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A Safety, Pharmacokinetic & Dose-Escalation Study of KD019 in Subjects With Autosomal Dominant Polycystic Kidney Disease

Primary Purpose

Polycystic Kidney, Autosomal Dominant

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Tesevatinib
Sponsored by
Kadmon, a Sanofi Company
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Polycystic Kidney, Autosomal Dominant

Eligibility Criteria

18 Years - 62 Years (Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • UCLA Medical Center
  • University of Colorado Denver
  • University of Kansas Medical Center
  • Beth Israel Deaconess Medical Center
  • Mayo Clinic
  • Washington University School of Medicine
  • New York University School of Medicine
  • Cleveland Clinic
  • Clinical Advancement Center, PLLC
  • University of Virginia - Nephrology Clinical Research Center
  • Medical College of Wisconsin

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

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: Safety in Larger Kidneys (SILK) Cohort: Tesevatinib 50 mg Once Daily Dosing

Arm Description

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).

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).

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).

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).

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).

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).

Outcomes

Primary Outcome Measures

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.
Phase 1b: Pharmacokinetics (PK): Plasma Concentrations of Tesevatinib 100 mg and 150 mg
Plasma concentrations of tesevatinib was analyzed using non-compartmental analysis.
Phase 1b: Pharmacokinetics: Plasma Concentrations of Tesevatinib 50 mg
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
Cmax was defined as maximum observed plasma concentration.
Phase 1b: Pharmacokinetics: Maximum Observed Plasma Concentration of Tesevatinib 50 mg
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
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
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
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
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
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
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
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
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
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
Ctrough was the plasma concentration observed at the time immediately before study drug administration.
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.
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.

Secondary Outcome Measures

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.
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.
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.
Phase 2a: Change From Baseline in Serum Creatinine Levels
Serum creatinine levels indicated the renal function (normal or abnormal) over time.
Phase 2a: Pharmacokinetics: Plasma Concentrations of Tesevatinib 150 mg
Plasma concentrations of tesevatinib was analyzed using non-compartmental analysis.
Phase 2a: Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) of Tesevatinib 150 mg
Cmax was defined as maximum observed plasma concentration.
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.
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.
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).
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.
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.

Full Information

First Posted
March 9, 2012
Last Updated
October 12, 2022
Sponsor
Kadmon, a Sanofi Company
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1. Study Identification

Unique Protocol Identification Number
NCT01559363
Brief Title
A Safety, Pharmacokinetic & Dose-Escalation Study of KD019 in Subjects With Autosomal Dominant Polycystic Kidney Disease
Official Title
A Phase 1b/2a, Safety, Pharmacokinetic and Dose-Escalation Study of KD019 (Tesevatinib) in Subjects With Autosomal Dominant Polycystic Kidney Disease (ADPKD)
Study Type
Interventional

2. Study Status

Record Verification Date
October 2022
Overall Recruitment Status
Completed
Study Start Date
October 11, 2012 (Actual)
Primary Completion Date
February 8, 2019 (Actual)
Study Completion Date
February 8, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Kadmon, a Sanofi Company

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Polycystic Kidney, Autosomal Dominant

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
69 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing
Arm Type
Experimental
Arm Description
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).
Arm Title
Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing
Arm Type
Experimental
Arm Description
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).
Arm Title
Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing
Arm Type
Experimental
Arm Description
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).
Arm Title
Phase 2a: Cohort 4: Tesevatinib: Bi-weekly Dosing
Arm Type
Experimental
Arm Description
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).
Arm Title
Phase 2a: Cohort 5: Tesevatinib: Tri-weekly Dosing
Arm Type
Experimental
Arm Description
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).
Arm Title
Phase 2a: Safety in Larger Kidneys (SILK) Cohort: Tesevatinib 50 mg Once Daily Dosing
Arm Type
Experimental
Arm Description
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).
Intervention Type
Drug
Intervention Name(s)
Tesevatinib
Other Intervention Name(s)
XL647 and KD019
Intervention Description
Pharmaceutical form: Tablets Route of administration: Oral
Primary Outcome Measure Information:
Title
Phase 1b: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAE)
Description
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)
Title
Phase 1b: Pharmacokinetics (PK): Plasma Concentrations of Tesevatinib 100 mg and 150 mg
Description
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
Title
Phase 1b: Pharmacokinetics: Plasma Concentrations of Tesevatinib 50 mg
Description
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
Title
Phase 1b: Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) of Tesevatinib 100 mg and 150 mg
Description
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
Title
Phase 1b: Pharmacokinetics: Maximum Observed Plasma Concentration of Tesevatinib 50 mg
Description
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
Title
Phase 1b: Pharmacokinetics: Time of the Maximum Observed Plasma Concentration (Tmax) of Tesevatinib 100 mg and 150 mg
Description
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
Title
Phase 1b: Pharmacokinetics: Time of the Maximum Observed Plasma Concentration of Tesevatinib 50 mg
Description
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
Title
Phase 1b: Pharmacokinetics: Time of the Last Quantifiable Plasma Concentration (Tlast) of Tesevatinib 100 mg and 150 mg
Description
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
Title
Phase 1b: Pharmacokinetics: Time of the Last Quantifiable Plasma Concentration of Tesevatinib 50 mg
Description
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
Title
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
Description
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
Title
Phase 1b: Pharmacokinetics: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of Last Quantifiable Concentration of Tesevatinib 50 mg
Description
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
Title
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
Description
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
Title
Phase 1b: Pharmacokinetics: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours Post-dose of Tesevatinib 50 mg
Description
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
Title
Phase 1b: Pharmacokinetics: Trough Plasma Concentrations (Ctrough) of Tesevatinib 100 mg and 500 mg
Description
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
Title
Phase 1b: Pharmacokinetics: Trough Plasma Concentrations of Tesevatinib 50 mg
Description
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
Title
Phase 1b: Maximum Tolerated Dose (MTD) of Tesevatinib
Description
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)
Title
Phase 2a: Annualized Percent Change From Baseline in Estimated Glomerular Filtration Rate (eGFR)
Description
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)
Secondary Outcome Measure Information:
Title
Phase 2a: Annualized Percent Change From Baseline in Height Adjusted Total Kidney Volume (htTKV) at Month 6, 12, 18, 24 and End of Study
Description
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)
Title
Phase 2a: Annualized Percent Change From Baseline in the Reciprocal of Serum Creatinine at End of Study
Description
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)
Title
Phase 2a: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (TESAE)
Description
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)
Title
Phase 2a: Change From Baseline in Serum Creatinine Levels
Description
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)
Title
Phase 2a: Pharmacokinetics: Plasma Concentrations of Tesevatinib 150 mg
Description
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
Title
Phase 2a: Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) of Tesevatinib 150 mg
Description
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
Title
Phase 2a: Pharmacokinetics: Time of the Maximum Observed Plasma Concentration (Tmax) of Tesevatinib 150 mg
Description
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
Title
Phase 2a: Pharmacokinetics: Time of the Last Quantifiable Plasma Concentration (Tlast) of Tesevatinib 150 mg
Description
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
Title
Phase 2a: Pharmacokinetics: Area Under the Plasma Concentration-time Curve From Time 0 to the Last Quantifiable Concentration (AUC0-t) of Tesevatinib 150 mg
Description
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
Title
Phase 2a: Pharmacokinetics: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours Post-dose (AUC0-24) of Tesevatinib 150 mg
Description
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
Title
Phase 2a: Pharmacokinetics: Concentration Immediately Before Dosing (Ctrough) of Tesevatinib 150 mg
Description
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
62 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Facility Information:
Facility Name
UCLA Medical Center
City
Los Angeles
State/Province
California
ZIP/Postal Code
90025
Country
United States
Facility Name
University of Colorado Denver
City
Denver
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
University of Kansas Medical Center
City
Kansas City
State/Province
Kansas
ZIP/Postal Code
66160
Country
United States
Facility Name
Beth Israel Deaconess Medical Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Facility Name
Mayo Clinic
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Facility Name
Washington University School of Medicine
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
New York University School of Medicine
City
New York
State/Province
New York
ZIP/Postal Code
10016
Country
United States
Facility Name
Cleveland Clinic
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44195
Country
United States
Facility Name
Clinical Advancement Center, PLLC
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78215
Country
United States
Facility Name
University of Virginia - Nephrology Clinical Research Center
City
Charlottesville
State/Province
Virginia
ZIP/Postal Code
22908
Country
United States
Facility Name
Medical College of Wisconsin
City
Milwaukee
State/Province
Wisconsin
ZIP/Postal Code
53226
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org

Learn more about this trial

A Safety, Pharmacokinetic & Dose-Escalation Study of KD019 in Subjects With Autosomal Dominant Polycystic Kidney Disease

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