Olutasidenib DDI Study in Patients With IDH1 Mutation Positive Malignancies

Official title

A Multi-Center, Open-Label, Drug-Drug Interaction Study to Evaluate the Effect of Olutasidenib on the Pharmacokinetics of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A4, and OATP1B1 Substrates in Patients With IDH1 Mutation-Positive Malignancies Being Treated With Olutasidenib

Overview

A open-label drug-drug interaction (DDI) study to evaluate the effects of olutasidenib on the pharmacokinetics (PK) of a CYP450 and OATP1B1 probe substrate cocktail in participants with IDH1 mutation-positive malignancies.

Interventions

• Drug Olutasidenib
  Participants will receive repeated dosing of olutasidenib from Day 5 to Day 22 until steady state, with an option to continue treatment up to Day 64
• Drug CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A4, and OATP1B1 Probe Substrates
  Participants will receive a single dose of each probe substrate on Day 1 and Day 18.

Primary outcome measures

• Area Under the Plasma Concentration-Time Curve (AUC) of Probe Drugs [Time frame: Up to 96 hours after each probe drug administration.]
• Maximum Plasma Concentration (Cmax) of Probe Drugs [Time frame: Up to 96 hours after each probe drug administration.]

Secondary outcome measures (7)

• Time to Maximum Plasma Concentration (Tmax) of Probe Drugs [Time frame: Up to 96 hours after each probe drug administration]
• Elimination Half-Life (t½) of Probe Drugs [Time frame: Up to 96 hours after each probe drug administration]
• Percent of Area Under the Curve Extrapolated (%AUCex) of Probe Drugs [Time frame: Up to 96 hours after each probe drug administration]
• Elimination Rate Constant (λz) of Probe Drugs [Time frame: Up to 96 hours after each probe drug administration]
• Apparent Total Body Clearance (CL/F) of Probe Drugs [Time frame: Up to 96 hours after each probe drug administration]
• Apparent Volume of Distribution (Vz/F) of Probe Drugs [Time frame: Up to 96 hours after each probe drug administration]
• Incidence, Frequency, and Severity of Treatment-Emergent Adverse Events (TEAEs) with Olutasidenib and Probe Substrates [Time frame: From the start of treatment through approximately 30 days after the last dose of study treatment]

Eligibility criteria

Inclusion criteria

• Adult male or female ≥ 18 years of age at the time of signing the informed consent form
• Must have an Eastern Cooperative Oncology Group performance status ≤ 2.
• Must have recovered from the non-hematologic toxic effects of prior treatment to Grade ≤ 1, or baseline value (excluding infertility, alopecia, or Grade 1 neuropathy)
• Must have a diagnosis of IDH1m+ malignancy to be treated with olutasidenib (e.g. acute myeloid leukemia \[AML\], gastrointestinal \[GI\] cancers, glioma). Patient should not have received olutasidenib within the 2 weeks prior to the first dose of study drug.
• Patient must have an adequate organ function, defined by the following:
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) values ≤ 2.5 × upper limit of normal (ULN).
• Bilirubin ≤ 1.5× ULN (≤ 3 × ULN in patients with Gilbert Syndrome) or ≤ 3 × ULN for patients with AML involvement.
• Creatinine clearance ≥ 30 mL/min using Cockcroft-Gault equation.
• Female patients who are women of childbearing potential (WOCBP) must have a negative serum (β-hCG) pregnancy test at screening and negative urine test (positive urine tests are to be confirmed by serum test) documented within the 24-hour period prior to the first dose of study drug. WOCBP are defined as sexually mature women without prior hysterectomy or who have had any evidence of menses in the past 12 months. However, women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, anti-estrogens, or ovarian suppression.
• WOCBP, must agree to use two methods of birth control (e.g. hormonal and a barrier method such as a condom), or must be considered highly unlikely to conceive during the dosing period and for 3 months after last study treatment.
• Male patients with female partners of childbearing potential may be enrolled if they both agree to use highly effective methods of contraception during the dosing period and for 3 months after last study treatment.
• Male patients must refrain from donating sperm during the dosing period and for 3 months after last study treatment.

Exclusion criteria

• Female patients who are pregnant or breastfeeding.
• Patients who are active smokers. Those who have ceased smoking > 1 month before the Screening Visit will be allowed.
• Ingestion of alcohol within 72 hours prior to first study drug administration and during the study period.
• Any patient's who plans to become pregnant or father a child (including ova or sperm donation) while enrolled in this study or within 3 months after last dose of study drug.
• Known allergy or history of hypersensitivity to study drugs or their excipients.
• Human immunodeficiency virus (HIV) positivity.
• Positive serology for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody or by RNA polymerase chain reaction (PCR) at screening.
• Any patient's with a serious infection requiring intravenous or systemic antibiotics within 7 days prior to initiation of study treatment, or any active infection that, in the opinion of the Investigator, could impact patient's safety (e.g. COVID-19).
• Use of concomitant medications that are moderate or strong CYP1A2, 2B6, 2C8, 2C9, 2C19, and/or 3A4 inhibitors within 14 days or 5 half-lives (whichever is longer) prior to the first dose of study drug
• Use of concomitant medications that are moderate or strong CYP1A2, 2B6, 2C8, 2C9, 2C19, and/or 3A4 inducers within 14 days or 5 half-lives (whichever is longer) prior to the first dose of study drug.
• History of or active, clinically significant, cardiovascular, respiratory, GI, renal, hepatic, neurological, psychiatric, musculoskeletal, genitourinary, dermatological, or other disorder that, in the Investigator's opinion (or following review by the Sponsor), could affect the conduct of the study or the absorption, metabolism or excretion of the study treatment.
• If less than the minimum time has elapsed from prior anticancer treatment to first dose of study treatment as follows:

• Cancer therapies, including chemotherapy, radiation, biologics or kinase inhibitors, or major surgery within 4 weeks prior to the first scheduled study treatment; for longer acting agents such as nitrosourea, mitomycin or antibody therapies, a minimum of 6 weeks.
• Use of investigational agents within 4 weeks prior to study enrollment (within 6 weeks if the treatment was with a long-acting agent).
• History of prior second malignancy unless disease-free for ≥ 12 months or considered surgically cured. Patients with nonmelanoma skin cancers or with carcinomas in situ at any time following curative intent surgery and low grade, early-stage prostate cancer (Gleason score 6 or below, stage 1 or 2) with no requirement for therapy at any time prior to the study, or previously resected are also eligible.
• Patients with symptomatic central nervous system metastases or other tumor location (such as spinal cord compression, other compressive mass, uncontrolled painful lesion, bone fracture, etc.) necessitating an urgent therapeutic intervention, palliative care, surgery or radiation therapy.
• Marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval > 480 milliseconds \[msec\]) (Common Terminology Criteria for Adverse Events \[CTCAE\] Grade 1) using Fridericia's QT correction formula.
• Patients with New York Heart Association Class III or IV heart failure.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Other

Study locations

United States · 2 centers

• UCI Irvine Health — Orange
• New York Presbyterian Hospital-Columbia University Medical Center — New York

Identifiers

NCT: NCT07486713 · C-002102-003

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗