Clinical trial NCT01356628
Conditions: Advanced Hepatocellular Carcinoma HCC Liver Cancer
Keywords: Advanced Hepatocellular Carcinoma HCC Liver Cancer PD-0332991
Sponsor: Sidney Kimmel Cancer Center at Thomas Jefferson University
Start date: 2011-05-25; Completion date: 2023-12-16
Enrollment: 23 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
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:
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.

Arms: arm 1: PD-0332991 in the Treatment in Patients with Advanced Hepatocellular Carcinoma
Interventions: intervention 1: PD-0332991
Intervention descriptions: intervention 1: PD-0332991, 125mg, 3 cycles

Protocol documents:
Prot_SAP_000.pdf: 
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CLINICAL PROTOCOL 
 
 
Protocol Title: A Phase II Study of PD-0332991 in Adult Patients with Advanced 
Hepatocellular Carcinoma 
 
 
 
 
Study Medication: PD-0332991 
 
IRB Number: 11D.14 
 
IND #: 110905 
 
 
 
Sponsor-Investigator: 
Susan J. Littman, MD 
 
Principal Investigator: 
Avnish Bhatia, MD 
 
Co-investigators: 
Edith P. Mitchell, MD, FACP 
Andrew Chapman, DO 
Lewis Rose, MD 
Ashlie Burkart, MD 
Michael Ramirez, MD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table of Contents 
 
Table of Contents 
 
 
 
 
 
 
 
 
 
2 
 
Protocol Summary  
 
 
 
 
 
 
 
 
4 
 
1.0 Background 
 
1.1 Current Treatment of Hepatocellular Carcinoma 
 
 
 
6 
 
1.2 Mechanism of Action, Pre-clinical and Clinical Data for PD-0332991 
 
1.3 Rationale for Treatment of Advanced HCC with PD-0332991 
 
2.0 Study Objectives and Endpoints 
 
 
 
 
 
 
8 
 
2.1 Study Objectives 
 
 
2.11 Primary Objectives 
 
 
2.12 Secondary Objectives 
 
2.2 Study Endpoints 
 
3.0 Study Design 
 
 
 
 
 
 
 
 
 
8 
 
4.0 Patient Recruitment, Eligibility and Exclusion 
 
 
 
 
9 
 
4.1 Eligibility Inclusion Criteria 
 
4.2 Exclusion Criteria 
 
5.0 Treatment Procedures  
 
 
 
 
 
 
 
11 
 
 
5.1 Visit 1 – Pre-study Evaluation 
 
5.2 Visit 2 – Study Drug Initiation 
 
5.3 Visit 3 – Toxicity Assessment 
 
5.4 Visit 4 – Response and Toxicity Assessment 
 
5.5 Follow-up Visit 
 
5.6 Withdrawal of Subjects 
 
5.7 Follow-up after Withdrawal from the Study 
 
6.0 Evaluation of Response  
 
 
 
 
 
 
 
13 
 
6.1 Definition of Progressive Disease 
 
6.2 Response Assessment 
 
 
7.0 Endpoints  
 
 
 
 
 
 
 
 
 
15 
 
7.1 Primary Endpoint 
 
7.2 Secondary Endpoints 
 
8.0 Drug Information 
 
 
 
 
 
 
 
 
16 
 
7.1 General 
 
7.2 Clinical Pharmacology 
 
7.3 Dispensing PD-0332991 
 
7.4 Rationale for Dose and Regimen 
 


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9.0 Safety Measurements 
 
 
 
 
 
 
 
 
17 
 
9.1 Definitions of Adverse Events 
 
9.2 Preexisting Conditions 
 
9.3 Procedures 
 
9.4 Adverse Event Reporting Period 
 
9.5 Seriousness (Gravity) of Adverse Event 
 
9.6 Eliciting Adverse Event Information 
 
9.7 Attribution of Causality of Adverse Events 
 
9.8 Reporting of Adverse Event 
 
9.9 Recording Instructions 
 
9.10 Expected Adverse Reactions for PD-0332991 
 
9.11 Exposure in Utero 
 
9.12 Follow-up of Adverse Event 
 
9.13 Non-Hematological and Hematological Adverse Events 
 
10. Concomitant Medications and Non-drug Therapies  
 
 
 
22 
 
10.1 Permitted Medications 
 
10.2 Permitted Medications use with caution 
 
10.3 Drug interactions 
 
11.0 Statistical Considerations 
 
 
 
 
 
 
 
23 
 
11.1 Evaluation of Efficacy 
 
11.2 Safety Analysis 
 
12.0 Data Disclosure and Patient Confidentiality  
 
 
 
 
23 
 
13.0 Ethical Considerations  
 
 
 
 
 
 
 
24 
 
13.1 Protection of Human Subjects from Research Risks 
 
13.2 Institutional Review Board 
 
13.3 Informed Consent 
 
14.0 Data Safety Monitoring 
 
 
 
 
 
 
 
25 
 
15.0 Audits 
 
 
 
 
 
 
 
 
 
 
26 
 
References 
 
 
 
 
 
 
 
 
 
 
27PROTOCOL SUMMARY 
 
 
Protocol Number: 
 
Protocol Title: 
A Phase II Study of PD-0332991 Treatment of Patients with 
Advanced Hepatocellular Carcinoma 
 
Study Objectives: 
Primary Objective:  


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To assess the time to disease progression (TTP) in patients with 
advanced hepatocellular carcinoma treated with PD-0332991  
 
 
Secondary Objectives: 
 
To assess the safety and tolerability of PD-0332991 in patients 
with advanced hepatocellular carcinoma 
 
 
 
To assess overall survival (OS) in patients with advanced 
hepatocellular carcinoma treated with PD-0332991 
 
 
To assess the response rate (RR) in patients with advanced 
hepatocellular carcinoma treated with PD-0332991 
  
Study Population: 
Patients with inoperable, therapy-refractory advanced HCC  
 
Study Design: 
Single-institution study 
 
Investigational Product: 
PD-0332991 
 
Dosage Form: 
Capsule 
 
Route of Administration: 
Oral 
 
Dosage and Treatment 
Schedule: 
125 mg oral capsules daily for 21 days, followed by week rest, 
with cycle consisting of 28 days, in repeated cycles 
 
Endpoints: 
Time to disease progression (TTP) defined as time from entry on 
study to progression of disease. 
 
 
Safety and Tolerability  
 
 
Overall survival (OS) 
 
 
 
Response rate (RR) 
 
Duration of Treatment: 
Until progression of disease 
 
Duration of Subject 
Participation in Study: 
Progression of disease, subject withdrawal or death  
 
Duration of Follow-up: 
Subjects will be followed after disease progression with visits at 28 
days, and 56 days post treatment discontinuation and every 3 
months until death, subject is lost to or declines follow up. Safety 
data will be collected until AEs are resolved after the last dose of 
treatment is given. 


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Number of Subjects 
Required: 
19 evaluable 
 
Maximum Total 
25 
Acrual: 


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1.0 Background 
 
1.1 Current Treatment of Hepatocellular Carcinoma 
 
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the 
third most frequent cause of cancer-related mortality (El-Serag et al. 2007). While the majority 
of HCC cases occur in developing countries due to the high prevalence of hepatitis B (HBV) and 
hepatitis C (HCV) infection, the incidence of HCC has significantly increased in the United 
States over the last three decades and is predicted to remain a major health risk for future 
generations (El-Serag 2004). 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 (Siegel et al. 2008). Furthermore, until very recently, 
there have been no standard systemic therapies for advanced HCC, as classical cytotoxic drugs 
(administered singularly or in combination) have not led to reproducible response rates or 
survival benefit (Llovet and Bruix 2003).  
Recently, the advent of promising “targeted” therapies has introduced new possibilities 
for the treatment of otherwise chemo-resistant tumors. Specifically, the multikinase inhibitor 
sorafenib displayed a significant increase in progression-free and overall survival of patients with 
advanced or metastatic HCC in two randomized phase III trials (Llovet et al. 2008, Cheng et al. 
2009). However, even with such favorable and landmark results, the response rate to sorafenib 
was remarkably low, and the overall benefits were reported to be relatively modest with a 
response rate of only 2% in both pivotal phase III trials. Thus, while the treatment of advanced 
HCC with targeted therapy has generated encouraging results, there is still a critical need for 
more key molecular targets and targeting compounds for truly successful therapeutic 
intervention.  
 
1.2 Mechanism of Action, Pre-clinical and Clinical Data for PD-0332991 
 
PD-0332991 is an orally available, pyridopyrimidine-derived, selective inhibitor of cyclin 
dependent kinase 4/6 (CDK4/6) (Fry et al. 2004, Toogood et al. 2005). Functionally, PD-
0332991 is a potent and highly selective inhibitor of CDK4/6-cyclin D1 kinase activity, which 
ultimately results in the inhibition of retinoblastoma (Rb) protein phosphorylation and cell cycle 
arrest. In vitro and in xenograft models, PD-0332991 was observed to inhibit a panel of Rb-
positive, solid tumor cell lines (Fry et al. 2004). A phase I clinical trial with PD-0332991 in 
patients with Rb-positive advanced solid tumors demonstrated a mean therapeutic dose (MTD) 
of 125 mg/d for 3 out of 4 weeks and a principal, dose-limiting toxicity of myelosuppression 
(O’Dwyer et al. 2007). Furthermore, in the context of metastatic teratoma, PD-0332991 as a 
single agent provided durable progression-free survival in excess of 18 months (Vaughn et al. 
2009). A phase II trial of PD-0332991 in the treatment of mantle cell lymphoma (MCL) is 
currently ongoing, as well as combination studies with letrozole for breast cancer and with 
bortezomib and dexamethasone for multiple myeloma.  
 
In preclinical studies, PD-0332991 has extensive cytostatic activity. In hepatoma cell 
lines this effect is dependent on the RB protein, and PD-0332991 was observed to be 
significantly more effective than the only currently approved therapeutic agent, sorafanib. 
Furthermore, in animal models, PD-0332991 was effective at inhibiting the proliferation of 


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hepatocytes in liver, indicating that effective doses can be achieved in vivo (Rivadeneira et al. 
2010). Finally, ongoing studies suggest that PD-0332991 is a potent inhibitor of tumor 
proliferation in the context of xenograft models. Combined, these findings suggest that PD-
0332991 could be effective in the treatment of therapy refractory HCC.  
 
1.3 Rationale for Treatment of Advanced HCC with PD-0332991 
     
 
The majority of patients with HCC present with advanced disease, and there are currently 
very limited options available that yield reproducible response rates or significant overall 
survival benefits. (Llovet, 2003) While targeted therapies such as sorafenib point the way to new, 
promising treatment options, there is an unmet need for trials using these agents in advanced 
HCC. Pre-clinical data with PD-0332991 demonstrates potent target-specificity and significant 
inhibition of tumor cell growth in vitro and in xenografts (Fry et al. 2004, Rivadeneira et al. 
2010). Furthermore, early clinical studies demonstrate acceptable toxicities of PD-0332991, a 
critical factor in the treatment of patients with advanced HCC that is often associated with 
compromised liver function (Bruix and Sherman 2005). Thus, PD-0332991 represents an ideal 
candidate for the treatment of patients with advanced HCC. 
 
2.0 Study Objectives and Endpoints 
2.1 Study Objectives: 
 
2.11 Primary Objective 
 
To assess the time to disease progression (TTP) in patients with advanced hepatocellular 
carcinoma treated with PD-0332991. 
 
2.12 Secondary Objectives 
 
1. To assess the safety and tolerability of PD-0332991 in patients with advanced 
hepatocellular carcinoma. 
 
2. To assess overall survival (OS) in patients with advanced hepatocellular carcinoma 
treated with PD-0332991. 
 
3. To assess the response rate (RR) in patients with advanced hepatocellular carcinoma 
treated with PD-0332991. 
 
2.2 Study Endpoints: 
 
1. Time to disease progression (TTP) defined as time from enrollment on study to 
documented progression of disease. 
 
2. Safety and Tolerability including adverse events, and significant laboratory 
abnormalities 


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3. Overall survival (OS) defined as the time from entry on trial to the time of death, 
from any cause. 
 
4. Objective Response Rate defined as the proportion of subjects with either a confirmed 
CR or a confirmed PR as determined using modified RECIST (Version 1.1) criteria 
 
3.0 Study Design 
This 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, sorafinib (Nexavar®).  Eligible subjects will receive 125 
mg PD-0332991 capsules orally once daily, administered days 1-21 of a 28-day cycle, in 
repeated cycles.  
 
Subjects will be permitted to receive protocol directed therapy until disease progression by 
modified RECIST (Version 1.1) (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 
using modified RECIST (Version 1.1) guidelines every 8 weeks.  Subjects who discontinue 
therapy for disease progression or other reasons will be followed for safety on Day 28 (± 3 days), 
Day 56 (± 3 days) and every 3 months thereafter or until death, from the last administration of 
protocol –directed therapy.  
 
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 and 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 (which can be viewed on-line at the following NCI web 
site: http://ctep.cancer.gov/reporting/ctc.html). 
 
 
4.0 Patient Recruitment, Eligibility, and Exclusion 
Subjects will be recruited from the outpatient oncology and multidisciplinary liver clinics of 
Thomas Jefferson University. 
 
4.1 Eligibility Inclusion Criteria 
 
1. Male or female, age 18 years with HCC refractory to currently available therapies. 
2. Documented HCC by pathologic criteria. 
 
 
Recommendations for diagnosis of HCC have been issued in a guideline from the 
American Association for the Study of Liver Diseases, which can be accessed through the 
AASLD web site at http://www.aasld.org/practiceguidelines/Pages/default.aspx. 


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3. Subject must be able to give written informed consent and be able to follow protocol 
requirements 
4. Life expectancy greater than 3 months 
5. Be Child’s-Pugh class A or B 
6. ECOG Performance status of ≤ 2 
7. If female of childbearing potential must have negative pregnancy test at screening and 
may not be breast-feeding 
8. 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. 
9. No other active malignancy requiring treatment in the last 3 years other than 
adequately treated non-melanomatous skin cancer, adequately treated cervical 
carcnoma in-situ, superficial adequately treated bladder cancer or prostatic 
intraepithelial neoplasia without evidence of prostate cancer.  
10. Adequate bone marrow, liver and renal function as assessed by the following: 
- Hemoglobin ≥ 8 g/dL  
- WBC ≥ 4,000/uL  
- Absolute neutrophil count ≥ 1,500/uL  
- Platelets ≥ 75,000/uL 
- Total bilirubin ≤ 1.5 times ULN 
- ALT and AST ≤ 5 times ULN 
- Creatinine ≤ 1.5 times ULN 
- Albumin ≥ 2.5 mg/dL 
 
11. 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. 
 
12.  Subjects with brain metastases or a history of previously treated brain metastasis are 
eligible but must: 
 
- Have been treated by surgery or stereotactic radiosurgery (SRS) at least 4 weeks 
prior to enrollment 


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- AND have a baseline MRI or CT that shows no evidence of active intercranial 
disease 
- AND be off steroids for at least 1 week prior to study enrollment 
 
4.2 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 
 


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16. Lack of positive staining for RB-function on tumor biopsy. 
 
 
5.0 Treatment Procedures 
Before subjects are entered into the study and any study-specific procedures are performed, 
he/she must personally sign and date consent form and an informed consent discussion must be 
conducted.  All appropriate committees and the Jefferson Institutional Review Board (IRB), prior 
to enrollment of any subjects on this study, must approve the study protocol, informed consent 
form and all study-related materials.    The patient will be asked to fast for 1 hour before and 2 
hours after dosing. 
 
Treatment Schedule 
Treatment will be divided into 28-day cycles. One cycle of treatment will consist of 21 days (3 
weeks) of daily oral administration of 125 mg PD-0332991 followed by 7 days without treatment 
for a total of 28 days (4 weeks) per cycle.  Subjects may continue to receive PD-332991 for 
additional cycles until disease progression, intolerability, death, failure to return for follow up, 
and/or withdraw of consent. Patients will be evaluated at each visit and treatment continued at 
the discretion the Investigator 
 
5.1 Visit 1 – Pre-study Evaluation 
Prior to performing study related procedures, subjects will read, understand and sign informed 
consent. Investigator and medical staff involved will discuss PD-0332991 treatment with 
potential candidate for the study and obtain informed consent. Pre-study evaluations (other than 
biopsy) are to be obtained within 28 days prior to start of treatment. These will include: 
1. MUGA scan or Echocardiogram if clinically indicated 
2. Pulmonary Function Test if clinically indicated 
3. CT scan of chest, abdomen, and pelvis  
4. MRI of the liver 
5. Biopsy if required to confirm diagnosis of HCC and assess RB-pathway status via 
immunohistochemistry (IHC). PD-0332991 is a highly selective inhibitor of CDK4/6 
that is dependent on a functional RB-pathway to exert its anti-proliferative effects. It 
is inactive against RB-negative tumors. The complete RB-pathway consists of several 
families of proteins: CDKN(INK4A), D-type cyclins, cyclin-dependent protein 
kinases (CDK4, CDK6), RB-family proteins, and E2F transcription factors. In 
addition to RB protein status, overexpression of CDKN (p16INK4A) protein is 
associated with lack of sensitivity to PD-0332991. In vitro efficacy tests have 
suggested that Ki67 may be used as a biomarker of cell proliferation and indirectly 
correlate with sensitivity to PD-0332991. For the current study, IHC of liver biopsy 
tissue will be used to assess protein expression of RB, p16INK4A and Ki67, which 
will then be used to determine whether a patient is eligible for trial participation (i.e. 
likely to show sensitivity to PD-0332991). 
 
The following pre-study evaluations are to be obtained within 14 days prior to start of treatment: 
1. Complete history, physical exam including height and weight 
2. Performance status, Child-Pugh status 


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3. Blood cell counts (CBC with differential, platelets) and comprehensive metabolic 
panel (albumin, alkaline phosphatase, total protein, BUN, creatinine, AST (SGOT), 
ALT (SGPT), total bilirubin, calcium, sodium, potassium, chloride, bicarbonate), 
lactate dehydrogenase (LDH), pregnancy test, and TSH, PT/PTT, INR 
4. Concomitant medication review 
 
5.2 Visit 2 – Study Initiation (Start of cycle 1) 
After the eligibility is confirmed, subject will be enrolled into the study. The following 
assessments should be completed before the study drug is dispensed on the first day of treatment:  
1. Clinical assessment – including complete physical examination to history, weight, 
vital signs, signs/symptoms, and performance status 
2. CBC, comprehensive metabolic panel, coagulation studies 
3. Serum AFP 
4. Concomitant medication review 
 
5.3 Visit 3 – Toxicity Assessment 
Initial safety and tolerability of the study drug will be assessed after 2 weeks on PD-0332991.   
The evaluation will include: 
1. Clinical assessment – including interval history, physical examination, weight, vital 
signs, signs/symptoms, and performance status. 
2. Toxicity assessment. Adverse events will be graded using the National Cancer 
Institute (NCI) Common Toxicity Terminology Criteria for Adverse Events v 4.0 
(CTCAE v 4.0). 
3. Concomitant medication review 
4. Blood cell counts (CBC with differential, platelets) and comprehensive chemistries 
(albumin, alkaline phosphatase, total protein, BUN, creatinine, AST (SGOT), ALT 
(SGPT), total bilirubin, calcium, sodium, potassium, chloride, bicarbonate), lactate 
dehydrogenase (LDH). 
If subject experiences a Grade 3 or greater toxicity deemed related to study drug, PD-0332991 
will be temporarily discontinued.  After the resolution of toxicity to Grade 2 or less, PD-0332991 
will be restarted at the initial dose. The study treatment will be continued until disease 
progression or unacceptable side effects (Grade 3 or greater). Subjects with unacceptable side 
effects (Grade 3 or greater) for a second time on PD-0332991 will be removed from the study. 
The only exception to this are: Grade 3 anorexia, nausea vomiting, stomatitis/mucositis or 
diarrhea that will lead to investigational product withdrawal only if not manageable despite 
maximum supportive care. 
 
5.4 Subsequent visits on study – Response and Toxicity Assessment 
Safety and tolerability of the study drug will be assessed every 2 weeks after the initiation of PD-
0332991 for the first 3 cycles of treatment, and every 4 weeks thereafter. Procedures will be as 
described for Visit 3.  Additionally, Serum AFP will be monitored every 4 weeks and imaging 
will occur every 8 weeks after initiation of therapy to determine response of the disease to 
treatment. Subjects will undergo tumor response assessment per modification of RECIST 
(Version 1.1) guidelines. Radiological assessments must include CT of the chest, abdomen and 
pelvis and MRI of the liver. Magnetic Resonance Imaging is the preferred study for imaging the 
liver and must include T1, T2/flair and diffusion weighted imaging.  Studies will be obtained at 


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baseline and according to schedule of observations until disease progression, death, withdrawal 
of consent, end of study or start of a new treatment. Unscheduled imaging may be conducted at 
the discretion of the Investigator.  
 
Adverse events are defined in section 9.0.  The investigator is responsible for reviewing all 
laboratory and clinical data, determining clinical significance and assessment of adverse events. 
It will be left to the investigator’s clinical judgment to determine whether an adverse event is 
related and of sufficient severity to require subject’s removal from treatment or from the study.  
The subject may also withdraw voluntarily from treatment due to what he/she perceives as an 
intolerable adverse event.  If this arises the subject will be observed with extra visits until 
symptoms cease or the condition becomes stable.  Adverse events will be graded using the 
National Cancer Institute (NCI) Common Toxicity Terminology Criteria for Adverse Events v 
4.0 (CTCAE v 4.0). 
  
5.5 Follow-up Visits 
After disease progression or drug intolerance, subjects will be scheduled for follow-up 
assessment approximately 30 days after the last administration of protocol specific therapy. 
At this visit subjects will undergo clinical assessment including: interval history, limited physical 
examination, weight, vital signs, signs/symptoms, and performance status. AEs and concomitant 
meds will be obtained. Bloodwork including: CBC, comprehensive metabolic panel, AFP will be 
collected and recorded. Subjects will be followed every 3 months in clinic to collect information 
on their general health status and their liver cancer.  This visit must include at a minimum 
interval history, physical exam, concomitant medications and toxicity assessment.  If possible 
other treatments, outcomes and survival should be obtained. 
 
5.6 Withdrawal of Subjects 
The following criteria will be used to withdraw subjects from the study: 
 
1. Evidence of progressive disease, as defined by RECIST (Version 1.1) criteria. 
2. If as judged by the investigator the subject would be best served by a change in 
therapy or that it is in the patient’s best interest to come off study. 
3. Unacceptable toxicity.  
4. Subject withdrawal of consent. 
5. Noncompliance with study medication or protocol-required evaluations and visits as 
determined by the investigator. 
6. If there is a major protocol violation, or if requested by a regulatory agency. 
7. Death of a subject. 
8. If subject receives less than 50% of the protocol-required dose of PD-0332991 for 2 
consecutive cycles, for any reason.                                                                                                           
 
At the investigator’s discretion, a subject may be continued on study drug for additional 
treatment cycles if he or she is deriving clinical benefit from PD-0332991 and interval imaging 
results demonstrate mild progression e.g. 25% increase in the sum of the longest diameter of 
target lesions rather than less than or equal to 20% used to define stable disease.  If at the next 
interval imaging the subject shows further progression rather than disease stabilization, he/she 


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must be withdrawn from the study. The Principal Investigator must approve of the continuation 
on study. 
  
5.7 Follow-up after Withdrawal from the Study 
Subjects will be followed after withdrawal from the study and scheduled for follow-up visits. 
Safety data after the last dose of treatment is given until toxicity has resolved. Survival 
information will be collected via phone or visit on a quarterly basis for each subject if subject not 
able to come for regular visits. 
 
6.0 Evaluation of Response  
 
6.1 Definition of Progressive Disease 
 
Progression will be evaluated in this study using the new international criteria proposed by the 
Response Evaluation Criteria in Solid Tumors (RECIST) Committee. Changes in only the largest 
diameter (unidimensional measurement) of the tumor lesions are used in the RECIST criteria. 
Note:  Lesions are either measurable or non-measurable using the criteria provided below. 
 
 Measurable Disease 
Measurable lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as >20 mm with conventional techniques (CT, MRI, 
x-ray) or as >10 mm with spiral CT scan.  All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters). 
 
 
Non-Measurable Disease 
All other lesions (or sites of disease), including small lesions (longest diameter <20 mm with 
conventional techniques or <10 mm using spiral CT scan), are considered non-measurable 
disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonis, inflammatory breast disease, abdominal masses (not followed by CT or MRI), 
and cystic lesions are all non-measurable. 
 
Target Lesions 
All measurable lesions up to a maximum of five lesions per organ and ten lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline.  Target lesions should be selected on the basis of their size (lesions with 
the longest diameter) and their suitability for accurate repeated measurements (either by imaging 
techniques or clinically).  A sum of the longest diameter (LD) for all target lesions will be 
calculated and reported at time of disease recurrence. 
 
Non-Target Lesions 
All other lesions (or sites of disease) should be identified as non-target lesions and should also 
be recorded at time of disease recurrence. Non-target lesions include measurable lesions that 
exceed the maximum numbers per organ or total of all involved organs as well as non-
measurable lesions.  Measurements of these lesions are not required but the presence or absence 
of each should be noted throughout follow-up.  
 
6.2 Response Assessment 
 


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Response is assessed on the basis of clinical, radiological, and pathological criteria. Standard 
imaging via MRI and/or CT scan will be used for evaluation of nodal disease based on RECIST 
criteria. These techniques should be performed with cuts of 10 mm or less in slice thickness 
contiguously. Spiral CT should be performed using a 5 mm contiguous reconstruction algorithm. 
 
The subject’s response will be assessed based on the response of the target lesions, the response 
of non-target lesions and the presence or absence of new lesions through out the course of the 
study. 
Response Criteria for Target Lesions: 
 
Complete Response (CR) 
Disappearance of all target lesions 
Partial Response (PR)  
At least 30% decrease in the sum of the LD of 
target lesions, taking as reference the baseline 
sum LD 
Progressive Disease (PD) 
At least 20% increase in the sum of the LD of 
target lesions, taking as reference the smallest 
sum LD recorded since the treatment started or 
the appearance of one or more new lesions. 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR 
nor sufficient increase to qualify for PD, taking 
as reference the smallest sum LD recorded 
since the treatment started 
 
 
Response Criteria for Non-target Lesions 
 
Complete Response (CR) 
Disappearance of all non-target lesions and 
normalization of tumor marker level 
Incomplete Response/Stable Disease (SD) 
Persistence of one or more non-target lesions 
and or maintenance of tumor marker above 
normal limits. 
Progressive Disease (PD) 
Appearance of one or more new lesions and or 
unequivocal progression of existing non target 
lesions  
 
Subjects with global deterioration in health status requiring discontinuation of treatment without 
objective evidence of disease progression will be classified as having symptomatic deterioration.   
Every effort will be made to document objective progression.  
 
7.0 Endpoints: 
 
7.1 Primary Endpoint 
 
Time to Progression (TTP) 
 
Progression-free survival (PFS) is the time elapsed between treatment initiation and tumor 
progression or death from any cause, with censoring of patients lost to follow up. Time to 


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Progression (TTP) is defined by the FDA as the time from subject randomization until tumor 
progression is documented. Time to treatment failure (TTF) is a composite endpoint defined as 
the time from randomization until the patient stops trial treatment for any reason including 
progression, adverse events, insufficient therapeutic response, death, failure to return, and 
refused treatment/did not cooperate/withdrew consent.  PFS assumes that patient deaths are 
randomly related to tumor progression.  Compared to TTP, PFS is the preferred regulatory 
endpoint however in situations where deaths may be unrelated to cancer such as in patients with 
HCC and cirrhosis, TTP is an acceptable endpoint. In this study, TTP will be defined as the date 
of enrollment on trial to the first observation of disease progression, as classified by modified 
RECIST (Version 1.1) 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 probability of 
a significant final result given the observed data at the time of the interim analysis (i.e., the 
conditional power) will be estimated (Lachin 2005).  The study will be stopped for futility if the 
conditional power is less than 60%.  That is, the study will be stopped if there is a preponderance 
of evidence that completion will not yield a significant result. 
 
7.2 Secondary Endpoints 
 
Safety and Tolerability 
 
Safety analysis will be conducted on all patients that received 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.  Causal relationships are not 
addressed in this nomenclature.  Adverse events will be collected from the time the subject signs 
the informed consent form throughout the period of follow-up.  
 
Overall Survival 
 
Overall survival (OS) is measured form the entry onto a 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. 
 
Overall Response Rate 
 
The best overall response is the best response recorded from the start of treatment until disease 
progression or recurrence. The objective response rate (ORR) is the proportion of subjects with 
either a confirmed CR or a confirmed PR as determined using modified RECIST (Version 1.1) 
criteria, as evaluated by the Investigator. A confirmed CR or PR requires repeat assessments no 
less than 28 days after the response criteria are first met. Subjects who have not met this criteria 
for response will be considered non-responders. As the clinical relevance of stable disease (SD) 
may be important in HCC, subjects with the response of SD will be recorded and documented. 
Disease control rate defined as CR + PR +SD will be calculated for all subjects treated with PD-
0332991.      
 


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8.0 Drug Information  
 
8.1 General 
PD-0332991 (molecular weight: 573.67 g/mol) is a highly selective, reversible inhibitor of 
cyclin-dependent kinases (Cdk) 4 and 6 that is being studied for use in the treatment of cancer. 
Inhibition of Cdk4/6 blocks DNA synthesis by prohibiting the progression of the cell cycle from 
G1 to S-phase. Thus, PD-0332991 functions as a cytostatic agent.  
 
PD-0332991 is delivered as on oral capsule that is packaged and stored at 15-25oC. 
 
8.2 Clinical Pharmacology 
 
Pharmacokinetics and Metabolism of PD-0332991 
As of March 1, 2008, three studies evaluating the safety, efficacy, pharmacodynamics and PK of 
PD-0332991 have started. Preliminary PK parameters are available from 73 subjects following a 
single-dose (Day 1) and 51 subjects at steady-state (Day 8) following administration of daily 
doses ranging from 25 to 225 mg of PD-0332991. Peak serum concentrations varied from 10-104 
ng/mL (Day 1) and 16-186 ng/mL (Day 8) with escalating PD-0332991 dose, and time to peak 
concentration was 4-7 hours (Day 1) and 3-7 hours (Day 8). Mean estimates of the 
pharmacokinetic parameters after oral administration of 200 mg of PD-0332991 at steady-state 
(Day 14 of Cycle 1) were 155 ng/mL peak serum concentration at 4 hours after dosing and 
effective plasma t1/2~32 hours.  
 
Absorption and Elimination of PD-0332991 
A pilot food effect assessment was conducted in 12 subjects following administration of 
either125 mg or 200 mg doses of PD-0332991. For the fed state, subjects completed an 800-1000 
calorie meal (at least 50% of which was from fat). The fasted condition was a 10-hour overnight 
fast. In general, no change in rate of absorption (median Tmax=7, range 4-24 hours) was observed 
between the fed and fasted state. Higher exposures and peak concentrations were observed in the 
fed state compared to the fasted state, but these were not considered to be clinically significant as 
the mean % increase in exposure was less than 25%. Thus, PD-0332991 can be administered 
without regard to food. 
 
Renal excretion of PD-0332991 was determined to be a minor route of elimination in humans 
(1.4% of unchanged drug in the urine; clearance rate = 6373 mL/hr).    
 
8.3 Dispensing PD-0332991 
PD-0332991 will be dispensed via the Jefferson Medical Oncology outpatient offices. 
 
8.4 Rationale for Dose and Regimen   
A single agent Phase I study in advanced cancer (N=74) determined the recommended Phase II 
dose for the Schedule 3/1 (3 weeks on and 1 week off, cycling) and Schedule 2/1 (2 weeks on 
and 1 week off, cycling) to be 125 mg/d and 200 mg/d, respectively. Two additional studies 
using the Schedule 3/1 are ongoing at Pfizer. For this study, Schedule 3/1 will be utilized unless 
adverse events require dose modifications as described below (Table 8.1).  
 


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  Table 8.1 Dose Modification Levels for PD0332991   
Dose Level 
Daily oral dose 
Number of tablets 
 
per day x 21d, 1 w off 
100 mg 
25 mg 
Standard Dose 
125 mg 
1 
1 
Dose Reduced – 1 
100 mg 
1 
0 
Dose Reduced – 2 
75 mg 
0 
3 
 
Table 8.1 outlines the recommended dose reductions for bone marrow toxicity due to PD-
0332991.   
 
Study eligible subjects potentially may have baseline myelosuppression due to their underlying 
liver disease or hypersplenism that is equivalent, according CTCAE v 4 scale to Grade 1 
leucopenia, neutropenia and thrombocytopenia and Grade 2 anemia.  For example, subjects are 
eligible to be enrolled on this study with:  
Hemoglobin ≥ 8.0 g/dl (CTCAE v 4 Grade 2) 
WBC ≥ 4,000/uL (CTCAE v 4 Grade 1) 
Absolute neutrophil count ≥ 1,500/uL (CTCAE v 4 Grade 1) 
Platelets ≥ 75,000/uL ((CTCAE v 4 Grade 1) 
 
See Table 8.2 for definitions and 4.1 Eligibility Inclusion Criteria. 
 
Table 8.2 Standard CTCAE v 4 scale  
Adverse 
Event 
0 
1 
2 
3 
4 
Hemoglobin 
(Hgb) 
WNL 
< LLN - 
10.0 g/dl 
8 -  < 10 g/dl 
6.5 - < 8 g/dl 
< 6.5 g/dl or life 
threatening 
WBC 
WNL 
< LLN - 3.0 
x 109 /L 
≥ 2.0 - < 3.0 x 
109 /L  
≥ 1.0  - < 2.0 
x 109 /L 
< 1.0 x 109 /L 
ANC 
WNL 
< LLN – 1.5 
x 109 /L 
≥ 1.0 - < 1.5 x 
109 /L  
≥ 0.5  - < 1.0 
x 109 /L 
< 0.5 x 109 /L 
Platelets 
WNL 
< LLN - 75 
x 109 /L 
≥ 50.0 - < 
75.0 x 109 /L  
≥ 25 - < 50.0 
x 109 /L 
< 25 x 109 /L 
 
PD-0332991 is a highly specific selective small molecule inhibitor of CDK 4 and 6 and induces 
G0-G1 cell cycle arrest.  Because it is a reversible inhibitor, PD-0332991 needs to be present 
continuously to inhibit CDK4 and CDK6, as withdrawal allows for reactivation of inhibited 
enzymes and stimulation of cell growth. In all Phase I studies of this agent as well as subsequent 
Phase II studies; the dose limiting toxicity (DLT) was dose-dependent neutropenia, consistent 
with cell cycle inhibition (11). In general, the myelosuppression observed is reversible, not 
cumulative, and uncomplicated. In this study, we have commonly observed up to a 50% 
reduction in WBC count, however there have been no instances of febrile neutropenia. Only one 
subject has had sepsis and this was in the setting of a normal WBC count following manipulation 
of the biliary system. He was treated successfully with broad-spectrum antibiotics.   
 
Due to these factors, to preserve drug efficacy in subjects with advanced HCC on PD-0332991, 
dose reduction is not allowed “prophylactically” for a decreased WBC count or low ANC. A 


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subject may be dose reduced after having a significant untoward event caused by drug-related 
myelo-suppression, including: A. febrile neutropenia or B. sepsis associated with neutropenia.  
For all other events, the procedure for bone marrow (mechanism-based) toxicity is as follows: 1. 
Hold study drug and have subject return in one (1) week for CBC. If count is CTCAE grade 2 or 
less, treat on time without dose modification. If count remains at grade 3 or 4 at one-week check, 
continue to hold PD-0332991. Administer pegfilgrastim (Neulasta) 6 mg subcutaneously. Obtain 
repeat CBC weekly and resume PD-0332991 without dose change when WBC count is CTCAE 
grade 2 or less. If leucopenia or neutropenia recur at this dose level, then dose reduction by one 
DL is allowed. If the WBC or ANC do not increase to Grade 2, preventing resumption of drug 
for an entire cycle (28 days), then PD-0332991 may be restarted at the -1 dose level. If 
pegfilgrastim successfully prevents the lowering of the WBC count associated with study drug it 
should be administered with subsequent cycles at standard dose of 6 mg subcut on day 1 once 
per cycle to prevent drug interruption. 
 
If a subject is not able to tolerate the 75 mg dose, then treatment should be discontinued.  If a 
dose reduction has been performed, the subject may be re-escalated by the treating physician 
provided toxicities have resolved to Grade 2.  
 
Table 8.3 outlines the procedures for dose modifications for bone marrow toxicity related to 
PD0332991.  
 
Due to baseline coagulopathy and tendency to have bleeding events due to underlying liver 
disease, dose modifications should not be based on hemoglobin values.  If a subject experiences 
bone marrow toxicity of both WBCs and platelets the recommended dose adjustment should be 
based on WBC count. It is recommended that standard of care be followed for administration of 
RBCs and platelets and for vitamin K in patients with ESLD.    
 
Table 8.3 Dose modifications/delays for bone marrow toxicity related to PD0332991 
Grade of Event 
CTCAE v 4.03 
Dose Interruption 
Dose Modification 
for Remainder of 
Cycle. 
Dose Modification for 
Subsequent Cycles 
0-2 
Treat on time 
No change 
No change 
3-4 
 Delay until ≤ 
Grade 2 
 Administer 6 mg 
pegfilgrastim 
(Neulasta) subcut 
if WBC/ANC 
does not recover 
to ≤ Grade 2 
after 1 week dose 
interruption 
 
 First episode:  
No change 
 Second episode 
within cycle after 
co-administration 
with 
pegfilgrastim: 
Reduce 1 dose 
level 
 
 Continue at dose level 
from previous cycle  
 If serious drug-related 
myelosuppression occurs 
including: A. febrile 
neutropenia or B. sepsis 
with neutropenia, in 
previous cycle institute 
permanent dose reduction 
at -1 dose level 
 If bone marrow toxicity 
recurs at ≥ Grade 3 with 
leucocyte growth factor 
administration then 


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institute permanent dose 
reduction at -1 dose level 
 If unable to resume PD-
0332991 due to BM 
toxicity for an entire 
cycle, institute permanent 
dose reduction at -1 dose 
level 
 If bone marrow toxicity 
remains at ≤ Grade 2 for 
remainder of a previous 
cycle after administration 
of pegfilgrastim, then 
administer with 
subsequent cycles, 6 mg 
subcut on day 1 once per 
cycle 
Note: if a subject does not have insurance coverage for pegfilgrastim it is permissible to 
substitute filgrastim (Neupogen) 5 mcg/kg, rounded up to nearest vial size, subcut daily x 3 days. 
 
The Sponsor-Investigator, Dr. Susan J. Littman, must approve dose adjustments.  
 
9.0 Safety Measurements 
 
9.1 Definitions of Adverse Event  
Adverse Event (AE) is any untoward medical occurrence in a patient or trial subject administered 
a drug or biologic (medicinal) product or using a medical device; the event does not necessarily 
have a causal relationship with that treatment or usage. 
 
AEs include the following: 
 All suspected adverse medication reactions 
 All reactions from medication, overdose, abuse, withdrawal, sensitivity, or toxicity 
 Apparently unrelated illnesses, including the worsening of a preexisting illness (see 
Preexisting Conditions below). 
 Injury or accidents.  Note that if a medical condition is known to have caused the injury 
or accident (e.g., a fall secondary to dizziness), the medical condition (dizziness) and the 
accident (fall) should be reported as two separate adverse events.  The outcome of the 
accident (e.g., hip fracture secondary to the fall) should be recorded under Comments. 
 Abnormalities in physiological testing or physical examination (findings that require 
clinical intervention or further investigation beyond ordering a repeat [confirmatory] 
test). 
 Laboratory abnormalities that require clinical intervention or further investigation 
(beyond ordering a repeat [confirmatory] test) unless they are associated with an already 
reported clinical event.  Laboratory abnormalities associated with a clinical event (e.g., 
elevated liver enzymes in a patient with jaundice) should be described under Comments 
on the report of the clinical event rather than listed as a separate adverse event. 


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9.2 Preexisting Conditions 
In this trial, a preexisting condition (i.e., a disorder present before the adverse event reporting 
period started and noted on the pretreatment medical history/physical examination form) should 
not be reported as an adverse event unless the condition worsens or episodes increase in 
frequency during the adverse event reporting period.  Recurrence or progression of tumor will 
not be regarded as an adverse event. 
 
9.3 Procedures 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not be 
reported as adverse events.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an adverse event.  For example, an 
acute appendicitis that begins during the adverse event reporting period should be reported as the 
adverse event and the resulting appendectomy noted under comments. 
 
9.4 Adverse Event Reporting Period 
The adverse event reporting period for this trial begins when the patient receives the first dose of 
investigational medication and ends 28 days after the patient receives the last dose of his/her 
study medication regimen for all non-serious adverse events. All serious adverse events will be 
followed through safety follow-up visits until resolution or return to baseline condition.  
 
All adverse events that occur in trial subjects during the adverse event reporting period specified 
in the protocol must be reported, whether or not the event is considered treatment-related. 
 
IN ADDITION, any known untoward event that occurs subsequent to the adverse event reporting 
period that the investigator assesses as possibly related to the investigational medication/product 
should also be reported as an adverse event. 
 
9.5 Seriousness (Gravity) of Adverse Event 
Each adverse event is to be classified by the investigator as SERIOUS (including life-
threatening) or NONSERIOUS.  This classification of the gravity of the event determines the 
reporting procedures to be followed. 
 
An adverse event that meets one or more of the following criteria/outcomes is classified as 
serious: 
 
 Death 
 Life-threatening (i.e., immediate risk of death) 
 Inpatient hospitalization, emergency room visit for a period > 24 hours or prolongation of 
existing hospitalization 
 Persistent or significant disability/incapacity 
 Congenital anomaly/birth defect 
 Other significant medical hazard. An important medical event that may not result in 
death, threaten life or require hospitalization may be considered a SAE when, based on 
appropriate medical judgment, it may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed above. Examples of such 


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medical events include allergic bronchospasm, requiring intensive treatment in an 
emergency room or at home, or convulsions that do not result in inpatient hospitalization. 
 
A nonserious event is one that does not meet the criteria described for a serious or life-
threatening event. Hospitalization for either elective surgery related to a pre-existing condition 
(without increase in severity or frequency) or routine clinical procedures that are not the result of 
an adverse event need not be considered as an AE and therefore are not a SAE. A routine clinical 
procedure is a procedure occurring during the study period that does not interfere with the study 
product administration or any of the ongoing protocol specific procedures. If anything untoward 
is reported during an elective procedure, that occurrence must be reported as an AE or SAE, 
according to the usual criteria. 
 
9.6 Eliciting Adverse Event Information 
The investigator is to report all directly observed adverse events and all adverse events 
spontaneously reported by the trial subject.  In addition, as part of the physical exam and clinical 
assessment, each trial subject will be questioned about adverse events and symptoms at each 
clinic visit, following initiation of treatment.  The question asked will be "Since your last clinic 
visit, have you had any health problems?" 
 
9.7 Attribution of Causality of Adverse Events 
The investigator will assign an attribution to each AE that occurs.  Attribution will be determined 
according to the criteria specified in CTC 4.0, which is summarized below: 
5-Definite – The AE is clearly related to the treatment. 
4-Probable – The AE is likely related to the treatment. 
3-Possible – The AE may be related to the treatment. 
2-Unlikely – The AE is doubtfully related to the treatment. 
1-Unrelated – The AE is clearly not related to the treatment. 
 
9.8 Reporting of Adverse Event 
Adverse events (AE) will be reported to the Thomas Jefferson University IRB and the Data 
Safety Monitoring Board (DMSB) via Clinical Research Management Office (CRMO) as 
specified in the TJU Data Safety and Monitoring Plan (Refer to Table). 
 
All unexpected on-site adverse events and serious adverse events (SAE) will be sent to the TJU 
IRB and the DSMC within 48 hours of first awareness of the event. Fatal adverse events which 
are unexpected must be reported to the TJU IRB and the DSMB within 24 hours of first 
awareness of the event. Fatalities not related to the study drug must be reported within 5 days. 
Quarterly safety updates will be submitted to the CRMO, and the DSMC. 
 
AEs will be reported according the table below: 
 
Unexpected Event: 
 


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GRADE 1-3 
 
Attribution 
of 
Possible, 
Probable or Definite  
(as defined in CTC 4.0) 
GRADE 4 
 
Regardless of Attribution  
(as defined in CTC 4.0) 
GRADE 5 
 
Death 
Report to CRMO via website 
within 48 hours. Report to 
TJU IRB within 48 hours. 
CRMO reports to DSMC 
immediately following receipt. 
Report to CRMO via website 
within 48 hours. Report to 
TJU IRB within 48 hours. 
CRMO reports to DSMC 
immediately following receipt. 
Report to CRMO via website 
and TJU IRB within 24 hours. 
 
 
Expected Event: 
 
GRADE 1-3 
 
Attribution 
of 
Possible, 
Probable or Definite  
(as defined in CTC 4.0) 
GRADE 4 
 
Regardless of Attribution  
(as defined in CTC 4.0) 
GRADE 5 
 
Death 
Report to CRMO via website 
within 
10 
working 
days. 
Summary of all adverse events 
submitted quarterly to DSMC. 
Report to CRMO via website 
and TJU IRB within 48 hours. 
CRMO reports to DSMC 
immediately following receipt. 
Summary of all adverse events 
submitted quarterly to DSMC. 
Report to CRMO via website 
and TJU IRB within 5 days. 
Summary of all adverse events 
submitted quarterly to DSMC. 
 
 
9.9 Safety Reporting Requirements for IND Holders 
 
In accordance with 21 CFR 212.32, sponsor-investigators of studies conducted 
under an IND must comply with following safety reporting requirements:  
 
Expedited IND Safety Reports: 
 
7 Calendar-Day Telephone or Fax Report:   
 
The Sponsor-Investigator is required to notify the FDA of any fatal or life-threatening adverse 
event that is unexpected and assessed by the investigator to be possibly related to the use of PD-
0332991.  An unexpected adverse event is one that is not already described in the Investigator 
Brochure.  Such reports are to be telephoned or faxed to the FDA within 7 calendar days and 
Pfizer within 24 hours of first learning of the event.  Each telephone call or fax transmission (see 
fax number below) should be directed to the FDA new drug review division in the Center for 
Drug Evaluation and Research or in the product review division for the Center for Biologics 
Evaluation and Research, whichever is responsible for the review of the IND. 
 
15 Calendar-Day Written Report:   
 
The Sponsor-Investigator is also required to notify the FDA and all participating investigators, in 


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a written IND Safety Report, of any serious, unexpected AE that is considered possibly related to 
the use of PD-0332991. An unexpected adverse event is one that is not already described in the 
Investigator Brochure. 
 
Written IND Safety Reports should include an Analysis of Similar Events in accordance with 
regulation 21 CFR § 312.32.  All safety reports previously filed with the IND concerning similar 
events should be analyzed.  The new report should contain comments on the significance of the 
new event in light of the previous, similar reports.   
 
Written IND safety reports with Analysis of Similar Events are to be submitted to the FDA, 
Pfizer, and all participating investigators within 15 calendar days of first learning of the 
event.  The FDA prefers these reports on a MedWatch 3500A Form but alternative formats are 
acceptable (e.g. summary letter). 
 
FDA fax number for IND Safety Reports: 
 
1 (800) FDA - 0178 
 
All written IND Safety Reports submitted to the FDA by the Sponsor-Investigator must also be 
faxed to:  
 
Pfizer   
Fax:    1-866-997-8322 
Any issues encountered with fax transmission can be reported by calling Diane Borst (610) 519-
0554  
 
AND: 
 
Thomas Jefferson University IRB 
 
For questions related to safety reporting, contact Diane Borst Tel:  (610) 519-0554 
 
IND Annual Reports 
 
In accordance with the regulation 21 CFR § 312.32, the Sponsor-Investigator shall within 60 
days of the anniversary date that the IND went into effect submit a brief report of the progress of 
the investigation.  Please refer to Code of Federal Regulations, 21 CFR § 312.32 for a list of the 
elements required for the annual report.  All IND annual reports submitted to the FDA by the 
Sponsor-Investigator should be copied to Pfizer.   
 
9.9 Recording Instructions 
On the adverse event case report forms, the investigator will use the NCI Common Toxicity 
Criteria (CTC) version 4.0 (http:// ctep.info.nih.gov/ CTC3/default.htm) to describe the 
maximum intensity of the adverse event.  The investigator will also be asked to assess the 
possible relationship between the adverse event and the investigational medication as well as any 
concomitant medications. 
 
9.10 Expected Adverse Reactions for PD-0332991  
The data described below represent Phase I study (N=74) of PD-0332991at escalating doses of 
25-225 mg/d at either Schedule 3/1 (25-125 mg/d) or Schedule 2/1 (150-225 mg/d). The most 
common adverse events (regardless of causality) include fatigue (51%), neutropenia (42%), 


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nausea (35%), anemia (30%), diarrhea (30%), constipation (27%), vomiting (23%), dyspnea 
(19%), thrombocytopenia (15%), abdominal pain (14%), anorexia (14%), cough (14%), 
leucopenia (11%), flatulence (11%), peripheral edema (11%), back pain (11%), decreased 
appetite (10%), and rash (10%). Eleven dose-limiting toxicities, which consisted of neutropenia 
and/or thrombocytopenia, were observed. Grade 3 adverse events (regardless of causality) 
included dyspnea (4 subjects), hyperbilirubinemia (1 subject), jaundice (1 subject), acute renal 
failure (1 subject), hyperglycemia (1 subject), pleural effusion (1 subject), and peripheral sensory 
neuropathy (1 subject). Grade 4 adverse events (regardless of causality) included neutropenia (2 
subjects), anemia (1 subject), thrombocytopenia (1 subject), increase in uric acid (1 subject), 
hyperglycemia (1 subject), and pulmonary embolism (1 subject). 
 
Effects on bone marrow: Based on nonclinical studies performed to date, bone marrow was a 
target organ for toxicity. In these studies, hematologic and bone marrow abnormalities were 
reversible after dosing of PD-0332991 ceased. Neutropenia, thrombocytopenia, leucopenia, and 
anemia have been commonly observed in the clinical program. These events were not cumulative 
and were reversible, and generally did not result in treatment discontinuation. Granulocyte-
colony stimulating factors should not be used prophylactically, but they may be used to treat 
treatment-emergent neutropenia as indicated by the current ASCO guidelines. Erythropoietin 
may be used for the supportive treatment of anemia. Complete blood counts with differential 
should be checked frequently during clinical studies, and dosing of PD-0332991 should be 
interrupted based on hematologic parameters specified above (Section 8.1).  
 
Effects on the respiratory tract: Based on nonclinical studies performed to date, the respiratory 
tract was a target organ for toxicity. Dyspnea and cough were commonly observed in the clinical 
program, but were Grade 3 in severity and were attributed to the disease. There was one Grade 4 
adverse event of pulmonary embolism, but this event was not considered to be treatment-related. 
 
Effects on the GI tract: GI adverse events including abdominal pain, constipation, diarrhea, 
flatulence, nausea and vomiting were commonly observed in the clinical program. Only those of 
Grade 1 severity were considered to be attributed to treatment.  
 
9.11 Exposure in Utero  
Fertility and teratology studies with PD-0332991 have not been conducted. Safety for women of 
childbearing capacity cannot be implied from the existing data. Thus, women should avoid 
becoming pregnant while on therapy, and women of childbearing potential must be apprised of 
the potential hazard to the fetus, which includes severe malformation (teratogenicity), failure to 
thrive and fetal death (embryotoxicity). 
 
9.12 Follow-Up of Adverse Event 
All adverse events should be followed until they are resolved or the subject's participation in the 
trial ends. In addition, all serious adverse events and those non-serious events assessed by the 
investigator as possibly related to the investigational medication/product should continue to be 
followed even after the subject's participation in the trial is over.  Such events should be followed 
until they resolve or until the investigator assesses them as "chronic" or "stable."  Resolution of 
such events is to be documented on the CRF. 
 


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9.13 Non-Hematological and Hematological Adverse Events 
Patients will be assessed clinically for toxicity prior to each dose using the National Cancer 
Institute (NCI) CTCAE Version 4. If patients experience Grade 3 or greater toxicity deemed 
related to study drug, PD-0332991 will be temporarily discontinued.  After the resolution of 
toxicity to Grade 1 or less, PD-0332991 will be restarted at the initial dose. The study treatment 
will be continued until disease progression or unacceptable side effects (Grade 3 or greater). 
Patients with unacceptable side effects (Grade 3 or greater) for a second time on PD-0332991 
will be removed from the study. The only exception to this are: Grade 3 anorexia, nausea 
vomiting, stomatitis/mucositis or diarrhea that will lead to investigational product withdrawal 
only if not manageable despite maximum supportive care.  Throughout the study investigators 
may prescribe any concomitant medications or treatments necessary to provide adequate 
supportive care other than experimental or approved anti-tumor therapies. All concomitant 
medications must be recorded. 
 
10. Concomitant Medications and Non-Drug Therapies 
All subjects will be asked to provide a complete list of all prescription and over the counter 
medications. The investigator must be informed of any new medication(s) as soon as possible for 
the time of screening to the completion of follow-up. 
 
10.1  Permitted medications 
All concomitant medications taken during the study will be recorded in the CRF with indication, 
dose, and dates of administration.  Subjects should receive full supportive care during the study 
including transfusion with blood and blood products, antibiotics, recombinant human 
granulocyte colony stimulating factor or erythropoiesis-stimulating agents, bisphosphonates 
when appropriate.  Anti-emetics may be administered prophylactically or in the event of nausea. 
Anti-diarrheals may be administered as needed for diarrhea.   
 
10.2 Permitted medications- use with caution  
Analgesics such as acetominophen and nonsteroidal anti-inflammatory medications should be 
administered with caution or not at all in subjects with impaired liver function. The use of 
heparin or low molecular weight heparin should be cautioned against in patients with HCC and 
cirrhosis, however may be indicated in specific situations. Due to dual potential for severe 
bleeding warfarin should not be administered. 
 
10.3 Drug Interactions  
Formal drug-drug interaction studies have not been conducted with PD-0332991. Pre-clinical 
data indicate that PD-0332991 is metabolized in vivo primarily via the cytochrome P-450 
enzyme, CYP3A4. Therefore concomitant use of certain medications (substrates of CYP3A4 
should be undertaken with caution due to potential for alterations in the pharmacological effects 
of these medications or an increased risk for serious or life threatening adverse events.  
Furthermore, there may be a risk of drug-drug interactions.  These medications include but are 
not limited to: ergot derivatives - dihydroergotamine, ergonovine, ergotamine, methylergonovine 
(potential for developing ergot toxicity including vasospasm leading to peripheral neuropathy 
and cerebral ischemia); neuroleptics - pimozide (potential increased risk for QT prolongation, 
ventricular arrhythmia and sudden death); antiarrhythmics - bepridil, flecainide,lidocaine, 
mexiletine, amiodarone, quinidine, propafenadone (potential increased risk for QT prolongation 


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and Torsades de Pointes); immune modulators - cyclosporine, tacrolimus, sirolimus (potential 
increased risk for nwephrotoicity and neurotoxicity; and miscellaneous drugs - quetiapine, 
rispiridone, clozapine and atomoxetine.  Concomitant administration of agents known to induce 
or inhibit CYP3A isoenzymes may increase plasma drug concentrations of PD-0332991.  
Selection of alternative concomitant medications with no potential to inhibit CYP3A4 is 
recommended. Medications which may induce CYP3A4 and may decrease plasma 
concentrations of PD-0332991 are glucocorticoids - high dose cortisone or hydrocortisone, 
prednisone, 
methylprednisolone 
and 
dexamethasone; 
anticonvulsants 
– 
phenytoin, 
carbamezepine, phenobarbital, oxcarbazepine; HIV antivirals – efavirenz, nevirapine,; 
antibiotics- rifampin, rifabutin, rifapentene and miscellaneous medications - St. John’s Wort, 
modafinil, pioglitazone, troglitazone, omeprazole, verapamil. Primidone. PROHIBITED during 
the study are the strong CYP3A4 inhibitors which includes but are not limited to antibiotics- 
erythromycin, clarithromycin, telithromycin, troleandomycin; HIV protease inhibitors- ritonavir 
indinavir, nelfinavir, saquinavir, amprenavir, lopinovir, delaviridine; antifungals- itraconazole, 
ketoconazole, voriconazole, fluconazole; antidepressants- nefazodone and grapefruit juice. 
 
11.0 Statistical Considerations  
This is Phase II open-label non-randomized single institution study with an anticipated 12-24 
month accrual.  The size of the study is based on biostatistical modeling of HCC and is powered 
to demonstrate an improved TTP. The sample size calculation is based on historical data, which 
demonstrates that median TTP for untreated patients with HCC is 12 weeks, and median TTP for 
patients treated with Sorafenib is 24 weeks (Llovet et al. 2008, Cheng et al. 2009). The proposed 
study will test whether PD-0332991 treatment results in at least a 24 week TTP versus the 
historical median of 12 weeks. For a trial with an alpha of 0.05 and power of 90%, a sample size 
of 19 evaluable patients is needed. 
 
11.1 Evaluation of Efficacy 
Efficacy endpoints will be estimated for all subjects.  The tumor response endpoints will be 
performed on all subjects. The population will be evaluated on an intent-to-treat analysis defined 
as subjects who received at least two cycles of study medication and have completed the week 8 
response assessments. TTP, ORR will be assessed by standard imaging (MRI and/or CT scans, 
as appropriate) utilizing modified RECIST (Version 1.1) criteria. Assessments will be performed 
at screening and after every 2 cycles of treatment (every 8 weeks) thereafter. TTP and overall 
survival will be evaluated using the Kaplan-Meier method. Median TTP and median survival 
will be estimated with corresponding 90% confidence intervals. Subjects that are not evaluable 
will be replaced with subjects with evaluable data.  
 
11.2 Safety Analysis 
The clinical safety data will be summarized using descriptive statistics. 
 
12.0 Data Disclosure and Patient Confidentiality 
Patient medical information obtained as a result of this study is considered confidential. 
Disclosure to third parties other than to the patient’s primary physician and to those noted below 
is prohibited.  All reports and communications relating to subjects in this study will identify each 
patient only by his/her number (and initials if allowed by local regulations).  Data generated as a 


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result of this study must be available for inspection upon request by the FDA (or other Health 
Authority or government agency), Data Safety Monitoring Board, and the IRB. 
 
Confidentiality will be maintained at all times unless government regulation or applicable law 
requires disclosure.  If local or national regulations are modified to require additional consent(s) 
or documentation for release of source documents or other medical information, required for the 
study, it is the responsibility of the investigator to obtain such consent and documentation with 
relevant approvals by the local IRB. 
12.1 Data Collection 
The investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and data pertinent to this investigation for each subject 
enrolled. 
 
12.2 Records Retention  
The Investigator must retain all source documents for the maximum period required by 
applicable regulations and guidelines, or Institution procedures. If the Investigator withdraws 
from the study (e.g., relocation, retirement), the records shall be transferred to a mutually agreed 
upon designee (e.g., another Investigator, IRB). Notice of such transfer will be given in writing 
to IRB. 
 
12.3 Protocol Deviations/Exceptions 
Deviations/exceptions from listed eligibility criteria will not be allowed under any 
circumstances.  An accidental or unintentional deviation from the approved protocol, 
that in the opinion of the investigator, places one or more subjects at increased risk, or 
affects the rights or welfare of subjects, must be reported to the IRB and DSMC 
immediately. 
 
13.0 Ethical Considerations 
 
13.1 Protection of Human Subjects from Research Risks 
The study will be conducted in accordance with the Declaration of Helsinki and with rules and 
regulations in accord with the U.S. Office of Protection from Research Risks (OPRR). 
 
13.2 Institutional Review Board 
The study will be reviewed and approved by a duly constituted IRB before patients are screened 
for entry. The investigator will ensure that all aspects of the IRB review are conducted in 
accordance with current institutional, local, and national regulations. Amendments to the 
protocol will be subject to the same requirements as the original protocol.  The Investigator will 
submit all periodic reports and updates that the IRB may require, including any final close out 
reports.  The Investigator will inform the IRB of any reportable adverse events as required by 
local regulations. 
 
13.3 Informed Consent 


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Each subject will be provided with oral and written information that describes the nature and 
duration of the study in a language he/she can understand.  The required schedule for treatment 
and interval safety evaluations (irrespective of holidays), plus the planned follow-up schedule, 
should be carefully reviewed and possibly reinforced with a calendar.  The patient must consent 
in writing to participate before undergoing therapy on the protocol.  The original signed consent 
form will be retained.  Each subject will be given a copy of his/her consent form. 
 
14.0 Data Safety Monitoring Board 
The study Principal Investigator will monitor toxicities   monthly, submitting quarterly safety 
and monitoring reports to the Clinical Research Management Office and The Data Safety 
Monitoring Committee (DSMC).  All unexpected on-site adverse events and serious adverse 
events (SAEs) are required to be submitted to the TJU IRB and the DSMC within 48 hours. Fatal 
adverse events which are unexpected must be reported within 24 hours to the TJU IRB and the 
DSMC. Fatalities not related to the study drug/device must be reported within 5 days.  
 
A medical monitor (a physician or other member of the DSMC who has expertise in the 
therapeutic area of the protocol and is not directly involved in this trial) will be identified for the 
protocol. The medical monitor will review all adverse events (in addition to unexpected adverse 
events), safety data and activity data observed in the ongoing clinical trial.  
The PI provides a report to the DSMC of all AE/SAEs, safety and toxicity data, and any 
corrective action that occurred on a quarterly basis. The medical monitor also provides a 
summary of their review. The summary of all discussions of adverse events are submitted to the 
DSMC, and these reports are reviewed during the DSMC meetings that take place quarterly. 
Patients are only identified by initials, and no other PHI is included in the reports.  
The medical monitor may recommend reporting adverse events and relevant safety data not 
previously reported, and may recommend suspension or termination of the trial based on their 
review of AE/SAE data observed throughout the life of a clinical trial. In such circumstances, 
and “ad hoc” DSMC meeting will be called to discuss corrective action with the PI.  
The summary of all discussions of adverse events are included in the Kimmel Cancer Center 
(KCC) investigator’s reports to the TJU IRBs as part of its annual progress report. The DSMC 
and the TJU IRB may, based on the monitor’s recommendation suspend or terminate the trial. 
The quarterly safety and monitoring reports include a statement as to whether this data has 
invoked any stopping criteria in the clinical protocol. 
 
15.0 Audits 
In addition to review by the DSMC, the study will be audited by an independent auditor once 
10% of target accrual has been achieved. The study will be re-audited once 50% of target accrual 
has been achieved.  However, a study can be audited at any time based on recommendations by 
the IRB, DSMC, CCRRC and/or the Director of Clinical Investigations, KCC.  Special audits 
may be recommended by the IRB, DSMC or CCRRC based on prior findings, allegations of 
scientific misconduct and where significant irregularities are found through quality control 
procedures. Any irregularities identified as part of this process would result in a full audit of that 
study.  
 
In addition to the audits at 10 and 50%, the CRMO randomly audits at least 10 percent of all 
patients entered into therapeutic KCC trials and other trials as necessary, on at least a bi-annual 


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basis, to verify that there is a signed and dated patient consent form, the patient has met the 
eligibility criteria, and that SAEs are documented and reported to the TJU IRB.  
 


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References 
 
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2. Cheng, A. L., et al. (2009). "Efficacy and safety of sorafenib in patients in the Asia-
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3. El-Serag, H. B. (2004). "Hepatocellular carcinoma: recent trends in the United States." 
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11. O’Dwyer, P. J., et al. (2007). “A phase I dose escalation trial of a daily oral CDK4/6 
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12. Rivadeneira, D. B., et al. (2010). “Proliferative Suppression by CDK4/6 Inhibition: 
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13. Siegel, A. B., et al. (2008). "Racial disparities in utilization of liver transplantation for 
hepatocellular carcinoma in the United States, 1998-2002." Am J Gastroenterol 103(1): 
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