A Study of [14 C]-Pevonedistat in Participants With Advanced Solid Tumors

Conditions

Advanced Solid Tumors, Neoplasms, Advanced Solid

Keywords

Drug therapy

Brief summary

The purpose of this study is to assess the mass balance (that is, cumulative excretion of total radioactivity \[TRA\] in urine and feces) and to characterize the pharmacokinetics (PK) of pevonedistat in whole blood, plasma, and urine, and of TRA in plasma and whole blood following a single 1-hour infusion of 25 milligram per square meter (mg/m\^2) \[14C\]-pevonedistat intravenous (IV) solution containing approximately 60 to 85 microcurie (mCi) (approximately 2.22-3.145 megabecquerel \[MBq\]) of TRA in participants with advanced solid tumors in Part A.

Detailed description

The drug being tested in this study is called Pevonedistat. Pevonedistat is being tested to treat people with advanced solid tumors. The study will enroll approximately 4 to 6 pharmacokinetics (PK)-evaluable participants in part A. After completion of the mass balance and absorption, distribution, metabolism, excretion (ADME) assessment in Part A of the study, eligible participants will have the opportunity to continue into Part B at a secondary study site, which would begin in approximately 2 weeks of completion of Part A. * \[14C\]-Pevonedistat 25 mg/m\^2 * Part B (optional): Pevonedistat in combination with chemotherapy regimens (Pevonedistat 25 mg/m\^2 + docetaxel 75 mg/m\^2 or pevonedistat 20 mg/m\^2 + carboplatin 20 mg/m\^2 + paclitaxel 175 mg/m\^2) All participants will receive study drug via intravenous route. This multi-center trial will be conducted in Hungary. Participants will remain confined to the study site for 9 to 14 days in Part A. Participation in Part B is optional, participants will be re-evaluated for inclusion/exclusion criteria before administrating treatment. Participants will undergo treatment in Part B for a maximum of 12 cycles (21 days cycle each) and will include approximately 36 weeks for Part A and B combined. Participants will attend an end of study visit 30 days after the last dose of study drug in both Part A and B.

Xiaofei Zhou, Farhad Sedarati, Douglas V. Faller, Dan Zhao, Hélène M. Faessel et al. (10 authors)

Investigational New Drugs2020-10-2234 citations

10.1007/s10637-020-01017-x

Phase Ib study of pevonedistat, a NEDD8-activating enzyme inhibitor, in combination with docetaxel, carboplatin and paclitaxel, or gemcitabine, in patients with advanced solid tumors.

Lockhart AC, Bauer TM, Aggarwal C, Lee CB, Harvey RD, Cohen RB, Sedarati F, Nip TK, Faessel H, Dash AB, Dezube BJ, Faller DV, Dowlati A.

2018-05-2164 citations

10.1007/s10637-018-0610-0

Interventions

DRUGPevonedistat

Pevonedistat intravenous infusion.

DRUG[14C]-Pevonedistat

\[14C\]-Pevonedistat intravenous infusion.

DRUGDocetaxel

Docetaxel intravenous infusion.

DRUGCarboplatin

Carboplatin intravenous infusion.

DRUGPaclitaxel

Paclitaxel intravenous infusion.

Study design

Intervention model

SEQUENTIAL

Primary purpose

OTHER

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

No

Inclusion criteria

1. Have a histologically or cytologically confirmed metastatic or locally advanced and incurable solid tumor that is felt to be appropriate for treatment with one of the 2 chemotherapy regimens in Part B of this study (carboplatin+paclitaxel or docetaxel), or have progressed despite prior standard therapy, or for whom conventional therapy is not considered effective. The tumor must be radiographically or clinically evaluable and/or measurable. 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, less than or equal to \[\<=\] Grade 1 toxicity) from the effects of prior antineoplastic therapy.

Exclusion criteria

1. Has irregular defecation patterns (less than 1 defecation per 2 days or excessive diarrhea) and/or has a history of changes in bowel habits with daily routine or environment changes. 2. Prior treatment with radiation therapy involving greater than or equal to (\>=) 25% of the hematopoietically active bone marrow.

Design outcomes

Primary

Measure	Time frame
Part A: Renal Clearance (CLR) for Pevonedistat	Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose
Part A: Aefeces,14C: Cumulative Amount of [14C]-Pevonedistat Excreted in Feces up to the Last Sampling Interval	Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose
Part A: Aetotal,14C: Total Cumulative Excretion of [14C]-Pevonedistat From the Body	Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose
Part A: Aeurine: Cumulative Amount of Pevonedistat Dose Excreted in Urine at 144-168 Hours Post-dose	Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose
Part A: Feurine: Cumulative Percentage of Pevonedistat Dose Excreted in Urine at 144-168 Hours Post-dose	Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose
Part A: Cmax: Maximum Observed Plasma and Whole Blood Concentration for Pevonedistat	Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose
Part A: Tmax: Time to Reach the Maximum Plasma and Whole Blood Concentration (Cmax) for Pevonedistat	Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose
Part A: AUClast: Area Under the Plasma and Whole Blood Concentration-time Curve From Time 0 to Time of the Last Quantifiable Concentration for Pevonedistat	Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose
Part A: Cmax: Maximum Observed Plasma and Whole Blood TRA Concentration for [14C]-Pevonedistat Drug-related Material	Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose
Part A: Tmax: Time to Reach the Maximum Plasma and Whole Blood TRA Concentration (Cmax) for [14C]-Pevonedistat Drug-related Material	Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose
Part A: AUClast: Area Under the Plasma and Whole Blood TRA Concentration Curve From Time 0 to Time of the Last Quantifiable Concentration for [14C]-Pevonedistat Drug-related Material	Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose
Part A: Aeurine,14C: Cumulative Amount of [14C]-Pevonedistat Excreted in Urine up to the Last Sampling Interval	Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose

Secondary

Measure	Time frame	Description
Part A: Percent Distribution of Total Radioactivity (TRA) for Pevonedistat and Its Metabolites in Plasma, Urine and Feces	Up to 168 hours post-dose	—
Part B: Number of Participants With Best Overall Response as Per Investigator's Assessment	Up to Cycle 11 (Cycle length =21 days)	The best overall response was defined as the participants with best response among complete response (CR) or partial response (PR) or stable disease (SD), or progressive disease (PD). It was assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. CR: disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to less than (\<) 10 millimeter (mm). PR: at least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters as the best overall response after randomization. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study).
Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	Part A: From first dose of study drug in Part A up to Day 31; Part B: From first dose of study drug in Part B up to Cycle 11 Day 35 (Cycle length is equal to [=] 21 days)	—

Countries

Hungary

Participant flow

Recruitment details

Participants took part in the study at 1 investigative site in Hungary from 11 May 2017 to 05 November 2018.

Pre-assignment details

Participants with advanced solid tumors were enrolled in this two-part study to receive intravenous infusion of pevonedistat in Part A and pevonedistat in combination with chemotherapy in Part B (optional part). One participant from Part A consented for Part B but did not meet the eligibility criteria and never received study treatment in Part B.

Participants by arm

Arm	Count
[14C]-Pevonedistat 25 mg/m^2 \[14C\]-pevonedistat (containing approximately 60-98 mCi \[approximately 2.22-3.626 MBq\] of radioactive tracer), infusion, intravenously, single dose on Day 1 of Week 1 in Part A. Participants who completed Part A and provided consent for Part B continued treatment in Part B. Participants received pevonedistat 20 mg/m\^2, infusion, intravenously, single dose, on Days 1, 3 and 5 of each 21-days treatment cycle (up to 11 cycles), in combination with paclitaxel 175 mg/m\^2, infusion, intravenously along with carboplatin AUC5, infusion, intravenously, on Day 1 of each 21-days treatment cycle (up to 11 cycles); or pevonedistat 25 mg/m\^2, infusion, intravenously, single dose on Days 1, 3 and 5 of each 21-days treatment cycle (up to 11 cycles), in combination with docetaxel 75 mg/m\^2, infusion, intravenously, on Day 1 of each 21-days treatment cycle (up to 11 cycles). Pevonedistat was administered after the chemotherapies in Part B.	8
Total	8

Arm

Count

[14C]-Pevonedistat 25 mg/m^2

\[14C\]-pevonedistat (containing approximately 60-98 mCi \[approximately 2.22-3.626 MBq\] of radioactive tracer), infusion, intravenously, single dose on Day 1 of Week 1 in Part A. Participants who completed Part A and provided consent for Part B continued treatment in Part B. Participants received pevonedistat 20 mg/m\^2, infusion, intravenously, single dose, on Days 1, 3 and 5 of each 21-days treatment cycle (up to 11 cycles), in combination with paclitaxel 175 mg/m\^2, infusion, intravenously along with carboplatin AUC5, infusion, intravenously, on Day 1 of each 21-days treatment cycle (up to 11 cycles); or pevonedistat 25 mg/m\^2, infusion, intravenously, single dose on Days 1, 3 and 5 of each 21-days treatment cycle (up to 11 cycles), in combination with docetaxel 75 mg/m\^2, infusion, intravenously, on Day 1 of each 21-days treatment cycle (up to 11 cycles). Pevonedistat was administered after the chemotherapies in Part B.

8

Total

8

Baseline characteristics

Characteristic	[14C]-Pevonedistat 25 mg/m^2
Age, Continuous	61.8 years STANDARD_DEVIATION 13.22
Body Mass Index (BMI)	29.58 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 4.674
Body Surface Area (BSA)	1.943 square meter (m^2) STANDARD_DEVIATION 0.2195
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	8 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants
Height	165.9 centimeter (cm) STANDARD_DEVIATION 8.85
Race (NIH/OMB) American Indian or Alaska Native	0 Participants
Race (NIH/OMB) Asian	0 Participants
Race (NIH/OMB) Black or African American	0 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	8 Participants
Region of Enrollment Hungary	8 Participants
Sex: Female, Male Female	5 Participants
Sex: Female, Male Male	3 Participants
Weight	82.38 kilogram (kg) STANDARD_DEVIATION 15.777

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	1 / 8	1 / 5	1 / 2
other Total, other adverse events	4 / 8	5 / 5	2 / 2
serious Total, serious adverse events	1 / 8	2 / 5	1 / 2