Polycystic Kidney, Autosomal Dominant
Conditions
Brief summary
The primary objective of this study Phase 1b was to determine the safety, plasma pharmacokinetics, and maximum tolerated dose (MTD) of tesevatinib when administered to participants with autosomal dominant polycystic kidney disease (ADPKD). The primary objective of this study Phase 2a was to evaluate the annualized change in glomerular filtration rate (GFR) in participants with ADPKD when treated with tesevatinib.
Detailed description
Phase 1b: * Primary objective was to determine the safety of tesevatinib. * Dosing was for 28 days daily. After the 28-day treatment period, participants would, at the discretion of the investigator, continue to receive study treatment for 24 months from their first dose or until the development of unacceptable toxicity, noncompliance, or withdrawal of consent by the participant, or investigator decision. Participants might continue beyond 24 months at the discretion of the investigator after consultation with the medical monitor. * All participants received active tesevatinib study drug. * Tesevatinib is an oral once daily tablet. Tablets were 50 milligrams (mg), 100 mg and 150 mg in strength. Participants were enrolled into three sequential dosing cohort levels (50 mg, 100 mg and 150 mg.). Participants in Phase 1b had their dose increased or decreased to the maximum tolerated dose (MTD). * Study participants had magnetic resonance imaging (MRI) of the abdomen (kidneys) at Screening and 6 months thereafter to explore effects of KD019. * Echocardiogram was performed at Screening, Day 28, months 3 and 6 and every 6 months thereafter. Phase 2a: * Primary objective was to compare the annualized change in GFR in participants with ADPKD when treated with tesevatinib. * Two alternate dosing schedules were explored to determine if they were more tolerable than daily dosing when used chronically in participants with ADPKD. * Participants received study treatment for 24 months from their first dose or until the development of unacceptable toxicity, noncompliance, or withdrawal of consent by the participant, or investigator decision. Participants continued beyond 24 months at the discretion of the investigator after consultation with the sponsor. * All participants received active tesevatinib study drug. * Tablets were 50 mg, 100 mg, and 150 mg in strength. * Study participants had MRI of the abdomen (kidneys) at Screening and Month 6 visit and every 6 months after to explore effects of tesevatinib. * Echocardiogram was performed at Screening, Day 28, and Months 3 and 6 and 6 months thereafter.
Interventions
DRUGTesevatinib
Pharmaceutical form: Tablets Route of administration: Oral
Sponsors
Kadmon, a Sanofi Company
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 62 Years
Healthy volunteers
No
Inclusion criteria
* The participant had a confirmed diagnosis of ADPKD. * The participant had a GFR \>=35 mL/min/1.73m\^2. * Cysts must be at least 1 centimeter in size. * Adequate bone marrow, kidney, and liver function. * Must agree to use two forms of birth control for those of child bearing potential. * Normal amylase and lipase levels. * The participant had a htTKV \>= 1000 mL (htTKV was calculated using total kidney volume obtained from magnetic resonance imaging divided by height in meters).
Exclusion criteria
* The participant has had a previous partial or total nephrectomy. * The participant had tuberous sclerosis, Hippel-Lindau disease, or acquired cystic disease. * The participant had congenital absence of one kidney and/or need for dialysis. * Presence of renal or hepatic calculi (stones) causing symptoms. * The participant had received any investigational therapy within 30 days prior to study entry. * Active treatment (within 4 weeks of study entry) for urinary tract infection. * Participant was known to be immunocompromised. * Participant was pregnant or nursing. * History of pericardial effusion or presence of pericardial effusion on screening echocardiogram * Uncontrolled hypertension. * History of pancreatitis or had known risk factors for pancreatitis. * Participant had received EGFR inhibitor at any time. * The participant was aphakic due to previous cataract surgery or congenital anomaly.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 2a: Annualized Percent Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | Baseline (Day 1), Months 6, 12, 18, 24 and at end of study (i.e., anytime up to 37 months) | eGFR: measures kidney function based on serum creatinine (Scr) and cystatin C (Scys). Annualized change in eGFR was calculated as: percent change from Baseline divided by total duration in days\*365.25. eGFR was estimated using 3 formulas and is reported separately for each formula: 1) 4-variable modification of diet in renal disease (MDRD-4) : Black/African-American males:175\*(Creatinine \[Cr\]\^-1.154)\*(Age\^-0.203)\*1.212, other males:175\*(Cr\^-1.154)\*(Age\^-0.203), females: male equation\*0.742.; 2) cystatin C-based chronic kidney disease (CKD) epidemiology (EPI) (CKD-EPI2012cys) equation: based on Scyc levels, for males if \<=0.8: 133\*(Scys/0.8)\^0.499\*0.996\^age, if \>0.8: 133\*(Scys/0.8)\^-1.238\*0.996\^age; for female: male equation\*0.932., 3) Scr- and Scys-based CKD-EPI (CKD EPI2012Scr-cys) equation: 135\*(Scr/0.9)\^XX\*(Scys/0.8)\^XXX\*0.995\^age\*(× 1.08, if black)- XX and XXX had variable values based on different values of Scr and Scys. |
| Phase 1b: Pharmacokinetics: Time of the Maximum Observed Plasma Concentration (Tmax) of Tesevatinib 100 mg and 150 mg | Pre-dose, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and pre-dose, 1, 2, 4, and 24 hours post-dose on Day 14 | Tmax was defined as time to reach maximum observed plasma concentration. |
| Phase 1b: Pharmacokinetics: Time of the Maximum Observed Plasma Concentration of Tesevatinib 50 mg | Pre-dose, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and pre-dose, 1, 2, 4, and 24 hours post-dose on Day 14 | Tmax was defined as time to reach maximum observed plasma concentration. |
| Phase 1b: Pharmacokinetics: Time of the Last Quantifiable Plasma Concentration (Tlast) of Tesevatinib 100 mg and 150 mg | Pre-dose, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and pre-dose, 1, 2, 4, and 24 hours post-dose on Day 14 | Tlast was defined as time to reach last quantifiable plasma concentration. |
| Phase 1b: Pharmacokinetics: Time of the Last Quantifiable Plasma Concentration of Tesevatinib 50 mg | Pre-dose, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and pre-dose, 1, 2, 4, and 24 hours post-dose on Day 14 | Tlast was defined as time to reach last quantifiable plasma concentration. |
| Phase 1b: Pharmacokinetics: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of Last Quantifiable Concentration (AUC0-t) of Tesevatinib 100 mg and 150 mg | Pre-dose, 1, 2, 4, 8, and 24 hours post-dose on day 1 and pre-dose, 1, 2, 4, and 24 hours post-dose on Day 14 | AUC0-last was defined as area under the concentration-time curve (AUC) from time 0 to the time of the last quantifiable concentration (tlast). |
| Phase 1b: Pharmacokinetics: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of Last Quantifiable Concentration of Tesevatinib 50 mg | Pre-dose, 1, 2, 4, 8, and 24 hours post-dose on day 1 and pre-dose, 1, 2, 4, and 24 hours post-dose on Day 14 | AUC0-last was defined as area under the concentration-time curve (AUC) from time 0 to the time of the last quantifiable concentration (tlast). |
| Phase 1b: Pharmacokinetics: Area Under the Plasma Concentration-time Curve From Time Zero to 24 Hours Post-dose (AUC0-24) of Tesevatinib 100 mg and 150 mg | Pre-dose, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and pre-dose, 1, 2, 4, and 24 hours post-dose on Day 14 | AUC0-24 was defined as area under the plasma concentration versus time curve of study drug from time 0 to 24 hours post-dose. |
| Phase 1b: Pharmacokinetics: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours Post-dose of Tesevatinib 50 mg | Pre-dose, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and pre-dose, 1, 2, 4, and 24 hours post-dose on Day 14 | AUC0-24 was defined as area under the plasma concentration versus time curve of study drug from time 0 to 24 hours post-dose. |
| Phase 1b: Pharmacokinetics: Trough Plasma Concentrations (Ctrough) of Tesevatinib 100 mg and 500 mg | Pre-dose on Days 7, 14, 21, 28 and Months 2, 3, 4, 5 and 6 | Ctrough was the plasma concentration observed at the time immediately before (pre-dose) study drug administration. |
| Phase 1b: Pharmacokinetics: Trough Plasma Concentrations of Tesevatinib 50 mg | Pre-dose on Days 7, 14, 21, 28 and Months 2, 3, 4, 5 and 6 | Ctrough was the plasma concentration observed at the time immediately before study drug administration. |
| Phase 1b: Maximum Tolerated Dose (MTD) of Tesevatinib | Cycle 1 (Up to 28 days) | The MTD was determined based on dose-limiting toxicities (DLTs) occurring in the first 28 days of study treatment. Any toxicity that the Investigator and the Sponsor deemed to be dose-limiting, regardless of the grade, was considered as DLT. |
| Phase 1b: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAE) | From Baseline (Day 1) until 30 days after the last dose of study drug (maximum duration: up to 37 months) | An adverse event (AE) was any untoward medical occurrence in a clinical study participant administered a medicinal product and which did not necessarily had to have a causal relationship with the treatment. An SAE was any untoward medical occurrence at any dose that: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. TEAEs were AEs that developed or worsened or became serious from the first dose (Day 1) of the study drug until 30 days after the last dose of study drug. |
| Phase 1b: Pharmacokinetics (PK): Plasma Concentrations of Tesevatinib 100 mg and 150 mg | Pre-dose, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and pre-dose, 1, 2, 4, and 24 hours post-dose on Day 14 | Plasma concentrations of tesevatinib was analyzed using non-compartmental analysis. |
| Phase 1b: Pharmacokinetics: Plasma Concentrations of Tesevatinib 50 mg | Pre-dose, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and pre-dose, 1, 2, 4, and 24 hours post-dose on Day 14 | Plasma concentrations of tesevatinib was analyzed using non-compartmental analysis. |
| Phase 1b: Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) of Tesevatinib 100 mg and 150 mg | Pre-dose, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and pre-dose, 1, 2, 4, and 24 hours post-dose on Day 14 | Cmax was defined as maximum observed plasma concentration. |
| Phase 1b: Pharmacokinetics: Maximum Observed Plasma Concentration of Tesevatinib 50 mg | Pre-dose, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and pre-dose, 1, 2, 4, and 24 hours post-dose on Day 14 | Cmax was defined as maximum observed plasma concentration. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 2a: Annualized Percent Change From Baseline in the Reciprocal of Serum Creatinine at End of Study | Baseline (Day 1), at end of study (i.e., anytime up to 37 months) | Reciprocal Creatinine was an indication for monitoring renal disease progression over time. The annualized percent change from Baseline was calculated as the percent change from Baseline divided by total duration in days\*365.25. |
| Phase 2a: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (TESAE) | From Baseline (Day 1) until 30 days after the last dose of study drug (i.e., up to 29 months) | An AE was any untoward medical occurrence in a clinical study participant administered a medicinal product and which did not necessarily had to have a causal relationship with the treatment. An SAE was any untoward medical occurrence at any dose that: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. TEAEs were AEs that developed or worsened or became serious from the first dose (Day 1) of the study drug until 30 days after the last dose of study drug. |
| Phase 2a: Change From Baseline in Serum Creatinine Levels | Baseline, Day 1, 3, 7, 11, 12, 14, 21, 25, 26, 28, Month 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 18, 20, 22, 24, and at end of study (i.e., anytime up to 37 months) | Serum creatinine levels indicated the renal function (normal or abnormal) over time. |
| Phase 2a: Pharmacokinetics: Plasma Concentrations of Tesevatinib 150 mg | Bi-weekly: pre-dose, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and Day 25; Tri-weekly: pre-dose, 1, 2, 4, 8, and 24 hours post-dose on Day 1; pre-dose, 1, 2, 4, and 24 hours post-dose on Day 12 | Plasma concentrations of tesevatinib was analyzed using non-compartmental analysis. |
| Phase 2a: Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) of Tesevatinib 150 mg | Bi-weekly: pre-dose, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and Day 25; Tri-weekly: pre-dose, 1, 2, 4, 8, and 24 hours post-dose on Day 1; pre-dose, 1, 2, 4, and 24 hours post-dose on Day 12 | Cmax was defined as maximum observed plasma concentration. |
| Phase 2a: Pharmacokinetics: Time of the Maximum Observed Plasma Concentration (Tmax) of Tesevatinib 150 mg | Bi-weekly: pre-dose, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and Day 25; Tri-weekly: pre-dose, 1, 2, 4, 8, and 24 hours post-dose on Day 1; pre-dose, 1, 2, 4, and 24 hours post-dose on Day 12 | Tmax was defined as time to reach maximum observed plasma concentration. |
| Phase 2a: Pharmacokinetics: Time of the Last Quantifiable Plasma Concentration (Tlast) of Tesevatinib 150 mg | Bi-weekly: pre-dose, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and Day 25; Tri-weekly: pre-dose, 1, 2, 4, 8, and 24 hours post-dose on Day 1; pre-dose, 1, 2, 4, and 24 hours post-dose on Day 12 | Tlast was defined as time to reach last quantifiable plasma concentration. |
| Phase 2a: Pharmacokinetics: Area Under the Plasma Concentration-time Curve From Time 0 to the Last Quantifiable Concentration (AUC0-t) of Tesevatinib 150 mg | Bi-weekly: pre-dose, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and Day 25; Tri-weekly: pre-dose, 1, 2, 4, 8, and 24 hours post-dose on Day 1; pre-dose, 1, 2, 4, and 24 hours post-dose on Day 12 | AUC0-last was defined as area under the concentration-time curve (AUC) from time 0 to the time of the last quantifiable concentration (tlast). |
| Phase 2a: Pharmacokinetics: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours Post-dose (AUC0-24) of Tesevatinib 150 mg | Bi-weekly: pre-dose, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and Day 25; Tri-weekly: pre-dose, 1, 2, 4, 8, and 24 hours post-dose on Day 1; pre-dose, 1, 2, 4, and 24 hours post-dose on Day 12 | AUC0-24 was defined as area under the plasma concentration versus time curve of study drug from time 0 to 24 hours post-dose. |
| Phase 2a: Pharmacokinetics: Concentration Immediately Before Dosing (Ctrough) of Tesevatinib 150 mg | Bi-weekly: Pre-dose on Days 8, 11, 18 and 25; pre-dose on Months 2, 3, 4, 5 and 6; Tri-weekly: pre-dose on Days 3, 5, 8 and 12 | Ctrough was the plasma concentration observed at the time immediately before study drug administration. |
| Phase 2a: Annualized Percent Change From Baseline in Height Adjusted Total Kidney Volume (htTKV) at Month 6, 12, 18, 24 and End of Study | Baseline (Day 1), Months 6, 12, 18, 24 and at end of study (i.e., anytime up to 37 months) | htTKV was calculated using total kidney volume obtained from magnetic resonance imaging (MRI) divided by height in meters. The annualized percent change from Baseline was calculated as the percent change from Baseline divided by total duration in days\*365.25. |
Countries
United States
Participant flow
Recruitment details
The study was conducted at 11 active sites in the United States. A total of 126 participants were screened between 11 October 2012 and 07 March 2017, of which 69 participants were enrolled and treated.
Pre-assignment details
Study consisted of 2 parts: Phase 1b with three sequential dosing cohort levels (50 milligrams \[mg\], 100 mg and 150 mg) and Phase 2a with two alternate dosing schedules cohorts (150 mg biweekly and triweekly) and one safety in larger kidneys (SILK) cohort.
Participants by arm
| Arm | Count |
|---|---|
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing Participants received tesevatinib 50 mg tablet orally QD for initial 28 days. After initial 28 days treatment, at the investigator's discretion, participants continued to receive tesevatinib for a total of 24 months (since treatment initiation) or until the development of unacceptable toxicity, noncompliance, or withdrawal of consent by the participant, or investigator decision (maximum duration: up to 36 months). | 24 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing Participants received tesevatinib 100 mg tablet orally QD for initial 28 days. After initial 28 days treatment, at the investigator's discretion, participants continued to receive tesevatinib for a total of 24 months (since treatment initiation) or until the development of unacceptable toxicity, noncompliance, or withdrawal of consent by the participant, or investigator decision (maximum exposure duration: up to 36 months). | 8 |
| Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing Participants received tesevatinib 150 mg tablet orally QD for initial 28 days. After initial 28 days treatment, at the investigator's discretion, participants continued to receive tesevatinib for a total of 24 months (since treatment initiation) or until the development of unacceptable toxicity, noncompliance, or withdrawal of consent by the participant, or investigator decision (maximum exposure duration: up to 36 months). | 5 |
| Phase 2a: Cohort 4: Tesevatinib: Bi-weekly Dosing Participants received tesevatinib 150 mg tablet orally bi-weekly in alternative dosing schedules on Monday and Thursday for initial 25 days. After initial 25 days treatment, at the investigator's discretion, participants continued to receive tesevatinib for a total of 24 months (since treatment initiation) or until the development of unacceptable toxicity, noncompliance, or withdrawal of consent by the participant, or investigator decision (maximum exposure duration: up to 28 months). | 10 |
| Phase 2a: Cohort 5: Tesevatinib: Tri-weekly Dosing Participants received tesevatinib 150 mg tablet orally tri-weekly in alternative dosing schedules on Monday, Wednesday and Friday for initial 26 days. After initial 26 days treatment, at the investigator's discretion, participants continued to receive tesevatinib for a total of 24 months (since treatment initiation) or until the development of unacceptable toxicity, noncompliance, or withdrawal of consent by the participant, or investigator decision (maximum exposure duration: up to 28 months). | 14 |
| Phase 2a: SILK Cohort: Tesevatinib 50 mg Once Daily Dosing Participants with ADPKD and Baseline eGFR \>=35 mL/min/1.73 m\^2 and \<=80 mL/min/1.73 m\^2, and htTKV \>=1000 mL were enrolled and received tesevatinib 50 mg tablet orally QD for initial 28 days. After initial 28 days treatment, at the investigator's discretion, participants continued to receive tesevatinib for a total of 24 months (since treatment initiation) or until the development of unacceptable toxicity, noncompliance, or withdrawal of consent by the participant, or investigator decision (maximum exposure duration: up to 28 months). | 8 |
| Total | 69 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Phase 1b: Up to 36 Months | Adverse event or Serious adverse event | 2 | 0 | 1 | 0 | 0 | 0 |
| Phase 1b: Up to 36 Months | Investigator decision | 1 | 0 | 0 | 0 | 0 | 0 |
| Phase 1b: Up to 36 Months | Lost to Follow-up | 1 | 1 | 0 | 0 | 0 | 0 |
| Phase 1b: Up to 36 Months | Unspecified reason | 0 | 1 | 0 | 0 | 0 | 0 |
| Phase 1b: Up to 36 Months | Withdrawal by Subject | 2 | 1 | 1 | 0 | 0 | 0 |
| Phase 2a: Up to 28 Months | Adverse event or Serious adverse event | 0 | 0 | 0 | 1 | 1 | 0 |
| Phase 2a: Up to 28 Months | Unspecified reason | 0 | 0 | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing | Phase 2a: Cohort 4: Tesevatinib: Bi-weekly Dosing | Phase 2a: Cohort 5: Tesevatinib: Tri-weekly Dosing | Phase 2a: SILK Cohort: Tesevatinib 50 mg Once Daily Dosing | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 37.9 years STANDARD_DEVIATION 9.1 | 36.6 years STANDARD_DEVIATION 7.4 | 42.6 years STANDARD_DEVIATION 4.4 | 34.9 years STANDARD_DEVIATION 11.3 | 37.7 years STANDARD_DEVIATION 11.1 | 52.1 years STANDARD_DEVIATION 9.5 | 39.3 years STANDARD_DEVIATION 10.5 |
| Race/Ethnicity, Customized Asian | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 20 Participants | 8 Participants | 5 Participants | 8 Participants | 14 Participants | 7 Participants | 62 Participants |
| Sex: Female, Male Female | 15 Participants | 3 Participants | 3 Participants | 6 Participants | 10 Participants | 3 Participants | 40 Participants |
| Sex: Female, Male Male | 9 Participants | 5 Participants | 2 Participants | 4 Participants | 4 Participants | 5 Participants | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 24 | 0 / 8 | 0 / 5 | 0 / 10 | 0 / 14 | 0 / 8 |
| other Total, other adverse events | 24 / 24 | 8 / 8 | 5 / 5 | 10 / 10 | 14 / 14 | 8 / 8 |
| serious Total, serious adverse events | 1 / 24 | 0 / 8 | 0 / 5 | 1 / 10 | 0 / 14 | 1 / 8 |
Outcome results
Primary
Phase 1b: Maximum Tolerated Dose (MTD) of Tesevatinib
The MTD was determined based on dose-limiting toxicities (DLTs) occurring in the first 28 days of study treatment. Any toxicity that the Investigator and the Sponsor deemed to be dose-limiting, regardless of the grade, was considered as DLT.
Time frame: Cycle 1 (Up to 28 days)
Population: Analysis was performed on safety population. Data for this OM was not planned to be collected and analyzed for Phase 2a participants as pre specified in protocol.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Maximum Tolerated Dose (MTD) of Tesevatinib | 100 milligrams |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 1b: Maximum Tolerated Dose (MTD) of Tesevatinib | 100 milligrams |
| Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing | Phase 1b: Maximum Tolerated Dose (MTD) of Tesevatinib | 100 milligrams |
Primary
Phase 1b: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAE)
An adverse event (AE) was any untoward medical occurrence in a clinical study participant administered a medicinal product and which did not necessarily had to have a causal relationship with the treatment. An SAE was any untoward medical occurrence at any dose that: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. TEAEs were AEs that developed or worsened or became serious from the first dose (Day 1) of the study drug until 30 days after the last dose of study drug.
Time frame: From Baseline (Day 1) until 30 days after the last dose of study drug (maximum duration: up to 37 months)
Population: Analysis was performed on safety population.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAE) | TEAEs | 24 Participants |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAE) | SAE | 1 Participants |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 1b: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAE) | TEAEs | 8 Participants |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 1b: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAE) | SAE | 0 Participants |
| Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing | Phase 1b: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAE) | TEAEs | 5 Participants |
| Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing | Phase 1b: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAE) | SAE | 0 Participants |
Primary
Phase 1b: Pharmacokinetics: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours Post-dose of Tesevatinib 50 mg
AUC0-24 was defined as area under the plasma concentration versus time curve of study drug from time 0 to 24 hours post-dose.
Time frame: Pre-dose, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and pre-dose, 1, 2, 4, and 24 hours post-dose on Day 14
Population: Analysis was performed on PK Population. Here, overall number of participants analyzed = participants evaluable for this OM and 'number analyzed' = participants with available data for each specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours Post-dose of Tesevatinib 50 mg | Day 1 | 272 hr*ng/mL | Standard Deviation 99.8 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours Post-dose of Tesevatinib 50 mg | Day 14 | 1430 hr*ng/mL | Standard Deviation 498 |
Primary
Phase 1b: Pharmacokinetics: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of Last Quantifiable Concentration (AUC0-t) of Tesevatinib 100 mg and 150 mg
AUC0-last was defined as area under the concentration-time curve (AUC) from time 0 to the time of the last quantifiable concentration (tlast).
Time frame: Pre-dose, 1, 2, 4, 8, and 24 hours post-dose on day 1 and pre-dose, 1, 2, 4, and 24 hours post-dose on Day 14
Population: Analysis was performed on PK Population. Here, 'number analyzed' = participants with available data for each specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of Last Quantifiable Concentration (AUC0-t) of Tesevatinib 100 mg and 150 mg | Day 1 | 508 hour*nanograms per milliliter (hr*ng/mL) | Standard Deviation 247 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of Last Quantifiable Concentration (AUC0-t) of Tesevatinib 100 mg and 150 mg | Day 14 | 2280 hour*nanograms per milliliter (hr*ng/mL) | Standard Deviation 741 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of Last Quantifiable Concentration (AUC0-t) of Tesevatinib 100 mg and 150 mg | Day 1 | 853 hour*nanograms per milliliter (hr*ng/mL) | Standard Deviation 130 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of Last Quantifiable Concentration (AUC0-t) of Tesevatinib 100 mg and 150 mg | Day 14 | 4200 hour*nanograms per milliliter (hr*ng/mL) | Standard Deviation 1180 |
Primary
Phase 1b: Pharmacokinetics: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of Last Quantifiable Concentration of Tesevatinib 50 mg
AUC0-last was defined as area under the concentration-time curve (AUC) from time 0 to the time of the last quantifiable concentration (tlast).
Time frame: Pre-dose, 1, 2, 4, 8, and 24 hours post-dose on day 1 and pre-dose, 1, 2, 4, and 24 hours post-dose on Day 14
Population: Analysis was performed on PK Population. Here, overall number of participants analyzed = participants evaluable for this OM and 'number analyzed' = participants with available data for each specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of Last Quantifiable Concentration of Tesevatinib 50 mg | Day 1 | 272 hr*ng/mL | Standard Deviation 99.9 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of Last Quantifiable Concentration of Tesevatinib 50 mg | Day 14 | 1410 hr*ng/mL | Standard Deviation 485 |
Primary
Phase 1b: Pharmacokinetics: Area Under the Plasma Concentration-time Curve From Time Zero to 24 Hours Post-dose (AUC0-24) of Tesevatinib 100 mg and 150 mg
AUC0-24 was defined as area under the plasma concentration versus time curve of study drug from time 0 to 24 hours post-dose.
Time frame: Pre-dose, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and pre-dose, 1, 2, 4, and 24 hours post-dose on Day 14
Population: Analysis was performed on PK Population. Here, 'number analyzed' = participants with available data for each specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Area Under the Plasma Concentration-time Curve From Time Zero to 24 Hours Post-dose (AUC0-24) of Tesevatinib 100 mg and 150 mg | Day 1 | 507 hr*ng/mL | Standard Deviation 246 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Area Under the Plasma Concentration-time Curve From Time Zero to 24 Hours Post-dose (AUC0-24) of Tesevatinib 100 mg and 150 mg | Day 14 | 2700 hr*ng/mL | Standard Deviation 750 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Area Under the Plasma Concentration-time Curve From Time Zero to 24 Hours Post-dose (AUC0-24) of Tesevatinib 100 mg and 150 mg | Day 1 | 853 hr*ng/mL | Standard Deviation 129 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Area Under the Plasma Concentration-time Curve From Time Zero to 24 Hours Post-dose (AUC0-24) of Tesevatinib 100 mg and 150 mg | Day 14 | 4200 hr*ng/mL | Standard Deviation 1180 |
Primary
Phase 1b: Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) of Tesevatinib 100 mg and 150 mg
Cmax was defined as maximum observed plasma concentration.
Time frame: Pre-dose, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and pre-dose, 1, 2, 4, and 24 hours post-dose on Day 14
Population: Analysis was performed on PK Population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) of Tesevatinib 100 mg and 150 mg | Day 1 | 27.5 ng/mL | Standard Deviation 12.2 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) of Tesevatinib 100 mg and 150 mg | Day 14 | 116 ng/mL | Standard Deviation 31.8 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) of Tesevatinib 100 mg and 150 mg | Day 1 | 44.3 ng/mL | Standard Deviation 7.5 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) of Tesevatinib 100 mg and 150 mg | Day 14 | 205 ng/mL | Standard Deviation 65.4 |
Primary
Phase 1b: Pharmacokinetics: Maximum Observed Plasma Concentration of Tesevatinib 50 mg
Cmax was defined as maximum observed plasma concentration.
Time frame: Pre-dose, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and pre-dose, 1, 2, 4, and 24 hours post-dose on Day 14
Population: Analysis was performed on PK Population. Here, overall number of participants analyzed = participants evaluable for this OM and 'number analyzed' = participants with available data for each specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Maximum Observed Plasma Concentration of Tesevatinib 50 mg | Day 1 | 14.5 ng/mL | Standard Deviation 5.34 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Maximum Observed Plasma Concentration of Tesevatinib 50 mg | Day 14 | 65.9 ng/mL | Standard Deviation 24.8 |
Primary
Phase 1b: Pharmacokinetics (PK): Plasma Concentrations of Tesevatinib 100 mg and 150 mg
Plasma concentrations of tesevatinib was analyzed using non-compartmental analysis.
Time frame: Pre-dose, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and pre-dose, 1, 2, 4, and 24 hours post-dose on Day 14
Population: Analysis was performed on PK Population which consisted of all participants who received at least one dose of tesevatinib 100 mg (in Phase 1b: Cohort 2) and 150 mg (in Phase 1b: Cohort 3) and had quantifiable PK data available. Here, 'number analyzed' = participants with available data for each specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics (PK): Plasma Concentrations of Tesevatinib 100 mg and 150 mg | Day 1: 4 hours post-dose | 21.1 nanograms per milliliter (ng/mL) | Standard Deviation 14.8 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics (PK): Plasma Concentrations of Tesevatinib 100 mg and 150 mg | Day 14: Pre-dose | 90.3 nanograms per milliliter (ng/mL) | Standard Deviation 29.1 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics (PK): Plasma Concentrations of Tesevatinib 100 mg and 150 mg | Day 1: 2 hours post-dose | 10.1 nanograms per milliliter (ng/mL) | Standard Deviation 10.2 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics (PK): Plasma Concentrations of Tesevatinib 100 mg and 150 mg | Day 14: 1 hour post-dose | 94.0 nanograms per milliliter (ng/mL) | Standard Deviation 26.9 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics (PK): Plasma Concentrations of Tesevatinib 100 mg and 150 mg | Day 1: 8 hours post-dose | 25.4 nanograms per milliliter (ng/mL) | Standard Deviation 12.1 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics (PK): Plasma Concentrations of Tesevatinib 100 mg and 150 mg | Day 14: 2 hours post-dose | 103 nanograms per milliliter (ng/mL) | Standard Deviation 29.4 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics (PK): Plasma Concentrations of Tesevatinib 100 mg and 150 mg | Day 1: 1 hour post-dose | 4.39 nanograms per milliliter (ng/mL) | Standard Deviation 2.78 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics (PK): Plasma Concentrations of Tesevatinib 100 mg and 150 mg | Day 14: 4 hours post-dose | 111 nanograms per milliliter (ng/mL) | Standard Deviation 39.7 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics (PK): Plasma Concentrations of Tesevatinib 100 mg and 150 mg | Day 1: 24 hours post-dose | 21.9 nanograms per milliliter (ng/mL) | Standard Deviation 9.69 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics (PK): Plasma Concentrations of Tesevatinib 100 mg and 150 mg | Day 14: 24 hours post-dose | 91.1 nanograms per milliliter (ng/mL) | Standard Deviation 28.9 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics (PK): Plasma Concentrations of Tesevatinib 100 mg and 150 mg | Day 1: Pre-dose | 0 nanograms per milliliter (ng/mL) | Standard Deviation 0 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 1b: Pharmacokinetics (PK): Plasma Concentrations of Tesevatinib 100 mg and 150 mg | Day 14: 24 hours post-dose | 150 nanograms per milliliter (ng/mL) | Standard Deviation 37 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 1b: Pharmacokinetics (PK): Plasma Concentrations of Tesevatinib 100 mg and 150 mg | Day 1: Pre-dose | 0 nanograms per milliliter (ng/mL) | Standard Deviation 0 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 1b: Pharmacokinetics (PK): Plasma Concentrations of Tesevatinib 100 mg and 150 mg | Day 1: 1 hour post-dose | 8.41 nanograms per milliliter (ng/mL) | Standard Deviation 5.84 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 1b: Pharmacokinetics (PK): Plasma Concentrations of Tesevatinib 100 mg and 150 mg | Day 1: 2 hours post-dose | 18.6 nanograms per milliliter (ng/mL) | Standard Deviation 12 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 1b: Pharmacokinetics (PK): Plasma Concentrations of Tesevatinib 100 mg and 150 mg | Day 1: 4 hours post-dose | 33.1 nanograms per milliliter (ng/mL) | Standard Deviation 8.24 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 1b: Pharmacokinetics (PK): Plasma Concentrations of Tesevatinib 100 mg and 150 mg | Day 1: 8 hours post-dose | 44.3 nanograms per milliliter (ng/mL) | Standard Deviation 7.5 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 1b: Pharmacokinetics (PK): Plasma Concentrations of Tesevatinib 100 mg and 150 mg | Day 1: 24 hours post-dose | 35.5 nanograms per milliliter (ng/mL) | Standard Deviation 7.1 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 1b: Pharmacokinetics (PK): Plasma Concentrations of Tesevatinib 100 mg and 150 mg | Day 14: Pre-dose | 164 nanograms per milliliter (ng/mL) | Standard Deviation 45.4 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 1b: Pharmacokinetics (PK): Plasma Concentrations of Tesevatinib 100 mg and 150 mg | Day 14: 1 hour post-dose | 160 nanograms per milliliter (ng/mL) | Standard Deviation 37.2 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 1b: Pharmacokinetics (PK): Plasma Concentrations of Tesevatinib 100 mg and 150 mg | Day 14: 2 hours post-dose | 180 nanograms per milliliter (ng/mL) | Standard Deviation 47.3 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 1b: Pharmacokinetics (PK): Plasma Concentrations of Tesevatinib 100 mg and 150 mg | Day 14: 4 hours post-dose | 204 nanograms per milliliter (ng/mL) | Standard Deviation 66.8 |
Primary
Phase 1b: Pharmacokinetics: Plasma Concentrations of Tesevatinib 50 mg
Plasma concentrations of tesevatinib was analyzed using non-compartmental analysis.
Time frame: Pre-dose, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and pre-dose, 1, 2, 4, and 24 hours post-dose on Day 14
Population: Analysis was performed on PK Population which consisted of all participants who received at least one dose of tesevatinib 50 mg in Phase 1b and had quantifiable PK data available. Here, overall number of participants analyzed = participants evaluable for this outcome measure (OM) and 'number analyzed' = participants with available data for each specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Plasma Concentrations of Tesevatinib 50 mg | Day 1: Pre-dose | 0 ng/mL | Standard Deviation 0 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Plasma Concentrations of Tesevatinib 50 mg | Day 1: 1 hour post-dose | 2.20 ng/mL | Standard Deviation 2.06 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Plasma Concentrations of Tesevatinib 50 mg | Day 1: 2 hours post-dose | 5.22 ng/mL | Standard Deviation 3.58 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Plasma Concentrations of Tesevatinib 50 mg | Day 1: 4 hours post-dose | 10.4 ng/mL | Standard Deviation 4.77 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Plasma Concentrations of Tesevatinib 50 mg | Day 1: 8 hours post-dose | 12.1 ng/mL | Standard Deviation 5.74 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Plasma Concentrations of Tesevatinib 50 mg | Day 1: 24 hours post-dose | 13.6 ng/mL | Standard Deviation 4.18 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Plasma Concentrations of Tesevatinib 50 mg | Day 14: Pre-dose | 54.4 ng/mL | Standard Deviation 20.5 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Plasma Concentrations of Tesevatinib 50 mg | Day 14: 1 hour post-dose | 56.8 ng/mL | Standard Deviation 22.3 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Plasma Concentrations of Tesevatinib 50 mg | Day 14: 2 hours post-dose | 58.5 ng/mL | Standard Deviation 23.2 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Plasma Concentrations of Tesevatinib 50 mg | Day 14: 4 hours post-dose | 63.2 ng/mL | Standard Deviation 23.3 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Plasma Concentrations of Tesevatinib 50 mg | Day 14: 24 hours post-dose | 55.8 ng/mL | Standard Deviation 19.1 |
Primary
Phase 1b: Pharmacokinetics: Time of the Last Quantifiable Plasma Concentration of Tesevatinib 50 mg
Tlast was defined as time to reach last quantifiable plasma concentration.
Time frame: Pre-dose, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and pre-dose, 1, 2, 4, and 24 hours post-dose on Day 14
Population: Analysis was performed on PK Population. Here, overall number of participants analyzed = participants evaluable for this OM and 'number analyzed' = participants with available data for each specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Time of the Last Quantifiable Plasma Concentration of Tesevatinib 50 mg | Day 1 | 23.9 hours | Standard Deviation 0.177 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Time of the Last Quantifiable Plasma Concentration of Tesevatinib 50 mg | Day 14 | 23.9 hours | Standard Deviation 0.266 |
Primary
Phase 1b: Pharmacokinetics: Time of the Last Quantifiable Plasma Concentration (Tlast) of Tesevatinib 100 mg and 150 mg
Tlast was defined as time to reach last quantifiable plasma concentration.
Time frame: Pre-dose, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and pre-dose, 1, 2, 4, and 24 hours post-dose on Day 14
Population: Analysis was performed on PK Population. Here, 'number analyzed' = participants with available data for each specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Time of the Last Quantifiable Plasma Concentration (Tlast) of Tesevatinib 100 mg and 150 mg | Day 1 | 23.9 hours | Standard Deviation 0.264 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Time of the Last Quantifiable Plasma Concentration (Tlast) of Tesevatinib 100 mg and 150 mg | Day 14 | 23.5 hours | Standard Deviation 0.606 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Time of the Last Quantifiable Plasma Concentration (Tlast) of Tesevatinib 100 mg and 150 mg | Day 1 | 23.9 hours | Standard Deviation 0.132 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Time of the Last Quantifiable Plasma Concentration (Tlast) of Tesevatinib 100 mg and 150 mg | Day 14 | 23.9 hours | Standard Deviation 0.154 |
Primary
Phase 1b: Pharmacokinetics: Time of the Maximum Observed Plasma Concentration of Tesevatinib 50 mg
Tmax was defined as time to reach maximum observed plasma concentration.
Time frame: Pre-dose, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and pre-dose, 1, 2, 4, and 24 hours post-dose on Day 14
Population: Analysis was performed on PK Population. Here, overall number of participants analyzed = participants evaluable for this OM and 'number analyzed' = participants with available data for each specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Time of the Maximum Observed Plasma Concentration of Tesevatinib 50 mg | Day 1 | 16.4 hours | Standard Deviation 8.86 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Time of the Maximum Observed Plasma Concentration of Tesevatinib 50 mg | Day 14 | 5.33 hours | Standard Deviation 6.34 |
Primary
Phase 1b: Pharmacokinetics: Time of the Maximum Observed Plasma Concentration (Tmax) of Tesevatinib 100 mg and 150 mg
Tmax was defined as time to reach maximum observed plasma concentration.
Time frame: Pre-dose, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and pre-dose, 1, 2, 4, and 24 hours post-dose on Day 14
Population: Analysis was performed on PK Population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Time of the Maximum Observed Plasma Concentration (Tmax) of Tesevatinib 100 mg and 150 mg | Day 1 | 10.9 hours | Standard Deviation 8.09 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Time of the Maximum Observed Plasma Concentration (Tmax) of Tesevatinib 100 mg and 150 mg | Day 14 | 6.25 hours | Standard Deviation 7.01 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Time of the Maximum Observed Plasma Concentration (Tmax) of Tesevatinib 100 mg and 150 mg | Day 1 | 7.99 hours | Standard Deviation 0.0434 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Time of the Maximum Observed Plasma Concentration (Tmax) of Tesevatinib 100 mg and 150 mg | Day 14 | 3.59 hours | Standard Deviation 0.891 |
Primary
Phase 1b: Pharmacokinetics: Trough Plasma Concentrations (Ctrough) of Tesevatinib 100 mg and 500 mg
Ctrough was the plasma concentration observed at the time immediately before (pre-dose) study drug administration.
Time frame: Pre-dose on Days 7, 14, 21, 28 and Months 2, 3, 4, 5 and 6
Population: Analysis was performed on PK Population. Here, 'number analyzed' = participants with available data for each specified category.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Trough Plasma Concentrations (Ctrough) of Tesevatinib 100 mg and 500 mg | Day 14: Pre-dose | 90.3 ng/mL |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Trough Plasma Concentrations (Ctrough) of Tesevatinib 100 mg and 500 mg | Month 3: Pre-dose | 113 ng/mL |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Trough Plasma Concentrations (Ctrough) of Tesevatinib 100 mg and 500 mg | Day 28: Pre-dose | 93.7 ng/mL |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Trough Plasma Concentrations (Ctrough) of Tesevatinib 100 mg and 500 mg | Month 4: Pre-dose | 128 ng/mL |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Trough Plasma Concentrations (Ctrough) of Tesevatinib 100 mg and 500 mg | Day 21: Pre-dose | 88.1 ng/mL |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Trough Plasma Concentrations (Ctrough) of Tesevatinib 100 mg and 500 mg | Month 5: Pre-dose | 89.0 ng/mL |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Trough Plasma Concentrations (Ctrough) of Tesevatinib 100 mg and 500 mg | Month 2: Pre-dose | 87.0 ng/mL |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Trough Plasma Concentrations (Ctrough) of Tesevatinib 100 mg and 500 mg | Month 6: Pre-dose | 84.7 ng/mL |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Trough Plasma Concentrations (Ctrough) of Tesevatinib 100 mg and 500 mg | Day 7: Pre-dose | 72.7 ng/mL |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Trough Plasma Concentrations (Ctrough) of Tesevatinib 100 mg and 500 mg | Month 6: Pre-dose | 119 ng/mL |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Trough Plasma Concentrations (Ctrough) of Tesevatinib 100 mg and 500 mg | Day 7: Pre-dose | 143 ng/mL |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Trough Plasma Concentrations (Ctrough) of Tesevatinib 100 mg and 500 mg | Day 14: Pre-dose | 164 ng/mL |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Trough Plasma Concentrations (Ctrough) of Tesevatinib 100 mg and 500 mg | Day 21: Pre-dose | 155 ng/mL |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Trough Plasma Concentrations (Ctrough) of Tesevatinib 100 mg and 500 mg | Day 28: Pre-dose | 180 ng/mL |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Trough Plasma Concentrations (Ctrough) of Tesevatinib 100 mg and 500 mg | Month 2: Pre-dose | 107 ng/mL |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Trough Plasma Concentrations (Ctrough) of Tesevatinib 100 mg and 500 mg | Month 3: Pre-dose | 130.25 ng/mL |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Trough Plasma Concentrations (Ctrough) of Tesevatinib 100 mg and 500 mg | Month 4: Pre-dose | 121 ng/mL |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Trough Plasma Concentrations (Ctrough) of Tesevatinib 100 mg and 500 mg | Month 5: Pre-dose | 227.5 ng/mL |
Primary
Phase 1b: Pharmacokinetics: Trough Plasma Concentrations of Tesevatinib 50 mg
Ctrough was the plasma concentration observed at the time immediately before study drug administration.
Time frame: Pre-dose on Days 7, 14, 21, 28 and Months 2, 3, 4, 5 and 6
Population: Analysis was performed on PK Population. Here, overall number of participants analyzed = participants evaluable for this OM and 'number analyzed' = participants with available data for each specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Trough Plasma Concentrations of Tesevatinib 50 mg | Day 7: Pre-dose | 45.4 ng/mL | Standard Deviation 14.8 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Trough Plasma Concentrations of Tesevatinib 50 mg | Day 14: Pre-dose | 54.4 ng/mL | Standard Deviation 20.5 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Trough Plasma Concentrations of Tesevatinib 50 mg | Day 21: Pre-dose | 59.9 ng/mL | Standard Deviation 23.8 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Trough Plasma Concentrations of Tesevatinib 50 mg | Day 28: Pre-dose | 59.5 ng/mL | Standard Deviation 26.7 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Trough Plasma Concentrations of Tesevatinib 50 mg | Month 2: Pre-dose | 54.9 ng/mL | Standard Deviation 24.5 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Trough Plasma Concentrations of Tesevatinib 50 mg | Month 3: Pre-dose | 50.0 ng/mL | Standard Deviation 21.8 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Trough Plasma Concentrations of Tesevatinib 50 mg | Month 4: Pre-dose | 45.5 ng/mL | Standard Deviation 17.4 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Trough Plasma Concentrations of Tesevatinib 50 mg | Month 5: Pre-dose | 46.5 ng/mL | Standard Deviation 16.3 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 1b: Pharmacokinetics: Trough Plasma Concentrations of Tesevatinib 50 mg | Month 6: Pre-dose | 44.8 ng/mL | Standard Deviation 17.9 |
Primary
Phase 2a: Annualized Percent Change From Baseline in Estimated Glomerular Filtration Rate (eGFR)
eGFR: measures kidney function based on serum creatinine (Scr) and cystatin C (Scys). Annualized change in eGFR was calculated as: percent change from Baseline divided by total duration in days\*365.25. eGFR was estimated using 3 formulas and is reported separately for each formula: 1) 4-variable modification of diet in renal disease (MDRD-4) : Black/African-American males:175\*(Creatinine \[Cr\]\^-1.154)\*(Age\^-0.203)\*1.212, other males:175\*(Cr\^-1.154)\*(Age\^-0.203), females: male equation\*0.742.; 2) cystatin C-based chronic kidney disease (CKD) epidemiology (EPI) (CKD-EPI2012cys) equation: based on Scyc levels, for males if \<=0.8: 133\*(Scys/0.8)\^0.499\*0.996\^age, if \>0.8: 133\*(Scys/0.8)\^-1.238\*0.996\^age; for female: male equation\*0.932., 3) Scr- and Scys-based CKD-EPI (CKD EPI2012Scr-cys) equation: 135\*(Scr/0.9)\^XX\*(Scys/0.8)\^XXX\*0.995\^age\*(× 1.08, if black)- XX and XXX had variable values based on different values of Scr and Scys.
Time frame: Baseline (Day 1), Months 6, 12, 18, 24 and at end of study (i.e., anytime up to 37 months)
Population: Analyzed on modified intent-to-treat (mITT) population which included all participants who completed 25 days (Phase 2a participants in the Monday/Thursday dosing cohort), 26 days (Phase 2a participants in the Monday/Wednesday/Friday dosing cohort), and 28 days (SILK Cohort). Here, 'number analyzed' = participants with available data for each specified category. Data for this OM was not planned to be collected and analyzed for Phase 1b participants as pre specified in protocol.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | Month 12: CKD-EPI2012Scr-cys | -0.028 percent change/participant-year | Standard Deviation 0.0721 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | Month 6: CKD-EPI2012Scr-cys | -0.031 percent change/participant-year | Standard Deviation 0.1522 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | Month 24: CKD-EPI2012cys | -0.000 percent change/participant-year | Standard Deviation 0.0245 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | Month 18: MDRD-4 | -0.087 percent change/participant-year | Standard Deviation 0.068 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | Month 6: CKD-EPI2012cys | 0.069 percent change/participant-year | Standard Deviation 0.215 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | Month 24: MDRD-4 | -0.010 percent change/participant-year | Standard Deviation 0.0657 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | Month 18: CKD-EPI2012cys | 0.006 percent change/participant-year | Standard Deviation 0.0251 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | End of study: MDRD-4 | -0.026 percent change/participant-year | Standard Deviation 0.2369 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | Month 18: CKD-EPI2012Scr-cys | -0.040 percent change/participant-year | Standard Deviation 0.0379 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | Month 12: MDRD-4 | -0.096 percent change/participant-year | Standard Deviation 0.1177 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | End of study: CKD-EPI2012Scr-cys | -0.018 percent change/participant-year | Standard Deviation 0.1259 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | Month 6: MDRD-4 | -0.125 percent change/participant-year | Standard Deviation 0.3236 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | Month 12: CKD-EPI2012cys | 0.040 percent change/participant-year | Standard Deviation 0.0644 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | End of study: CKD-EPI2012cys | 0.005 percent change/participant-year | Standard Deviation 0.0937 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | Month 24: CKD-EPI2012Scr-cys | -0.008 percent change/participant-year | Standard Deviation 0.024 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | Month 24: CKD-EPI2012Scr-cys | -0.015 percent change/participant-year | Standard Deviation 0.0251 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | Month 6: MDRD-4 | -0.150 percent change/participant-year | Standard Deviation 0.1515 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | Month 6: CKD-EPI2012cys | 0.125 percent change/participant-year | Standard Deviation 0.1795 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | Month 6: CKD-EPI2012Scr-cys | -0.009 percent change/participant-year | Standard Deviation 0.1277 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | Month 12: MDRD-4 | -0.103 percent change/participant-year | Standard Deviation 0.1222 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | Month 12: CKD-EPI2012cys | 0.031 percent change/participant-year | Standard Deviation 0.0696 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | Month 12: CKD-EPI2012Scr-cys | -0.040 percent change/participant-year | Standard Deviation 0.0861 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | Month 18: MDRD-4 | -0.060 percent change/participant-year | Standard Deviation 0.0402 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | Month 18: CKD-EPI2012cys | 0.055 percent change/participant-year | Standard Deviation 0.0674 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | Month 18: CKD-EPI2012Scr-cys | 0.000 percent change/participant-year | Standard Deviation 0.0463 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | Month 24: MDRD-4 | -0.049 percent change/participant-year | Standard Deviation 0.05 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | Month 24: CKD-EPI2012cys | 0.029 percent change/participant-year | Standard Deviation 0.0388 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | End of study: MDRD-4 | -0.084 percent change/participant-year | Standard Deviation 0.1903 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | End of study: CKD-EPI2012cys | 0.128 percent change/participant-year | Standard Deviation 0.2872 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | End of study: CKD-EPI2012Scr-cys | 0.014 percent change/participant-year | Standard Deviation 0.0451 |
| Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | Month 12: CKD-EPI2012Scr-cys | -0.113 percent change/participant-year | Standard Deviation 0.0565 |
| Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | End of study: CKD-EPI2012cys | -0.061 percent change/participant-year | Standard Deviation 0.0827 |
| Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | Month 24: CKD-EPI2012cys | -0.017 percent change/participant-year | Standard Deviation 0.1081 |
| Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | Month 12: CKD-EPI2012cys | -0.037 percent change/participant-year | Standard Deviation 0.0966 |
| Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | Month 12: MDRD-4 | -0.173 percent change/participant-year | Standard Deviation 0.0515 |
| Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | Month 24: CKD-EPI2012Scr-cys | -0.051 percent change/participant-year | Standard Deviation 0.0734 |
| Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | Month 6: CKD-EPI2012Scr-cys | -0.043 percent change/participant-year | Standard Deviation 0.1341 |
| Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | Month 6: MDRD-4 | -0.195 percent change/participant-year | Standard Deviation 0.1851 |
| Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | End of study: MDRD-4 | -0.021 percent change/participant-year | Standard Deviation 0.0836 |
| Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | Month 18: CKD-EPI2012cys | 0.024 percent change/participant-year | Standard Deviation 0.1167 |
| Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | Month 6: CKD-EPI2012cys | 0.131 percent change/participant-year | Standard Deviation 0.231 |
| Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | Month 18: CKD-EPI2012Scr-cys | -0.056 percent change/participant-year | Standard Deviation 0.1049 |
| Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | Month 18: MDRD-4 | -0.121 percent change/participant-year | Standard Deviation 0.1002 |
| Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | End of study: CKD-EPI2012Scr-cys | -0.045 percent change/participant-year | Standard Deviation 0.0723 |
| Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | Month 24: MDRD-4 | -0.077 percent change/participant-year | Standard Deviation 0.0752 |
Secondary
Phase 2a: Annualized Percent Change From Baseline in Height Adjusted Total Kidney Volume (htTKV) at Month 6, 12, 18, 24 and End of Study
htTKV was calculated using total kidney volume obtained from magnetic resonance imaging (MRI) divided by height in meters. The annualized percent change from Baseline was calculated as the percent change from Baseline divided by total duration in days\*365.25.
Time frame: Baseline (Day 1), Months 6, 12, 18, 24 and at end of study (i.e., anytime up to 37 months)
Population: Analysis was performed on mITT population. Here, 'number analyzed' = participants with available data for each specified category. Data for this OM was not planned to be collected and analyzed for Phase 1b participants as pre specified in protocol.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Height Adjusted Total Kidney Volume (htTKV) at Month 6, 12, 18, 24 and End of Study | Month 24 | 0.0702 percent change/participant-year | Standard Deviation 0.0517 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Height Adjusted Total Kidney Volume (htTKV) at Month 6, 12, 18, 24 and End of Study | Month 18 | 0.0632 percent change/participant-year | Standard Deviation 0.0512 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Height Adjusted Total Kidney Volume (htTKV) at Month 6, 12, 18, 24 and End of Study | Month 6 | 0.0696 percent change/participant-year | Standard Deviation 0.1161 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Height Adjusted Total Kidney Volume (htTKV) at Month 6, 12, 18, 24 and End of Study | Month 12 | 0.0503 percent change/participant-year | Standard Deviation 0.0758 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Height Adjusted Total Kidney Volume (htTKV) at Month 6, 12, 18, 24 and End of Study | End of study | 0.0943 percent change/participant-year | — |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Height Adjusted Total Kidney Volume (htTKV) at Month 6, 12, 18, 24 and End of Study | Month 18 | 0.0353 percent change/participant-year | Standard Deviation 0.0483 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Height Adjusted Total Kidney Volume (htTKV) at Month 6, 12, 18, 24 and End of Study | Month 6 | 0.0544 percent change/participant-year | Standard Deviation 0.1292 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Height Adjusted Total Kidney Volume (htTKV) at Month 6, 12, 18, 24 and End of Study | Month 12 | 0.0422 percent change/participant-year | Standard Deviation 0.0687 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Height Adjusted Total Kidney Volume (htTKV) at Month 6, 12, 18, 24 and End of Study | Month 24 | 0.0540 percent change/participant-year | Standard Deviation 0.0584 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Height Adjusted Total Kidney Volume (htTKV) at Month 6, 12, 18, 24 and End of Study | End of study | 0.0517 percent change/participant-year | Standard Deviation 0.0327 |
| Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Height Adjusted Total Kidney Volume (htTKV) at Month 6, 12, 18, 24 and End of Study | End of study | 0.0731 percent change/participant-year | — |
| Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Height Adjusted Total Kidney Volume (htTKV) at Month 6, 12, 18, 24 and End of Study | Month 24 | 0.1080 percent change/participant-year | Standard Deviation 0.0536 |
| Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Height Adjusted Total Kidney Volume (htTKV) at Month 6, 12, 18, 24 and End of Study | Month 6 | 0.1570 percent change/participant-year | Standard Deviation 0.0943 |
| Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Height Adjusted Total Kidney Volume (htTKV) at Month 6, 12, 18, 24 and End of Study | Month 18 | 0.0841 percent change/participant-year | Standard Deviation 0.0277 |
| Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in Height Adjusted Total Kidney Volume (htTKV) at Month 6, 12, 18, 24 and End of Study | Month 12 | 0.1145 percent change/participant-year | Standard Deviation 0.0722 |
Secondary
Phase 2a: Annualized Percent Change From Baseline in the Reciprocal of Serum Creatinine at End of Study
Reciprocal Creatinine was an indication for monitoring renal disease progression over time. The annualized percent change from Baseline was calculated as the percent change from Baseline divided by total duration in days\*365.25.
Time frame: Baseline (Day 1), at end of study (i.e., anytime up to 37 months)
Population: Analysis was performed on mITT Population. Data for this OM was not planned to be collected and analyzed for Phase 1b participants as pre specified in protocol.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in the Reciprocal of Serum Creatinine at End of Study | -8.2923 percent change per participant-year | Standard Deviation 29.0965 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in the Reciprocal of Serum Creatinine at End of Study | -6.9630 percent change per participant-year | Standard Deviation 20.2475 |
| Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing | Phase 2a: Annualized Percent Change From Baseline in the Reciprocal of Serum Creatinine at End of Study | 4.0189 percent change per participant-year | Standard Deviation 20.0561 |
Secondary
Phase 2a: Change From Baseline in Serum Creatinine Levels
Serum creatinine levels indicated the renal function (normal or abnormal) over time.
Time frame: Baseline, Day 1, 3, 7, 11, 12, 14, 21, 25, 26, 28, Month 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 18, 20, 22, 24, and at end of study (i.e., anytime up to 37 months)
Population: Analysis was performed on safety population. Here, 'number analyzed' = participants with available data for each specified category and '0' in the number analyzed field signifies that none of the participants were evaluable at the specified timepoint. Data for this OM was not planned to be collected and analyzed for Phase 1b participants as pre specified in protocol.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Month 22 | 6.7 micromoles per liter | Standard Deviation 11.2 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Month 10 | 7.5 micromoles per liter | Standard Deviation 13.7 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Month 2 | 9.6 micromoles per liter | Standard Deviation 14.1 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Month 11 | 12.1 micromoles per liter | Standard Deviation 11.3 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Month 12 | 8.6 micromoles per liter | Standard Deviation 10.4 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Month 24 | 2.8 micromoles per liter | Standard Deviation 10.6 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Month 3 | 8.4 micromoles per liter | Standard Deviation 11.6 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Month 14 | 6.1 micromoles per liter | Standard Deviation 10 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Month 16 | 11.7 micromoles per liter | Standard Deviation 11.5 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Day 11 | 4.5 micromoles per liter | Standard Deviation 9 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Month 18 | 11.4 micromoles per liter | Standard Deviation 11.3 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Month 4 | 10.6 micromoles per liter | Standard Deviation 14 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Month 20 | 5.7 micromoles per liter | Standard Deviation 11.4 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | End of study | 5.5 micromoles per liter | Standard Deviation 10.1 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Month 5 | 4.4 micromoles per liter | Standard Deviation 12.9 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Month 6 | 5.4 micromoles per liter | Standard Deviation 11 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Month 7 | 9.6 micromoles per liter | Standard Deviation 9.6 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Day 25 | 5.3 micromoles per liter | Standard Deviation 10.9 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Month 8 | 11.4 micromoles per liter | Standard Deviation 11.1 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Month 9 | 10.6 micromoles per liter | Standard Deviation 11.8 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Month 8 | 5.4 micromoles per liter | Standard Deviation 6.7 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Month 4 | 4.5 micromoles per liter | Standard Deviation 12 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Month 10 | 2.6 micromoles per liter | Standard Deviation 7.8 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Month 7 | 6.1 micromoles per liter | Standard Deviation 6 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | End of study | 3.6 micromoles per liter | Standard Deviation 8.3 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Month 11 | 9.2 micromoles per liter | Standard Deviation 9.5 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Month 2 | 5.8 micromoles per liter | Standard Deviation 7.3 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Month 20 | 4.6 micromoles per liter | Standard Deviation 9.1 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Month 12 | 8.0 micromoles per liter | Standard Deviation 9.8 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Day 12 | 12.5 micromoles per liter | Standard Deviation 8.5 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Day 26 | 8.2 micromoles per liter | Standard Deviation 6.4 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Month 5 | 4.6 micromoles per liter | Standard Deviation 6.9 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Month 14 | 13.6 micromoles per liter | Standard Deviation 9.8 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Month 3 | 7.3 micromoles per liter | Standard Deviation 8.6 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Month 24 | 7.0 micromoles per liter | Standard Deviation 7 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Month 16 | 6.7 micromoles per liter | Standard Deviation 7.2 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Month 9 | 6.5 micromoles per liter | Standard Deviation 7.7 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Month 6 | 5.5 micromoles per liter | Standard Deviation 5.6 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Month 18 | 6.6 micromoles per liter | Standard Deviation 4.2 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Month 22 | 5.9 micromoles per liter | Standard Deviation 10.3 |
| Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | End of study | 6.3 micromoles per liter | Standard Deviation 17.4 |
| Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Month 20 | 12.3 micromoles per liter | Standard Deviation 26.9 |
| Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Month 22 | 12.3 micromoles per liter | Standard Deviation 20.3 |
| Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Day 1 | 35.5 micromoles per liter | Standard Deviation 34.6 |
| Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Day 3 | 9.8 micromoles per liter | Standard Deviation 11.4 |
| Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Day 7 | 11.1 micromoles per liter | Standard Deviation 15.6 |
| Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Day 14 | 8.3 micromoles per liter | Standard Deviation 12.2 |
| Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Day 21 | 14.9 micromoles per liter | Standard Deviation 17.5 |
| Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Day 28 | 14.9 micromoles per liter | Standard Deviation 15.2 |
| Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Month 2 | 7.4 micromoles per liter | Standard Deviation 20.5 |
| Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Month 3 | 10.8 micromoles per liter | Standard Deviation 10.7 |
| Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Month 4 | 14.6 micromoles per liter | Standard Deviation 12.4 |
| Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Month 5 | 7.1 micromoles per liter | Standard Deviation 10.6 |
| Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Month 6 | 10.4 micromoles per liter | Standard Deviation 9.9 |
| Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Month 7 | 24.9 micromoles per liter | Standard Deviation 26.2 |
| Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Month 8 | 9.4 micromoles per liter | Standard Deviation 8.3 |
| Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Month 9 | 12.0 micromoles per liter | Standard Deviation 17.2 |
| Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Month 10 | 14.6 micromoles per liter | Standard Deviation 9 |
| Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Month 11 | 13.3 micromoles per liter | Standard Deviation 18.7 |
| Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Month 12 | 20.7 micromoles per liter | Standard Deviation 9.7 |
| Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Month 13 | 0.0 micromoles per liter | — |
| Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Month 14 | 13.3 micromoles per liter | Standard Deviation 8.7 |
| Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Month 16 | 15.6 micromoles per liter | Standard Deviation 13.1 |
| Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Month 18 | 21.6 micromoles per liter | Standard Deviation 17.4 |
| Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing | Phase 2a: Change From Baseline in Serum Creatinine Levels | Month 24 | 18.0 micromoles per liter | Standard Deviation 20.6 |
Secondary
Phase 2a: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (TESAE)
An AE was any untoward medical occurrence in a clinical study participant administered a medicinal product and which did not necessarily had to have a causal relationship with the treatment. An SAE was any untoward medical occurrence at any dose that: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. TEAEs were AEs that developed or worsened or became serious from the first dose (Day 1) of the study drug until 30 days after the last dose of study drug.
Time frame: From Baseline (Day 1) until 30 days after the last dose of study drug (i.e., up to 29 months)
Population: Analysis was performed on safety population.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (TESAE) | TEAEs | 10 Participants |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (TESAE) | SAEs | 1 Participants |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (TESAE) | TEAEs | 14 Participants |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (TESAE) | SAEs | 0 Participants |
| Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing | Phase 2a: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (TESAE) | TEAEs | 8 Participants |
| Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing | Phase 2a: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (TESAE) | SAEs | 1 Participants |
Secondary
Phase 2a: Pharmacokinetics: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours Post-dose (AUC0-24) of Tesevatinib 150 mg
AUC0-24 was defined as area under the plasma concentration versus time curve of study drug from time 0 to 24 hours post-dose.
Time frame: Bi-weekly: pre-dose, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and Day 25; Tri-weekly: pre-dose, 1, 2, 4, 8, and 24 hours post-dose on Day 1; pre-dose, 1, 2, 4, and 24 hours post-dose on Day 12
Population: Analysis was performed on PK population. Here, overall number of participants analyzed = participants evaluable for this OM and 'number analyzed' = participants with available data for each specified category and '0' in the number analyzed field signifies that none of the participants were evaluable at the specified timepoint. Data for this OM was not planned to be collected and analyzed for Phase 2a SILK cohort participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours Post-dose (AUC0-24) of Tesevatinib 150 mg | Day 1 | 1090 hr*ng/mL | Standard Deviation 277 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours Post-dose (AUC0-24) of Tesevatinib 150 mg | Day 25 | 1740 hr*ng/mL | Standard Deviation 551 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours Post-dose (AUC0-24) of Tesevatinib 150 mg | Day 1 | 1020 hr*ng/mL | Standard Deviation 424 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours Post-dose (AUC0-24) of Tesevatinib 150 mg | Day 12 | 2280 hr*ng/mL | Standard Deviation 791 |
Secondary
Phase 2a: Pharmacokinetics: Area Under the Plasma Concentration-time Curve From Time 0 to the Last Quantifiable Concentration (AUC0-t) of Tesevatinib 150 mg
AUC0-last was defined as area under the concentration-time curve (AUC) from time 0 to the time of the last quantifiable concentration (tlast).
Time frame: Bi-weekly: pre-dose, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and Day 25; Tri-weekly: pre-dose, 1, 2, 4, 8, and 24 hours post-dose on Day 1; pre-dose, 1, 2, 4, and 24 hours post-dose on Day 12
Population: Analysis was performed on PK population. Here, overall number of participants analyzed = participants evaluable for this OM and 'number analyzed' = participants with available data for each specified category and '0' in the number analyzed field signifies that none of the participants were evaluable at the specified timepoint. Data for this OM was not planned to be collected and analyzed for Phase 2a SILK cohort participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Area Under the Plasma Concentration-time Curve From Time 0 to the Last Quantifiable Concentration (AUC0-t) of Tesevatinib 150 mg | Day 1 | 1090 hr*ng/mL | Standard Deviation 274 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Area Under the Plasma Concentration-time Curve From Time 0 to the Last Quantifiable Concentration (AUC0-t) of Tesevatinib 150 mg | Day 25 | 1760 hr*ng/mL | Standard Deviation 559 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Area Under the Plasma Concentration-time Curve From Time 0 to the Last Quantifiable Concentration (AUC0-t) of Tesevatinib 150 mg | Day 1 | 866 hr*ng/mL | Standard Deviation 509 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Area Under the Plasma Concentration-time Curve From Time 0 to the Last Quantifiable Concentration (AUC0-t) of Tesevatinib 150 mg | Day 12 | 1860 hr*ng/mL | Standard Deviation 1160 |
Secondary
Phase 2a: Pharmacokinetics: Concentration Immediately Before Dosing (Ctrough) of Tesevatinib 150 mg
Ctrough was the plasma concentration observed at the time immediately before study drug administration.
Time frame: Bi-weekly: Pre-dose on Days 8, 11, 18 and 25; pre-dose on Months 2, 3, 4, 5 and 6; Tri-weekly: pre-dose on Days 3, 5, 8 and 12
Population: Analysis was performed on PK population. Here, overall number of participants analyzed = participants evaluable for this OM and 'number analyzed' = participants with available data for each specified category and '0' in the number analyzed field signifies that none of the participants were evaluable at the specified timepoint. Data for this OM was not planned to be collected and analyzed for Phase 2a SILK cohort participants.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Concentration Immediately Before Dosing (Ctrough) of Tesevatinib 150 mg | Month 6: Pre-dose | 21.6 ng/mL |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Concentration Immediately Before Dosing (Ctrough) of Tesevatinib 150 mg | Month 2: Pre-dose | 34.1 ng/mL |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Concentration Immediately Before Dosing (Ctrough) of Tesevatinib 150 mg | Month 3: Pre-dose | 14.6 ng/mL |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Concentration Immediately Before Dosing (Ctrough) of Tesevatinib 150 mg | Month 4: Pre-dose | 47.55 ng/mL |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Concentration Immediately Before Dosing (Ctrough) of Tesevatinib 150 mg | Month 5: Pre-dose | 45.0 ng/mL |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Concentration Immediately Before Dosing (Ctrough) of Tesevatinib 150 mg | Day 8: Pre-dose | 28.0 ng/mL |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Concentration Immediately Before Dosing (Ctrough) of Tesevatinib 150 mg | Day 11: Pre-dose | 38.8 ng/mL |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Concentration Immediately Before Dosing (Ctrough) of Tesevatinib 150 mg | Day 18: Pre-dose | 33.6 ng/mL |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Concentration Immediately Before Dosing (Ctrough) of Tesevatinib 150 mg | Day 25: Pre-dose | 29.6 ng/mL |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Concentration Immediately Before Dosing (Ctrough) of Tesevatinib 150 mg | Day 5: Pre-dose | 57.6 ng/mL |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Concentration Immediately Before Dosing (Ctrough) of Tesevatinib 150 mg | Day 12: Pre-dose | 53.7 ng/mL |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Concentration Immediately Before Dosing (Ctrough) of Tesevatinib 150 mg | Day 8: Pre-dose | 57.3 ng/mL |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Concentration Immediately Before Dosing (Ctrough) of Tesevatinib 150 mg | Day 3: Pre-dose | 37.2 ng/mL |
Secondary
Phase 2a: Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) of Tesevatinib 150 mg
Cmax was defined as maximum observed plasma concentration.
Time frame: Bi-weekly: pre-dose, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and Day 25; Tri-weekly: pre-dose, 1, 2, 4, 8, and 24 hours post-dose on Day 1; pre-dose, 1, 2, 4, and 24 hours post-dose on Day 12
Population: Analysis was performed on PK population. Here, overall number of participants analyzed = participants evaluable for this OM and 'number analyzed' = participants with available data for each specified category and '0' in the number analyzed field signifies that none of the participants were evaluable at the specified timepoint. Data for this OM was not planned to be collected and analyzed for Phase 2a SILK cohort participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) of Tesevatinib 150 mg | Day 1 | 56.1 ng/mL | Standard Deviation 15.3 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) of Tesevatinib 150 mg | Day 25 | 84.0 ng/mL | Standard Deviation 29.2 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) of Tesevatinib 150 mg | Day 1 | 49.9 ng/mL | Standard Deviation 20.3 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) of Tesevatinib 150 mg | Day 12 | 102 ng/mL | Standard Deviation 41.5 |
Secondary
Phase 2a: Pharmacokinetics: Plasma Concentrations of Tesevatinib 150 mg
Plasma concentrations of tesevatinib was analyzed using non-compartmental analysis.
Time frame: Bi-weekly: pre-dose, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and Day 25; Tri-weekly: pre-dose, 1, 2, 4, 8, and 24 hours post-dose on Day 1; pre-dose, 1, 2, 4, and 24 hours post-dose on Day 12
Population: Analysis was performed on PK population. Here, overall number of participants analyzed = participants evaluable for this OM and 'number analyzed' = participants with available data for each specified category and '0' in the number analyzed field signifies that none of the participants were evaluable at the specified timepoint. Data for this OM was not planned to be collected and analyzed for Phase 2a SILK cohort participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Plasma Concentrations of Tesevatinib 150 mg | Day 1: 24 hours post-dose | 45.4 ng/mL | Standard Deviation 8.81 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Plasma Concentrations of Tesevatinib 150 mg | Day 25: pre-dose | 29.6 ng/mL | Standard Deviation 6.05 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Plasma Concentrations of Tesevatinib 150 mg | Day 25: 1 hour post-dose | 31.9 ng/mL | Standard Deviation 10.8 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Plasma Concentrations of Tesevatinib 150 mg | Day 25: 2 hours post-dose | 50.5 ng/mL | Standard Deviation 21.2 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Plasma Concentrations of Tesevatinib 150 mg | Day 25: 4 hours post-dose | 76.2 ng/mL | Standard Deviation 21.9 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Plasma Concentrations of Tesevatinib 150 mg | Day 25: 8 hours post-dose | 83.9 ng/mL | Standard Deviation 29.4 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Plasma Concentrations of Tesevatinib 150 mg | Day 25: 24 hours post-dose | 69.4 ng/mL | Standard Deviation 20.4 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Plasma Concentrations of Tesevatinib 150 mg | Day 1: pre-dose | 0 ng/mL | Standard Deviation 0 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Plasma Concentrations of Tesevatinib 150 mg | Day 1: 8 hours post-dose | 55.0 ng/mL | Standard Deviation 16.7 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Plasma Concentrations of Tesevatinib 150 mg | Day 1: 1 hour post-dose | 14.8 ng/mL | Standard Deviation 18.9 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Plasma Concentrations of Tesevatinib 150 mg | Day 1: 2 hours post-dose | 21.7 ng/mL | Standard Deviation 14.7 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Plasma Concentrations of Tesevatinib 150 mg | Day 1: 4 hours post-dose | 46.0 ng/mL | Standard Deviation 16.2 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Plasma Concentrations of Tesevatinib 150 mg | Day 1: 1 hour post-dose | 13.0 ng/mL | Standard Deviation 11.2 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Plasma Concentrations of Tesevatinib 150 mg | Day 1: 2 hours post-dose | 20.9 ng/mL | Standard Deviation 12.7 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Plasma Concentrations of Tesevatinib 150 mg | Day 1: 4 hours post-dose | 41.1 ng/mL | Standard Deviation 25.4 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Plasma Concentrations of Tesevatinib 150 mg | Day 1: 8 hours post-dose | 49.8 ng/mL | Standard Deviation 19.9 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Plasma Concentrations of Tesevatinib 150 mg | Day 1: 24 hours post-dose | 42.4 ng/mL | Standard Deviation 13 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Plasma Concentrations of Tesevatinib 150 mg | Day 12: pre-dose | 53.7 ng/mL | Standard Deviation 24.8 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Plasma Concentrations of Tesevatinib 150 mg | Day 12: 1 hour post-dose | 58.5 ng/mL | Standard Deviation 21.1 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Plasma Concentrations of Tesevatinib 150 mg | Day 12: 2 hours post-dose | 70.1 ng/mL | Standard Deviation 26.5 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Plasma Concentrations of Tesevatinib 150 mg | Day 12: 4 hours post-dose | 100 ng/mL | Standard Deviation 42.6 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Plasma Concentrations of Tesevatinib 150 mg | Day 12: 24 hours post-dose | 90.5 ng/mL | Standard Deviation 26.2 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Plasma Concentrations of Tesevatinib 150 mg | Day 1: pre-dose | 0 ng/mL | Standard Deviation 0 |
Secondary
Phase 2a: Pharmacokinetics: Time of the Last Quantifiable Plasma Concentration (Tlast) of Tesevatinib 150 mg
Tlast was defined as time to reach last quantifiable plasma concentration.
Time frame: Bi-weekly: pre-dose, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and Day 25; Tri-weekly: pre-dose, 1, 2, 4, 8, and 24 hours post-dose on Day 1; pre-dose, 1, 2, 4, and 24 hours post-dose on Day 12
Population: Analysis was performed on PK population. Here, overall number of participants analyzed = participants evaluable for this OM and 'number analyzed' = participants with available data for each specified category and '0' in the number analyzed field signifies that none of the participants were evaluable at the specified timepoint. Data for this OM was not planned to be collected and analyzed for Phase 2a SILK cohort participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Time of the Last Quantifiable Plasma Concentration (Tlast) of Tesevatinib 150 mg | Day 1 | 24.1 hours | Standard Deviation 0.163 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Time of the Last Quantifiable Plasma Concentration (Tlast) of Tesevatinib 150 mg | Day 25 | 24.2 hours | Standard Deviation 0.163 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Time of the Last Quantifiable Plasma Concentration (Tlast) of Tesevatinib 150 mg | Day 1 | 20.8 hours | Standard Deviation 7.17 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Time of the Last Quantifiable Plasma Concentration (Tlast) of Tesevatinib 150 mg | Day 12 | 20.0 hours | Standard Deviation 8.95 |
Secondary
Phase 2a: Pharmacokinetics: Time of the Maximum Observed Plasma Concentration (Tmax) of Tesevatinib 150 mg
Tmax was defined as time to reach maximum observed plasma concentration.
Time frame: Bi-weekly: pre-dose, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and Day 25; Tri-weekly: pre-dose, 1, 2, 4, 8, and 24 hours post-dose on Day 1; pre-dose, 1, 2, 4, and 24 hours post-dose on Day 12
Population: Analysis was performed on PK population. Here, overall number of participants analyzed = participants evaluable for this OM and 'number analyzed' = participants with available data for each specified category and '0' in the number analyzed field signifies that none of the participants were evaluable at the specified timepoint. Data for this OM was not planned to be collected and analyzed for Phase 2a SILK cohort participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Time of the Maximum Observed Plasma Concentration (Tmax) of Tesevatinib 150 mg | Day 1 | 14.5 hours | Standard Deviation 8.84 |
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Time of the Maximum Observed Plasma Concentration (Tmax) of Tesevatinib 150 mg | Day 25 | 7.03 hours | Standard Deviation 2.02 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Time of the Maximum Observed Plasma Concentration (Tmax) of Tesevatinib 150 mg | Day 1 | 7.20 hours | Standard Deviation 1.76 |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Phase 2a: Pharmacokinetics: Time of the Maximum Observed Plasma Concentration (Tmax) of Tesevatinib 150 mg | Day 12 | 12.0 hours | Standard Deviation 11 |