Clinical trial NCT02828930: A Study to Determine the Excretion Balance, Pharmacokinetics, Metabolism and Absolute Oral Bioavailability of a Single Oral Dose of [14C]-Labeled Idasanutlin and an Intravenous Tracer Dose of [13C]-Labeled Idasanutlin in a Single Cohort of Participants With Solid Tumors (Malignancies)
Official title: A Single-Center, Open-Label Study Investigating the Excretion Balance, Pharmacokinetics, Metabolism, and Absolute Oral Bioavailability of a Single Oral Dose of [14C]-Labeled Idasanutlin and an Intravenous Tracer Dose of [13C]-Labeled Idasanutlin in a Single Cohort of Patients With Solid Tumors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Solid Tumors
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2016-07-12
Enrollment: 8
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this single-center, open-label, non-randomized study is to assess the excretion balance, pharmacokinetics, metabolism and absolute oral bioavailability of \[14C\]-labeled idasanutlin administered orally and \[13C\]-labeled idasanutlin administered intravenously in a single cohort of eligible participants. Participants will be screened for participation in this study within 21 days of receiving the first dose of study drug on Day 1. Treatment period will continue up to Day 28 after which participants will enter 28 day follow-up or the optional treatment extension of idasanutlin, depending on safety parameters and as per opinion of the Investigator.


Eligibility criteria: Inclusion Criteria:

* Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, at the discretion of the Investigator
* Histologically or cytologically confirmed advanced malignancy, except leukemia and lymphoma
* Measureable or evaluable disease by Response evaluation criteria in solid tumors (RECIST) version 1.1, with no more than a single active malignancy in the previous 3 to 5 years prior to the administration of study drug
* Life expectancy of at least 12 weeks
* Participants taking opioid analgesics for pain should be on a stable pain and palliative care bowel regimen for one month prior to the first dose of study medication
* Adequate bone marrow, hepatic, and renal function
* Agreement to remain abstinent or use contraceptive methods specified in the study

Exclusion Criteria:

* History of any form of leukemia, except for Stage 0 - 1 chronic lymphocytic leukemia, not requiring treatment in addition to their underlying malignancy
* Have received hormonal therapy within the two weeks prior to the first dose of study drug
* Have pre-existing gastrointestinal disorders that may interfere with proper absorption of the drug
* History of seizure disorders or unstable Central Nervous System metastases (participants with stable CNS metastases allowed)
* Have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study
* Receive certain per protocol prohibited medications while on study. These medications must be discontinued 7 days prior to start of study drug
* Have bone marrow disorders, electrolyte imbalance, infrequent bowel movements (less than once per 48 hours), coagulopathy, platelet disorder or history of non-drug induced thrombocytopenia
* Positive for human immunodeficiency virus currently receiving combination anti-retroviral therapy
* Regular work with ionizing radiation or radioactive material or treated with radiotherapy within 3 weeks prior to the first dose of study drug
* Refuse to potentially receive blood products and/or have a hypersensitivity to blood products

Primary outcomes:
measure: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Unlabeled Idasanutlin
timeFrame: 0 Hour (hr) predose, 1, 3, 6, 7, 24, 48, 96, 120, 144, 240 hrs postdose
measure: Maximum Observed Plasma Concentration (Cmax) of Unlabeled Idasanutlin
timeFrame: 0 hr predose, 1, 3, 6, 7, 24, 48, 96, 120, 144, 240 hrs postdose
measure: Area Under the Plasma Concentration Time-Curve From Time Zero to Extrapolated Infinite Time (AUC [0-inf]) of Unlabeled Idasanutlin
timeFrame: 0 hr predose, 1, 3, 6, 7, 24, 48, 96, 120, 144, 240 hrs postdose
measure: Area Under the Plasma Concentration Time-Curve From Zero to the Last Measured Concentration (AUC[0-last]) of Unlabeled Idasanutlin
timeFrame: 0 hr predose, 1, 3, 6, 7, 24, 48, 96, 120, 144, 240 hrs postdose
measure: Plasma Elimination Half-Life (t1/2) of Unlabeled Idasanutlin
timeFrame: 0 hr predose, 1, 3, 6, 7, 24, 48, 96, 120, 144, 240 hrs postdose
measure: Plasma Apparent Elimination Rate Constant of Unlabeled Idasanutlin
timeFrame: 0 hr predose, 1, 3, 6, 7, 24, 48, 96, 120, 144, 240 hrs postdose
measure: Apparent Oral Clearance (CL/F) of Unlabeled Idasanutlin
timeFrame: 0 hr predose, 1, 3, 6, 7, 24, 48, 96, 120, 144, 240 hrs postdose
measure: Renal Clearance (CLr) of Unlabeled Idasanutlin
timeFrame: 0 hr predose, 1, 3, 6, 7, 24, 48, 96, 120, 144, 240 hrs postdose
measure: Apparent Volume of Distribution (Vz/F) of Unlabeled Idasanutlin
timeFrame: 0 hr predose, 1, 3, 6, 7, 24, 48, 96, 120, 144, 240 hrs postdose
measure: Cumulative Amount Excreted in Urine of Unlabeled Idasanutlin
timeFrame: 0 hr (within 24 hrs of dosing), pooled sample collected over time interval: 0-6, 6-12, 12-24, 24-48, 48-72, 72-96, 96-120, 120-144, 144-168, 168-192, 192-216, 216-240, 240-264 hrs postdose
measure: Cumulative Amount Excreted in Feces of Unlabeled Idasanutlin
timeFrame: 0 hr (within 24 hrs of dosing), pooled sample collected over time interval: 0-6, 6-12, 12-24, 24-48, 48-72, 72-96, 96-120, 120-144, 144-168, 168-192, 192-216, 216-240, 240-264 hrs postdose
measure: Tmax of Idasanutlin Metabolite
timeFrame: 0 hr predose, 1, 3, 6, 7, 24, 48, 96, 120, 144, 240 hrs postdose
measure: Cmax of Idasanutlin Metabolite
timeFrame: 0 hr predose, 1, 3, 6, 7, 24, 48, 96, 120, 144, 240 hrs postdose
measure: AUC (0-inf) of Idasanutlin Metabolite
timeFrame: 0 hr predose, 1, 3, 6, 7, 24, 48, 96, 120, 144, 240 hrs postdose
measure: AUC(0-last) of Idasanutlin Metabolite
timeFrame: 0 hr predose, 1, 3, 6, 7, 24, 48, 96, 120, 144, 240 hrs postdose
measure: Plasma t1/2 of Idasanutlin Metabolite
timeFrame: 0 hr predose, 1, 3, 6, 7, 24, 48, 96, 120, 144, 240 hrs postdose
measure: Plasma Apparent Elimination Rate Constant of Idasanutlin Metabolite
timeFrame: 0 hr predose, 1, 3, 6, 7, 24, 48, 96, 120, 144, 240 hrs postdose
measure: CL/F of Idasanutlin Metabolite
timeFrame: 0 hr predose, 1, 3, 6, 7, 24, 48, 96, 120, 144, 240 hrs postdose
measure: CLr of Idasanutlin Metabolite
timeFrame: 0 hr predose, 1, 3, 6, 7, 24, 48, 96, 120, 144, 240 hrs postdose
measure: Vz/F of Idasanutlin Metabolite
timeFrame: 0 hr predose, 1, 3, 6, 7, 24, 48, 96, 120, 144, 240 hrs postdose
measure: Cumulative Amount Excreted in Urine of Idasanutlin Metabolite
timeFrame: 0 hr (within 24 hrs of dosing), pooled sample collected over time interval: 0-6, 6-12, 12-24, 24-48, 48-72, 72-96, 96-120, 120-144, 144-168, 168-192, 192-216, 216-240, 240-264 hrs postdose
measure: Cumulative Amount Excreted in Feces of Idasanutlin Metabolite
timeFrame: 0 hr (within 24 hrs of dosing), pooled sample collected over time interval: 0-6, 6-12, 12-24, 24-48, 48-72, 72-96, 96-120, 120-144, 144-168, 168-192, 192-216, 216-240, 240-264 hrs postdose
measure: Tmax of [13C]-Labeled Idasanutlin
timeFrame: 0 hr predose, 5hr 55 minutes (min), 6hr, 6hr 5min, 6hr 10min, 6hr 15min, 6hr 30min, 7, 10, 24, 48, 96, 120, 144, 240 hrs postdose
measure: Cmax of [13C]-Labeled Idasanutlin
timeFrame: 0 hr predose, 5hr 55 min, 6hr, 6hr 5min, 6hr 10min, 6hr 15min, 6hr 30min, 7, 10, 24, 48, 96, 120, 144, 240 hrs postdose
measure: AUC(0-inf) of [13C]-Labeled Idasanutlin
timeFrame: 0 hr predose, 5hr 55 min, 6hr, 6hr 5min, 6hr 10min, 6hr 15min, 6hr 30min, 7, 10, 24, 48, 96, 120, 144, 240 hrs postdose
measure: AUC(0-last) of [13C]-Labeled Idasanutlin
timeFrame: 0 hr predose, 5hr 55min, 6hr, 6hr 5min, 6hr 10min, 6hr 15min, 6hr 30min, 7, 10, 24, 48, 96, 120, 144, 240 hrs postdose
measure: Plasma t1/2 of [13C]-Labeled Idasanutlin
timeFrame: 0 hr predose, 5hr 55min, 6hr, 6hr 5min, 6hr 10min, 6hr 15min, 6hr 30min, 7, 10, 24, 48, 96, 120, 144, 240 hrs postdose
measure: Absolute Oral Bioavailability of [13C]-Labeled Idasanutlin
timeFrame: Oral administration: 0 hr predose, 1, 3, 6, 7, 24, 48, 96, 120, 144, 240 hrs postdose; IV administration: 0 hr predose, 5hr 55min, 6hr, 6hr 5min, 6hr 10min, 6hr 15min, 6hr 30min, 7, 10, 24, 48, 96, 120, 144, 240 hrs postdose
measure: Whole Blood and Plasma Cmax of [14C]-Labeled Idasanutlin
timeFrame: 0 hr predose, 1, 3, 6, 7, 24, 48, 96, 120, 144, 240 hrs postdose
measure: Whole Blood and Plasma AUC(0-inf) of [14C]-Labeled Idasanutlin
timeFrame: 0 hr predose, 1, 3, 6, 7, 24, 48, 96, 120, 144, 240 hrs postdose0 hr predose, 1, 3, 6, 7, 24, 48, 96, 120, 144, 240 hrs postdose
measure: Whole Blood and Plasma AUC(0-last) of [14C]-Labeled Idasanutlin
timeFrame: 0 hr predose, 1, 3, 6, 7, 24, 48, 96, 120, 144, 240 hrs postdose
measure: Whole Blood and Plasma Apparent Elimination Rate Constant of [14C]-Labeled Idasanutlin
timeFrame: 0 hr predose, 1, 3, 6, 7, 24, 48, 96, 120, 144, 240 hrs postdose
measure: Cumulative Amount of Radioactivity Excreted in Urine as Percentage of Dosed Radioactivity of [14C]-Labeled Idasanutlin
timeFrame: 0 hr (within 24 hrs of dosing), pooled sample collected over time interval: 0-6, 6-12, 12-24, 24-48, 48-72, 72-96, 96-120, 120-144, 144-168, 168-192, 192-216, 216-240, 240-264 hrs postdose
measure: Cumulative Amount of Radioactivity Excreted in Feces as Percentage of Dosed Radioactivity of [14C]-Labeled Idasanutlin
timeFrame: 0 hr (within 24 hrs of dosing), pooled sample collected over time interval: 0-6, 6-12, 12-24, 24-48, 48-72, 72-96, 96-120, 120-144, 144-168, 168-192, 192-216, 216-240, 240-264 hrs postdose
measure: CL/F of [13C]-Labeled Idasanutlin
timeFrame: 0 hr predose, 5hr 55min, 6hr, 6hr 5min, 6hr 10min, 6hr 15min, 6hr 30min, 7, 10, 24, 48, 96, 120, 144, 240 hrs postdose
measure: Vz/F of [13C]-Labeled Idasanutlin
timeFrame: 0 hr predose, 5hr 55min, 6hr, 6hr 5min, 6hr 10min, 6hr 15min, 6hr 30min, 7, 10, 24, 48, 96, 120, 144, 240 hrs postdose
measure: Whole Blood and Plasma Tmax of [14C]-Labeled Idasanutlin
timeFrame: 0 hr predose, 1, 3, 6, 7, 24, 48, 96, 120, 144, 240 hrs postdose
measure: Cumulative Amount of Radioactivity Excreted in Feces on Toilet Tissue as Percentage of Dosed Radioactivity of [14C]-Labeled Idasanutlin
timeFrame: 0 hr (within 24 hrs of dosing), pooled sample collected over time interval: 0-6, 6-12, 12-24, 24-48, 48-72, 72-96, 96-120, 120-144, 144-168, 168-192, 192-216, 216-240, 240-264 hrs postdose
Secondary outcomes:
measure: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Baseline through 28 days after the last dose of study drug (maximum up to approximately 76 days)
measure: Palatability Assessment Questionnaire Score for Aqueous Dispersion of Idasanutlin
timeFrame: 0 hr (pre-Day 11-dose), 0.5 hr, 1 hr, 1.5 hr, 2 hr, and 3 hr post-Day 11-dose
measure: Aftertaste Survey Questionnaire Score for Aqueous Dispersion of Idasanutlin
timeFrame: 0 hr (pre-Day 11-dose), 0.5 hr, 1 hr, 1.5 hr, 2 hr, and 3 hr post-Day 11-dose
Other outcomes:
Locations:
city: Budapest
country: Hungary
facility: Magyar Honvedseg Egeszsegugyi Kozpont
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: