This research is being done to find out if the study drug (ketoconazole) can enter brain
tumors at a high enough amount to stop the tumor cells from dividing. Ketoconazole is a drug
which doctors already use for fungal infections and is thought to be able to effect tumor
cells. As treatments for this type of brain tumor are limited, it is hoped that the results
of this study will help to determine if the study drug should be studied further as a
possible treatment.
Both ketoconazole and posaconazole are FDA-approved anti-fungal agents with a
well-established side effect and safety profile. Ketoconazole and posaconazole have shown
efficacy in reducing tumor cell proliferation in in-vitro studies. Furthermore, both have
also shown efficacy, mediated at least in part through inhibition of hexokinase 2 (HK2)
activity, in animal models with dosing concentration and schedules that are documented as
safe in humans. As a drug, posaconazole has a more predictable half-life than ketoconazole
and has less off-target effects. Therefore, the proposed trial will focus on the role of
posaconazole exclusively. As a first step, demonstration of adequate penetrance of study drug
in brain and tumor tissue (pharmacokinetics) and biological effect (inhibition of glycolysis
and subsequent tumor cell death) is necessary prior to large scale clinical studies. A total
of 5 control participants will be included in this study as the investigator specifically
wants to assess for pharmacodynamic differences too. The addition of a control group to this
study rather to both the studies (ketoconazole study is a separate protocol) is because the
investigator feels posaconazole may be a more promising drug for moving forward.
Plasma drug concentration measurements are an unreliable method to assess delivery of drugs
across the blood-brain barrier. In contrast, intracerebral microdialysis catheters (MDC)
monitoring allows for approximate measurements within extracellular fluid (ECF) sampling of
the brain. MDC placement within the brain is not a novel technique and has been utilized
routinely in the ICU setting to measure brain metabolism by sampling of ECF of traumatic
brain injury patients.
MDC are now FDA-approved and are being placed routinely with intracranial pressure monitors.
This method allows for continuous measurement of ECF within a tumor or normal tissue. The
dialysis probe has a semipermeable membrane which is less than 1 mm in diameter into which
two sections of microcatheter are fused. Previous studies have demonstrated the feasibility
of keeping the catheters in place of critically injured patients for up to 2 weeks.
When placed at the time of surgical resection, the microcatheters are stereotactically
implanted, placing the probe within the desired brain and/or tumor region. Externally, the
catheter is connected to a syringe pump, which delivers a low flow rate (μl/min) of
continuous perfusion fluid (Lactated Ringers or artificial CSF) and dialysate is collected in
a microvial from the outlet tube. This sterile, single use catheter is minimally invasive and
developed to achieve optimal diffusing characteristics similar to passive diffusion of a
capillary blood vessel. Just as in the function of brain capillary vessel, water, inorganic
ions and small organic molecules freely diffuse across the membrane of the probe, whereas
proteins and protein bound compounds are impermeable. Additionally, lipophilic compounds are
poorly recovered. Therefore, assessment of pharmacokinetics of drug using MDC provides
valuable insight relevant to its anti-neoplastic properties.
Inclusion Criteria:
- Age ≥18 years
- Evidence of primary or recurrent high-grade gliomas (HGG) that in the opinion of the
treating team would require surgical resection
- Karnofsky Performance Score (KPS) ≥ 60%
- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
- Life expectancy greater than 12 weeks
- Adequate liver function defined as Alanine aminotransferase (ALT),Aspartate
transaminase (AST), Alkaline phosphatase (ALP) within 1.5x institutional upper limit
of normal
- Adequate renal function defined as estimated glomerular filtration rate (eGFR) levels
within 1.5x the institutional upper limit of normal
- Ability to swallow medication
- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) for the duration of study
participation.
- Ability to understand and willingness to sign a written informed consent document
- Be able to comply with treatment plan, study procedures and follow-up examinations
Exclusion Criteria:
- Patients may not be receiving any other investigational agents while on study
- Patients who have known allergy to ketoconazole or other azoles
- Patients who have previously had a severe side effect, such as agranulocytosis and
neutropenia, in conjunction with previous azole class drugs for a parasitic infection
- Patients with a history of acute or chronic hepatitis
- Patients with liver enzymes (ALT, AST, ALP) >1.5x above normal range for the
laboratory performing the test
- Patients who are taking metronidazole and cannot be safely moved to a different
antibiotic greater than 7 days prior to starting ketoconazole therapy
- Patients who are taking any anti-convulsant medication that interferes with the
cytochrome P450 pathway (e.g. phenytoin, phenobarbital, carbamazepine, etc.) and who
cannot be switched to alternative medications such as keppra (levetiracetam)
- Uncontrolled intercurrent illness such as chronic hepatitis, acute hepatitis, or
psychiatric illness/social situation that would limit compliance with study
requirements
- Patients with a history of Addison's disease or other forms of adrenal insufficiency
- Patient with little or no stomach acid production (achlorhydria)
- Pregnant and breast feeding women
- Patients with a history of any medical or psychiatric condition or laboratory
abnormality that in the opinion of the investigator may increase the risks associated
with the study participation or investigational product administration or may
interfere with the interpretation of the results.
- Patients who are not available for follow-up assessments or unable to comply with
study requirements.
- Patients who are currently taking medications that induce the metabolism of
ketoconazole, such as isoniazid, nevirapine, rifamycins (such as rifabutin, rifampin),
or St. John's wort and cannot be safely discontinued off of them for the duration of
the trial.
- Patients who are currently taking medications for which the metabolism may be affected
by ketoconazole, which include but are not limited to: benzodiazepines (such as
alprazolam, midazolam, triazolam), domperidone, eletriptan, eplerenone, ergot drugs
(such as ergotamine), nisoldipine, drugs used to treat erectile dysfunction (ED) or
pulmonary hypertension (such as sildenafil, tadalafil), some drugs used to treat
seizures (such as carbamazepine, phenytoin), some statin drugs (such as atorvastatin,
lovastatin, simvastatin).
- Patients who are non-English speakers
- Patients who are not capable of understanding the consent form and would need a
legally authorized representative.
