Phase I Trial of AZD8055, An Oral MTOR Kinase Inhibitor, for Adults With Recurrent Gliomas

Inclusion Criteria

- INCLUSION CRITERIA:

- Patients with histologically proven malignant primary gliomas who have progressive
disease after radiotherapy will be eligible for this protocol. These include
glioblastoma (GBM), gliosarcoma, anaplastic astrocytoma (AA), anaplastic
oligodendroglioma (AO), anaplastic mixed oligoastrocytoma (AMO), and malignant
glioma/astrocytoma NOS. Additionally, patients with progressive low-grade gliomas and
patients with infiltrative brainstem gliomas, diagnosed radiographically rather than
by biopsy, will be eligible.

- Patients must have an MRI scan performed within 14 days prior to registration and on
a fixed dose of steroids for at least 5 days. If the steroid dose is increased
between the date of imaging and registration a new baseline MRI is required.

- Patients having undergone recent resection of recurrent or progressive tumor will be
eligible for the non-surgical arm as long as all of the following conditions apply:

1. Patients will be eligible four weeks after surgery if they have recovered from
the effects of surgery.

2. Residual disease following resection of recurrent tumor is not mandated for
eligibility into the study. To best assess the extent of residual disease
postoperatively, an MRI should be done:

- no later than 96 hours in the immediate post-operative period or

- at least 4 weeks post-operatively, and

- within 14 days of registration, and

- on a stable steroid dosage for at least 5 days.

If the 96 hour scan is more than 14 days before registration, the scan needs to be
repeated. If the steroid dose is increased between the date of imaging and registration, a
new baseline MRI is required on a stable steroid dosage for at least 5 days.

- Patients must have failed prior radiation therapy.

- All patients or their previously designated DPA (if the patient is deemed by the
treating physician to be cognitively impaired or questionably impaired in such a way
that the ability of the patient to give informed consent is questionable) must sign
an informed consent indicating that they are aware of the investigational nature of
this study.

- Patients must be greater than or equal to 18 years old, and must have a life
expectancy > 8 weeks.

- Patients must have a Karnofsky performance status of greater than or equal to 60.

- Patients must be at least 4 weeks from radiation therapy. Additionally, patients must
be at least 6 weeks from nitrosoureas, 4 weeks from temozolomide, 3 weeks from
procarbazine, 2 weeks from vincristine and 2 weeks from last bevacizumab
administration. Patients must be at least 4 weeks from other cytotoxic therapies not
listed above and 2 weeks for non-cytotoxic agents (e.g., interferon, tamoxifen)
including investigative agents. With the exception of alopecia, all toxicities from
prior therapies should be resolved to CTCAE less than or equal to grade 1.

- Patients must have adequate bone marrow function (WBC greater than or equal to
3,000/microL, ANC greater than or equal to 1,500/mm(3), platelet count of greater
than or equal to 100,000/mm(3), and hemoglobin greater than or equal to 9 gm/dl),
adequate liver function (AST, ALT and alkaline phosphatase 2.5 less than or equal to
ULN and bilirubin less than or equal to 1.5 times ULN), and adequate renal function
(creatinine less than or equal to 1.5 times ULN and/or creatinine clearance greater
than or equal to 50 cc/min calculated by Cockcroft-Gault) before starting therapy.
Patients must also have serum potassium greater than or equal to 3.5 mmol/L,
magnesium greater than or equal to 0.75 mmol/L and calcium levels within normal
levels; supplementation is allowed. In cases where the serum calcium is below the
normal range, 2 options would be available: 1) the calcium adjusted for albumin is to
be obtained and substituted for the measured serum value. Exclusion is to then be
based on the adjusted for albumin values falling below the normal limit. 2) Determine
the ionized calcium levels. Exclusion is then to be based if these ionized calcium
levels are out of normal range despite supplementation. These tests must be performed
within 14 days prior to registration. Eligibility level for hemoglobin may be reached
by transfusion.

- Patients must either not be receiving steroids, or be on a stable dose of steroids
for at least five days prior to registration.

- This study was designed to include women and minorities, but was not designed to
measure differences of intervention effects. Males and females will be recruited with
no preference to gender. No exclusion to this study will be based on race. Minorities
will actively be recruited to participate.

- Male patients should be willing to use barrier contraception (condoms).

- Female patients should be using adequate contraceptive measures, should not be breast
feeding and must have a negative pregnancy test prior to start of dosing if of
child-bearing potential or must have evidence of non-childbearing potential by
fulfilling one of the following criteria at screening:

- Post-menopausal defined as aged more than 50 years and amenorrheic for at least
12 months following cessation of all exogenous hormonal treatments.

- Documentation of irreversible surgical sterilization by hysterectomy, bilateral
oophorectomy or bilateral salpingectomy but not tubal ligation.

- A 12 lead electrocardiogram (ECG) to be performed within 2 weeks of trial entry with
QTc less than or equal to 470 msec.

- Patients must have normal left ventricular ejection fraction (LVEF greater than or
equal to 55% or normal by NIH Clinical Center criteria).

EXCLUSION CRITERIA:

- Patients who, in the view of the treating physician, have significant active hepatic,
renal, pulmonary or psychiatric diseases are ineligible.

- Prior treatment with AZD8055 or AZD2014.

- History of hypersensitivity to active or excipients of AZD8055 or drugs with a
similar chemical structure or class to AZD8055.

- Clinically significant cardiovascular event (e.g. myocardial infarction, angina
pectoris, coronary artery bypass graft, angioplasty, vascular stent, superior vena
cava syndrome (SVC), New York Heart Association (NYHA) classification of heart
disease greater than or equal to 2 within 6 months before entry; or presence of
cardiac disease that, in the opinion of the investigator, increases the risk of
ventricular arrhythmia.

- Hemorrhagic or ischemic stroke, including transient ischemic attacks and other
central nervous system bleeding in the preceding 6 months that were not related to
glioma surgery. History of prior intratumoral bleeding is not an exclusion criteria;
patients with history of prior intratumoral bleeding, however, need to undergo a
non-contrast head CT to exclude acute blood.

- Ventricular arrhythmias requiring continuous therapy or asymptomatic sustained
ventricular tachycardia within 12 months before study entry. Atrial fibrillation,
controlled on medication is not excluded. Patients with significant ECG abnormalities
such as complete left bundle block and third degree heart block are not eligible.

- QTc prolongation with other medications that required discontinuation of that
medication.

- Congenital long QT syndrome or 1st degree relative with unexplained sudden death
under 40 years of age.

- QTc with Bazett's correction that is unmeasurable, or > 470 msec on screening ECG.
(Note: If a subject has a QTc interval > 470 msec on screening ECG, the screen ECG
may be repeated twice (at least 24 hours apart). The average QTc from the three
screening ECGs must be less than or equal to 470 msec in order for the subject to be
eligible for the study. Patients who are receiving a drug that has a risk of QTc
prolongation are excluded if QTc is greater than or equal to 460 msec.

- Any concurrent medication that may cause QTc prolongation or induce Torsades de
Pointes Drugs, that in the investigator's opinion cannot be discontinued are allowed;
however, must be monitored closely.

- Concomitant medications that are moderate or potent inducers of CYP3A4 or CYP2C8
function (with the exception of dexamethasone) are not permitted within the specified
wash-out periods prior to or during treatment with AZD8055.

- Patients with uncontrolled hypercholesterolemia or hypertriglyceridemia (fasting
state) despite lipid-lowering therapy.

- Patients with manifest diabetes mellitus type 1 and patients with uncontrolled
diabetes mellitus type 2 or corticosteroid-induced hyperglycemia despite optimal
therapy.

- Refractory nausea and vomiting or significant gastrointestinal impairment, as judged
by the investigator, that would significantly affect the absorption of AZD8055,
including the ability to swallow the tablet whole.

- Patients known to have active hepatitis B or C or HIV on anti-retrovirals (testing is
not required for entry on study).

- Other concomitant anti-cancer therapy except corticosteroids.

- Patients with a peripheral neuropathy CTCAE > 1 in the prior 4 weeks or active
muscle diseases (including dermatomyositis, polymyositis, inclusion body myositis,
muscular dystrophy and metabolic myopathy) or family history of myopathy.

- Patients with pre-existing renal disease including glomerulonephritis, nephritic
syndrome, Fanconi syndrome or renal tubular acidosis.

- Evidence of active infection or active bleeding diatheses.

- Patients with an abnormal LVEF on echocardiogram at baseline.

- Women who are currently pregnant or breast feeding.

- Patients known to have a malignancy (other than their malignant glioma) that has
required treatment in the last 12 months and/or is expected to require treatment in
the next 12 months (except for non-melanoma skin cancer, carcinoma in situ in the
cervix or ductal carcinoma in situ).

- Major surgery within 4 weeks or incompletely healed surgical incision before starting
therapy.