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Phase 1 and Pharmacokinetic Study of AZD6244 for Recurrent or Refractory Pediatric Low Grade Glioma


Phase 1
12 Years
21 Years
Open (Enrolling)
Both
Optic Glioma, Pilocytic Astrocytoma, Low Grade Glioma, Fibriullary Astrocytoma

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Trial Information

Phase 1 and Pharmacokinetic Study of AZD6244 for Recurrent or Refractory Pediatric Low Grade Glioma


Background

Low Grade Gliomas are among the most common primary CNS neoplasms of childhood.

Debulking surgery and chemotherapy are temporizing strategies that ideally allow tumor
stabilization until definitive radiation maybe used. Radiation therapy is associated with
long term morbidity.

Patients with high risk features such as hypothalamic location and young age at diagnosis
have shown overall survival as low as 60% at 10 years despite multimodal therapies.

AZD6244 (ARRY-142886) is a potent, selective, orally-available, and non-ATP competitive
small molecule inhibitor of the mitogen-activated protein (MAP) kinase, MEK-1/2.

Overexpression of growth factors or growth factor receptors involved in the RAS/RAF/MEK/ERK
pathway and activating genetic mutations of the signaling proteins may lead to uncontrolled
proliferation and tumor formation.

Primary Objectives

To estimate the maximum tolerated dose (MTD) or recommend a Phase II dose of AZD6244 in
children with recurrent or refractory low-grade glioma.

To describe the toxicity profile and define the dose limiting toxicity of AZD6244 in
children with recurrent or refractory low-grade glioma.

Eligibility

Age: Patient must be greater than or equal to 12 and less than or equal to 21 years of age.

Tumor: Patients with a histologically confirmed diagnosis of low grade gliomas (WHO Grades
I& II). Patients with optic pathway gliomas are eligible with clinical and/or radiographic
evidence of progression.

Performance status: Karnofsky Performance Scale (if greater than 16 yrs) or Lansky
Performance Score (if less than 16 years) greater than or equal to 60% assessed within two
weeks prior to Registration.

Prior/Concurrent therapy: The patient has received prior therapy with radiation prior to
study registration. Patients must have fully recovered from the acute toxic effects of all
prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.

Design

Patients will receive AZD6244 orally twice daily approximately 12 hours apart.

Four consecutive weeks will constitute one course and subsequent courses will immediately
follow, with no break in the administration of the drug.

AZD6244 on an empty stomach either 1 hour before or 2 hours after meals.

AZD6244 capsules should be taken with water only

Inclusion Criteria


- INCLUSION CRITERIA:

Both men and women of all races and ethnic groups are eligible for this study.

Age: Patient must be greater than or equal to 12 but less than or equal to 21 years of
age at registration.

Tumor: Patients with a histologically confirmed diagnosis of low grade gliomas (WHO
Grades I & II). Patients with optic pathway gliomas are eligible with clinical and/or
radiographic evidence of progression.

Neurological Status: Patients with neurological deficits should have deficits that are
stable for a minimum of 1 week prior to registration.

- Patients must be able to swallow capsules.

Performance Status: Karnofsky Performance Scale (KPS for greater than 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.

Prior Therapy:

The patient has received prior therapy with radiation prior to study registration.
Patients must have fully recovered from the acute toxic effects of all prior chemotherapy,
immunotherapy, or radiotherapy prior to entering this study.

- Myelosuppressive chemotherapy: Patients must have received their last dose of known
myelosuppressive anticancer chemotherapy at least four weeks prior to study
registration or at least six weeks if nitrosourea.

- Biologic agent: Patient must have recovered from any toxicity potentially related to
the agent and received their last dose of the biologic agent greater than or equal to
7 days prior to study registration.

- For agents that have known adverse events occurring beyond 7 days after
administration, this period must be extended beyond the time during which
adverse events are known to occur. The duration of this interval should be
discussed with the study chair.

- For biologic agents that have a prolonged half-life, the appropriate interval
since last treatment should be discussed with the study chair prior to
registration.

- Monoclonal antibody treatment: At least three half-lives must have elapsed prior to
registration. Such patients should be discussed with the study chair prior to
registration.

- Radiation: Patients must have:

--Had their last fraction of local irradiation to primary tumor greater than or equal
to 12 weeks prior to registration; investigators are reminded to review potentially
eligible cases to avoid confusion with pseudo-progression.

- Had their last fraction of craniospinal irradiation (greater than 24Gy) or total body
irradiation greater than 3 months prior to registration

- Bone Marrow Transplant: Patient must be:

- Greater than or equal to 6 months since allogeneic bone marrow transplant prior
to registration

- Greater than or equal to 3 months since autologous bone marrow/stem cell prior
to registration

- Corticosteroids: Patients who are receiving dexamethasone must be on a stable or
decreasing dose for at least 1 week prior to registration.

- Growth factors: 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.

Organ Function: Documented within 14 days of registration and within 7 days of the start
of treatment.

- Bone Marrow:

- Absolute neutrophil count greater than or equal to 1000/microL (unsupported)

- Platelets greater than or equal to 100,000/microL (unsupported)

- Hemoglobin greater than or equal to 8 g/dL (may be supported)

- Renal: Creatinine clearance or radioisotope GFR greater than or equal to 70
ml/min/1.73m(2) or a serum creatinine based on age as follows:

- less than or equal to 5 years of age: the maximum serum creatinine is 0.8

- greater than 5 years of age but less than or equal to 10 years of age: the
maximum serum creatinine is 1

- greater than 10 years of age but less than or equal to 15 years of age: the
maximum serum creatinine is 1.2

- greater than 15 years of age: the maximum serum creatinine is 1.5

- Hepatic:

- Bilirubin less than 1.5 times upper limit of normal for age

- SGPT/SGOT (ALT/AST) less than or equal to 2.5 times institutional upper limit of
normal for age

- Electrolytes:

- Sodium: greater than or equal to 130 and less than or equal to 145 mmol/L

- Potassium: 3.4- 4.8 mmol/L

- Calcium: greater than or equal to 7 mg/dL

- Magnesium: greater than or equal to 0.7 mmol/L

- Nutrition: Albumin greater than or equal to 3 g/dL

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.

Pregnancy Prevention: The effects of AZD6244 on the developing human fetus at the
recommended therapeutic dose 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, 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 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.

Informed Consent: Signed informed consent according to institutional guidelines must be
obtained.

EXCLUSION CRITERIA:

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.

Patients receiving any other anticancer or investigational drug therapy.

Patients with uncontrolled seizures are not eligible for the study.

Previous MEK inhibitor use such as PD-0325901; CI1040; AS73026; GDC 0973; ARRY43182;
GSK110212.

Prior treatment with a BRAF inhibitor

Patients with QTc interval greater than450 msecs or other factors that increase the risk
of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history
of long QT interval syndrome) including heart failure that meets New York Heart
Association (NYHA) class III and IV definitions (see Appendix IV) are excluded.

Required use of a concomitant medication that can prolong the QT interval. See Appendix V
for a table of medications with the potential to prolong the QTc interval. A comprehensive
list of agents with the potential to cause QTc prolongation can be found at
http://www.azcert.org/medical-pros/drug-lists/browse-drug-list.cfm?alpha=A

Patients with inability to return for follow-up visits or obtain follow-up studies
required to assess toxicity to therapy.

History of allergic reactions attributed to compounds of similar chemical or biologic
composition to AZD6244.

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To estimate the maximum tolerated dose (MTD) or recommend a Phase II dose

Principal Investigator

Katherine E Warren, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)

Authority:

United States: Federal Government

Study ID:

110191

NCT ID:

NCT01386450

Start Date:

June 2011

Completion Date:

Related Keywords:

  • Optic Glioma
  • Pilocytic Astrocytoma
  • Low Grade Glioma
  • Fibriullary Astrocytoma
  • Recurrent
  • Low Grade Glioma
  • BRAF
  • Chemotherapy
  • Brain Tumor
  • Glioma
  • Astrocytoma
  • Glioma
  • Optic Nerve Glioma

Name

Location

National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892