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NCT Number: NCT01559363

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

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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Key information

Conditions

Polycystic Kidney, Autosomal Dominant Abnormalities, Multiple Ciliopathies Congenital Abnormalities Congenital, Hereditary, and Neonatal Diseases and Abnormalities Female Urogenital Diseases Female Urogenital Diseases and Pregnancy Complications Genetic Diseases, Inborn Kidney Diseases Kidney Diseases, Cystic Male Urogenital Diseases Polycystic Kidney Diseases Urogenital Diseases Urologic Diseases

Age range

18 year–62 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1 / Phase 2

Primary location

UCLA Medical Center, Los Angeles, California, United States

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About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

Tesevatinib

Drug

Pharmaceutical form: Tablets Route of administration: Oral

Other names: XL647 and KD019

Primary outcomes

  1. Phase 1b: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAE)

    Time frame: 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.

  2. Phase 1b: Pharmacokinetics (PK): Plasma Concentrations of Tesevatinib 100 mg and 150 mg

    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

    Plasma concentrations of tesevatinib was analyzed using non-compartmental analysis.

  3. Phase 1b: Pharmacokinetics: Plasma Concentrations of Tesevatinib 50 mg

    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

    Plasma concentrations of tesevatinib was analyzed using non-compartmental analysis.

  4. Phase 1b: Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) of Tesevatinib 100 mg and 150 mg

    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

    Cmax was defined as maximum observed plasma concentration.

  5. Phase 1b: Pharmacokinetics: Maximum Observed Plasma Concentration of Tesevatinib 50 mg

    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

    Cmax was defined as maximum observed plasma concentration.

  6. Phase 1b: Pharmacokinetics: Time of the Maximum Observed Plasma Concentration (Tmax) of Tesevatinib 100 mg and 150 mg

    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

    Tmax was defined as time to reach maximum observed plasma concentration.

  7. Phase 1b: Pharmacokinetics: Time of the Maximum Observed Plasma Concentration of Tesevatinib 50 mg

    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

    Tmax was defined as time to reach maximum observed plasma concentration.

  8. Phase 1b: Pharmacokinetics: Time of the Last Quantifiable Plasma Concentration (Tlast) of Tesevatinib 100 mg and 150 mg

    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

    Tlast was defined as time to reach last quantifiable plasma concentration.

  9. Phase 1b: Pharmacokinetics: Time of the Last Quantifiable Plasma Concentration of Tesevatinib 50 mg

    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

    Tlast was defined as time to reach last quantifiable plasma concentration.

  10. 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

    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

    AUC0-last was defined as area under the concentration-time curve (AUC) from time 0 to the time of the last quantifiable concentration (tlast).

  11. Phase 1b: Pharmacokinetics: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of Last Quantifiable Concentration of Tesevatinib 50 mg

    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

    AUC0-last was defined as area under the concentration-time curve (AUC) from time 0 to the time of the last quantifiable concentration (tlast).

  12. 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

    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

    AUC0-24 was defined as area under the plasma concentration versus time curve of study drug from time 0 to 24 hours post-dose.

  13. Phase 1b: Pharmacokinetics: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours Post-dose of Tesevatinib 50 mg

    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

    AUC0-24 was defined as area under the plasma concentration versus time curve of study drug from time 0 to 24 hours post-dose.

  14. Phase 1b: Pharmacokinetics: Trough Plasma Concentrations (Ctrough) of Tesevatinib 100 mg and 500 mg

    Time frame: 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.

  15. Phase 1b: Pharmacokinetics: Trough Plasma Concentrations of Tesevatinib 50 mg

    Time frame: 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.

  16. Phase 1b: Maximum Tolerated Dose (MTD) of Tesevatinib

    Time frame: 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.

  17. Phase 2a: Annualized Percent Change From Baseline in Estimated Glomerular Filtration Rate (eGFR)

    Time frame: 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

  1. Phase 2a: Annualized Percent Change From Baseline in Height Adjusted Total Kidney Volume (htTKV) at Month 6, 12, 18, 24 and End of Study

    Time frame: 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.

  2. Phase 2a: Annualized Percent Change From Baseline in the Reciprocal of Serum Creatinine at End of Study

    Time frame: 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.

  3. Phase 2a: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (TESAE)

    Time frame: 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.

  4. Phase 2a: Change From Baseline in Serum Creatinine Levels

    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)

    Serum creatinine levels indicated the renal function (normal or abnormal) over time.

  5. Phase 2a: Pharmacokinetics: Plasma Concentrations of Tesevatinib 150 mg

    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

    Plasma concentrations of tesevatinib was analyzed using non-compartmental analysis.

  6. Phase 2a: Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) of Tesevatinib 150 mg

    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

    Cmax was defined as maximum observed plasma concentration.

  7. Phase 2a: Pharmacokinetics: Time of the Maximum Observed Plasma Concentration (Tmax) of Tesevatinib 150 mg

    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

    Tmax was defined as time to reach maximum observed plasma concentration.

  8. Phase 2a: Pharmacokinetics: Time of the Last Quantifiable Plasma Concentration (Tlast) of Tesevatinib 150 mg

    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

    Tlast was defined as time to reach last quantifiable plasma concentration.

  9. Phase 2a: Pharmacokinetics: Area Under the Plasma Concentration-time Curve From Time 0 to the Last Quantifiable Concentration (AUC0-t) of Tesevatinib 150 mg

    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

    AUC0-last was defined as area under the concentration-time curve (AUC) from time 0 to the time of the last quantifiable concentration (tlast).

  10. Phase 2a: Pharmacokinetics: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours Post-dose (AUC0-24) of Tesevatinib 150 mg

    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

    AUC0-24 was defined as area under the plasma concentration versus time curve of study drug from time 0 to 24 hours post-dose.

  11. Phase 2a: Pharmacokinetics: Concentration Immediately Before Dosing (Ctrough) of Tesevatinib 150 mg

    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

    Ctrough was the plasma concentration observed at the time immediately before study drug administration.

Sponsors and collaborators

Lead sponsor

Kadmon, a Sanofi Company

Industry

Registry information

Official study title

A Phase 1b/2a, Safety, Pharmacokinetic and Dose-Escalation Study of KD019 (Tesevatinib) in Subjects With Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Important dates

Study start
2012
Primary completion
2019
Study completion
2019
First posted
Mar 21, 2012
Registry last updated
Nov 8, 2022

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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