Clinical trial NCT01311713: Study to Determine the Maximum Tolerated Dose of the PARP Inhibitor CEP-9722 in Participants With Solid Tumors
Official title: 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: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Solid Tumors
Keywords: cancer
tumors
PARP
Lead sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
Sponsor class: INDUSTRY
First posted: 2011-03-09
Enrollment: 45
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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 participants 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.


Eligibility criteria: Inclusion Criteria:

* The participant has histologically confirmed, locally advanced or metastatic solid tumor considered incurable and unresponsive to standard therapies.
* The participant has disease progression following at least 1 prior standard chemotherapy regimen.
* The participant is a man or woman at least 18 years of age.
* The participant has a European Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
* The participant has a life expectancy of 12 weeks or more.
* The participant has adequate hematologic function as evidenced by:
* absolute neutrophil cell (ANC) count 1.5 x10\^9/liter (L) or more
* hemoglobin 10 grams (g)/deciliter (dL) or more
* platelets 100 x 10\^9/L or more
* The participant 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 participant has adequate renal function as defined by creatinine of less than 1.5 times ULN or less.
* The participant 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, participants 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 participant has any serious or uncontrolled surgical, medical, or psychiatric history that could pose an unacceptable health risk to the participant, 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 millimeters of mercury (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 participant has previously received a PARP inhibitor.
* The participant has received antitumor therapy or other investigational agent within 4 weeks (with the exception of LHRH therapy in participants with prostate cancer) or nitrosourea therapy within 6 weeks.
* The participant has clinically symptomatic brain metastases or required treatment for brain metastases within 4 weeks (stable sequelae acceptable if treatment has been completed).
* The participant has residual adverse events of greater than grade 1 severity from prior radiotherapy or chemotherapy agents.
* The participant has known immunodeficiency virus (HIV) infection, acute or chronic hepatitis B infection,or hepatitis C infection.
* The participant is a pregnant or breast-feeding woman. (Any women becoming pregnant during the study will be withdrawn from the study.)
* The participant has medical or surgical gastrointestinal history that would interfere with the absorption of study drug.
* The participant 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 participant 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 milliseconds (msec) at screening

Primary outcomes:
measure: Part 1: Maximum Tolerated Dose (MTD) of Oral CEP-9722
timeFrame: Cycle 1 (28 days)
measure: Part 2: Number of Participants With Adverse Events
timeFrame: Up to 8 months
Secondary outcomes:
measure: Part 1: Maximum Observed Plasma Concentration (Cmax) of CEP-8983 (the Active Moiety of CEP-9722)
timeFrame: Predose (0 hour), 0.5, 1, 2, 3, 4, 6, 8, and 12 hours postdose on Days 1 and 15 of Cycle 1
measure: Part 1: Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Time of Last Measurable Drug Concentration (AUC0-t) of CEP-8983 (the Active Moiety of CEP-9722)
timeFrame: Predose (0 hour), 0.5, 1, 2, 3, 4, 6, 8, and 12 hours postdose on Days 1 and 15 of Cycle 1
measure: Poly Adenosine Diphosphate-ribose (PAR) Concentration in Peripheral Blood Monocyte or Mononuclear Cells of CEP-8983 (the Active Moiety of CEP-9722)
timeFrame: Predose (0 hour), 2 and 6 hours postdose on Days 1 and 15 of Cycle 1
measure: Part 1: Overall Response Rate (ORR) - Percentage of Participants With the Best Tumor Response
timeFrame: From the start of the treatment until disease progression/recurrence (up to 168 days)
measure: Part 2: Change in QT Interval
timeFrame: Day 1 and Day 15, Cycle 1
Other outcomes:
Locations:
city: Aurora
country: United States
facility: Teva Investigational Site 1
state: Colorado
city: Detroit
country: United States
facility: Teva Investigational Site 3
state: Michigan
city: Saint Louis
country: United States
facility: Teva Investigational Site 4
state: Missouri
city: Philadelphia
country: United States
facility: Teva Investigational Site 2
state: Pennsylvania
Study officials:
affiliation: Teva Branded Pharmaceutical Products R&D, Inc.
name: Teva Medical Expert
role: STUDY_DIRECTOR
References: