A Clinical Trial of the Safety, Pharmacokinetics and Hematologic Effects of Imatinib on Myelopoiesis in Adults When Given With and Without Isoniazid and Rifabutin

Study Overview
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Brief Summary
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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, pyrazinamide (PZA), isoniazid (INH) and ethambutol) for drug-sensitive TB.

Detailed Description
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With existing anti-tubercular drug therapies, treatment of drug-susceptible TB takes at least 6 months and success rates for multi-drug resistant tuberculosis (MDR-TB) and extensively drug resistant TB (XDR-TB) are a dismal 50 and 20%, respectively, highlighting the urgent need for new TB drugs. The cancer drug imatinib limits mycobacterial infections in culture and animal models by reducing both entry into macrophages and augmenting phagolysosomal fusion (autophagy), which may facilitate antigen presentation and pathogen killing. Additionally, imatinib induces increases in myeloid cells (myelopoiesis), and an innate immune response to infection that mimics so-called emergency hematopoiesis, a response that Mycobacterium tuberculosis (Mtb) appears to suppress. Importantly, these mechanisms can be induced in animal models by oral doses substantially lower than those used in people to combat cancer. The dose-dependence has important implications for TB clinical studies in humans, as it suggests that imatinib could improve TB treatment using doses that impart minimal, if any, toxicity. This study will evaluate the safety, pharmacokinetics, and effects of imatinib on myelopoiesis in adults when given with and without isoniazid and rifabutin (antibiotics to treat mycobacterial infections). 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. After safety evaluations of participants enrolled into the first two dose levels of Cohort 1, the intervention of imatinib followed by imatinib in combination with rifabutin and isoniazid was discontinued. The study protocol was amended to evaluate the effects of imatinib alone, at 3 escalating doses. 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.

Official Title
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IMPACT-TB (Imatinib Mesylate Per Oral as a Clinical Therapeutic for TB): A Phase II Clinical Trial of the Safety, Pharmacokinetics and Hematologic Effects of Imatinib on Myelopoiesis in Adults When Given With and Without Isoniazid and Rifabutin

Conditions
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Tuberculosis

Intervention / Treatment
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* Drug: Imatinib
* Drug: Isoniazid
* Drug: Rifabutin


Participation Criteria
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Eligibility Criteria
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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; For those in the imatinib only study arms: use of hormone-based contraceptives (pill, patch, implant, ring, or injectable) and a barrier method: condoms (male or female, with or without spermicide) or a diaphragm or cervical cap with spermicide (participants in study arms receiving isoniazid and rifabutin are not eligible if they are relying hormonal contraceptives other than an IUD) Tubal ligation. 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: White blood cell count: 3.4 10E3/microliter (mcL) - 11 10E3/mcL Hemoglobin: Female- 11.1 - 16.7 gm/dL, Male- 12.5 - 16.5 gm/dL Platelet count: 150-400 10E3/mcL Absolute neutrophil count: Female- 0.91-5.53 10E3/mcL, Male- 0.67-6.41 10E3/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: Serum potassium: 3.5-5.4 mmol/L Alkaline phosphatase (ALP): 34 - 104 unit/L Alanine aminotransferase (ALT): 4 - 52 unit/L Aspartate aminotransferase (AST): 13 - 39 unit/L Total Bilirubin: 0.2 - 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid<br>Participants will receive 50 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid. | Drug: Imatinib<br>* Tablets, administered orally<br>Drug: Isoniazid<br>* 300 mg tablets, administered orally<br>Drug: Rifabutin<br>* 300 mg capsules, administered orally<br>|
| Experimental: Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid<br>Participants will receive 100 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid. | Drug: Imatinib<br>* Tablets, administered orally<br>Drug: Isoniazid<br>* 300 mg tablets, administered orally<br>Drug: Rifabutin<br>* 300 mg capsules, administered orally<br>|
| Experimental: Cohort 1c: Imatinib (200 mg) + Rifabutin + Isoniazid<br>Participants will receive 200 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid. | Drug: Imatinib<br>* Tablets, administered orally<br>Drug: Isoniazid<br>* 300 mg tablets, administered orally<br>Drug: Rifabutin<br>* 300 mg capsules, administered orally<br>|
| Experimental: Cohort 1d: Imatinib (400 mg) + Rifabutin + Isoniazid<br>Participants will receive 400 mg imatinib for 14 days, followed by 14 days of imatinib together with rifabutin and isoniazid. | Drug: Imatinib<br>* Tablets, administered orally<br>Drug: Isoniazid<br>* 300 mg tablets, administered orally<br>Drug: Rifabutin<br>* 300 mg capsules, administered orally<br>|
| Experimental: Cohort 2a: Imatinib + Rifabutin + Isoniazid<br>Participants will receive isoniazid and rifabutin for 14 days, followed by 14 days of combination isoniazid, rifabutin, and imatinib. Imatinib dose will be determined after analyzing data from Cohort 1. | Drug: Imatinib<br>* Tablets, administered orally<br>Drug: Isoniazid<br>* 300 mg tablets, administered orally<br>Drug: Rifabutin<br>* 300 mg capsules, administered orally<br>|
| Experimental: Cohort 2b: Imatinib + Rifabutin + Isoniazid<br>Participants will receive isoniazid and rifabutin for 14 days, followed by 14 days of combination isoniazid, rifabutin, and imatinib. Imatinib dose will be determined after analyzing data from Cohort 1. | Drug: Imatinib<br>* Tablets, administered orally<br>Drug: Isoniazid<br>* 300 mg tablets, administered orally<br>Drug: Rifabutin<br>* 300 mg capsules, administered orally<br>|
| Experimental: Imatinib (100 mg)<br>Participants will receive 100 mg imatinib daily for 28 days. | Drug: Imatinib<br>* Tablets, administered orally<br>|
| Experimental: Imatinib (200 mg)<br>Participants will receive 200 mg imatinib daily for 28 days. | Drug: Imatinib<br>* Tablets, administered orally<br>|
| Experimental: Imatinib (400 mg)<br>Participants will receive 400 mg imatinib daily for 28 days. | Drug: Imatinib<br>* Tablets, administered orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Myelomonocytic Cells in the Blood | Immunologic effects of the study treatment are assessed by counting myelomonocytic cells in blood samples. An increase in myelomonocytic cells is used to determine the appropriate therapeutic dose of imatinib. | Days 1, 7, 14, 21, 28, 42 | 
| Frequency of Grade 3 or 4 Adverse Events (AEs) | The number of grade 3 or 4 adverse events occurring among study participants is presented here. Adverse events are graded using the FDA Guidance Document, Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials Guidance for Industry, September 2007, or other guidance, as applicable. | Measured through Day 50 | 
| Frequency of Serious Adverse Events (SAEs) | The number of serious adverse events occurring among study participants is presented here. Adverse events are graded using the FDA Guidance Document, Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials Guidance for Industry, September 2007, or other guidance, as applicable. | Measured through Day 50 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| White Blood Cell Count | The normal range for white blood cell counts is between 4,000 and 11,000 cells per microliter. White blood cell counts increase during infections, autoimmune diseases and some types of cancer. Low white blood cell counts occur with immune system diseases and certain types of cancer. | Days 1, 7, 14, 21, 28, 42 | 
| Maximum Concentration (Cmax) of Imatinib | Blood samples for pharmacokinetic (PK) analyses of imatinib were collected at 6 time points over approximately 24 hours. Samples collection occurred at hour 0 (pre-dose), and 0.5 hours, 2 hours, 4.0 hours, 8.0 hours, and 24 hours post-dose. PK samples were taken after 14 days of imatinib alone (all study arms) and after 14 days of imatinib with rifabutin and isoniazid (Cohorts 1a and 1b). The PK parameter Cmax is the highest concentration of imatinib in blood following dosing. | Day 14, Day 28 | 
| Half-life (T1/2) of Imatinib | Blood samples for pharmacokinetic (PK) analyses of imatinib were collected at 6 time points over approximately 24 hours. Samples collection occurred at hour 0 (pre-dose), and 0.5 hours, 2 hours, 4.0 hours, 8.0 hours, and 24 hours post-dose. PK samples were taken after 14 days of imatinib alone (all study arms) and after 14 days of imatinib with rifabutin and isoniazid (Cohorts 1a and 1b). The PK parameter T1/2 is the time when imatinib in blood is half of the maximum concentration. | Day 14, Day 28 | 
| Area Under the Curve (AUC) for Imatinib | Blood samples for pharmacokinetic (PK) analyses of imatinib were collected at 6 time points over approximately 24 hours. Samples collection occurred at hour 0 (pre-dose), and 0.5 hours, 2 hours, 4.0 hours, 8.0 hours, and 24 hours post-dose. PK samples were taken after 14 days of imatinib alone (all study arms) and after 14 days of imatinib with rifabutin and isoniazid (Cohorts 1a and 1b). The PK parameter AUC is the overall exposure to imatinib. | Day 14, Day 28 | 
| Elimination Rate Constant (Ke) of Imatinib | Blood samples for pharmacokinetic (PK) analyses of imatinib were collected at 6 time points over approximately 24 hours. Samples collection occurred at hour 0 (pre-dose), and 0.5 hours, 2 hours, 4.0 hours, 8.0 hours, and 24 hours post-dose. PK samples were taken after 14 days of imatinib alone (all study arms) and after 14 days of imatinib with rifabutin and isoniazid (Cohorts 1a and 1b). The elimination rate constant is the rate that imatinib is removed from the body. | Day 14, Day 28 | 
| Maximum Concentration (Cmax) of Isoniazid | Blood samples for pharmacokinetic (PK) analyses of isoniazid were collected at 6 time points over approximately 24 hours. Samples collection occurred at hour 0 (pre-dose), and 0.5 hours, 2 hours, 4.0 hours, 8.0 hours, and 24 hours post-dose. PK samples were taken after 14 days of imatinib with rifabutin and isoniazid (Cohorts 1a and 1b). The PK parameter Cmax is the highest concentration of the drug in blood following dosing. | Day 28 | 
| Half-life (T1/2) of Isoniazid | Blood samples for pharmacokinetic (PK) analyses of isoniazid were collected at 6 time points over approximately 24 hours. Samples collection occurred at hour 0 (pre-dose), and 0.5 hours, 2 hours, 4.0 hours, 8.0 hours, and 24 hours post-dose. PK samples were taken after 14 days of imatinib with rifabutin and isoniazid (Cohorts 1a and 1b). The PK parameter T1/2 is the time when the drug in blood is half of the maximum concentration. | Day 28 | 
| Area Under the Curve (AUC) for Isoniazid | Blood samples for pharmacokinetic (PK) analyses of isoniazid were collected at 6 time points over approximately 24 hours. Samples collection occurred at hour 0 (pre-dose), and 0.5 hours, 2 hours, 4.0 hours, 8.0 hours, and 24 hours post-dose. PK samples were taken after 14 days of imatinib with rifabutin and isoniazid (Cohorts 1a and 1b). The PK parameter AUC is the overall exposure to the drug. | Day 28 | 
| Elimination Rate Constant (Ke) of Isoniazid | Blood samples for pharmacokinetic (PK) analyses of isoniazid were collected at 6 time points over approximately 24 hours. Samples collection occurred at hour 0 (pre-dose), and 0.5 hours, 2 hours, 4.0 hours, 8.0 hours, and 24 hours post-dose. PK samples were taken after 14 days of imatinib with rifabutin and isoniazid (Cohorts 1a and 1b). The elimination rate constant is the rate that the drug is removed from the body. | Day 28 | 
| Maximum Concentration (Cmax) of Rifabutin | Blood samples for pharmacokinetic (PK) analyses of rifabutin were collected at 6 time points over approximately 24 hours. Samples collection occurred at hour 0 (pre-dose), and 0.5 hours, 2 hours, 4.0 hours, 8.0 hours, and 24 hours post-dose. PK samples were taken after 14 days of imatinib with rifabutin and isoniazid (Cohorts 1a and 1b). The PK parameter Cmax is the highest concentration of the drug in blood following dosing. | Day 28 | 
| Half-life (T1/2) of Rifabutin | Blood samples for pharmacokinetic (PK) analyses of rifabutin were collected at 6 time points over approximately 24 hours. Samples collection occurred at hour 0 (pre-dose), and 0.5 hours, 2 hours, 4.0 hours, 8.0 hours, and 24 hours post-dose. PK samples were taken after 14 days of imatinib with rifabutin and isoniazid (Cohorts 1a and 1b). The PK parameter T1/2 is the time when the drug in blood is half of the maximum concentration. | Day 28 | 
| Area Under the Curve (AUC) for Rifabutin | Blood samples for pharmacokinetic (PK) analyses of rifabutin were collected at 6 time points over approximately 24 hours. Samples collection occurred at hour 0 (pre-dose), and 0.5 hours, 2 hours, 4.0 hours, 8.0 hours, and 24 hours post-dose. PK samples were taken after 14 days of imatinib with rifabutin and isoniazid (Cohorts 1a and 1b). The PK parameter AUC is the overall exposure to the drug. | Day 28 | 
| Elimination Rate Constant (Ke) of Rifabutin | Blood samples for pharmacokinetic (PK) analyses of rifabutin were collected at 6 time points over approximately 24 hours. Samples collection occurred at hour 0 (pre-dose), and 0.5 hours, 2 hours, 4.0 hours, 8.0 hours, and 24 hours post-dose. PK samples were taken after 14 days of imatinib with rifabutin and isoniazid (Cohorts 1a and 1b). The elimination rate constant is the rate that the drug is removed from the body. | Day 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Imatinib, Rifabutin, Isoniazid