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.

This is a three-part study. Participants will be enrolled in Part 1 (Effects of Itraconazole), Part 2 (Effects of Phenytoin), or Part 3 (Effects of Paroxetine) on the Pharmacokinetics of Poziotinib. Each part will be an open-label, fixed-sequence, 2-period study and may be conducted concurrently. For each study part, participants will be housed on Day -1 of Treatment Period 1 in the Clinical Research Unit (CRU) and will remain confined in the CRU until after the last scheduled blood draw and/or study procedures in Treatment Period 2. In each part, there will be a washout period of at least 8 days between poziotinib doses.

A total of 75 (25 in each part) healthy, adult male and female participants will be enrolled targeting a female/male ratio greater than or equal to (≥) 1:3 in each study part.

In part 1, CYP2D6 extensive metabolizers will be primarily enrolled with a goal of enrolling at least 2 CYP2D6 poor metabolizers. In Parts 2 and 3, only CYP2D6 extensive metabolizers will be enrolled. In Part 2, CYP2C9 and CYP2C19 poor metabolizers will be excluded.

Key Inclusion Criteria:

• 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.

Key Exclusion Criteria:

• 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.

• Has platelet, hemoglobin, or hematocrit that are below the lower limit of normal at screening or at check-in.

• Has alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), or total bilirubin that are greater than the upper limit of normal at screening or at check-in.

• Estimated creatinine clearance <90 milliliter per minute (mL/min) at screening.

• Participation in another clinical study within 30 days prior to the first dosing.

• Prior exposure to poziotinib.

• For Part 1 Only:History or presence of any of the following, deemed clinically significant by the Investigator (or designee), and as confirmed by the Sponsor:

  • Ventricular dysfunction or risk factors for Torsades de Pointes (e.g., heart failure, cardiomyopathy, family history of Long QT Syndrome).
  • Uncorrected hypokalemia (potassium levels < 3.7) and/or hypomagnesemia (magnesium levels < 1.9).
  • Myasthenia gravis.

• For Part 2 Only: History of seizure (excluding simple febrile seizure), epilepsy, severe head injury, multiple sclerosis, or other known neurological conditions which the Investigator considers to be clinically significant.

• Is at suicidal risk in the opinion of the PI as per the following criteria:

  • Any suicidal attempts within 12 months prior to screening.
  • any suicidal intent including a plan or C-SSRS answer of "YES" on suicidal ideation currently or within 3 months.