Study to Determine the Maximum Tolerated Dose of the PARP Inhibitor CEP-9722 in Patients With Solid Tumors

Overview

CEP-9722 is an inhibitor of poly-adenosine diphosphate (ADP) ribose polymerase -1 and -2 (PARP). The primary purpose of this study is to (Part 1) determine the maximum tolerated dose (MTD) of CEP-9722 administered daily to patients with advanced or metastatic solid tumors, (Part 2) to evaluate the safety and tolerability of that dose, and to investigate whether CEP-9722 has antitumor activity as a single agent.

Full Title of Study: “An Open-Label Study to Determine the Maximum Tolerated Dose of the PARP Inhibitor CEP-9722 When Administered as a Single Agent in Patients With Advanced or Metastatic Solid Tumors”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Non-Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: October 2013

Interventions

  • Drug: CEP-9722
    • CEP-9722 is administered daily or twice-daily for six 28-day cycles. Dose escalation will proceed until the MTD is identified.
  • Drug: CEP-9722
    • CEP-9722 is administered daily or twice-daily for six 28-day cycles. Patients will be administered CEP-9722 at the MTD identified in Part 1.

Arms, Groups and Cohorts

  • Experimental: (Part 1): CEP-9722
  • Experimental: (Part 2): CEP-9722

Clinical Trial Outcome Measures

Primary Measures

  • part 1: to determine the maximum tolerated dose (MTD) of single-agent oral CEP-9722 administered daily to patients with advanced or metastatic solid tumors, as defined by first-cycle dose-limiting toxicities (DLTs)
    • Time Frame: up to 8 months
  • part 2: to evaluate the safety and tolerability of the MTD of CEP-9722 identified in part 1, as defined by numbers and severity of adverse events
    • Time Frame: up to 8 months

Secondary Measures

  • to characterize the pharmacokinetic profile of CEP-8983 (the active moiety of CEP-9722) following administration of CEP-9722, including the maximum observed drug concentration (Cmax) and area under the plasma concentration-time curve (AUC)
    • Time Frame: up to 8 months
  • to evaluate the pharmacodynamic effects of CEP-8983 by evaluating the profile of poly-adenosine diphosphate ribose polymerase (PARP) inhibition in peripheral blood mononuclear cells following administration of CEP-9722
    • Time Frame: up to 8 months
  • to evaluate the antitumor activity of single-agent CEP-9722, measured by overall response rate (ORR)
    • Time Frame: up to 8 months
    • as assessed by the best tumor response (complete response [CR], partial response [PR], stable disease, and progressive disease) during the study using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1)
  • to understand the effect of CEP-8983 on cardiac repolarization by evaluating the concentration-QT interval relationship
    • Time Frame: up to 8 months

Participating in This Clinical Trial

Inclusion Criteria

  • The patient has histologically confirmed, locally advanced or metastatic solid tumor considered incurable and unresponsive to standard therapies. – The patient has disease progression following at least 1 prior standard chemotherapy regimen. – The patient is a man or woman at least 18 years of age. – The patient has a European Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. – The patient has a life expectancy of 12 weeks or more. – The patient has adequate hematologic function as evidenced by: – absolute neutrophil cell (ANC) count 1.5 x109/L or more – hemoglobin 10 g/dL or more – platelets 100 x 109/L or more – The patient has adequate hepatic function as evidenced by: – total bilirubin 1.5 times the upper limit of normal (ULN) or less, unless secondary to Gilbert's disease (any Gilbert's disease must be documented, and bilirubin must be 3 times the ULN or less.) – alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase of 2.5 times ULN or less – The patient has adequate renal function as defined by creatinine of less than 1.5 times ULN or less. – The patient must take precautions to not become pregnant or produce offspring. Women must be of non-childbearing potential (surgically sterile or postmenopausal for at least 12 months, confirmed by follicle-stimulating hormone [FSH] >40 IU/L) or agree to use a medically accepted method of contraception for the duration of the study and 90 days after treatment. Men must be surgically sterile or agree to use a medically accepted method of contraception for the duration of the study and 90 days after treatment. Acceptable methods of contraception include abstinence, barrier method with spermicide (excluding cervical cap and sponge), intrauterine device (IUD), or steroidal contraceptive (oral, transdermal, implanted, and injected) in conjunction with a barrier method. – Written informed consent is obtained. – In Part 2: In addition to the criteria above, patients should have documented deficiencies of DNA repair pathways, such as BRCA1/2, or have prostate, breast, or gastric cancer and ability to provide fresh or archived tumor specimens. Exclusion Criteria:

  • Other than malignancy, the patient has any serious or uncontrolled surgical, medical, or psychiatric history that could pose an unacceptable health risk to the patient, prevent compliance with study procedures, or compromise the study integrity, including, but not limited to the following: 1. recent history of cardiac ischemic disease (acute myocardial infarction within 6 months, unstable angina) 2. cardiac arrhythmia that is uncontrolled or that requires medication 3. recent transient ischemic attack or stroke (within 6 months) or residual dysfunction from stroke 4. history of seizure disorder (part 1 only) 5. clinically significant pulmonary disease (eg, fibrosis on chest x-ray or significant dyspnea as assessed by investigator) 6. poorly controlled hypertension (systolic >140 mm Hg or diastolic >90 mm Hg) 7. uncontrolled active infection within the past 7 days 8. poorly controlled diabetes mellitus as assessed by investigator 9. recent major surgery (within 4 weeks prior to study day 1) or minor surgery (within 2 weeks prior to study day 1) – The patient has previously received a PARP inhibitor. – The patient has received antitumor therapy or other investigational agent within 4 weeks (with the exception of LHRH therapy in patients with prostate cancer) or nitrosourea therapy within 6 weeks. – The patient has clinically symptomatic brain metastases or required treatment for brain metastases within 4 weeks (stable sequelae acceptable if treatment has been completed). – The patient has residual adverse events of greater than grade 1 severity from prior radiotherapy or chemotherapy agents. – The patient has known immunodeficiency virus (HIV) infection, acute or chronic hepatitis B infection,or hepatitis C infection. – The patient is a pregnant or breast-feeding woman. (Any women becoming pregnant during the study will be withdrawn from the study.) – The patient has medical or surgical gastrointestinal history that would interfere with the absorption of study drug. – The patient requires treatment with a proton pump inhibitor or H2 antagonist or has taken a proton pump inhibitor or H2 antagonist within 4 days before CEP-9722 administration. – The patient has risk factors for Torsades de Pointes as follows: – history of Long QT syndrome or unexplained syncope – history of congestive heart failure (New York Heart Association class III or IV) – concomitant treatment with medication known to prolong QT/QTc interval – QTc greater than 450 msec at screening

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Cephalon
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Sponsor’s Medical Expert, Study Director, Cephalon

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