Advanced Solid Neoplasm
Conditions
Keywords
Drug therapy
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).
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.
Interventions
DRUGPevonedistat
Pevonedistat intravenous infusion.
DRUGDocetaxel
Docetaxel intravenous infusion.
DRUGCarboplatin
Carboplatin intravenous infusion.
DRUGPaclitaxel
Paclitaxel intravenous infusion.
Sponsors
Millennium Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part A: Change From Time-matched Baseline in Fridericia-corrected QT Interval (QTcF) After Pevonedistat Administration | Baseline up to Day 8 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part A: Change From Time-matched Baseline in QRS After Pevonedistat Administration | Predose, and at multiple time points post dose up to 24 hours on Day 1 or Day 8 in Part A | 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. |
| Part A: Change From Time-matched Baseline in PR After Pevonedistat Administration | Predose, and at multiple time points post dose up to 24 hours on Day 1 or Day 8 in Part A | 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. |
| Part A: Change From Time-matched Baseline in Heart Rate (HR) After Pevonedistat Administration | Predose, and at multiple time points post dose up to 24 hours on Day 1 or Day 8 in Part A | 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. |
| Part A: Change From Time-matched Baseline in Individual Corrected QT Interval (QTcI) After Pevonedistat Administration | Predose, and at multiple time points up to 24 hours post dose on Day 1 or Day 8 in Part A | 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. |
| Part A: AUC(0-24): Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours Postdose for Pevonedistat | Days 1 or 8 predose and at multiple time points (up to 24 hours) post dose in Part A | — |
| Part A: Terminal Phase Elimination Half-life (t1/2) for Pevonedistat | Days 1 or 8 predose and at multiple time points (up to 24 hours) post dose in Part A | — |
| Part B: Overall Response Rate (ORR) | Up to Cycle 45 (end of treatment) (Cycle length=21 days) | 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. |
| Part A: Cmax: Maximum Observed Plasma Concentration for Pevonedistat | Days 1 or 8 predose and at multiple time points (up to 24 hours) post dose in Part A | — |
Countries
United States
Participant flow
Recruitment details
A total of 44 participants took part in this study at 8 investigative sites in the United States from 15 November 2017 to 21 June 2021.
Pre-assignment details
Participants with histologically or cytologically confirmed metastatic or locally advanced solid tumor were enrolled in this 2-part study to receive intravenous infusion of pevonedistat in Part A and pevonedistat in combination with chemotherapy agents in Part B (optional part). After completion of Part A, participants had an opportunity to continue into optional Part B.
Participants by arm
| Arm | Count |
|---|---|
| Part A: Pevonedistat 25 mg/m^2 + Pevonedistat 50 mg/m^2 Pevonedistat 25 mg/m\^2, infusion, intravenously (IV), once on Day 1, followed by pevonedistat 50 mg/m\^2, infusion, IV, once on Day 8 in Part A. | 22 |
| Part A: Pevonedistat 50 mg/m^2 + Pevonedistat 25 mg/m^2 Pevonedistat 50 mg/m\^2, infusion, IV, once on Day 1, followed by pevonedistat 25 mg/m\^2, infusion, IV, once on Day 8 in Part A. | 22 |
| Total | 44 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Part A | Adverse Event | 0 | 1 | 0 | 0 |
| Part A | Death | 2 | 1 | 0 | 0 |
| Part A | Progressive Disease | 0 | 1 | 0 | 0 |
| Part A | Subjects Outside Eligibility Window for Part B due to Serious Adverse Event (SAE) | 0 | 1 | 0 | 0 |
| Part A | Withdrawal by Subject | 1 | 1 | 0 | 0 |
| Part A | Worsening Creatinine Clearance and Thrombocytopenia | 1 | 0 | 0 | 0 |
| Part B | Clinical Progression | 0 | 0 | 1 | 1 |
| Part B | Death | 0 | 0 | 2 | 0 |
| Part B | Lost to Follow-up | 0 | 0 | 0 | 1 |
| Part B | Progressive Disease | 0 | 0 | 11 | 4 |
| Part B | Symptomatic Deterioration | 0 | 0 | 0 | 1 |
| Part B | Symptomatic Deterioration, Participant Placed on Hospice | 0 | 0 | 0 | 1 |
| Part B | Withdrawal by Subject | 0 | 0 | 4 | 0 |
Baseline characteristics
| Characteristic | Part A: Pevonedistat 25 mg/m^2 + Pevonedistat 50 mg/m^2 | Total | Part A: Pevonedistat 50 mg/m^2 + Pevonedistat 25 mg/m^2 |
|---|---|---|---|
| Age, Continuous | 61.1 years STANDARD_DEVIATION 9.15 | 60.3 years STANDARD_DEVIATION 10.23 | 59.5 years STANDARD_DEVIATION 11.36 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 9 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 17 Participants | 35 Participants | 18 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) White | 16 Participants | 33 Participants | 17 Participants |
| Region of Enrollment United States | 22 Participants | 44 Participants | 22 Participants |
| Sex: Female, Male Female | 13 Participants | 31 Participants | 18 Participants |
| Sex: Female, Male Male | 9 Participants | 13 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 22 | 4 / 22 | 2 / 23 | 0 / 12 |
| other Total, other adverse events | 13 / 22 | 17 / 22 | 23 / 23 | 12 / 12 |
| serious Total, serious adverse events | 3 / 22 | 5 / 22 | 13 / 23 | 5 / 12 |
Outcome results
Primary
Part A: Change From Time-matched Baseline in Fridericia-corrected QT Interval (QTcF) After Pevonedistat Administration
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.
Time frame: Baseline up to Day 8
Population: QT Population included all participants who received the protocol-specified pevonedistat dosing and had sufficient electrocardiogram (ECG) assessments in the Baseline period (Day -1) and at least one period of assessment of effect of pevonedistat (Day 1 or Day 8) to permit reliable analysis. Overall number analyzed are the number of participants with evaluable data for analyses by dose. Number analyzed is the number of participants with data available for analysis at the given time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Pevonedistat 25 mg/m^2 | Part A: Change From Time-matched Baseline in Fridericia-corrected QT Interval (QTcF) After Pevonedistat Administration | 1 Hour Postdose | 3.180 milliseconds |
| Pevonedistat 25 mg/m^2 | Part A: Change From Time-matched Baseline in Fridericia-corrected QT Interval (QTcF) After Pevonedistat Administration | 6 Hours Postdose | 0.598 milliseconds |
| Pevonedistat 25 mg/m^2 | Part A: Change From Time-matched Baseline in Fridericia-corrected QT Interval (QTcF) After Pevonedistat Administration | 3 Hours Postdose | 1.754 milliseconds |
| Pevonedistat 25 mg/m^2 | Part A: Change From Time-matched Baseline in Fridericia-corrected QT Interval (QTcF) After Pevonedistat Administration | 9 Hours Postdose | -2.998 milliseconds |
| Pevonedistat 25 mg/m^2 | Part A: Change From Time-matched Baseline in Fridericia-corrected QT Interval (QTcF) After Pevonedistat Administration | 2 Hours Postdose | 0.840 milliseconds |
| Pevonedistat 25 mg/m^2 | Part A: Change From Time-matched Baseline in Fridericia-corrected QT Interval (QTcF) After Pevonedistat Administration | 11 Hours Postdose | -2.478 milliseconds |
| Pevonedistat 25 mg/m^2 | Part A: Change From Time-matched Baseline in Fridericia-corrected QT Interval (QTcF) After Pevonedistat Administration | 4 Hours Postdose | 2.567 milliseconds |
| Pevonedistat 25 mg/m^2 | Part A: Change From Time-matched Baseline in Fridericia-corrected QT Interval (QTcF) After Pevonedistat Administration | 24 Hours Postdose | -2.930 milliseconds |
| Pevonedistat 25 mg/m^2 | Part A: Change From Time-matched Baseline in Fridericia-corrected QT Interval (QTcF) After Pevonedistat Administration | Predose | 1.310 milliseconds |
| Pevonedistat 50 mg/m^2 | Part A: Change From Time-matched Baseline in Fridericia-corrected QT Interval (QTcF) After Pevonedistat Administration | 24 Hours Postdose | -7.653 milliseconds |
| Pevonedistat 50 mg/m^2 | Part A: Change From Time-matched Baseline in Fridericia-corrected QT Interval (QTcF) After Pevonedistat Administration | Predose | -2.231 milliseconds |
| Pevonedistat 50 mg/m^2 | Part A: Change From Time-matched Baseline in Fridericia-corrected QT Interval (QTcF) After Pevonedistat Administration | 1 Hour Postdose | -0.639 milliseconds |
| Pevonedistat 50 mg/m^2 | Part A: Change From Time-matched Baseline in Fridericia-corrected QT Interval (QTcF) After Pevonedistat Administration | 2 Hours Postdose | -2.127 milliseconds |
| Pevonedistat 50 mg/m^2 | Part A: Change From Time-matched Baseline in Fridericia-corrected QT Interval (QTcF) After Pevonedistat Administration | 3 Hours Postdose | -1.184 milliseconds |
| Pevonedistat 50 mg/m^2 | Part A: Change From Time-matched Baseline in Fridericia-corrected QT Interval (QTcF) After Pevonedistat Administration | 4 Hours Postdose | -1.127 milliseconds |
| Pevonedistat 50 mg/m^2 | Part A: Change From Time-matched Baseline in Fridericia-corrected QT Interval (QTcF) After Pevonedistat Administration | 6 Hours Postdose | -3.465 milliseconds |
| Pevonedistat 50 mg/m^2 | Part A: Change From Time-matched Baseline in Fridericia-corrected QT Interval (QTcF) After Pevonedistat Administration | 9 Hours Postdose | -6.898 milliseconds |
| Pevonedistat 50 mg/m^2 | Part A: Change From Time-matched Baseline in Fridericia-corrected QT Interval (QTcF) After Pevonedistat Administration | 11 Hours Postdose | -8.638 milliseconds |
Secondary
Part A: AUC(0-24): Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours Postdose for Pevonedistat
Time frame: Days 1 or 8 predose and at multiple time points (up to 24 hours) post dose in Part A
Population: PK Population included all participants who received the protocol-specified pevonedistat dosing during Part A and had sufficient PK assessments to permit reliable estimation of PK parameters. Overall number analyzed are the number of participants with evaluable data for analyses by dose.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Pevonedistat 25 mg/m^2 | Part A: AUC(0-24): Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours Postdose for Pevonedistat | 1190 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 22 |
| Pevonedistat 50 mg/m^2 | Part A: AUC(0-24): Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours Postdose for Pevonedistat | 2510 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 25.2 |
Secondary
Part A: Change From Time-matched Baseline in Heart Rate (HR) After Pevonedistat Administration
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.
Time frame: Predose, and at multiple time points post dose up to 24 hours on Day 1 or Day 8 in Part A
Population: QT Population included all participants who received the protocol-specified pevonedistat dosing and had sufficient ECG assessments in the Baseline period (Day -1) and at least one period of assessment of effect of pevonedistat (Day 1 or Day 8) to permit reliable analysis. Overall number analyzed are the number of participants with evaluable data for analyses by dose. Number analyzed is the number of participants with data available for analysis at the given time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Pevonedistat 25 mg/m^2 | Part A: Change From Time-matched Baseline in Heart Rate (HR) After Pevonedistat Administration | 1 Hour Postdose | -2.068 beats per minute (bpm) |
| Pevonedistat 25 mg/m^2 | Part A: Change From Time-matched Baseline in Heart Rate (HR) After Pevonedistat Administration | 6 Hours Postdose | 2.712 beats per minute (bpm) |
| Pevonedistat 25 mg/m^2 | Part A: Change From Time-matched Baseline in Heart Rate (HR) After Pevonedistat Administration | 3 Hours Postdose | -0.993 beats per minute (bpm) |
| Pevonedistat 25 mg/m^2 | Part A: Change From Time-matched Baseline in Heart Rate (HR) After Pevonedistat Administration | 9 Hours Postdose | 2.545 beats per minute (bpm) |
| Pevonedistat 25 mg/m^2 | Part A: Change From Time-matched Baseline in Heart Rate (HR) After Pevonedistat Administration | 2 Hours Postdose | -1.812 beats per minute (bpm) |
| Pevonedistat 25 mg/m^2 | Part A: Change From Time-matched Baseline in Heart Rate (HR) After Pevonedistat Administration | 11 Hours Postdose | 2.794 beats per minute (bpm) |
| Pevonedistat 25 mg/m^2 | Part A: Change From Time-matched Baseline in Heart Rate (HR) After Pevonedistat Administration | 4 Hours Postdose | -0.279 beats per minute (bpm) |
| Pevonedistat 25 mg/m^2 | Part A: Change From Time-matched Baseline in Heart Rate (HR) After Pevonedistat Administration | 24 Hours Postdose | 4.432 beats per minute (bpm) |
| Pevonedistat 25 mg/m^2 | Part A: Change From Time-matched Baseline in Heart Rate (HR) After Pevonedistat Administration | Predose | 0.602 beats per minute (bpm) |
| Pevonedistat 50 mg/m^2 | Part A: Change From Time-matched Baseline in Heart Rate (HR) After Pevonedistat Administration | 24 Hours Postdose | 7.609 beats per minute (bpm) |
| Pevonedistat 50 mg/m^2 | Part A: Change From Time-matched Baseline in Heart Rate (HR) After Pevonedistat Administration | Predose | 0.981 beats per minute (bpm) |
| Pevonedistat 50 mg/m^2 | Part A: Change From Time-matched Baseline in Heart Rate (HR) After Pevonedistat Administration | 1 Hour Postdose | -1.595 beats per minute (bpm) |
| Pevonedistat 50 mg/m^2 | Part A: Change From Time-matched Baseline in Heart Rate (HR) After Pevonedistat Administration | 2 Hours Postdose | -0.556 beats per minute (bpm) |
| Pevonedistat 50 mg/m^2 | Part A: Change From Time-matched Baseline in Heart Rate (HR) After Pevonedistat Administration | 3 Hours Postdose | 1.929 beats per minute (bpm) |
| Pevonedistat 50 mg/m^2 | Part A: Change From Time-matched Baseline in Heart Rate (HR) After Pevonedistat Administration | 4 Hours Postdose | 2.736 beats per minute (bpm) |
| Pevonedistat 50 mg/m^2 | Part A: Change From Time-matched Baseline in Heart Rate (HR) After Pevonedistat Administration | 6 Hours Postdose | 6.411 beats per minute (bpm) |
| Pevonedistat 50 mg/m^2 | Part A: Change From Time-matched Baseline in Heart Rate (HR) After Pevonedistat Administration | 9 Hours Postdose | 7.134 beats per minute (bpm) |
| Pevonedistat 50 mg/m^2 | Part A: Change From Time-matched Baseline in Heart Rate (HR) After Pevonedistat Administration | 11 Hours Postdose | 7.511 beats per minute (bpm) |
Secondary
Part A: Change From Time-matched Baseline in Individual Corrected QT Interval (QTcI) After Pevonedistat Administration
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.
Time frame: Predose, and at multiple time points up to 24 hours post dose on Day 1 or Day 8 in Part A
Population: QT Population included all participants who received the protocol-specified pevonedistat dosing and had sufficient ECG assessments in the Baseline period (Day -1) and at least one period of assessment of effect of pevonedistat (Day 1 or Day 8) to permit reliable analysis. Overall number analyzed are the number of participants with evaluable data for analyses by dose. Number analyzed is the number of participants with data available for analysis at the given time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Pevonedistat 25 mg/m^2 | Part A: Change From Time-matched Baseline in Individual Corrected QT Interval (QTcI) After Pevonedistat Administration | 1 Hour Postdose | 3.580 milliseconds |
| Pevonedistat 25 mg/m^2 | Part A: Change From Time-matched Baseline in Individual Corrected QT Interval (QTcI) After Pevonedistat Administration | 6 Hours Postdose | 2.143 milliseconds |
| Pevonedistat 25 mg/m^2 | Part A: Change From Time-matched Baseline in Individual Corrected QT Interval (QTcI) After Pevonedistat Administration | 3 Hours Postdose | 3.074 milliseconds |
| Pevonedistat 25 mg/m^2 | Part A: Change From Time-matched Baseline in Individual Corrected QT Interval (QTcI) After Pevonedistat Administration | 9 Hours Postdose | -1.419 milliseconds |
| Pevonedistat 25 mg/m^2 | Part A: Change From Time-matched Baseline in Individual Corrected QT Interval (QTcI) After Pevonedistat Administration | 2 Hours Postdose | 1.477 milliseconds |
| Pevonedistat 25 mg/m^2 | Part A: Change From Time-matched Baseline in Individual Corrected QT Interval (QTcI) After Pevonedistat Administration | 11 Hours Postdose | 0.020 milliseconds |
| Pevonedistat 25 mg/m^2 | Part A: Change From Time-matched Baseline in Individual Corrected QT Interval (QTcI) After Pevonedistat Administration | 4 Hours Postdose | 3.816 milliseconds |
| Pevonedistat 25 mg/m^2 | Part A: Change From Time-matched Baseline in Individual Corrected QT Interval (QTcI) After Pevonedistat Administration | 24 Hours Postdose | -1.897 milliseconds |
| Pevonedistat 25 mg/m^2 | Part A: Change From Time-matched Baseline in Individual Corrected QT Interval (QTcI) After Pevonedistat Administration | Predose | 2.099 milliseconds |
| Pevonedistat 50 mg/m^2 | Part A: Change From Time-matched Baseline in Individual Corrected QT Interval (QTcI) After Pevonedistat Administration | 24 Hours Postdose | -3.105 milliseconds |
| Pevonedistat 50 mg/m^2 | Part A: Change From Time-matched Baseline in Individual Corrected QT Interval (QTcI) After Pevonedistat Administration | Predose | -1.884 milliseconds |
| Pevonedistat 50 mg/m^2 | Part A: Change From Time-matched Baseline in Individual Corrected QT Interval (QTcI) After Pevonedistat Administration | 1 Hour Postdose | -0.206 milliseconds |
| Pevonedistat 50 mg/m^2 | Part A: Change From Time-matched Baseline in Individual Corrected QT Interval (QTcI) After Pevonedistat Administration | 2 Hours Postdose | -0.099 milliseconds |
| Pevonedistat 50 mg/m^2 | Part A: Change From Time-matched Baseline in Individual Corrected QT Interval (QTcI) After Pevonedistat Administration | 3 Hours Postdose | 1.877 milliseconds |
| Pevonedistat 50 mg/m^2 | Part A: Change From Time-matched Baseline in Individual Corrected QT Interval (QTcI) After Pevonedistat Administration | 4 Hours Postdose | 1.305 milliseconds |
| Pevonedistat 50 mg/m^2 | Part A: Change From Time-matched Baseline in Individual Corrected QT Interval (QTcI) After Pevonedistat Administration | 6 Hours Postdose | 0.198 milliseconds |
| Pevonedistat 50 mg/m^2 | Part A: Change From Time-matched Baseline in Individual Corrected QT Interval (QTcI) After Pevonedistat Administration | 9 Hours Postdose | -2.482 milliseconds |
| Pevonedistat 50 mg/m^2 | Part A: Change From Time-matched Baseline in Individual Corrected QT Interval (QTcI) After Pevonedistat Administration | 11 Hours Postdose | -5.250 milliseconds |
Secondary
Part A: Change From Time-matched Baseline in PR After Pevonedistat Administration
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.
Time frame: Predose, and at multiple time points post dose up to 24 hours on Day 1 or Day 8 in Part A
Population: QT Population included all participants who received the protocol-specified pevonedistat dosing and had sufficient ECG assessments in the Baseline period (Day -1) and at least one period of assessment of effect of pevonedistat (Day 1 or Day 8) to permit reliable analysis. Overall number analyzed are the number of participants with evaluable data for analyses by dose. Number analyzed is the number of participants with data available for analysis at the given time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Pevonedistat 25 mg/m^2 | Part A: Change From Time-matched Baseline in PR After Pevonedistat Administration | 1 Hour Postdose | 1.152 milliseconds |
| Pevonedistat 25 mg/m^2 | Part A: Change From Time-matched Baseline in PR After Pevonedistat Administration | 6 Hours Postdose | -4.665 milliseconds |
| Pevonedistat 25 mg/m^2 | Part A: Change From Time-matched Baseline in PR After Pevonedistat Administration | 3 Hours Postdose | -1.557 milliseconds |
| Pevonedistat 25 mg/m^2 | Part A: Change From Time-matched Baseline in PR After Pevonedistat Administration | 9 Hours Postdose | -4.499 milliseconds |
| Pevonedistat 25 mg/m^2 | Part A: Change From Time-matched Baseline in PR After Pevonedistat Administration | 2 Hours Postdose | -0.090 milliseconds |
| Pevonedistat 25 mg/m^2 | Part A: Change From Time-matched Baseline in PR After Pevonedistat Administration | 11 Hours Postdose | -3.018 milliseconds |
| Pevonedistat 25 mg/m^2 | Part A: Change From Time-matched Baseline in PR After Pevonedistat Administration | 4 Hours Postdose | -3.406 milliseconds |
| Pevonedistat 25 mg/m^2 | Part A: Change From Time-matched Baseline in PR After Pevonedistat Administration | 24 Hours Postdose | -5.245 milliseconds |
| Pevonedistat 25 mg/m^2 | Part A: Change From Time-matched Baseline in PR After Pevonedistat Administration | Predose | -2.894 milliseconds |
| Pevonedistat 50 mg/m^2 | Part A: Change From Time-matched Baseline in PR After Pevonedistat Administration | 24 Hours Postdose | -6.499 milliseconds |
| Pevonedistat 50 mg/m^2 | Part A: Change From Time-matched Baseline in PR After Pevonedistat Administration | Predose | -1.220 milliseconds |
| Pevonedistat 50 mg/m^2 | Part A: Change From Time-matched Baseline in PR After Pevonedistat Administration | 1 Hour Postdose | 3.360 milliseconds |
| Pevonedistat 50 mg/m^2 | Part A: Change From Time-matched Baseline in PR After Pevonedistat Administration | 2 Hours Postdose | 1.514 milliseconds |
| Pevonedistat 50 mg/m^2 | Part A: Change From Time-matched Baseline in PR After Pevonedistat Administration | 3 Hours Postdose | -0.167 milliseconds |
| Pevonedistat 50 mg/m^2 | Part A: Change From Time-matched Baseline in PR After Pevonedistat Administration | 4 Hours Postdose | -1.802 milliseconds |
| Pevonedistat 50 mg/m^2 | Part A: Change From Time-matched Baseline in PR After Pevonedistat Administration | 6 Hours Postdose | -4.463 milliseconds |
| Pevonedistat 50 mg/m^2 | Part A: Change From Time-matched Baseline in PR After Pevonedistat Administration | 9 Hours Postdose | -3.608 milliseconds |
| Pevonedistat 50 mg/m^2 | Part A: Change From Time-matched Baseline in PR After Pevonedistat Administration | 11 Hours Postdose | -2.333 milliseconds |
Secondary
Part A: Change From Time-matched Baseline in QRS After Pevonedistat Administration
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.
Time frame: Predose, and at multiple time points post dose up to 24 hours on Day 1 or Day 8 in Part A
Population: QT Population included all participants who received the protocol-specified pevonedistat dosing and had sufficient ECG assessments in the Baseline period (Day -1) and at least one period of assessment of effect of pevonedistat (Day 1 or Day 8) to permit reliable analysis. Overall number analyzed are the number of participants with evaluable data for analyses by dose. Number analyzed is the number of participants with data available for analysis at the given time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Pevonedistat 25 mg/m^2 | Part A: Change From Time-matched Baseline in QRS After Pevonedistat Administration | 11 Hours Postdose | -0.551 milliseconds |
| Pevonedistat 25 mg/m^2 | Part A: Change From Time-matched Baseline in QRS After Pevonedistat Administration | Predose | -0.459 milliseconds |
| Pevonedistat 25 mg/m^2 | Part A: Change From Time-matched Baseline in QRS After Pevonedistat Administration | 1 Hour Postdose | 1.447 milliseconds |
| Pevonedistat 25 mg/m^2 | Part A: Change From Time-matched Baseline in QRS After Pevonedistat Administration | 2 Hours Postdose | -0.212 milliseconds |
| Pevonedistat 25 mg/m^2 | Part A: Change From Time-matched Baseline in QRS After Pevonedistat Administration | 3 Hours Postdose | 0.138 milliseconds |
| Pevonedistat 25 mg/m^2 | Part A: Change From Time-matched Baseline in QRS After Pevonedistat Administration | 4 Hours Postdose | -1.068 milliseconds |
| Pevonedistat 25 mg/m^2 | Part A: Change From Time-matched Baseline in QRS After Pevonedistat Administration | 6 Hours Postdose | -0.192 milliseconds |
| Pevonedistat 25 mg/m^2 | Part A: Change From Time-matched Baseline in QRS After Pevonedistat Administration | 9 Hours Postdose | -0.791 milliseconds |
| Pevonedistat 25 mg/m^2 | Part A: Change From Time-matched Baseline in QRS After Pevonedistat Administration | 24 Hours Postdose | -0.946 milliseconds |
| Pevonedistat 50 mg/m^2 | Part A: Change From Time-matched Baseline in QRS After Pevonedistat Administration | 9 Hours Postdose | -0.221 milliseconds |
| Pevonedistat 50 mg/m^2 | Part A: Change From Time-matched Baseline in QRS After Pevonedistat Administration | 4 Hours Postdose | -0.241 milliseconds |
| Pevonedistat 50 mg/m^2 | Part A: Change From Time-matched Baseline in QRS After Pevonedistat Administration | Predose | -0.482 milliseconds |
| Pevonedistat 50 mg/m^2 | Part A: Change From Time-matched Baseline in QRS After Pevonedistat Administration | 11 Hours Postdose | -0.769 milliseconds |
| Pevonedistat 50 mg/m^2 | Part A: Change From Time-matched Baseline in QRS After Pevonedistat Administration | 1 Hour Postdose | 0.850 milliseconds |
| Pevonedistat 50 mg/m^2 | Part A: Change From Time-matched Baseline in QRS After Pevonedistat Administration | 6 Hours Postdose | -0.319 milliseconds |
| Pevonedistat 50 mg/m^2 | Part A: Change From Time-matched Baseline in QRS After Pevonedistat Administration | 2 Hours Postdose | -0.043 milliseconds |
| Pevonedistat 50 mg/m^2 | Part A: Change From Time-matched Baseline in QRS After Pevonedistat Administration | 24 Hours Postdose | -0.470 milliseconds |
| Pevonedistat 50 mg/m^2 | Part A: Change From Time-matched Baseline in QRS After Pevonedistat Administration | 3 Hours Postdose | 0.184 milliseconds |
Secondary
Part A: Cmax: Maximum Observed Plasma Concentration for Pevonedistat
Time frame: Days 1 or 8 predose and at multiple time points (up to 24 hours) post dose in Part A
Population: Pharmacokinetic (PK) Population included all participants who received the protocol-specified pevonedistat dosing during Part A and had sufficient PK assessments to permit reliable estimation of PK parameters. Overall number analyzed are the number of participants with evaluable data for analyses by dose.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Pevonedistat 25 mg/m^2 | Part A: Cmax: Maximum Observed Plasma Concentration for Pevonedistat | 197 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 38.7 |
| Pevonedistat 50 mg/m^2 | Part A: Cmax: Maximum Observed Plasma Concentration for Pevonedistat | 509 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 35.6 |
Secondary
Part A: Terminal Phase Elimination Half-life (t1/2) for Pevonedistat
Time frame: Days 1 or 8 predose and at multiple time points (up to 24 hours) post dose in Part A
Population: PK Population included all participants who received the protocol-specified pevonedistat dosing during Part A and had sufficient PK assessments to permit reliable estimation of PK parameters. Overall number analyzed are the number of participants with evaluable data for analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pevonedistat 25 mg/m^2 | Part A: Terminal Phase Elimination Half-life (t1/2) for Pevonedistat | 7.21 hours (h) | Standard Deviation 1.35 |
| Pevonedistat 50 mg/m^2 | Part A: Terminal Phase Elimination Half-life (t1/2) for Pevonedistat | 6.73 hours (h) | Standard Deviation 1.15 |
Secondary
Part B: Overall Response Rate (ORR)
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.
Time frame: Up to Cycle 45 (end of treatment) (Cycle length=21 days)
Population: Disease-response population included participants who received at least 1 dose of study drug in Part B, had measurable disease as entry criteria for Part B, and had at least 1 postbaseline disease assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pevonedistat 25 mg/m^2 | Part B: Overall Response Rate (ORR) | 9.1 percentage of participants |
| Pevonedistat 50 mg/m^2 | Part B: Overall Response Rate (ORR) | 8.3 percentage of participants |