Advanced Solid Neoplasm
Conditions
Keywords
Drug therapy
Brief summary
The purpose of this study is to assess the effect of multiple-dose administration of rifampin on the single dose PK of pevonedistat in adult participants with advanced solid tumors.
Detailed description
The study will enroll approximately 20 participants. The study will be conducted in two Parts: Part A and optional Part B. Part A will have a drug-drug interaction (DDI) assessment. In Part A, participants will be assigned to: • Pevonedistat 50 mg/m\^2 + Rifampin Eligible participants from Part A will continue treatment in optional Part B with pevonedistat in combination with SoC chemotherapy, docetaxel or carboplatin plus paclitaxel. The investigator will decide which SoC combination partner 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 18 months. Participants will make a final visit to the clinic 30 days after receiving their last dose of study drug or before the start of subsequent therapy.
Interventions
DRUGPevonedistat
Pevonedistat intravenous infusion.
DRUGRifampin
Rifampin capsules.
DRUGDocetaxel
Docetaxel intravenous infusion.
DRUGCarboplatin
Carboplatin intravenous infusion.
DRUGPaclitaxel
Paclitaxel intravenous infusion.
Sponsors
Millennium Pharmaceuticals, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Adult participants who have a histologically or cytologically confirmed metastatic or locally advanced solid tumor that is appropriate for treatment with either docetaxel or carboplatin + paclitaxel in Part B of this study, or 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 of at least 3 months from the date of enrollment in the study. 4. Recovered (that is, less than or equal to (\<=) Grade 1 toxicity) from the effects of prior antineoplastic therapy. 5. Adequate organ functions (kidney, liver, cardiac, bone marrow). 6. Suitable venous access for the study-required blood sampling (including PK sampling).
Exclusion criteria
1. Prior treatment with radiation therapy involving greater than or equal to (\>=) 25% of the hematopoietically active bone marrow. 2. Life-threatening illness or serious (acute or chronic) medical or psychiatric illness unrelated to cancer. 3. Active, uncontrolled infection or severe infectious disease. 4. Known human immunodeficiency virus (HIV) seropositive or known hepatitis B or hepatitis C infection. 5. With significant heart or pulmonary disease. 6. Requiring chronic treatment with breast cancer resistance protein (BCRP) inhibitors. Criteria for Continuation into Optional Part B: To be eligible for Part B, participants must have completed Part A and be reassessed to determine if they meet the continuation criteria for Part B.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part A: Ratio of Maximum Observed Plasma Concentration (Cmax) for Pevonedistat Without Rifampin (Day 1) and With Rifampin (Day 10) | Days 1 and 10 pre-dose and at multiple time points (up to 48 hours) post-dose | The Least square (LS) means ratio of Day 10 over Day 1 were calculated from a mixed-model analysis of variance model. |
| Part A: Ratio of Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) for Pevonedistat Without Rifampin (Day 1) and With Rifampin (Day 10) | Days 1 and 10 pre-dose and at multiple time points (up to 48 hours) post-dose | The LS means ratio of Day 10 over Day 1 were calculated from a mixed-model analysis of variance model. |
| Part A: Ratio of Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC∞) for Pevonedistat Without Rifampin (Day 1) and With Rifampin (Day 10) | Days 1 and 10 pre-dose and at multiple time points (up to 48 hours) post-dose | The LS means ratio of Day 10 over Day 1 were calculated from a mixed-model analysis of variance model. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part A: Total Clearance After Intravenous Administration (CL) for Pevonedistat Without Rifampin (Day 1) and With Rifampin (Day 10) | Days 1 and 10 pre-dose and at multiple time points (up to 48 hours) post-dose | — |
| Part B: Number of Participants With Best Overall Response as Per Investigator's Assessment | Up to Cycle 17 (end of treatment) (Cycle length =21 days) | Best overall response was defined as participants with best response among complete response (CR) or partial response (PR) or stable disease (SD), or progressive disease (PD). It was assessed by investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. CR: disappearance of all target lesions. Any pathological lymph nodes (whether target and non-target) must have reduction in short axis to less than (\<) 10 millimeter (mm). PR: at least 30 percent (%) decrease in sum of diameter of target lesions, taking as reference baseline sum of diameter. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference smallest sum of diameter. PD: at least 20% increase in sum of diameter of target lesions, taking as reference, smallest sum on study. |
| Part A: Volume of Distribution at Steady State After Intravenous Administration (Vss) for Pevonedistat Without Rifampin (Day 1) and With Rifampin (Day 10) | Days 1 and 10 pre-dose and at multiple time points (up to 48 hours) post-dose | — |
| Part A: Terminal Disposition Phase Half-life (T1/2z) for Pevonedistat Without Rifampin (Day 1) and With Rifampin (Day 10) | Days 1 and 10 pre-dose and at multiple time points (up to 48 hours) post-dose | — |
Countries
United States
Participant flow
Recruitment details
Participants took part in the study at 4 investigative sites in the United States from 13 August 2018 to 28 February 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 along with rifampin capsule 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 50 mg/m^2 + Rifampin 600 mg Pevonedistat 50 mg/m\^2, infusion, intravenously, once on Days 1 and 10, and then rifampin 600 mg, capsule, orally, once daily from Day 3 up to Day 11 in Part A. Pevonedistat was not administered from Day 2 through Day 9. | 20 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Part A | Adverse Event | 1 | 0 | 0 |
| Part A | Symptomatic Deterioration | 2 | 0 | 0 |
Baseline characteristics
| Characteristic | Part A: Pevonedistat 50 mg/m^2 + Rifampin 600 mg |
|---|---|
| Age, Continuous | 64.9 years STANDARD_DEVIATION 8.7 |
| Body Surface Area (BSA) | 2.03 square meter (m^2) STANDARD_DEVIATION 0.307 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 20 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Height | 171.91 centimeter (cm) STANDARD_DEVIATION 10.235 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 15 Participants |
| Region of Enrollment United States | 20 Participants |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 10 Participants |
| Weight | 87.13 kilogram (kg) STANDARD_DEVIATION 22.667 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 20 | 0 / 9 | 1 / 8 |
| other Total, other adverse events | 11 / 20 | 9 / 9 | 8 / 8 |
| serious Total, serious adverse events | 3 / 20 | 3 / 9 | 4 / 8 |
Outcome results
Primary
Part A: Ratio of Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC∞) for Pevonedistat Without Rifampin (Day 1) and With Rifampin (Day 10)
The LS means ratio of Day 10 over Day 1 were calculated from a mixed-model analysis of variance model.
Time frame: Days 1 and 10 pre-dose and at multiple time points (up to 48 hours) post-dose
Population: The PK-evaluable population was defined as all enrolled participants who a) received the protocol specified single pevonedistat dose in Part A; b) did not receive any excluded medications throughout the completion of Part A; and c) had sufficient concentration-time data to permit reliable estimation of PK parameters. As planned, this outcome measure was only assessed in Part A. Here overall number of participants analyzed are those who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Part A: Pevonedistat 50 mg/m^2 + Rifampin 600 mg | Part A: Ratio of Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC∞) for Pevonedistat Without Rifampin (Day 1) and With Rifampin (Day 10) | 0.790 ratio |
Primary
Part A: Ratio of Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) for Pevonedistat Without Rifampin (Day 1) and With Rifampin (Day 10)
The LS means ratio of Day 10 over Day 1 were calculated from a mixed-model analysis of variance model.
Time frame: Days 1 and 10 pre-dose and at multiple time points (up to 48 hours) post-dose
Population: The PK-evaluable population was defined as all enrolled participants who a) received the protocol specified single pevonedistat dose in Part A; b) did not receive any excluded medications throughout the completion of Part A; and c) had sufficient concentration-time data to permit reliable estimation of PK parameters. As planned, this outcome measure was only assessed in Part A. Here overall number of participants analyzed are those who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Part A: Pevonedistat 50 mg/m^2 + Rifampin 600 mg | Part A: Ratio of Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) for Pevonedistat Without Rifampin (Day 1) and With Rifampin (Day 10) | 0.785 ratio |
Primary
Part A: Ratio of Maximum Observed Plasma Concentration (Cmax) for Pevonedistat Without Rifampin (Day 1) and With Rifampin (Day 10)
The Least square (LS) means ratio of Day 10 over Day 1 were calculated from a mixed-model analysis of variance model.
Time frame: Days 1 and 10 pre-dose and at multiple time points (up to 48 hours) post-dose
Population: The pharmacokinetic (PK) evaluable population was defined as all enrolled participants who a) received the protocol specified single pevonedistat dose in Part A; b) did not receive any excluded medications throughout the completion of Part A; and c) had sufficient concentration-time data to permit reliable estimation of PK parameters. As planned, this outcome measure was only assessed in Part A. Here overall number of participants analyzed are those who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Part A: Pevonedistat 50 mg/m^2 + Rifampin 600 mg | Part A: Ratio of Maximum Observed Plasma Concentration (Cmax) for Pevonedistat Without Rifampin (Day 1) and With Rifampin (Day 10) | 0.962 ratio |
Secondary
Part A: Terminal Disposition Phase Half-life (T1/2z) for Pevonedistat Without Rifampin (Day 1) and With Rifampin (Day 10)
Time frame: Days 1 and 10 pre-dose and at multiple time points (up to 48 hours) post-dose
Population: The PK-evaluable population was defined as all enrolled participants who a) received the protocol specified single pevonedistat dose in Part A; b) did not receive any excluded medications throughout the completion of Part A; and c) had sufficient concentration-time data to permit reliable estimation of PK parameters. As planned, this outcome measure was only assessed in Part A. Here number analyzed n signifies participants who were evaluable for this outcome measure at given time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Pevonedistat 50 mg/m^2 + Rifampin 600 mg | Part A: Terminal Disposition Phase Half-life (T1/2z) for Pevonedistat Without Rifampin (Day 1) and With Rifampin (Day 10) | Pevonedistat without rifampin (Day 1) | 7.442 hour | Standard Deviation 1.3846 |
| Part A: Pevonedistat 50 mg/m^2 + Rifampin 600 mg | Part A: Terminal Disposition Phase Half-life (T1/2z) for Pevonedistat Without Rifampin (Day 1) and With Rifampin (Day 10) | Pevonedistat with rifampin (Day 10) | 5.708 hour | Standard Deviation 1.3665 |
Secondary
Part A: Total Clearance After Intravenous Administration (CL) for Pevonedistat Without Rifampin (Day 1) and With Rifampin (Day 10)
Time frame: Days 1 and 10 pre-dose and at multiple time points (up to 48 hours) post-dose
Population: The PK-evaluable population was defined as all enrolled participants who a) received the protocol specified single pevonedistat dose in Part A; b) did not receive any excluded medications throughout the completion of Part A; and c) had sufficient concentration-time data to permit reliable estimation of PK parameters. As planned, this outcome measure was only assessed in Part A. Here number analyzed n signifies participants who were evaluable for this outcome measure at given time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Pevonedistat 50 mg/m^2 + Rifampin 600 mg | Part A: Total Clearance After Intravenous Administration (CL) for Pevonedistat Without Rifampin (Day 1) and With Rifampin (Day 10) | Pevonedistat without rifampin (Day 1) | 35.22 liter per hour (L/h) | Standard Deviation 10.98 |
| Part A: Pevonedistat 50 mg/m^2 + Rifampin 600 mg | Part A: Total Clearance After Intravenous Administration (CL) for Pevonedistat Without Rifampin (Day 1) and With Rifampin (Day 10) | Pevonedistat with rifampin (Day 10) | 43.77 liter per hour (L/h) | Standard Deviation 12.604 |
Secondary
Part A: Volume of Distribution at Steady State After Intravenous Administration (Vss) for Pevonedistat Without Rifampin (Day 1) and With Rifampin (Day 10)
Time frame: Days 1 and 10 pre-dose and at multiple time points (up to 48 hours) post-dose
Population: The PK-evaluable population was defined as all enrolled participants who a) received the protocol specified single pevonedistat dose in Part A; b) did not receive any excluded medications throughout the completion of Part A; and c) had sufficient concentration-time data to permit reliable estimation of PK parameters. As planned, this outcome measure was only assessed in Part A. Here number analyzed n signifies participants who were evaluable for this outcome measure at given time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Pevonedistat 50 mg/m^2 + Rifampin 600 mg | Part A: Volume of Distribution at Steady State After Intravenous Administration (Vss) for Pevonedistat Without Rifampin (Day 1) and With Rifampin (Day 10) | Pevonedistat without rifampin (Day 1) | 312.82 liter | Standard Deviation 144.495 |
| Part A: Pevonedistat 50 mg/m^2 + Rifampin 600 mg | Part A: Volume of Distribution at Steady State After Intravenous Administration (Vss) for Pevonedistat Without Rifampin (Day 1) and With Rifampin (Day 10) | Pevonedistat with rifampin (Day 10) | 296.10 liter | Standard Deviation 136.297 |
Secondary
Part B: Number of Participants With Best Overall Response as Per Investigator's Assessment
Best overall response was defined as participants with best response among complete response (CR) or partial response (PR) or stable disease (SD), or progressive disease (PD). It was assessed by investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. CR: disappearance of all target lesions. Any pathological lymph nodes (whether target and non-target) must have reduction in short axis to less than (\<) 10 millimeter (mm). PR: at least 30 percent (%) decrease in sum of diameter of target lesions, taking as reference baseline sum of diameter. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference smallest sum of diameter. PD: at least 20% increase in sum of diameter of target lesions, taking as reference, smallest sum on study.
Time frame: Up to Cycle 17 (end of treatment) (Cycle length =21 days)
Population: The response-evaluable population was defined as all 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. As planned, this outcome measure was only assessed in Part B.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: Pevonedistat 50 mg/m^2 + Rifampin 600 mg | Part B: Number of Participants With Best Overall Response as Per Investigator's Assessment | CR | 0 Participants |
| Part A: Pevonedistat 50 mg/m^2 + Rifampin 600 mg | Part B: Number of Participants With Best Overall Response as Per Investigator's Assessment | PR | 2 Participants |
| Part A: Pevonedistat 50 mg/m^2 + Rifampin 600 mg | Part B: Number of Participants With Best Overall Response as Per Investigator's Assessment | SD | 2 Participants |
| Part A: Pevonedistat 50 mg/m^2 + Rifampin 600 mg | Part B: Number of Participants With Best Overall Response as Per Investigator's Assessment | PD | 2 Participants |
| Part B: Pevonedistat 20 mg/m^2 + Carboplatin AUC5 + Paclitaxel 175 mg/m^2 | Part B: Number of Participants With Best Overall Response as Per Investigator's Assessment | PD | 3 Participants |
| Part B: Pevonedistat 20 mg/m^2 + Carboplatin AUC5 + Paclitaxel 175 mg/m^2 | Part B: Number of Participants With Best Overall Response as Per Investigator's Assessment | CR | 0 Participants |
| Part B: Pevonedistat 20 mg/m^2 + Carboplatin AUC5 + Paclitaxel 175 mg/m^2 | Part B: Number of Participants With Best Overall Response as Per Investigator's Assessment | SD | 3 Participants |
| Part B: Pevonedistat 20 mg/m^2 + Carboplatin AUC5 + Paclitaxel 175 mg/m^2 | Part B: Number of Participants With Best Overall Response as Per Investigator's Assessment | PR | 1 Participants |