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

Kadmon

Status and phase: Completed; Phase 2; Phase 1

Conditions: Polycystic Kidney, Autosomal Dominant

Treatments: Drug: Tesevatinib

Study type: Interventional

Funder types: Industry

Identifiers

NCT01559363

KD019-101

MAD17715 (Other Identifier)

U1111-1279-2764 (Other Identifier)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 69 patients

Sex: All

Ages: 18 to 62 years old

Volunteers: No 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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

---

69 participants in 6 patient groups

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

Experimental group

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).

Treatment:

Drug: Tesevatinib

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

Experimental group

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).

Treatment:

Drug: Tesevatinib

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

Experimental group

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).

Treatment:

Drug: Tesevatinib

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

Experimental group

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).

Treatment:

Drug: Tesevatinib

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

Experimental group

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).

Treatment:

Drug: Tesevatinib

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

Experimental group

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).

Treatment:

Drug: Tesevatinib