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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Solid Tumors

Intervention / Treatment
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* Drug: CEP-9722


Participation Criteria
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Eligibility Criteria
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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: recent history of cardiac ischemic disease (acute myocardial infarction within 6 months, unstable angina) cardiac arrhythmia that is uncontrolled or that requires medication recent transient ischemic attack or stroke (within 6 months) or residual dysfunction from stroke history of seizure disorder (part 1 only) clinically significant pulmonary disease (eg, fibrosis on chest x-ray or significant dyspnea as assessed by investigator) poorly controlled hypertension (systolic >140 millimeters of mercury (mm Hg) or diastolic >90 mm Hg) uncontrolled active infection within the past 7 days poorly controlled diabetes mellitus as assessed by investigator 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CEP-9722 Dose 1 QD<br>Participants will receive Dose 1 of CEP-9722 tablet once daily (QD) orally with a standard meal for up to 6 cycles of 28 days each. | Drug: CEP-9722<br>* CEP-9722 will be administered per dose and schedule specified in the arm description.<br>* Other names: poly ADP ribose polymerase Inhibitor;|
| Experimental: CEP-9722 Dose 1 BID<br>Participants will receive Dose 1 of CEP-9722 tablets twice daily (BID) orally with a standard meal for up to 6 cycles of 28 days each. | Drug: CEP-9722<br>* CEP-9722 will be administered per dose and schedule specified in the arm description.<br>* Other names: poly ADP ribose polymerase Inhibitor;|
| Experimental: CEP-9722 Dose 2 BID<br>Participants will receive Dose 2 of CEP-9722 tablets BID orally with a standard meal for up to 6 cycles of 28 days each. | Drug: CEP-9722<br>* CEP-9722 will be administered per dose and schedule specified in the arm description.<br>* Other names: poly ADP ribose polymerase Inhibitor;|
| Experimental: CEP-9722 Dose 3 BID<br>Participants will receive Dose 3 of CEP-9722 tablets BID orally with a standard meal for up to 6 cycles of 28 days each. | Drug: CEP-9722<br>* CEP-9722 will be administered per dose and schedule specified in the arm description.<br>* Other names: poly ADP ribose polymerase Inhibitor;|
| Experimental: CEP-9722 Dose 4 BID<br>Participants will receive Dose 4 of CEP-9722 tablets BID orally with a standard meal for up to 6 cycles of 28 days each. | Drug: CEP-9722<br>* CEP-9722 will be administered per dose and schedule specified in the arm description.<br>* Other names: poly ADP ribose polymerase Inhibitor;|
| Experimental: CEP-9722 Dose 5 BID<br>Participants will receive Dose 5 of CEP-9722 tablets BID orally with a standard meal for up to 6 cycles of 28 days each. | Drug: CEP-9722<br>* CEP-9722 will be administered per dose and schedule specified in the arm description.<br>* Other names: poly ADP ribose polymerase Inhibitor;|
| Experimental: CEP-9722 Dose 6 BID<br>Participants will receive Dose 6 of CEP-9722 tablets BID orally with a standard meal for up to 6 cycles of 28 days each. | Drug: CEP-9722<br>* CEP-9722 will be administered per dose and schedule specified in the arm description.<br>* Other names: poly ADP ribose polymerase Inhibitor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Maximum Tolerated Dose (MTD) of Oral CEP-9722 |  | Cycle 1 (28 days) | 
| Part 2: Number of Participants with Adverse Events |  | Up to 8 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Maximum Observed Plasma Concentration (Cmax) of CEP-8983 (the Active Moiety of CEP-9722) |  | Predose (0 hour), 0.5, 1, 2, 3, 4, 6, 8, and 12 hours postdose on Days 1 and 15 of Cycle 1 | 
| 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) |  | Predose (0 hour), 0.5, 1, 2, 3, 4, 6, 8, and 12 hours postdose on Days 1 and 15 of Cycle 1 | 
| Poly adenosine diphosphate-ribose (PAR) Concentration in Peripheral Blood Monocyte or Mononuclear Cells of CEP-8983 (the Active Moiety of CEP-9722) |  | Predose (0 hour), 2 and 6 hours postdose on Days 1 and 15 of Cycle 1 | 
| Part 1: Overall Response Rate (ORR) - Percentage of Participants With the Best Tumor Response |  | From the start of the treatment until disease progression/recurrence (up to 168 days) | 
| Part 2: Change in QT Interval |  | Day 1 and Day 15, Cycle 1 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cancer, tumors, PARP