A Study of AG-120 (Ivosidenib) in Subjects With Mild or Moderate Hepatic Impairment or Normal Hepatic Function

NCT03282513 | Completed Phase 1 FDA Drug

• 1 other identifier: AG120-C-012
• Study Type: interventional
• Target: 33
• Locations: 1 country
• Sites: 2

Brief Summary

Study AG120-C-012 is a Phase 1, open-label, single-dose study designed to evaluate the PK, safety, and tolerability of a single 500 mg AG-120 (Ivosidenib) dose in subjects with mild or moderate hepatic impairment (HI) compared to subjects with normal hepatic function. The study will be conducted at 2 US centers.

Conditions

Hepatic Impairment

Keywords

AG-120; Healthy Volunteer; Clinical Pharmacology; Hepatic Impairment

Outcome Measures

Primary Outcomes (2)

• Maximum observed plasma concentration (Cmax)

  AG-120 Cmax, derived from plasma concentration-time curves

  Predose; 0.5hr, 1hr, 2hr, 3hr, 4hr, 6hr, 9hr, 12hr, 24hr, 48hr, 72hr, 120hr, 168hr, 240hr, 336hr, and 504hr post dose

• Area under plasma concentration-time curve (AUC)

  AG-120 AUC, derived from plasma concentration-time curves

  Predose; 0.5hr, 1hr, 2hr, 3hr, 4hr, 6hr, 9hr, 12hr, 24hr, 48hr, 72hr, 120hr, 168hr, 240hr, 336hr, and 504hr post dose

Secondary Outcomes (2)

• Adverse Events (AE) and treatment-related AE

  From the time of study drug administration through the end of study (Day 29 or early termination)

• Plasma Protein Binding

  Time Frame: Pre-dose, Day 1 and Day 2

Study Arms (4)

Cohort 1A: Mild Hepatic Impairment

EXPERIMENTAL

Drug: AG-120 (Ivosidenib) A single 500 mg oral dose of AG-120 (Ivosidenib) in subjects with mild hepatic impairment(Child-Pugh Score A.)

Drug: AG-120 (Ivosidenib)

Cohort 1B: Healthy Volunteers

ACTIVE COMPARATOR

Drug: AG-120 (Ivosidenib) A single 500 mg oral dose of AG-120 (Ivosidenib) in subjects with normal hepatic function.

Drug: AG-120 (Ivosidenib)

Cohort 2A: Moderate Hepatic Impairment

EXPERIMENTAL

Drug: AG-120 (Ivosidenib) A single 500 mg oral dose of AG-120 (Ivosidenib) in subjects with moderate hepatic impairment (Child-Pugh Score B.)

Drug: AG-120 (Ivosidenib)

Cohort 2B: Healthy Volunteers

ACTIVE COMPARATOR

Drug: AG-120 (Ivosidenib) A single 500 mg oral dose of AG-120 (Ivosidenib) in subjects with normal hepatic function.

Drug: AG-120 (Ivosidenib)

Interventions

AG-120 (Ivosidenib) DRUG

Single 500 mg dose of AG-120 (Ivosidenib).

Cohort 1A: Mild Hepatic Impairment; Cohort 1B: Healthy Volunteers; Cohort 2A: Moderate Hepatic Impairment; Cohort 2B: Healthy Volunteers

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• All subjects:
• Body Mass Index BMI of 19 to 40 kg/m2 (inclusive).
• Willing and able to comply with all study restrictions and requirements.
• Non- smoker, or uses no more nicotine-containing product than the equivalent of smoking ≤10 cigarettes per day, as judged by the investigator.
• Female subjects must be non pregnant and non-lactating and either be post-menopausal, surgically sterile, practice total abstinence from sexual intercourse as the preferred lifestyle or agree to use an appropriate method of birth control consistently throughout the study, from screening until 90 days after study drug administration.
• Male subjects with a partner of child bearing potential must either be sterile, practice total abstinence from sexual intercourse as the preferred life style or agree to use an appropriate method of birth control consistently throughout the study, from screening until 90 days after study drug administration.
• Subjects with hepatic impairment (Cohorts 1a, 2a)
• Diagnosis of chronic (≥3 months prior to Screening) or stable (no acute episodes of illness within 2 months prior to Screening due to deterioration in hepatic function) hepatic insufficiency, with a Child-Pugh classification score in the mild or moderate range.
• Hepatic insufficiency may be of any etiology associated with an unambiguous medical history (such as evidence of portal hypertension).
• Other than hepatic insufficiency with features of cirrhosis, subjects are in good health based on medical history, physical exam, ECG, clinical laboratory tests, and Investigator's assessment.
• Healthy matched subjects (Cohorts 1b, 2b)
• Have normal hepatic function and considered by the Investigator to be in good health, based on medical and surgical history review, physical exam, ECG, clinical laboratory tests, and Investigator's assessment.

You may not qualify if:

• All subjects:
• Significant acute, new-onset illness (eg, flu, gastroenteritis) within 2 weeks prior to dosing.
• Positive test for drugs of abuse and/or positive alcohol test at Screening or prior to dosing.
• Medical history of clinically significant ECG abnormalities or a family history of prolonged QT interval syndromes.
• History of immunocompromise, including positivity for HIV, or active viral hepatitis B or C.
• Use of over the counter (OTC) medications, herbal supplements, grapefruit juice, Seville oranges, or vitamins 14 days prior to dosing.
• A recent (within 6 months prior to dosing) history of acute or chronic bronchospastic disease, including asthma and chronic obstructive pulmonary disease.
• Current or history of hepatic carcinoma, hepatorenal syndrome, portacaval shunt surgery, or pleural effusion. Malignancy, including leukemia and lymphoma, within the last 5 years.
• Any surgical or medical condition that might significantly alter the absorption, distribution, or excretion of AG-120.
• Treatment with strong cytochrome P450 (CYP)3A4 inhibitors or inducers within 14 days prior to AG 120 dosing or during the study.
• Subjects with hepatic impairment (Cohorts 1a, 2a)
• Clinical evidence of moderate to severe ascites.
• Significant history or clinical manifestation of any significant metabolic/endocrine, allergic, dermatologic, renal, hematologic, pulmonary, immune, cardiovascular, gastrointestinal, genitourinary, neurologic, or psychiatric disorder, as determined by the Investigator and/or Sponsor's medical monitor (MM) to be clinically significant (CS.)
• Any evidence of progressive liver disease (within the last 4 weeks prior to dosing)
• Severe or uncontrolled medical conditions within 4 weeks prior to AG-120 dosing, with the exception of illness related to HI.

Sponsors & Collaborators

• Agios Pharmaceuticals, Inc.: lead

Study Sites (2)

DaVita Clinical Research- Colorado

Lakewood, Colorado, 80228, United States

Location

DaVita Clinical Research- Minnesota

Minneapolis, Minnesota, 55404, United States

Location

Related Publications (1)

• Fan B, Dai D, Cohen M, Xu H, Yin F, Nagaraja R, Mobilia M, Almon C, Basile FG, Yang H. Effect of Mild and Moderate Hepatic Impairment on the Pharmacokinetics, Safety, and Tolerability of a Single Dose of Oral Ivosidenib in Otherwise Healthy Participants. Clin Pharmacol Drug Dev. 2021 Jan;10(1):99-109. doi: 10.1002/cpdd.821. Epub 2020 Jul 9.

  PMID: 32648303 DERIVED

MeSH Terms

Interventions

ivosidenib

Study Design

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

Study Record Dates

• First Submitted: September 8, 2017
• First Posted: September 14, 2017
• Study Start: September 26, 2017
• Primary Completion: March 31, 2018
• Study Completion: March 31, 2018
• Last Updated: April 27, 2018

Record last verified: 2018-04

Locations

US (2)