Brief Summary
The purpose of this study is to characterize the effects of 25 and 50 milligram per square meter (mg/m\^2) pevonedistat on the Fridericia corrected QT interval (QTcF) of the electrocardiogram (ECG).
Brief Title
A Study to Evaluate the Effects of Pevonedistat on the Corrected QT (QTc) Interval in Participants With Advanced Solid Tumors
Detailed Description
The drug being tested in this study is called pevonedistat. Pevonedistat in combination with standard of care will be used to treat participants who have advanced solid tumors. This study will assess the effects of pevonedistat on the QTc interval in participants with advanced solid tumors.
The study will enroll approximately 45 participants. The study will be conducted in two Parts: Part A and Part B. Part A will have a 2-way crossover design and will involve the collection of triplicate ECGs. In Part A, participants will be randomly assigned to one of the two treatment groups as follow:
* Pevonedistat 25 mg/m\^2 + Pevonedistat 50 mg/m\^2
* Pevonedistat 50 mg/m\^2 + Pevonedistat 25 mg/m\^2
Eligible participants from Part A will continue treatment in optional Part B with pevonedistat in combination with SoC, docetaxel or carboplatin plus paclitaxel. The investigator will decide which pevonedistat combination a participant will receive.
* Pevonedistat 25 mg/m\^2 + Docetaxel
* Pevonedistat 20 mg/m\^2 + Carboplatin + Paclitaxel
This multi-center trial will be conducted in the United States. The overall time to participate in this study is 9.6 months. Participants will make a final visit to the clinic 30 days after receiving their last dose of study drug for a follow-up assessment.
The study will enroll approximately 45 participants. The study will be conducted in two Parts: Part A and Part B. Part A will have a 2-way crossover design and will involve the collection of triplicate ECGs. In Part A, participants will be randomly assigned to one of the two treatment groups as follow:
* Pevonedistat 25 mg/m\^2 + Pevonedistat 50 mg/m\^2
* Pevonedistat 50 mg/m\^2 + Pevonedistat 25 mg/m\^2
Eligible participants from Part A will continue treatment in optional Part B with pevonedistat in combination with SoC, docetaxel or carboplatin plus paclitaxel. The investigator will decide which pevonedistat combination a participant will receive.
* Pevonedistat 25 mg/m\^2 + Docetaxel
* Pevonedistat 20 mg/m\^2 + Carboplatin + Paclitaxel
This multi-center trial will be conducted in the United States. The overall time to participate in this study is 9.6 months. Participants will make a final visit to the clinic 30 days after receiving their last dose of study drug for a follow-up assessment.
Completion Date
Completion Date Type
Actual
Conditions
Advanced Solid Neoplasm
Eligibility Criteria
Inclusion Criteria:
1. Participants must have a histologically or cytologically confirmed metastatic or locally advanced solid tumor(s) appropriate for treatment with one of the 2 combination therapies in Part B of this study, have progressed despite standard therapy, or for whom conventional therapy is not considered effective.
2. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
3. Expected survival longer than 3 months from enrollment in the study.
4. Recovered (that is, grade less than or equal to \[\<=\] 1 toxicity) from the reversible effects of prior anticancer therapy.
5. Suitable venous access for the study-required blood sampling (including pharmacokinetic \[PK\] sampling).
Exclusion Criteria:
1. Treatment with strong cytochrome P3A (CYP3A) inducers within 14 days before the first dose of pevonedistat. Participants must have no history of amiodarone use within 6 months before the first dose of pevonedistat nor require the use of these medications during the study.
2. Treatment with QT-prolonging drugs with a risk of causing torsades de pointes (TdP. Participants taking drugs with a possible or conditional risk of QT prolongation or drugs that are to be avoided by participants with congenital long QT syndrome may be considered if on a stable dose, pending discussion and agreement between the investigator and the sponsor.
3. History of Brugada syndrome, risk factors for TdP, or family history of long QT syndrome.
4. Implantable cardioverter defibrillator.
5. Cardiac pacemaker with heart rate (HR) set at a fixed rate and treatment with concomitant medication that may limit increase in HR in response to hypotension (example, high-dose beta blocker).
6. Known moderate to severe aortic stenosis, moderate to severe mitral stenosis, or other valvulopathy (ongoing).
7. Admission or evidence of illicit drug use, drug abuse, or alcohol abuse.
Entry Criteria for Continuation to Optional Part B:
After completing Part A of the study, participants may choose to enter the optional Part B of the study. To be eligible for the optional Part B, participants must have completed Part A and be reassessed to determine if they meet the entry criteria for optional Part B. Only participants who meet the following criteria may enter into Part B:
* ECOG performance status of 0 to 1.
* Absolute neutrophil count (ANC) greater than or equal to (\>=) 1500 per cubic millimeter (/mm\^3).
* Platelet count \>=100,000/mm\^3.
* Laboratory values for hemoglobin, total bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and serum creatinine or calculated/measured creatinine clearance.
* Diarrhea symptoms resolved to Grade 1 or better.
* QTc interval \<480 millisecond (msec).
* Computed tomography (CT) scan or magnetic resonance imaging (MRI) of the chest, abdomen, and pelvis within 28 days of Cycle 1 Day 1.
1. Participants must have a histologically or cytologically confirmed metastatic or locally advanced solid tumor(s) appropriate for treatment with one of the 2 combination therapies in Part B of this study, have progressed despite standard therapy, or for whom conventional therapy is not considered effective.
2. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
3. Expected survival longer than 3 months from enrollment in the study.
4. Recovered (that is, grade less than or equal to \[\<=\] 1 toxicity) from the reversible effects of prior anticancer therapy.
5. Suitable venous access for the study-required blood sampling (including pharmacokinetic \[PK\] sampling).
Exclusion Criteria:
1. Treatment with strong cytochrome P3A (CYP3A) inducers within 14 days before the first dose of pevonedistat. Participants must have no history of amiodarone use within 6 months before the first dose of pevonedistat nor require the use of these medications during the study.
2. Treatment with QT-prolonging drugs with a risk of causing torsades de pointes (TdP. Participants taking drugs with a possible or conditional risk of QT prolongation or drugs that are to be avoided by participants with congenital long QT syndrome may be considered if on a stable dose, pending discussion and agreement between the investigator and the sponsor.
3. History of Brugada syndrome, risk factors for TdP, or family history of long QT syndrome.
4. Implantable cardioverter defibrillator.
5. Cardiac pacemaker with heart rate (HR) set at a fixed rate and treatment with concomitant medication that may limit increase in HR in response to hypotension (example, high-dose beta blocker).
6. Known moderate to severe aortic stenosis, moderate to severe mitral stenosis, or other valvulopathy (ongoing).
7. Admission or evidence of illicit drug use, drug abuse, or alcohol abuse.
Entry Criteria for Continuation to Optional Part B:
After completing Part A of the study, participants may choose to enter the optional Part B of the study. To be eligible for the optional Part B, participants must have completed Part A and be reassessed to determine if they meet the entry criteria for optional Part B. Only participants who meet the following criteria may enter into Part B:
* ECOG performance status of 0 to 1.
* Absolute neutrophil count (ANC) greater than or equal to (\>=) 1500 per cubic millimeter (/mm\^3).
* Platelet count \>=100,000/mm\^3.
* Laboratory values for hemoglobin, total bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and serum creatinine or calculated/measured creatinine clearance.
* Diarrhea symptoms resolved to Grade 1 or better.
* QTc interval \<480 millisecond (msec).
* Computed tomography (CT) scan or magnetic resonance imaging (MRI) of the chest, abdomen, and pelvis within 28 days of Cycle 1 Day 1.
Inclusion Criteria
Inclusion Criteria:
1. Participants must have a histologically or cytologically confirmed metastatic or locally advanced solid tumor(s) appropriate for treatment with one of the 2 combination therapies in Part B of this study, have progressed despite standard therapy, or for whom conventional therapy is not considered effective.
2. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
3. Expected survival longer than 3 months from enrollment in the study.
4. Recovered (that is, grade less than or equal to \[\<=\] 1 toxicity) from the reversible effects of prior anticancer therapy.
5. Suitable venous access for the study-required blood sampling (including pharmacokinetic \[PK\] sampling).
1. Participants must have a histologically or cytologically confirmed metastatic or locally advanced solid tumor(s) appropriate for treatment with one of the 2 combination therapies in Part B of this study, have progressed despite standard therapy, or for whom conventional therapy is not considered effective.
2. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
3. Expected survival longer than 3 months from enrollment in the study.
4. Recovered (that is, grade less than or equal to \[\<=\] 1 toxicity) from the reversible effects of prior anticancer therapy.
5. Suitable venous access for the study-required blood sampling (including pharmacokinetic \[PK\] sampling).
Gender
All
Gender Based
false
Keywords
Drug therapy
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Minimum Age
18 Years
NCT Id
NCT03330106
Org Class
Industry
Org Full Name
Takeda
Org Study Id
Pevonedistat-1014
Overall Status
Completed
Phases
Phase 1
Primary Completion Date
Primary Completion Date Type
Actual
Official Title
A Randomized, Crossover Phase 1 Study to Evaluate the Effects of Pevonedistat on the QTc Interval in Patients With Advanced Solid Tumors
Primary Outcomes
Outcome Description
Change from time-matched baseline in QTcF was assessed following a single intravenous dose administration of pevonedistat at 25 and 50 mg/m\^2 and was analysed by dose. Some participants were treated with pevonedistat 25 mg/m\^2 or 50 mg/m\^2 on Day 1 while others received treatment on Day 8. Data is reported at pre-dose and at multiple timepoints (1, 2, 3, 4, 6, 9, 11 and 24 hours) postdose up to Day 8 in Part A. Analysis of variance (ANOVA) was used for the analysis.
Outcome Measure
Part A: Change From Time-matched Baseline in Fridericia-corrected QT Interval (QTcF) After Pevonedistat Administration
Outcome Time Frame
Baseline up to Day 8
Secondary Ids
Secondary Id
2017-002610-31
Secondary Id
U1111-1201-10111
Secondary Outcomes
Outcome Description
Change from time-matched baseline in QTcI was assessed following a single intravenous dose administration of pevonedistat at 25 and 50 mg/m\^2 and was analysed by dose. Some participants were treated with pevonedistat 25 mg/m\^2 or 50 mg/m\^2 on Day 1 while others received treatment on Day 8. ANOVA was used for the analysis.
Outcome Time Frame
Predose, and at multiple time points up to 24 hours post dose on Day 1 or Day 8 in Part A
Outcome Measure
Part A: Change From Time-matched Baseline in Individual Corrected QT Interval (QTcI) After Pevonedistat Administration
Outcome Description
Change from time-matched baseline in QRS was assessed following a single intravenous dose administration of pevonedistat at 25 and 50 mg/m\^2 and was analysed by dose. Some participants were treated with pevonedistat 25 mg/m\^2 or 50 mg/m\^2 on Day 1 while others received treatment on Day 8. ANOVA was used for the analysis.
Outcome Time Frame
Predose, and at multiple time points post dose up to 24 hours on Day 1 or Day 8 in Part A
Outcome Measure
Part A: Change From Time-matched Baseline in QRS After Pevonedistat Administration
Outcome Description
Change from time-matched baseline in PR was assessed following a single intravenous dose administration of pevonedistat at 25 and 50 mg/m\^2 and was analysed by dose. Some participants were treated with pevonedistat 25 mg/m\^2 or 50 mg/m\^2 on Day 1 while others received treatment on Day 8. ANOVA was used for the analysis.
Outcome Time Frame
Predose, and at multiple time points post dose up to 24 hours on Day 1 or Day 8 in Part A
Outcome Measure
Part A: Change From Time-matched Baseline in PR After Pevonedistat Administration
Outcome Description
Change from time-matched baseline in HR was assessed following a single intravenous dose administration of pevonedistat at 25 and 50 mg/m\^2 and was analysed by dose. Some participants were treated with pevonedistat 25 mg/m\^2 or 50 mg/m\^2 on Day 1 while others received treatment on Day 8. ANOVA was used for the analysis.
Outcome Time Frame
Predose, and at multiple time points post dose up to 24 hours on Day 1 or Day 8 in Part A
Outcome Measure
Part A: Change From Time-matched Baseline in Heart Rate (HR) After Pevonedistat Administration
Outcome Time Frame
Days 1 or 8 predose and at multiple time points (up to 24 hours) post dose in Part A
Outcome Measure
Part A: Cmax: Maximum Observed Plasma Concentration for Pevonedistat
Outcome Time Frame
Days 1 or 8 predose and at multiple time points (up to 24 hours) post dose in Part A
Outcome Measure
Part A: AUC(0-24): Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours Postdose for Pevonedistat
Outcome Time Frame
Days 1 or 8 predose and at multiple time points (up to 24 hours) post dose in Part A
Outcome Measure
Part A: Terminal Phase Elimination Half-life (t1/2) for Pevonedistat
Outcome Description
Percentage of participants who achieve an overall response per investigator's assessment at end of treatment,according to Response Evaluation Criteria in Solid Tumor(RECIST),version 1.1 guideline. Complete response(CR):Disappearance of all target lesions.Any pathological lymph nodes(whether target and non target)must have reduction in short axis to \<10 millimeter(mm).Partial Response(PR):atleast 30% decrease in sum of diameter of target lesions,taking as reference baseline sum of diameter.Stable Disease(SD):Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression(PD),taking as reference smallest sum of diameter; PD:atleast 20% increase in sum of diameter of target lesions,taking as reference,smallest sum on study(this includes baseline sum if that is smallest on study).In addition to relative increase of 20%,sum must also demonstrate an absolute increase of atleast 5 mm.Appearance of 1 or more new lesions is also considered progression.
Outcome Time Frame
Up to Cycle 45 (end of treatment) (Cycle length=21 days)
Outcome Measure
Part B: Overall Response Rate (ORR)
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Actual
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
Sanjay Goel
Investigator Email
sgoel@montefiore.org
Investigator Phone
718-405-8404
MeSH Terms
PEVONEDISTAT
DOCETAXEL
CARBOPLATIN
PACLITAXEL
TAXOIDS
CYCLODECANES
CYCLOPARAFFINS
HYDROCARBONS, ALICYCLIC
HYDROCARBONS, CYCLIC
HYDROCARBONS
ORGANIC CHEMICALS
DITERPENES
TERPENES
COORDINATION COMPLEXES