breast-feeding 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. 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. 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 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. 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: 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) 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 Renal failure requiring hemo- or peritoneal dialysis Unstable systemic diseases or active uncontrolled infection Known history of HIV infection Clinically significant gastrointestinal bleeding within 30 days prior to study entry Major surgery, open biopsy or significant traumatic injury within 4 weeks prior to study entry Child's-Pugh Class C Any malabsorption problem that, in the investigator's opinion, would prevent adequate absorption of the study drug Presence of any other medical complications that in the investigator's opinion, suggests a survival of < 3 months 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 Patient inability to swallow oral medications Any condition that is unstable or which could jeopardize the safety of the patient and his/her compliance in the study Pregnant or breast-feeding patients Being of reproductive potential and unable or unwilling to practice an effective contraceptive method Lack of positive staining for RB-function on tumor biopsy.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PD-0332991<br>PD-0332991 in the Treatment in Patients with Advanced Hepatocellular Carcinoma | Drug: PD-0332991<br>* PD-0332991, 125mg, 3 cycles<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Disease Progression | Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST Version 1.1), as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The appearance of one or more new lesions is also considered progression. | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Adverse Events | 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. | From date of randomization through study completion, assessed up to 100 months | 
| Overall Survival (OS) | 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. | 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 | 
| Response Rate (RR) | 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. | Every 8 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Advanced Hepatocellular Carcinoma, HCC, Liver Cancer, PD-0332991