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

• Sponsor: Sidney Kimmel Cancer Center at Thomas Jefferson University (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT01356628
• Collaborator: Pfizer (Industry)
• Enrollment: 23
• Location: 1
• Arm: 1
• Anticipated Duration (Months): 126.3
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Advanced Hepatocellular Carcinoma; HCC; Liver Cancer	Drug: PD-0332991	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 23 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of PD-0332991 in Adult Patients With Advanced Hepatocellular Carcinoma
• Actual Study Start Date: May 25, 2011
• Actual Primary Completion Date: Apr 9, 2015
• Anticipated Study Completion Date: Dec 1, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: PD-0332991 PD-0332991 in the Treatment in Patients with Advanced Hepatocellular Carcinoma	Drug: PD-0332991; PD-0332991, 125mg, 3 cycles

Outcome Measures

Primary Outcome Measures

1. Time to Disease 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]

   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.

Secondary Outcome Measures

1. Number of Adverse Events [From date of randomization through study completion, assessed up to 100 months]

   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.

2. Overall Survival (OS) [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]

   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.

3. Response Rate (RR) [Every 8 weeks]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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:

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

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

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

3. Life expectancy greater than 3 months

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

5. ECOG Performance status of < or = 2

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

7. 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.

8. 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.

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

1. 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

1. 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.

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

1. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Thomas Jefferson University	Philadelphia	Pennsylvania	United States	19107

Sponsors and Collaborators

• Sidney Kimmel Cancer Center at Thomas Jefferson University
• Pfizer

Investigators

• Principal Investigator: Avnish Bhatia, MD, Sidney Kimmel Cancer Center at Thomas Jefferson University

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Kimmel Cancer Center at Thomas Jefferson University, an NCI-Designated Cancer Center
• Thomas Jefferson University Hospitals

Publications

• Fry DW, Harvey PJ, Keller PR, Elliott WL, Meade M, Trachet E, Albassam M, Zheng X, Leopold WR, Pryer NK, Toogood PL. Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol Cancer Ther. 2004 Nov;3(11):1427-38.
• Rivadeneira DB, Mayhew CN, Thangavel C, Sotillo E, Reed CA, Graña X, Knudsen ES. Proliferative suppression by CDK4/6 inhibition: complex function of the retinoblastoma pathway in liver tissue and hepatoma cells. Gastroenterology. 2010 May;138(5):1920-30. doi: 10.1053/j.gastro.2010.01.007. Epub 2010 Jan 25.
• Toogood PL, Harvey PJ, Repine JT, Sheehan DJ, VanderWel SN, Zhou H, Keller PR, McNamara DJ, Sherry D, Zhu T, Brodfuehrer J, Choi C, Barvian MR, Fry DW. Discovery of a potent and selective inhibitor of cyclin-dependent kinase 4/6. J Med Chem. 2005 Apr 7;48(7):2388-406.

• Responsible Party: Sidney Kimmel Cancer Center at Thomas Jefferson University
• ClinicalTrials.gov Identifier: NCT01356628
• Other Study ID Numbers: 11D.14; 2010-41
• First Posted: May 19, 2011
• Last Update Posted: Oct 18, 2021
• Last Verified: Sep 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Sidney Kimmel Cancer Center at Thomas Jefferson University: Advanced Hepatocellular Carcinoma; HCC; Liver Cancer; PD-0332991
• Additional relevant MeSH terms: Carcinoma; Carcinoma, Hepatocellular; Liver Neoplasms; Palbociclib

Study Results

Participant Flow

Arm/Group Title	PD-0332991
Arm/Group Description	PD-0332991 in the Treatment in Patients with Advanced Hepatocellular Carcinoma PD-0332991: PD-0332991, 125mg, 3 cycles
Period Title: Overall Study
STARTED	23
COMPLETED	23
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	PD-0332991
Arm/Group Description	PD-0332991 in the Treatment in Patients with Advanced Hepatocellular Carcinoma PD-0332991: PD-0332991, 125mg, 3 cycles
Overall Participants	23
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	15 65.2%
>=65 years	8 34.8%
Sex: Female, Male (Count of Participants)
Female	3 13%
Male	20 87%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	22 95.7%
Unknown or Not Reported	1 4.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	7 30.4%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	4 17.4%
White	12 52.2%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
United States	23 100%

Outcome Measures

1. Primary Outcome

Title	Time to Disease Progression
Description	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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	PD-0332991
Arm/Group Description	PD-0332991 in the Treatment in Patients with Advanced Hepatocellular Carcinoma PD-0332991: PD-0332991, 125mg, 3 cycles
Measure Participants	23
Mean (Full Range) [months]	8

2. Secondary Outcome

Title	Number of Adverse Events
Description	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.
Time Frame	From date of randomization through study completion, assessed up to 100 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	PD-0332991
Arm/Group Description	PD-0332991 in the Treatment in Patients with Advanced Hepatocellular Carcinoma PD-0332991: PD-0332991, 125mg, 3 cycles
Measure Participants	23
Number [Adverse Events]	504

3. Secondary Outcome

Title	Overall Survival (OS)
Description	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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Response Rate (RR)
Description	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.
Time Frame	Every 8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Arm/Group Title	PD-0332991
Arm/Group Description	PD-0332991 in the Treatment in Patients with Advanced Hepatocellular Carcinoma PD-0332991: PD-0332991, 125mg, 3 cycles
All Cause Mortality
	PD-0332991
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	PD-0332991
	Affected / at Risk (%)	# Events
Total	11/23 (47.8%)
Blood and lymphatic system disorders
Leukopenia	3/23 (13%)	3
Neutropenia	3/23 (13%)	4
Hyperbilirubinema	3/23 (13%)	4
Hypercalcemia	1/23 (4.3%)	1
Hyperkalemia	1/23 (4.3%)	1
Anemia	1/23 (4.3%)	1
Thrombocytopenia	2/23 (8.7%)	2
Gastrointestinal disorders
Vomiting	2/23 (8.7%)	2
Peritoneal Infection	1/23 (4.3%)	1
Lower abdomen pain	3/23 (13%)	3
Lower Gastrointestinal Hemorrhage	1/23 (4.3%)	1
Ascites	1/23 (4.3%)	1
Diarrhea	1/23 (4.3%)	1
General disorders
Fracture of left Humorous	1/23 (4.3%)	1
Dehydration	1/23 (4.3%)	1
Hepatobiliary disorders
Hepatic Failure	2/23 (8.7%)	2
Infections and infestations
Fever	1/23 (4.3%)	1
Sepsis	1/23 (4.3%)	1
Musculoskeletal and connective tissue disorders
Lower leg weakness	1/23 (4.3%)	1
Nervous system disorders
Spinal cord compression	1/23 (4.3%)	1
Psychiatric disorders
Confusion	1/23 (4.3%)	1
Other (Not Including Serious) Adverse Events
	PD-0332991
	Affected / at Risk (%)	# Events
Total	23/23 (100%)
Blood and lymphatic system disorders
Thrombocytopenia	20/23 (87%)	56
Alanine Aminotransferase Increased	10/23 (43.5%)	28
Alkaline Phosphate Increase	8/23 (34.8%)	15
Anemia	13/23 (56.5%)	23
Aspartate Aminotransferase Increased	5/23 (21.7%)	8
Creatine increase	5/23 (21.7%)	7
Diabetes	5/23 (21.7%)	9
Hyperbilirubinema	3/23 (13%)	5
Hypercalemia	3/23 (13%)	4
Hyperglycemia	5/23 (21.7%)	8
Hyperkalemia	2/23 (8.7%)	3
Hyperlipidemia	4/23 (17.4%)	5
Hypermagnesemia	1/23 (4.3%)	1
Hypertension	2/23 (8.7%)	3
Hypoalbuminemia	4/23 (17.4%)	5
Hyponatremia	3/23 (13%)	4
Hypocalcemia	4/23 (17.4%)	6
Hypokalemia	1/23 (4.3%)	1
Hypomagnesemia	4/23 (17.4%)	10
Hypophosphatemia	2/23 (8.7%)	2
Hypotension	3/23 (13%)	4
Increase in Creatine	3/23 (13%)	3
INR increased	1/23 (4.3%)	1
Leukopenia	5/23 (21.7%)	9
Low ANC	3/23 (13%)	7
Lymphocytopenia	2/23 (8.7%)	5
Neutropenia	2/23 (8.7%)	2
ANC decreased	1/23 (4.3%)	2
Eye disorders
Blurred Vision	3/23 (13%)	3
Vision Change	1/23 (4.3%)	2
Gastrointestinal disorders
Blood in Stool	2/23 (8.7%)	2
Constipation	1/23 (4.3%)	2
Diarrhea	5/23 (21.7%)	10
Diverticulitis	4/23 (17.4%)	9
Emesis	4/23 (17.4%)	6
Epigastric	3/23 (13%)	4
Gas	1/23 (4.3%)	1
GERD	2/23 (8.7%)	2
GI Bleeding	6/23 (26.1%)	7
Heartburn	3/23 (13%)	4
Inguinal hernia	3/23 (13%)	8
Mucositis	4/23 (17.4%)	4
Stomach Virus	1/23 (4.3%)	1
Hemorrhoids	1/23 (4.3%)	1
General disorders
Body Aches/Pan	7/23 (30.4%)	8
Chills	3/23 (13%)	5
Cold	6/23 (26.1%)	9
Dizzyness	4/23 (17.4%)	7
Edema	10/23 (43.5%)	13
Epistaxis	2/23 (8.7%)	3
Fall	6/23 (26.1%)	6
Fatigue	1/23 (4.3%)	1
Gas reflex	3/23 (13%)	3
Gout	1/23 (4.3%)	1
Injection Site Reaction	1/23 (4.3%)	1
Lightheadedness	1/23 (4.3%)	1
Nausea	5/23 (21.7%)	14
Night Sweats	2/23 (8.7%)	2
Pain	3/23 (13%)	4
Weakness	1/23 (4.3%)	1
Infections and infestations
Fever	2/23 (8.7%)	3
Fungal Esophageal Infection	3/23 (13%)	5
Hepatitis C	1/23 (4.3%)	3
Infection, C.Diff	2/23 (8.7%)	2
Polymicrobial Bacteremia	1/23 (4.3%)	1
Sinusitis	1/23 (4.3%)	1
Metabolism and nutrition disorders
Decreased Appetite	2/23 (8.7%)	5
Metabolism and nutrition disorder	1/23 (4.3%)	1
Musculoskeletal and connective tissue disorders
leg pain	1/23 (4.3%)	1
Muscle cramping	1/23 (4.3%)	1
Muscle weakness	2/23 (8.7%)	2
Neck Fracture	1/23 (4.3%)	1
Cramping hands and legs	1/23 (4.3%)	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasm benign	1/23 (4.3%)	1
Nervous system disorders
Dysphasia	1/23 (4.3%)	1
Insomnia	5/23 (21.7%)	9
Neuropathy	6/23 (26.1%)	8
Taste Alteration	1/23 (4.3%)	1
Psychiatric disorders
Anorexia	7/23 (30.4%)	9
Delirium, Post-Op	2/23 (8.7%)	4
Depression	4/23 (17.4%)	14
Renal and urinary disorders
Ascites	10/23 (43.5%)	22
Cirrhosis	3/23 (13%)	4
Jaundice	1/23 (4.3%)	1
Urinary Frequency and burning	1/23 (4.3%)	1
Urine Discoloration	1/23 (4.3%)	1
Reproductive system and breast disorders
Dyspnea	1/23 (4.3%)	1
Respiratory, thoracic and mediastinal disorders
COPD	2/23 (8.7%)	2
Sleep Apnea	1/23 (4.3%)	1
Emphesyma	1/23 (4.3%)	1
Skin and subcutaneous tissue disorders
Dry cracked palms	3/23 (13%)	6
Pruritus (Itching)	2/23 (8.7%)	2
Rash	2/23 (8.7%)	2
Rash Pustular	1/23 (4.3%)	1
Dry Skin	1/23 (4.3%)	1
Surgical and medical procedures
Tonsillectomy	1/23 (4.3%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.