A Phase 1b/2a, Safety, Pharmacokinetic and Dose-Escalation Study of KD019 (Tesevatinib) in Subjects With Autosomal Dominant Polycystic Kidney Disease (ADPKD)
| Registry | NCT01559363 |
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| Status | Completed |
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| Phase | Phase 1 / Phase 2 |
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| Study type | Interventional; non randomized, sequential, masking: none, treatment |
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| Enrollment | 69 (Actual) |
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| Sponsor | Kadmon, a Sanofi Company (Industry) |
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| Conditions | Polycystic Kidney, Autosomal Dominant |
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| Interventions | Tesevatinib (Drug) |
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| Dates | start 2012-10-11, primary completion 2019-02-08, completion 2019-02-08, first posted 2012-03-21, last updated 2022-11-08 |
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| Locations | 11 sites in United States |
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Related Papers Related Patents Related Grants Related Experts
All trials for Polycystic Kidney, Autosomal Dominant All trials of Tesevatinib
-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.
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+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.
+Arms and interventions
| Arm | Type | Interventions | Description |
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| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | Experimental | Drug: Tesevatinib | Participants received tesevatinib 50 milligrams (mg) tablet orally once daily (QD) for 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). |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | Experimental | Drug: Tesevatinib | Participants received tesevatinib 100 mg tablet orally QD for 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). |
| Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing | Experimental | Drug: Tesevatinib | Participants received tesevatinib 150 mg tablet orally QD for 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). |
| Phase 2a: Cohort 4: Tesevatinib: Bi-weekly Dosing | Experimental | Drug: Tesevatinib | 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). |
| Phase 2a: Cohort 5: Tesevatinib: Tri-weekly Dosing | Experimental | Drug: Tesevatinib | 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). |
| Phase 2a: Safety in Larger Kidneys (SILK) Cohort: Tesevatinib 50 mg Once Daily Dosing | Experimental | Drug: Tesevatinib | Participants with autosomal dominant polycystic kidney disease (and Baseline estimated glomerular filtration rate (eGFR) greater than or equal to (>=) 35 milliliters per minute per 1.73 square meter (mL/min/1.73 m\^2) and less than or equal to (<=) 80 mL/min/1.73 m\^2, and height-adjusted total kidney volume (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). |
- Tesevatinib (Drug), also known as XL647 and KD019: Pharmaceutical form: Tablets Route of administration: Oral
+Outcome measures
Primary outcomes
- 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.
- 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 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.
Secondary outcomes
- 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.
- 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.
+Eligibility
Sex: All, ages: 18 Years to 62 Years
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.
+Posted results
Participant flow
| Milestone | 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 |
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| Started | 24 | 8 | 5 | 0 | 0 | 0 |
| Completed | 18 | 5 | 3 | 0 | 0 | 0 |
| Not completed | 6 | 3 | 2 | 0 | 0 | 0 |
Outcome results
- Phase 1b: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAE) (Primary), Count of participants, Participants: Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing 24; Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing 8; Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing 5
- Phase 1b: Pharmacokinetics (PK): Plasma Concentrations of Tesevatinib 100 mg and 150 mg (Primary), Mean, nanograms per milliliter (ng/mL): Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing 0 +/- 0; Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing 0 +/- 0
- Phase 1b: Pharmacokinetics: Plasma Concentrations of Tesevatinib 50 mg (Primary), Mean, ng/mL: Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing 0 +/- 0
- Phase 1b: Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) of Tesevatinib 100 mg and 150 mg (Primary), Mean, ng/mL: Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing 27.5 +/- 12.2; Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing 44.3 +/- 7.50
- Phase 1b: Pharmacokinetics: Maximum Observed Plasma Concentration of Tesevatinib 50 mg (Primary), Mean, ng/mL: Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing 14.5 +/- 5.34
- Phase 1b: Pharmacokinetics: Time of the Maximum Observed Plasma Concentration (Tmax) of Tesevatinib 100 mg and 150 mg (Primary), Mean, hours: Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing 10.9 +/- 8.09; Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing 7.99 +/- 0.0434
- Phase 1b: Pharmacokinetics: Time of the Maximum Observed Plasma Concentration of Tesevatinib 50 mg (Primary), Mean, hours: Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing 16.4 +/- 8.86
- Phase 1b: Pharmacokinetics: Time of the Last Quantifiable Plasma Concentration (Tlast) of Tesevatinib 100 mg and 150 mg (Primary), Mean, hours: Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing 23.9 +/- 0.264; Phase 1b: Cohort 3: Tesevatinib 150 mg 23.9 +/- 0.132
- Phase 1b: Pharmacokinetics: Time of the Last Quantifiable Plasma Concentration of Tesevatinib 50 mg (Primary), Mean, hours: Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing 23.9 +/- 0.177
- 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 (Primary), Mean, hour*nanograms per milliliter (hr*ng/mL): Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing 508 +/- 247; Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing 853 +/- 130
- Phase 1b: Pharmacokinetics: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of Last Quantifiable Concentration of Tesevatinib 50 mg (Primary), Mean, hr*ng/mL: Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing 272 +/- 99.9
- 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 (Primary), Mean, hr*ng/mL: Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing 507 +/- 246; Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing 853 +/- 129
- Phase 1b: Pharmacokinetics: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours Post-dose of Tesevatinib 50 mg (Primary), Mean, hr*ng/mL: Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing 272 +/- 99.8
- Phase 1b: Pharmacokinetics: Trough Plasma Concentrations (Ctrough) of Tesevatinib 100 mg and 500 mg (Primary), Mean, ng/mL: Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing 72.7 (52.0 to 108); Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing 143 (75.5 to 173)
- Phase 1b: Pharmacokinetics: Trough Plasma Concentrations of Tesevatinib 50 mg (Primary), Mean, ng/mL: Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing 45.4 +/- 14.8
- Phase 1b: Maximum Tolerated Dose (MTD) of Tesevatinib (Primary), Number, milligrams: Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing 100; Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing 100; Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing 100
- Phase 2a: Annualized Percent Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) (Primary), Mean, percent change/participant-year: Phase 2a: Cohort 4: Tesevatinib: Bi-weekly Dosing -0.125 +/- 0.3236; Phase 2a: Cohort 5: Tesevatinib: Tri-weekly Dosing -0.150 +/- 0.1515; Phase 2a: SILK Cohort: Tesevatinib 50 mg Once Daily Dosing -0.195 +/- 0.1851
- Phase 2a: Annualized Percent Change From Baseline in Height Adjusted Total Kidney Volume (htTKV) at Month 6, 12, 18, 24 and End of Study (Secondary), Mean, percent change/participant-year: Phase 2a: Cohort 4: Tesevatinib: Bi-weekly Dosing 0.0696 +/- 0.1161; Phase 2a: Cohort 5: Tesevatinib: Tri-weekly Dosing 0.0544 +/- 0.1292; Phase 2a: SILK Cohort: Tesevatinib 50 mg Once Daily Dosing 0.1570 +/- 0.0943
- Phase 2a: Annualized Percent Change From Baseline in the Reciprocal of Serum Creatinine at End of Study (Secondary), Mean, percent change per participant-year: Phase 2a: Cohort 4: Tesevatinib: Bi-weekly Dosing -8.2923 +/- 29.0965; Phase 2a: Cohort 5: Tesevatinib: Tri-weekly Dosing -6.9630 +/- 20.2475; Phase 2a: SILK Cohort: Tesevatinib 50 mg Once Daily Dosing 4.0189 +/- 20.0561
- Phase 2a: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (TESAE) (Secondary), Count of participants, Participants: Phase 2a: Cohort 4: Tesevatinib: Bi-weekly Dosing 10; Phase 2a: Cohort 5: Tesevatinib: Tri-weekly Dosing 14; Phase 2a: SILK Cohort: Tesevatinib 50 mg Once Daily Dosing 8
- 8 more outcome measures not shown.
Adverse events
Time frame: Phase 1b: From Baseline (Day 1) until 30 days after the last dose of study drug (i.e., up to 37 months) and Phase 2a: From Baseline (Day 1) until 30 days after the last dose of study drug (i.e., up to 29 months)
| Arm | Deaths | Serious adverse events | Other adverse events |
|---|
| Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing | 0/24 (0.0%) | 1/24 (4.2%) | 24/24 (100.0%) |
| Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing | 0/8 (0.0%) | 0/8 (0.0%) | 8/8 (100.0%) |
| Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing | 0/5 (0.0%) | 0/5 (0.0%) | 5/5 (100.0%) |
| Phase 2a: Cohort 4: Tesevatinib: Bi-weekly Dosing | 0/10 (0.0%) | 1/10 (10.0%) | 10/10 (100.0%) |
| Phase 2a: Cohort 5: Tesevatinib: Tri-weekly Dosing | 0/14 (0.0%) | 0/14 (0.0%) | 14/14 (100.0%) |
| Phase 2a: SILK Cohort: Tesevatinib 50 mg Once Daily Dosing | 0/8 (0.0%) | 1/8 (12.5%) | 8/8 (100.0%) |
Serious adverse events by term
| Term | Organ system | 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 |
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| Gastrooesophageal reflux disease | Gastrointestinal disorders | 0/24 | 0/8 | 0/5 | 1/10 | 0/14 | 0/8 |
| Herpes zoster | Infections and infestations | 0/24 | 0/8 | 0/5 | 0/10 | 0/14 | 1/8 |
| Laceration | Injury, poisoning and procedural complications | 0/24 | 0/8 | 0/5 | 1/10 | 0/14 | 0/8 |
| Depression | Psychiatric disorders | 0/24 | 0/8 | 0/5 | 1/10 | 0/14 | 0/8 |
| Suicidal ideation | Psychiatric disorders | 0/24 | 0/8 | 0/5 | 1/10 | 0/14 | 0/8 |
| Angioedema | Skin and subcutaneous tissue disorders | 1/24 | 0/8 | 0/5 | 0/10 | 0/14 | 0/8 |
Other adverse events by term
| Term | Organ system | 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 |
|---|
| Diarrhoea | Gastrointestinal disorders | 10/24 | 4/8 | 2/5 | 5/10 | 6/14 | 2/8 |
| Nausea | Gastrointestinal disorders | 10/24 | 2/8 | 2/5 | 2/10 | 5/14 | 1/8 |
| Vomiting | Gastrointestinal disorders | 5/24 | 2/8 | 0/5 | 3/10 | 3/14 | 1/8 |
| Abdominal pain | Gastrointestinal disorders | 2/24 | 1/8 | 1/5 | 0/10 | 2/14 | 0/8 |
| Abdominal discomfort | Gastrointestinal disorders | 1/24 | 0/8 | 0/5 | 1/10 | 2/14 | 1/8 |
| Abdominal pain upper | Gastrointestinal disorders | 2/24 | 0/8 | 1/5 | 0/10 | 1/14 | 0/8 |
| Dry mouth | Gastrointestinal disorders | 2/24 | 0/8 | 0/5 | 1/10 | 1/14 | 0/8 |
| Dyspepsia | Gastrointestinal disorders | 1/24 | 1/8 | 0/5 | 0/10 | 1/14 | 1/8 |
| Constipation | Gastrointestinal disorders | 1/24 | 1/8 | 0/5 | 1/10 | 0/14 | 0/8 |
| Food poisoning | Gastrointestinal disorders | 1/24 | 0/8 | 0/5 | 0/10 | 2/14 | 0/8 |
| Abdominal distension | Gastrointestinal disorders | 0/24 | 0/8 | 0/5 | 1/10 | 1/14 | 0/8 |
| Flatulence | Gastrointestinal disorders | 1/24 | 0/8 | 0/5 | 0/10 | 1/14 | 0/8 |
| Haematochezia | Gastrointestinal disorders | 1/24 | 0/8 | 0/5 | 1/10 | 0/14 | 0/8 |
| Inguinal hernia | Gastrointestinal disorders | 1/24 | 0/8 | 0/5 | 0/10 | 0/14 | 1/8 |
| Umbilical hernia | Gastrointestinal disorders | 0/24 | 0/8 | 0/5 | 0/10 | 1/14 | 1/8 |
| Abdominal pain lower | Gastrointestinal disorders | 0/24 | 0/8 | 0/5 | 0/10 | 1/14 | 0/8 |
| Colitis ulcerative | Gastrointestinal disorders | 0/24 | 0/8 | 0/5 | 0/10 | 1/14 | 0/8 |
| Dental caries | Gastrointestinal disorders | 0/24 | 0/8 | 0/5 | 0/10 | 1/14 | 0/8 |
| Gastritis | Gastrointestinal disorders | 0/24 | 0/8 | 0/5 | 1/10 | 0/14 | 0/8 |
| Haemorrhoidal haemorrhage | Gastrointestinal disorders | 0/24 | 0/8 | 0/5 | 0/10 | 1/14 | 0/8 |
| Hiatus hernia | Gastrointestinal disorders | 0/24 | 0/8 | 0/5 | 0/10 | 0/14 | 1/8 |
| Irritable bowel syndrome | Gastrointestinal disorders | 0/24 | 0/8 | 0/5 | 1/10 | 0/14 | 0/8 |
| Pancreatic cyst | Gastrointestinal disorders | 0/24 | 0/8 | 0/5 | 0/10 | 0/14 | 1/8 |
| Blood creatine phosphokinase increased | Investigations | 7/24 | 3/8 | 0/5 | 4/10 | 5/14 | 1/8 |
| Blood creatinine increased | Investigations | 4/24 | 3/8 | 1/5 | 1/10 | 2/14 | 2/8 |
| Alanine aminotransferase increased | Investigations | 4/24 | 2/8 | 0/5 | 2/10 | 1/14 | 2/8 |
| Amylase increased | Investigations | 4/24 | 0/8 | 0/5 | 0/10 | 5/14 | 0/8 |
| Aspartate aminotransferase increased | Investigations | 2/24 | 2/8 | 0/5 | 2/10 | 1/14 | 0/8 |
| Electrocardiogram QT prolonged | Investigations | 2/24 | 2/8 | 0/5 | 1/10 | 1/14 | 0/8 |
| Blood bicarbonate decreased | Investigations | 3/24 | 0/8 | 0/5 | 0/10 | 2/14 | 0/8 |
| Urine leukocyte esterase positive | Investigations | 1/24 | 1/8 | 0/5 | 0/10 | 1/14 | 1/8 |
| Blood lactate dehydrogenase increased | Investigations | 1/24 | 1/8 | 0/5 | 1/10 | 0/14 | 0/8 |
| Glomerular filtration rate decreased | Investigations | 1/24 | 0/8 | 1/5 | 0/10 | 0/14 | 1/8 |
| Bacterial test positive | Investigations | 0/24 | 0/8 | 0/5 | 1/10 | 1/14 | 0/8 |
| Blood glucose increased | Investigations | 1/24 | 0/8 | 0/5 | 1/10 | 0/14 | 0/8 |
| Blood urine present | Investigations | 0/24 | 1/8 | 0/5 | 0/10 | 1/14 | 0/8 |
| Cystatin C increased | Investigations | 2/24 | 0/8 | 0/5 | 0/10 | 0/14 | 0/8 |
| Lipase increased | Investigations | 1/24 | 0/8 | 0/5 | 0/10 | 1/14 | 0/8 |
| Lymphocyte count decreased | Investigations | 0/24 | 1/8 | 0/5 | 0/10 | 1/14 | 0/8 |
| Monocyte count decreased | Investigations | 0/24 | 1/8 | 0/5 | 0/10 | 1/14 | 0/8 |
| Neutrophil count decreased | Injury, poisoning and procedural complications | 0/24 | 1/8 | 0/5 | 0/10 | 1/14 | 0/8 |
| Neutrophil count increased | Investigations | 1/24 | 0/8 | 0/5 | 0/10 | 1/14 | 0/8 |
| Weight decreased | Investigations | 1/24 | 0/8 | 0/5 | 0/10 | 1/14 | 0/8 |
| Weight increased | Investigations | 1/24 | 0/8 | 0/5 | 0/10 | 1/14 | 0/8 |
| White blood cell count decreased | Investigations | 0/24 | 1/8 | 0/5 | 0/10 | 1/14 | 0/8 |
| White blood cells urine positive | Investigations | 0/24 | 0/8 | 0/5 | 1/10 | 1/14 | 0/8 |
| Blood bicarbonate increased | Investigations | 0/24 | 0/8 | 1/5 | 0/10 | 0/14 | 0/8 |
| Blood bilirubin increased | Investigations | 0/24 | 1/8 | 0/5 | 0/10 | 0/14 | 0/8 |
| Blood glucose decreased | Investigations | 0/24 | 1/8 | 0/5 | 0/10 | 0/14 | 0/8 |
| Blood phosphorus decreased | Investigations | 0/24 | 0/8 | 0/5 | 0/10 | 0/14 | 1/8 |
| Blood phosphorus increased | Investigations | 0/24 | 1/8 | 0/5 | 0/10 | 0/14 | 0/8 |
| Blood potassium increased | Investigations | 0/24 | 0/8 | 0/5 | 0/10 | 1/14 | 0/8 |
| Blood pressure increased | Investigations | 0/24 | 0/8 | 0/5 | 0/10 | 0/14 | 1/8 |
| Electrocardiogram T wave amplitude decreased | Investigations | 0/24 | 0/8 | 0/5 | 0/10 | 0/14 | 1/8 |
| Haematocrit increased | Investigations | 0/24 | 0/8 | 0/5 | 0/10 | 1/14 | 0/8 |
| Heart rate increased | Investigations | 0/24 | 0/8 | 0/5 | 0/10 | 1/14 | 0/8 |
| International normalised ratio increased | Investigations | 0/24 | 0/8 | 0/5 | 1/10 | 0/14 | 0/8 |
| Nitrite urine present | Investigations | 0/24 | 0/8 | 0/5 | 1/10 | 0/14 | 0/8 |
| Protein total decreased | Investigations | 0/24 | 1/8 | 0/5 | 0/10 | 0/14 | 0/8 |
| Red blood cells urine positive | Investigations | 0/24 | 0/8 | 0/5 | 1/10 | 0/14 | 0/8 |
161 more terms not shown.
+Locations (11)
| Facility | City | Country | Status |
|---|
| UCLA Medical Center | Los Angeles, California | United States | |
| University of Colorado Denver | Denver, Colorado | United States | |
| University of Kansas Medical Center | Kansas City, Kansas | United States | |
| Beth Israel Deaconess Medical Center | Boston, Massachusetts | United States | |
| Mayo Clinic | Rochester, Minnesota | United States | |
| Washington University School of Medicine | St Louis, Missouri | United States | |
| New York University School of Medicine | New York, New York | United States | |
| Cleveland Clinic | Cleveland, Ohio | United States | |
| Clinical Advancement Center, PLLC | San Antonio, Texas | United States | |
| University of Virginia - Nephrology Clinical Research Center | Charlottesville, Virginia | United States | |
| Medical College of Wisconsin | Milwaukee, Wisconsin | United States | |
+Study documents