Patients with sporadic (non NF-1 associated), histologically diagnosed pilocytic astrocytoma who have pre- treatment tumor tissue available for BRAF analysis are eligible. NF-1 patients with radiographic evidence of low grade glioma, with or without histological diagnosis are also eligible. Patients will be assigned to one of 4 strata following enrollment.
- Stratum 1: Patients with progressive, recurrent or refractory pilocytic astrocytoma with pre-trial tumor material available and with a BRAF aberration i.e. BRAF (V600E) mutation and/or BRAF KIAA1549 fusion as determined by IHC and FISH, respectively.
- Stratum 2: Patients with progressive, recurrent or refractory pilocytic astrocytoma with pre-trial tumor material available and without a BRAF aberration i.e. BRAF (V600E) mutation and/or BRAF KIAA1549 fusion as determined by IHC and FISH, respectively.
- Stratum 3: Patients with Neuro-fibromatosis 1 (NF-1) associated progressive, recurrent or refractory low grade glioma (WHO Grade I & II), with or without tissue
- Stratum 4: Non-NF-1 recurrent or refractory pilocytic astrocytoma patients who cannot be classified into Stratum 1 or 2 due to inadequate tissue quality or assay failure.
3.1.2 Patients must have bi-dimensionally measureable disease defined as at least one lesion that can be accurately measured in at least two planes in order to be eligible for this study.
3.1.3 Prior Therapy
Patients must have received prior therapy other than surgery and must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, biologic therapy or radiotherapy prior to entering this study.
188.8.131.52 Myelosuppressive chemotherapy: Patients must have received their last dose of known myelosuppressive anticancer chemotherapy at least three weeks prior to study registration or at least six weeks if nitrosourea.
184.108.40.206 Biologic agent: Patient must have received their last dose of the biologic agent (Bullet) 7 days prior to study registration.
--For biologic agents that have a prolonged half-life, at least three half-lives must have elapsed prior to registration
220.127.116.11 Monoclonal antibody treatment: At least three half-lives must have elapsed prior to registration.
Note: A list of the half-lives of commonly used monoclonal antibodies is available on the PBTC webpage under Generic Forms and Templates.
18.104.22.168 Radiation: Patients must have:
- Had their last fraction of local irradiation to primary tumor (Bullet)12 months prior to registration; investigators are reminded to review potentially eligible cases to avoid confusion with pseudo-progression.
- Had their last fraction of craniospinal irradiation (> 24Gy) > 3 months prior to registration
22.214.171.124 Corticosteroids: Patients who are receiving dexamethasone must be on a stable or decreasing dose for at least 1 week prior to registration.
126.96.36.199 Growth factors: Patients must be off all colony-forming growth factor(s) for at least 1 week prior to registration (filgrastim, sargramostim, erythropoietin) and at least 2 weeks for long-acting formulations.
Patient must be greater than or equal to 3 but less than or equal to 21 years of age at registration.
Patients must have BSA greater than or equal to 0.55 m(2).
3.1.6 Neurological Status
Patients with neurological deficits should have deficits that are stable for a minimum of 1 week prior to registration.
188.8.131.52 Patients must be able to swallow capsules
3.1.7 Performance Status
Karnofsky Performance Scale (KPS for > 16 yrs. of age) or Lansky Performance Score (LPS for less than or equal to 16 years of age) greater than or equal to 60 assessed within two weeks prior to registration.
3.1.8 Organ Function
Patients must have normal organ and marrow function documented within 14 days of registration and within 7 days of the start of treatment as noted below:
3.1.9 Cardiac Function
Adequate cardiac function defined as:
- LVEF greater than or equal to 50%
- QTc interval less than or equal to 450 msecs
Patients, 3-17 years of age must have a blood pressure that is less than or equal to 95th percentile for age, height and gender at the time of registration.
--The normal blood pressure by height, age and gender tables can be accessed in the Generic Forms section of the PBTC members webpage.
- Patients who are greater than or equal to 18 years of age must have a blood pressure that is < 140/90 mm of Hg at the time of registration.
Note: If a BP reading prior to registration is above the 95th percentile for age, height and gender it must be rechecked and documented to be less than or equal to the 95th percentile for age, height and gender prior to patient registration.
3.1.11 Pregnancy Status
Female patients of childbearing potential must not be pregnant or breast-feeding. Female patients of childbearing potential must have a negative serum or urine pregnancy test.
3.1.12 Pregnancy Prevention
The effects of AZD6244 on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation, and for four weeks after dosing with AZD6244 ceases. Women of child-bearing potential must have a negative pregnancy test prior to entry. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Please note that the AZD6244 manufacturer recommends that adequate contraception for male patients should be used for 16 weeks post-last dose due to sperm life cycle.
3.1.13 Informed Consent
Ability to understand and the willingness to sign a written informed consent document according to institutional guidelines.
3.2.1 Patients with any clinically significant unrelated systemic illness (serious infections or significant cardiac, pulmonary, hepatic or other organ dysfunction), likely interfere with the study procedures or results.
3.2.2 Patients who are receiving any other anticancer or investigational agents.
3.2.3 Patients with uncontrolled seizures are not eligible for the study.
3.2.4 Previous MEK inhibitor use such as PD-0325901; CI1040; AS73026; GDC 0973; ARRY43182; GSK110212.
3.2.5 Prior treatment with a BRAF inhibitor such as Venurafenib or Debrafenib
3.2.6 Patients with other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome) that meets New York Heart Association (NYHA) class II or above (APPENDIX B) are excluded.
3.2.7 Required use of a concomitant medication that can prolong the QT interval. See APPENDIX C for a table of medications with the potential to prolong the QTc interval.
3.2.8 History of allergic reactions attributed to compounds of similar chemical or biologic composition to AZD6244.