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

Phase 1

Terminated

Conditions: Solid Tumors

Interventions: Drug: CEP-9722

Registration Number: NCT01311713

Lead Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 45

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
CEP-9722 Dose 2 BID	CEP-9722	Participants will receive Dose 2 of CEP-9722 tablets BID orally with a standard meal for up to 6 cycles of 28 days each.
CEP-9722 Dose 3 BID	CEP-9722	Participants will receive Dose 3 of CEP-9722 tablets BID orally with a standard meal for up to 6 cycles of 28 days each.
CEP-9722 Dose 4 BID	CEP-9722	Participants will receive Dose 4 of CEP-9722 tablets BID orally with a standard meal for up to 6 cycles of 28 days each.
CEP-9722 Dose 5 BID	CEP-9722	Participants will receive Dose 5 of CEP-9722 tablets BID orally with a standard meal for up to 6 cycles of 28 days each.
CEP-9722 Dose 6 BID	CEP-9722	Participants will receive Dose 6 of CEP-9722 tablets BID orally with a standard meal for up to 6 cycles of 28 days each.
CEP-9722 Dose 1 QD	CEP-9722	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.
CEP-9722 Dose 1 BID	CEP-9722	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.

Primary Outcome Measures

Name	Time	Method
Part 1: Maximum Tolerated Dose (MTD) of Oral CEP-9722	Cycle 1 (28 days)	MTD was defined as the highest dose level with 0 or 1 participant experiencing a dose-limiting toxicity (DLT) during cycle 1. DLT was defined as any adverse event (AE) that was considered by the investigator as related or potentially related to CEP-9722 as follows: 1) hematologic: grade 4 hematologic adverse events, grade 3 or greater febrile neutropenia, grade 3 thrombocytopenia lasting 7 days or more, grade 3 thrombocytopenia with bleeding; 2) nonhematologic: grade 3 or 4 nonhematologic AEs; grade 4 vomiting or diarrhea; grade 3 nausea, vomiting, or diarrhea that persisted for 48 hours or more despite optimal medical intervention; QTcF (QTc by Fridericia's cube root formula) greater than 500 milliseconds (msec) (confirmed by a repeat measurement on the same visit). During Cycle 1 of Part 1, any toxicity possibly related to treatment with CEP-9722 that caused a cumulative interruption of dosing for 7 or more days was considered dose limiting.
Part 2: Number of Participants With Adverse Events	Up to 8 months	An AE was defined as any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAEs were defined as death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized participant and required medical intervention to prevent 1 of the outcomes listed in this definition. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.

Secondary Outcome Measures

Name	Time	Method
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)	ORR was assessed by the best tumor response (complete response \[CR\], partial response \[PR\], stable disease \[SD\], and progressive disease \[PD\]) during the study using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). CR: Disappearance of all target and non-target lesions. PR: At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started. PD: At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of 1 or more new lesions and/or unequivocal progression of existing nontarget lesions.
Part 2: Change in QT Interval	Day 1 and Day 15, Cycle 1

Trial Locations

Locations (4): Teva Investigational Site 4
🇺🇸
Saint Louis, Missouri, United States
Teva Investigational Site 1
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Aurora, Colorado, United States
Teva Investigational Site 2
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Philadelphia, Pennsylvania, United States
Teva Investigational Site 3
🇺🇸
Detroit, Michigan, United States