Clinical trial NCT01559363: 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
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Polycystic Kidney, Autosomal Dominant
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2012-03-21
Enrollment: 69
Sex: ALL
Minimum age (years): 18
Maximum age (years): 62
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Phase 1b: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAE)
timeFrame: From Baseline (Day 1) until 30 days after the last dose of study drug (maximum duration: up to 37 months)
measure: Phase 1b: Pharmacokinetics (PK): Plasma Concentrations of Tesevatinib 100 mg and 150 mg
timeFrame: 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
measure: Phase 1b: Pharmacokinetics: Plasma Concentrations of Tesevatinib 50 mg
timeFrame: 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
measure: Phase 1b: Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) of Tesevatinib 100 mg and 150 mg
timeFrame: 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
measure: Phase 1b: Pharmacokinetics: Maximum Observed Plasma Concentration of Tesevatinib 50 mg
timeFrame: 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
measure: Phase 1b: Pharmacokinetics: Time of the Maximum Observed Plasma Concentration (Tmax) of Tesevatinib 100 mg and 150 mg
timeFrame: 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
measure: Phase 1b: Pharmacokinetics: Time of the Maximum Observed Plasma Concentration of Tesevatinib 50 mg
timeFrame: 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
measure: Phase 1b: Pharmacokinetics: Time of the Last Quantifiable Plasma Concentration (Tlast) of Tesevatinib 100 mg and 150 mg
timeFrame: 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
measure: Phase 1b: Pharmacokinetics: Time of the Last Quantifiable Plasma Concentration of Tesevatinib 50 mg
timeFrame: 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
measure: 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
timeFrame: 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
measure: Phase 1b: Pharmacokinetics: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of Last Quantifiable Concentration of Tesevatinib 50 mg
timeFrame: 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
measure: 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
timeFrame: 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
measure: Phase 1b: Pharmacokinetics: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours Post-dose of Tesevatinib 50 mg
timeFrame: 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
measure: Phase 1b: Pharmacokinetics: Trough Plasma Concentrations (Ctrough) of Tesevatinib 100 mg and 500 mg
timeFrame: Pre-dose on Days 7, 14, 21, 28 and Months 2, 3, 4, 5 and 6
measure: Phase 1b: Pharmacokinetics: Trough Plasma Concentrations of Tesevatinib 50 mg
timeFrame: Pre-dose on Days 7, 14, 21, 28 and Months 2, 3, 4, 5 and 6
measure: Phase 1b: Maximum Tolerated Dose (MTD) of Tesevatinib
timeFrame: Cycle 1 (Up to 28 days)
measure: Phase 2a: Annualized Percent Change From Baseline in Estimated Glomerular Filtration Rate (eGFR)
timeFrame: Baseline (Day 1), Months 6, 12, 18, 24 and at end of study (i.e., anytime up to 37 months)
Secondary outcomes:
measure: Phase 2a: Annualized Percent Change From Baseline in Height Adjusted Total Kidney Volume (htTKV) at Month 6, 12, 18, 24 and End of Study
timeFrame: Baseline (Day 1), Months 6, 12, 18, 24 and at end of study (i.e., anytime up to 37 months)
measure: Phase 2a: Annualized Percent Change From Baseline in the Reciprocal of Serum Creatinine at End of Study
timeFrame: Baseline (Day 1), at end of study (i.e., anytime up to 37 months)
measure: Phase 2a: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (TESAE)
timeFrame: From Baseline (Day 1) until 30 days after the last dose of study drug (i.e., up to 29 months)
measure: Phase 2a: Change From Baseline in Serum Creatinine Levels
timeFrame: 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)
measure: Phase 2a: Pharmacokinetics: Plasma Concentrations of Tesevatinib 150 mg
timeFrame: 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
measure: Phase 2a: Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) of Tesevatinib 150 mg
timeFrame: 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
measure: Phase 2a: Pharmacokinetics: Time of the Maximum Observed Plasma Concentration (Tmax) of Tesevatinib 150 mg
timeFrame: 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
measure: Phase 2a: Pharmacokinetics: Time of the Last Quantifiable Plasma Concentration (Tlast) of Tesevatinib 150 mg
timeFrame: 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
measure: Phase 2a: Pharmacokinetics: Area Under the Plasma Concentration-time Curve From Time 0 to the Last Quantifiable Concentration (AUC0-t) of Tesevatinib 150 mg
timeFrame: 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
measure: Phase 2a: Pharmacokinetics: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours Post-dose (AUC0-24) of Tesevatinib 150 mg
timeFrame: 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
measure: Phase 2a: Pharmacokinetics: Concentration Immediately Before Dosing (Ctrough) of Tesevatinib 150 mg
timeFrame: 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
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: UCLA Medical Center
state: California
city: Denver
country: United States
facility: University of Colorado Denver
state: Colorado
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: New York
country: United States
facility: New York University School of Medicine
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: San Antonio
country: United States
facility: Clinical Advancement Center, PLLC
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia - Nephrology Clinical Research Center
state: Virginia
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
Study officials:
References: