AZD8055 for Adults With Recurrent Gliomas
Condition: Glioblastoma Multiforme; Anaplastic Astrocytoma; Anaplastic Oligodendroglioma; Malignant Glioma; Brainstem Glioma
MeSH terms: Glioblastoma; Glioma; Astrocytoma; Oligodendroglioma
Study type: Interventional
Phase: Phase 1

Summary: 
      Background:

      - AZD8055 is an experimental cancer treatment drug that works by inhibiting a protein called
      mTOR, which is known to promote tumor cell and blood vessel growth and to control tumor s
      energy and nutrient levels. AZD8055 is the first drug that inhibits both types of mTOR
      protein and is expected to be more effective than prior mTOR inhibitors. However, more
      research is needed to determine its safety and effectiveness in treating brain tumors known
      as gliomas that have not responded to standard treatments.

      Objectives:

      - To evaluate the safety and effectiveness of AZD8055 in individuals with gliomas that have
      not responded to standard treatments.

      Eligibility:

      - Individuals at least 18 years of age who have been diagnosed with gliomas that have not
      responded to standard chemotherapy, surgery, or radiation.

      Design:

        -  Participants will be screened with a physical examination, medical history, blood tests,
           and tumor imaging studies.

        -  Participants will be separated into two treatment groups: one group that will receive
           surgery to remove the glioma and one that will not have surgical treatment.

        -  Participants in the nonsurgical treatment group will take AZD8055 by mouth daily for a
           42-day cycle of treatment. Participants will keep a diary to record doses and keep track
           of any side effects.

        -  Participants in the surgical treatment group will take AZD8055 by mouth daily for 7
           days, and then will have tumor removal surgery. At least 3 weeks after surgery,
           participants will resume doses of AZD8055 and will continue to take the drug for as long
           as the tumor does not recur.

        -  During treatment, participants will have regular visits to the clinical center,
           involving frequent blood and urine tests and other examinations to monitor the effects
           of treatment. Participants will have imaging studies to study the cancer's response to
           the treatment.

        -  Participants will continue to have cycles of treatment for as long as the treatment
           continues to be effective and the side effects are not severe enough to stop
           participation in the study....
    

Detailed description: 
      Background:

        -  Recurrent glioma patients have very limited treatment options. A significant percentage
           of gliomas have increased activity of the PI3K/Akt/mTOR pathway, mostly due to loss of
           PTEN.

        -  AZD8055 is a first in-class inhibitor of the kinase activity of mTOR, specifically
           inhibiting both mTORC1 and mTORC2 complexes. Preclinical data generated in the
           Neuro-Oncology Branch Laboratory of Dr. Howard Fine demonstrated that AZD8055 has
           significant anti-glioma activity in vivo and in vitro.

      Objectives:

        -  To establish the maximally tolerated dose (MTD) of continuous once daily AZD8055 in
           patients with recurrent malignant gliomas not on enzyme-inducing anti-epileptic drugs
           (EIAED).

        -  To generate pharmacokinetic data on continuous once daily AZD8055 dosing.

      Eligibility:

      -Patients with histologically proven glioma are eligible for this study. Patients should have
      failed prior standard treatment with radiotherapy.

      Design:

        -  This study will accrue up to 24 evaluable patients (non-surgical arm). Cohorts of 3 or 6
           patients will receive continuous AZD8055 once daily orally for 42 days. The MTD will be
           based on the tolerability observed during the first 6 weeks of treatment only. Up to
           three patients may be enrolled simultaneously at each dose level. The dose of AZD8055
           can be progressively escalated if only 0/3 or 1/6 patients experience a dose limiting
           toxicity at the prior dose level.

        -  A subset of patients in whom tumor re-resection is considered standard of care will
           receive 1-week treatment with AZD8055 and then undergo resection. Patients will be
           treated at the highest dose level shown to be safe at the time of enrollment. Once
           patients recover from surgery, they will restart treatment with AZD8055 and stay on
           treatment as long as there is no tumor progression or protocol-mandated removal
           criteria. Management of toxicity will be the same as non-surgical patients receiving
           their second and subsequent cycles of therapy as delineated in the protocol. Up to 12
           patients will enter the surgical arm of this trial.

        -  The accrual ceiling will be open to 42 patients to factor in replacing those who come
           off

      treatment prior to cycle 1.

      -At the end of Cycle 1, patients in both treatment arms (surgical and non-surgical) may
      choose to continue to receive AZD8055 until disease progression or until they experience
      unmanageable drug related toxicity, as long as they are continuing to derive clinical benefit
      and do not fulfill any of the criteria for removal from protocol therapy.
    

Intervention name(s): AZD8055
Intervention type(s): Drug
Intervention description(s): Patients will start at 120 mg once daily
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Brain; Tumor; Recurrent; Surgery; Radiation; Glioma; Brain Tumor; Glioblastoma Multiforme; Astrocytoma; Brainstem Glioma