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

NCT01559363 | Completed Phase 1 Results

• 3 other identifiers: KD019-101U1111-1279-2764MAD17715
• Study Type: interventional
• Target: 69
• Locations: 1 country
• Sites: 11

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.

Conditions

Polycystic Kidney, Autosomal Dominant

Outcome Measures

Primary Outcomes (17)

• 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.

  From Baseline (Day 1) until 30 days after the last dose of study drug (maximum duration: up to 37 months)

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

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

  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

• Phase 1b: Pharmacokinetics: Plasma Concentrations of Tesevatinib 50 mg

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

  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

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

  Cmax was defined as maximum observed plasma concentration.

  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

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

  Cmax was defined as maximum observed plasma concentration.

  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

• 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.

  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

• 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.

  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

• 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.

  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

• 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.

  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

• 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).

  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

• 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).

  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

• 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.

  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

• 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.

  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

• 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.

  Pre-dose on Days 7, 14, 21, 28 and Months 2, 3, 4, 5 and 6

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

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

  Pre-dose on Days 7, 14, 21, 28 and Months 2, 3, 4, 5 and 6

• 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.

  Cycle 1 (Up to 28 days)

• 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.

  Baseline (Day 1), Months 6, 12, 18, 24 and at end of study (i.e., anytime up to 37 months)

Secondary Outcomes (11)

• 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)

• 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)

• 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)

• 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)

• 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

Study Arms (6)

Phase 1b: Cohort 1: Tesevatinib 50 mg Once Daily Dosing

EXPERIMENTAL

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).

Drug: Tesevatinib

Phase 1b: Cohort 2: Tesevatinib 100 mg Once Daily Dosing

EXPERIMENTAL

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).

Drug: Tesevatinib

Phase 1b: Cohort 3: Tesevatinib 150 mg Once Daily Dosing

EXPERIMENTAL

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).

Drug: Tesevatinib

Phase 2a: Cohort 4: Tesevatinib: Bi-weekly Dosing

EXPERIMENTAL

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).

Drug: Tesevatinib

Phase 2a: Cohort 5: Tesevatinib: Tri-weekly Dosing

EXPERIMENTAL

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).

Drug: Tesevatinib

Phase 2a: Safety in Larger Kidneys (SILK) Cohort: Tesevatinib 50 mg Once Daily Dosing

EXPERIMENTAL

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).

Drug: Tesevatinib

Interventions

Tesevatinib DRUG

Pharmaceutical form: Tablets Route of administration: Oral

Also known as: XL647 and KD019

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

Eligibility Criteria

• Age: 18 Years - 62 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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).

You may not qualify if:

• 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.

Sponsors & Collaborators

• Kadmon, a Sanofi Company: lead

Study Sites (11)

UCLA Medical Center

Los Angeles, California, 90025, United States

Location

University of Colorado Denver

Denver, Colorado, 80045, United States

Location

University of Kansas Medical Center

Kansas City, Kansas, 66160, United States

Location

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

Location

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

New York University School of Medicine

New York, New York, 10016, United States

Location

Cleveland Clinic

Cleveland, Ohio, 44195, United States

Location

Clinical Advancement Center, PLLC

San Antonio, Texas, 78215, United States

Location

University of Virginia - Nephrology Clinical Research Center

Charlottesville, Virginia, 22908, United States

Location

Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

MeSH Terms

Conditions

Polycystic Kidney, Autosomal Dominant

Interventions

XL647

Condition Hierarchy (Ancestors)

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

Results Point of Contact

• Title: Trial Transparency Team
• Organization: Kadmon, a Sanofi Company

Contact-US@Sanofi.com

800-633-1610

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 9, 2012
• First Posted: March 21, 2012
• Study Start: October 11, 2012
• Primary Completion: February 8, 2019
• Study Completion: February 8, 2019
• Last Updated: November 8, 2022
• Results First Posted: November 8, 2022

Record last verified: 2022-10

Data Sharing

• IPD Sharing: Will share

Locations

US (11)