A Study to Evaluate the Effect of Multiple Doses of Itraconazole, Phenytoin, and Paroxetine on the Single-Dose Pharmacokinetics of Poziotinib in Healthy Adult Participants

NCT04981704 | Completed Phase 1 FDA Drug

• 1 other identifier: SPI-POZ-103
• Study Type: interventional
• Target: 74
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of the study is to evaluate the effect of multiple-doses of itraconazole, phenytoin and paroxetine on the single-dose pharmacokinetics (PK) of poziotinib in healthy adult participants.

Conditions

Healthy

Keywords

Healthy Volunteers

Outcome Measures

Primary Outcomes (4)

• Area Under the Curve (AUC) of Poziotinib and Metabolites (M1 and M2) Following Poziotinib Administrations With and Without Itraconazole [Part 1], Phenytoin [Part 2], or Paroxetine [Part 3]

  Part 1 and Part 3, predose and up to 120 hours postdose; Part 2, predose and up to 96 hours postdose

• Maximum Observed Concentration (Cmax) of Poziotinib and Metabolites (M1 and M2) Following Poziotinib Administration With and Without Itraconazole [Part 1], Phenytoin [Part 2], or Paroxetine [Part 3]

  Part 1 and Part 3, predose and up to 120 hours postdose; Part 2, predose and up to 96 hours postdose

• Apparent Clearance (CL/F) of Poziotinib Following Poziotinib Administration With and Without Itraconazole [Part 1], Phenytoin [Part 2], or Paroxetine [Part 3]

  Part 1 and Part 3, predose and up to 120 hours postdose; Part 2, predose and up to 96 hours postdose

• Time to Maximum Observed Concentration (Tmax) for Poziotinib and Metabolites (M1 and M2) Following Poziotinib Administration With and Without Itraconazole [Part 1], Phenytoin [Part 2], or Paroxetine [Part 3]

  Part 1 and Part 3, predose and up to 120 hours postdose; Part 2, predose and up to 96 hours postdose

Secondary Outcomes (4)

• Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

  Screening, and up to 14 days post last dose of Poziotinib

• Number of Participants With Clinically Significant Changes in Clinical Laboratory Parameters From Baseline

  Screening, and up to 14 days post last dose of Poziotinib

• Number of Participants With Clinically Significant Changes in 12-Lead Electrocardiogram (ECG) Findings From Baseline

  Screening, and up to 14 days post last dose of Poziotinib

• Number of Participants With Clinically Significant Changes in Vital Signs From Baseline

  Screening, and up to 14 days post last dose of Poziotinib

Study Arms (3)

Part 1: Itraconazole/Poziotinib Drug-drug interaction (DDI)

EXPERIMENTAL

On Day 1 of Treatment period 1, a single oral dose of 8 milligrams (mg) poziotinib will be administered. On Day 1 of Treatment Period 2, 200 mg itraconazole oral solution will be administered twice a day (BID) followed by 200 mg itraconazole oral solution once daily (QD) for 7 consecutive days (Day 2 to Day 8) with a single oral dose of 8 mg poziotinib coadministered on Day 4.

Drug: Poziotinib; Drug: Itraconazole

Part 2: Phenytoin/Poziotinib DDI

EXPERIMENTAL

On Day 1 of Treatment period 1, a single oral dose of 16 mg poziotinib will be administered. In treatment period 2, an oral dose of 100 mg phenytoin will be administered three times daily (TID) for 17 consecutive days (Day 1 to Day 17) with a single oral dose of 16 mg poziotinib coadministered on Day 14.

Drug: Poziotinib; Drug: Phenytoin

Part 3: Paroxetine/Poziotinib DDI

EXPERIMENTAL

On Day 1 of Treatment Period 1, a single oral dose of 8 mg poziotinib will be administered. On Day 1 and Day 2 of Treatment Period 2, an oral dose of 20 mg paroxetine will be administered BID followed by 20 mg paroxetine QD for 9 consecutive days (Day 3 to Day 11) with a single oral dose of 8 mg poziotinib coadministered on Day 7.

Drug: Poziotinib; Drug: Paroxetine

Interventions

Poziotinib DRUG

Poziotinib Tablets

Part 1: Itraconazole/Poziotinib Drug-drug interaction (DDI); Part 2: Phenytoin/Poziotinib DDI; Part 3: Paroxetine/Poziotinib DDI

Itraconazole DRUG

Itraconazole Oral solution

Part 1: Itraconazole/Poziotinib Drug-drug interaction (DDI)

Phenytoin DRUG

Phenytoin Capsules

Part 2: Phenytoin/Poziotinib DDI

Paroxetine DRUG

Paroxetine Tablets

Also known as: Paxil ®

Part 3: Paroxetine/Poziotinib DDI

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy, adult, male or female (of non-childbearing potential only), 18-55 years of age.
• Body mass index (BMI) ≥ 18.0 and ≤ 32.0 kilogram per meter square (kg/m\^2) at screening, and a minimum weight of 50.0 kg and a maximum weight of 100.0 kg at screening.
• Continuous non-smoker who has not used nicotine-containing products for at least 3 months prior to the first dosing and throughout the study.
• Medically healthy with no clinically significant findings from medical history, physical examination, 12-lead ECG, vital signs, and laboratory evaluations.
• Female must be of non-childbearing potential only and must have undergone a sterilization procedure at least 6 months prior to the first dosing, or
• Postmenopausal women should have amenorrhea for at least 1 year prior to the first dosing.
• A non-vasectomized male participant must agree to use a highly effective method of birth control with female partners of childbearing potential or with pregnant partners during the study and for 120 days following last dosing.
• Able to comprehend and willing to sign an Informed Consent Form (ICF) and abide by the clinical protocol, study procedures, and restrictions.
• For Part 1 only: Participant must be a CYP2D6 extensive metabolizer or CYP2D6 poor metabolizer as determined by a valid genotyping method.
• For Part 2 only: Participant must not be a CYP2C9 and CYP2C19 poor metabolizer as determined by a valid genotyping method and must be a CYP2D6 extensive metabolizer as determined by a valid genotyping method.
• For Part 3 only: Participant must be a CYP2D6 extensive metabolizer as determined by a valid genotyping method.

You may not qualify if:

• Significant history or clinical manifestation of any metabolic, allergic, dermatological, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, neurological, respiratory, endocrine, or psychiatric disorder, as determined by the PI (or designee).
• History of a developing or established acute event or infection in the prior 2 weeks to screening.
• History of significant hypersensitivity, or idiosyncratic reaction to poziotinib, itraconazole, phenytoin, paroxetine, or related drugs, food, or other substances.
• Any surgical or medical condition within 6 months prior to first dosing that may potentially alter absorption, distribution, metabolism or excretion of the study drugs, in the opinion of the PI (or designee).
• History or presence of alcoholism or drug/chemical abuse within 2 years prior to check-in.
• Female participants with a positive pregnancy test result or lactating.
• Positive urine drug or alcohol test results at screening or check-in.
• Positive hepatitis panel (hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) and/or positive human immunodeficiency virus (HIV) test at screening. Automatic reflex Differential and ribonucleic acid testing will be conducted in the event of a reactive antibody/antigen screen.
• Seated blood pressure is less than 90/40 millimetre of mercury (mmHg) or greater than 140/90 mmHg at screening.
• Seated heart rate is lower than 40 beats per minute (bpm) or higher than 99 bpm at screening.
• QT interval with Fridericia's correction (QTcF) interval is \>450 millisecond (msec) (males) or \>470 msec (females).
• Unable to refrain from or anticipates the use of:
• Any drug, including prescription and non-prescription medications, herbal remedies, or vitamin supplements beginning 14 days prior to the first dosing and throughout the study. Hormone replacement therapy will not be allowed.
• Any drugs known to be inhibitors and/or inducers of CYP3A, CYP2D6, CYP2C9, or CYP2C19 enzymes; and/or P-gp; and/or gastric acid reducing agents (proton-pump inhibitors, H2-receptor antagonists, antacids) for 28 days prior to the first dosing and throughout the study (except those required as part of the study).
• Has a coagulation test (i.e., prothrombin time and activated partial thromboplastin time) outside of normal ranges at screening or at check-in.

Sponsors & Collaborators

• Spectrum Pharmaceuticals, Inc: lead

Study Sites (1)

Celerion, Phoenix clinical facility

Tempe, Arizona, 85283, United States

Location

MeSH Terms

Interventions

HM781-36B; Itraconazole; Phenytoin; Paroxetine

Intervention Hierarchy (Ancestors)

Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Piperazines; Hydantoins; Imidazolidines; Imidazoles; Piperidines

Study Officials

• Shanta Chawla, MD

  Spectrum Pharmaceuticals, Inc

  STUDY DIRECTOR

Study Design

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

Study Record Dates

• First Submitted: June 23, 2021
• First Posted: July 29, 2021
• Study Start: April 8, 2021
• Primary Completion: June 30, 2021
• Study Completion: August 17, 2021
• Last Updated: September 5, 2021

Record last verified: 2021-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)