A Clinical Trial of the Safety, Pharmacokinetics and Hematologic Effects of Imatinib on Myelopoiesis in Adults When Given With and Without Isoniazid and Rifabutin
A Clinical Trial of the Safety, Pharmacokinetics and Hematologic Effects of Imatinib on Myelopoiesis in Adults When Given With and Without Isoniazid and Rifabutin
The purpose of this study is to evaluate the safety, pharmacokinetics, and effects of
 imatinib on myelopoiesis in adults when given with and without isoniazid and rifabutin. The
 results of this trial will determine the imatinib dose to be studied in a subsequent Phase
 IIB treatment trial of imatinib as an adjunctive therapy with an antimicrobial regimen
 (rifabutin, PZA, INH and ethambutol) for drug-sensitive TB.
This study will evaluate the safety, pharmacokinetics, and effects of imatinib on
 myelopoiesis in adults when given with and without isoniazid and rifabutin.

 Participants will be enrolled into one of two cohorts. In Cohort 1, participants will be
 enrolled in a dose-escalating fashion to receive one of four doses of imatinib alone for 14
 days, followed by imatinib in combination with rifabutin and isoniazid for another 14 days.

 In Cohort 2, participants will receive rifabutin and isoniazid for 14 days, followed by 14
 days of rifabutin and isoniazid in combination with one of the two selected doses of
 imatinib. The exact doses of imatinib administered in Cohort 2 will be determined after
 analyzing data from Cohort 1.

 Total study duration for participants will be 50 days, during which time participants will
 attend several study visits. Study visits may include a physical exam, electrocardiogram,
 blood and urine collection, and pharmacokinetic assessments.
Inclusion Criteria:

 -  Adult age between 18 years and 55 years

 -  Body mass index (BMI) greater than 18.5 kg/m^2

 -  At least 8 years formal education, with appropriate reading and comprehension skills

 -  Able and willing to provide written informed consent

 -  Males must agree to using contraception during the study and for 2 weeks after the
 last dose of study drug.

 -  If a female participant is of reproductive potential, the participant (and her
 partner) must agree to use of one of the following combinations of birth control
 during the study and for 2 weeks after the last dose of study drug (or tubal ligation
 as a single method):

 -  Use of a double-barrier method of contraception: condoms (male or female) and a
 diaphragm or cervical cap with spermicide;

 -  Use of an intrauterine device (IUD) and a barrier method: condoms (male or
 female, with or without spermicide) or a diaphragm or cervical cap with
 spermicide;

 -  Tubal ligation.

 -  Important Note: Due to documented effects of rifabutin on effectiveness of
 hormonal contraceptives (16-18), these are not included as options here with the
 exception of an IUD. Women who are post-menopausal, defined as age greater than
 45 and no menses for at least 1 year, or who have had a hysterectomy, are
 considered not of reproductive potential.

 Exclusion Criteria:

 -  Current or imminent treatment for significant infection

 -  Pregnant or breastfeeding

 -  HIV positive status as determined by a U.S. Food and Drug Administration
 (FDA)-approved HIV assay

 -  Hepatitis B infection, as determined by an FDA-approved hepatitis B surface antigen
 assay

 -  Hepatitis C infection, as determined by an FDA-approved positive Hepatitis C antibody
 assay

 -  Known infection with Mycobacterium tuberculosis (MTB)

 -  History of allergy or hypersensitivity to imatinib, isoniazid or rifabutin.

 -  History of enrollment in other clinical trials with investigational agents within 8
 weeks

 -  Cardiac arrhythmia requiring medication, or any clinically significant
 electrocardiogram (ECG) abnormality

 -  Exam consistent with congestive heart failure (e.g., edema)

 -  Random blood glucose greater than 140 mg/dL or history of unstable diabetes mellitus
 requiring hospitalization for hyper or hypoglycemia within the past year prior to
 start of screening

 -  Use of systemic corticosteroids within the past 28 days

 -  Any of the following readings from a complete blood count that fall outside the normal
 ranges as listed here (Emory Medical Lab Reference Ranges, 2019, with some variation
 for different ethnic groups incorporated in the system):

 -  White blood cell count: Female- 4.0-10.0 10E3/mcL, Male- 4.2-9.1 10E3/mcL

 -  Hemoglobin: Female-11.4-14.4 gm/dL, Male-12.9-16.1 gm/dL

 -  Platelet count: Female-150-400 10E3/mcL, Male-150-400 10E3/mcL

 -  Absolute neutrophil count: Female- 0.91-5.53 10E3/mcL, Male- 0.67-6.4110E3/mcL

 -  Absolute lymphocyte count: Female- 0.65-3.05 10E3/mcL, Male- 0.72-3.29 10E3/mcL

 -  Any of the following chemistry panel and liver function test readings that fall
 outside the normal ranges as listed here (Emory Medical Lab Reference Ranges, 2019):

 -  Serum potassium: Female- 3.5-5.1 mmol/L, Male- 3.5-5.1 mmol/L

 -  Alkaline phosphatase (ALP): Female- 34-104unit/L, Male- 34-104unit/L

 -  Alanine aminotransferase (ALT): Female- 7-52 unit/L, Male-7-52 unit/L

 -  Aspartate aminotransferase (AST): Female-13-39 unit/L, Male-13-39 unit/L

 -  Gamma-glutamyl transferase (GGT): Female- 9-64 unit/L, Male- 9-64 unit/L

 -  Total Bilirubin: Female- 0.3-1.0 mg/dL, Male- 0.3-1.0 mg/dL

 -  Creatinine: Female- 0.60-1.20 mg/dL, Male- 0.7-1.3mg/dL

 -  Cirrhosis of the liver, or any known active or chronic liver disease

 -  Current or past alcohol or elicit/recreational drug use, which in the expert judgment
 of the Investigator, will interfere with the participant's ability to comply with the
 protocol requirements.

 -  Any experimental medications for less than 8 weeks prior to screening or anticipated
 use during the trial

 -  Current (within 30 days prior to the first dose of study drug) or anticipated use of
 antimetabolites; alkylating agents; or other drugs or herbal preparations (including
 St. John's wort), known to affect activity of the CYP3A4 enzyme pathway

 -  Consumption of grapefruit, grapefruit juice, or grapefruit-related citrus fruits
 (e.g., pomelos) within 7 days before assessment for eligibility

 -  Unwilling to avoid grapefruit or grapefruit-related citrus fruits/pomelo during the
 course of the study

 -  Unwilling to avoid alcohol for the duration of the study

 -  Unwilling to abstain from taking acetaminophen-containing medications during the
 28-day study drug dosing period, due to increased risk of liver toxicity

 -  History of major medical disorders including metabolic, endocrine, hypothyroid,
 hepatic, renal, hematologic, pulmonary, gastrointestinal, autoimmune or cardiovascular
 disorders

 -  Uncontrolled hypertension (persistent measurements at or above 150/100)

 -  Participants who are, in the opinion of the Investigator, unable to comply with the
 dosing schedule and protocol evaluations

 -  Diarrhea defined as 4 or more stools per day

 -  Active involvement (by the participant or the participant's partner) in In Vitro
 Fertilization or another assisted reproductive technology procedure

 -  Emory students currently enrolled in a course taught by the principal investigator
 (PI) or a Co-Investigator

 -  Emory employees currently working under supervision of the PI or a Co-Investigator