PBTC-029: Phase 1 and Pharmacokinetic Study of AZD6244 for Recurrent or Refractory Pediatric Low Grade Glioma

What is the purpose of this study?

To test the safety and effectiveness of AZD6244 in older children and young adults who have gliomas that have not responded to standard treatments.

Who can participate?

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 than 450 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.

Ages

  • From 12 To 21  years old

Conditions

  • Cancer - Brain and Spinal Tumors

What is involved?

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

Who should I contact for more information?

For more information contact:
Cincinnati Children’s Hospital Medical Center
Division of Hematology/Oncology
3333 Burnet Ave., Cincinnati, OH 45229-3039
Phone: 513-636-2799
cancer@cchmc.org

Where can I find additional information?