A Clinical Trial of the Safety, Pharmacokinetics and Hematologic Effects of Imatinib on Myelopoiesis in Adults When Given With and Without Isoniazid and Rifabutin
Condition: Tuberculosis
MeSH terms: Tuberculosis
Study type: Interventional
Phase: Phase 2

Summary: 
      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: 
      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.
    

Intervention name(s): Imatinib; Isoniazid; Rifabutin
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Tablets, administered orally; 300 mg tablets, administered orally; 300 mg capsules, administered orally
Intervention MeSH terms: Isoniazid; Rifabutin; Imatinib Mesylate
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Imatinib; Rifabutin; Isoniazid