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

This study is currently recruiting participants.
Verified March 2014 by Thomas Jefferson University
Sponsor:
Collaborators:
Pfizer
Susan Littman, MD
Information provided by (Responsible Party):
Thomas Jefferson University
ClinicalTrials.gov Identifier:
NCT01356628
First received: May 10, 2011
Last updated: March 11, 2014
Last verified: March 2014
  Purpose

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 Intervention Phase
Advanced Hepatocellular Carcinoma
HCC
Liver Cancer
Drug: PD-0332991
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Study of PD-0332991 in Adult Patients With Advanced Hepatocellular Carcinoma

Resource links provided by NLM:


Further study details as provided by Thomas Jefferson University:

Primary Outcome Measures:
  • Time to Disease Progression [ Time Frame: Every 8 weeks ] [ Designated as safety issue: No ]
    Time to progression (TTP) will be defined as the date of enrollment on trial to the first observation of disease progression, as classified by modified RECIST (Response Evaluation Criteria In Solid Tumors) 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 study will be stopped for futility if the conditional power is less than 60%.


Secondary Outcome Measures:
  • Number and Nature of Adverse Events [ Time Frame: Every 2 weeks during first 3 cycles, then monthly ] [ Designated as safety issue: Yes ]
    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.

  • Overall Survival (OS) [ 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 ] [ Designated as safety issue: No ]
    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.

  • Response Rate (RR) [ Time Frame: Every 8 weeks ] [ Designated as safety issue: No ]
    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.


Estimated Enrollment: 19
Study Start Date: June 2011
Estimated Study Completion Date: June 2015
Estimated Primary Completion Date: June 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: PD-0332991
PD-0332991 in the Treatment in Patients with Advanced Hepatocellular Carcinoma
Drug: PD-0332991
PD-0332991, 125mg, 3 cycles

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Male or female, age > or = 18 years with HCC refractory to currently available therapies.
  2. Documented HCC by at least 2 out of 3 mentioned criteria and evidence of non-resectability by a multidisciplinary team:

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

  3. Positive staining for RB-function on tumor biopsy.
  4. Subject must be able to give written informed consent and be able to follow protocol requirements
  5. Life expectancy greater than 3 months
  6. Be Child's-Pugh class A or B
  7. ECOG Performance status of < or = 2
  8. If female of childbearing potential must have negative pregnancy test at screening and may not be breast-feeding
  9. Females of child-bearing potential (< one year post-menopausal with documented FSH greater than 30 IU/L or surgically not sterile), must agree to practice an effective method of avoiding pregnancy (including oral or implanted contraceptives, intrauterine device, condom, diaphragm with spermicidal, cervical cap, abstinence or sterile sex partner) from the time informed consent is signed through follow-up. Males must agree to take appropriate precautions to avoid fathering a child from screening through follow-up.
  10. No other active malignancy requiring treatment in the last 3 years other than adequately treated non-melanomatous skin cancer, adequately treated cervical carcinoma in-situ, superficial adequately treated bladder cancer or prostatic intraepithelial neoplasia without evidence of prostate cancer.
  11. Adequate bone marrow, liver and renal function as assessed by the following:

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

  12. Subjects who have received previous radiotherapy, loco-regional, or systemic therapy are eligible. A minimum interval of 4 weeks since the last anti-cancer treatment of any kind is required.
  13. Subjects with brain metastases or a history of previously treated brain metastasis are eligible but must:

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

Exclusion Criteria:

  1. Any concurrent active malignancy requiring treatment (other than basal or squamous cell carcinoma of the skin, carcinoma in situ of the cervix, superficial bladder tumors, or other malignancies curatively treated > 3 years prior to study entry)
  2. History of severe cardiovascular disease within the last 12 months: symptomatic congestive heart failure, myocardial infarction, coronary artery disease (CAD), life threatening arrhythmias, uncontrolled hypertension
  3. Renal failure requiring hemo- or peritoneal dialysis
  4. Unstable systemic diseases or active uncontrolled infection
  5. Known history of HIV infection
  6. Clinically significant gastrointestinal bleeding within 30 days prior to study entry
  7. Major surgery, open biopsy or significant traumatic injury within 4 weeks prior to study entry
  8. Child's-Pugh Class C
  9. Any malabsorption problem that, in the investigator's opinion, would prevent adequate absorption of the study drug
  10. Presence of any other medical complications that in the investigator's opinion, suggests a survival of < 3 months
  11. Substance abuse, or medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results
  12. Patient inability to swallow oral medications
  13. Any condition that is unstable or which could jeopardize the safety of the patient and his/her compliance in the study
  14. Pregnant or breast-feeding patients
  15. Being of reproductive potential and unable or unwilling to practice an effective contraceptive method
  16. Lack of positive staining for RB-function on tumor biopsy.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01356628

Contacts
Contact: Christina Brus, MD 215-955-8874
Contact: Clinical Research Management Office 215-955-1661

Locations
United States, Pennsylvania
Thomas Jefferson University Recruiting
Philadelphia, Pennsylvania, United States, 19107
Contact: Christina Brus, MD    215-955-8874      
Contact: Clinical Research Management Office    215-955-1661      
Principal Investigator: Christina Brus, MD         
Sub-Investigator: Edith Mitchell, MD, FACP         
Sub-Investigator: Andrew Chapman, DO         
Sub-Investigator: Avnish Bhatia, MD         
Sub-Investigator: Lewis Rose, MD         
Sub-Investigator: Nancy Lewis, MD         
Sub-Investigator: Michael Ramirez, MD         
Sub-Investigator: Ashlie Burkart, MD         
Sponsors and Collaborators
Thomas Jefferson University
Pfizer
Susan Littman, MD
Investigators
Principal Investigator: Christina Brus, MD Thomas Jefferson University
  More Information

Additional Information:
Publications:
Responsible Party: Thomas Jefferson University
ClinicalTrials.gov Identifier: NCT01356628     History of Changes
Other Study ID Numbers: 11D.14, 2010-41
Study First Received: May 10, 2011
Last Updated: March 11, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Thomas Jefferson University:
Advanced Hepatocellular Carcinoma
HCC
Liver Cancer
PD-0332991

Additional relevant MeSH terms:
Carcinoma
Liver Neoplasms
Carcinoma, Hepatocellular
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Adenocarcinoma

ClinicalTrials.gov processed this record on April 21, 2014