AZD6244 in Children With Low-Grade Gliomas

Low Grade Glioma Clinical Trial

Official title:

Phase 1 and Phase II and Re-Treatment Study of AZD6244 for Recurrent or Refractory Pediatric Low Grade Glioma

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT01386450
• Other study ID #: 110191
• Secondary ID: 11-C-0191
• Status: Recruiting
• Phase: Phase 1/Phase 2
• First received: June 30, 2011
• Last updated: October 6, 2015
• Start date: June 2011
• Est. completion date: November 2018

Study information

• Verified date: September 2015
• Source: National Institutes of Health Clinical Center (CC)
• Contact: Katherine E Warren, M.D.
• Phone: (301) 435-4683
• Email: warrenk[@]mail.nih.gov
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial Summary

Background:

• AZD6244 is an experimental drug designed to prevent tumor growth and shrink existing tumors. It has been studied in adults with cancer, but it has not been studied in children with cancer. Researchers want to see if AZD6244 is a safe and effective treatment for older children and young adults who have gliomas (brain tumors) that have not responded to standard treatments.

Objectives:

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

Eligibility:

• People between 12 and 21 years of age who have gliomas that have not responded to standard treatments.

Design:

• Participants will be screened with a medical history and physical exam. They will also have blood tests and tumor imaging studies. Those in the study may also have their spinal fluid tested to see whether the cancer has spread to other parts of the nervous system.

• Participants will take AZD6244 as a capsule. It must be swallowed whole on an empty stomach twice a day for 28 days. Those in the study will have up to 13 cycles (4 weeks each) of treatment (1 year).

• Participants will keep a diary to record doses taken and any side effects of the treatment.

• Participants will have frequent blood tests and imaging studies.

Description:

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.COMPLETED April 29, 2013

Phase II

To assess sustained response rate of AZD6244 administered at 25 mg/m (2)/ dose BID, in a single arm Phase II setting in patients in strata based on NF-1 status and presence or absence of BRAF aberrations, specifically BRAF (V600E) mutations and/ or BRAF KIAA1549 fusion identified by IHC and FISH in six (6) patient strata.

Eligibility

Age: Patient must be greater than or equal to 3 and less than or equal to 21 years of age.

Tumor: Patients with refractory low grade glioma (other than pilocytic astrocytoma or optic

pathway glioma) (Stratum 5) must provide consent for BRAF testing. Patients in Stratum 1

or 2 (non-NF-1 non-optic pathway pilocytic astrocytoma) histologically diagnosed may be

required to have pre- treatment tumor tissue available for BRAF analysis. NF-1 patients

with radiographic evidence of low grade glioma, with or without histological diagnosis are

also eligible (Stratum 4). Patients must have bi-dimensionally measureable disease.

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%

Must have normal organ and marrow function.

Prior/Concurrent therapy: The patient has received prior therapy other than surgery and 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 25mg/m(2)/ dose 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 should be taken on an empty stomach either 1 hour before or 2 hours after meals. AZD6244 capsules should be taken with water only.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 18
• Est. completion date: November 2018
• Est. primary completion date: October 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 3 Years to 21 Years

Eligibility

• INCLUSION CRITERIA

3.1.1 Tumor

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.

3.1.3.1 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.

3.1.3.2 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

3.1.3.3 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.

3.1.3.4 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

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

3.1.3.6 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.

3.1.4 Age

Patient must be greater than or equal to 3 but less than or equal to 21 years of age at registration.

3.1.5 BSA

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.

3.1.6.1 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:

• Absolute neutrophil count greater than or equal to 1,000/ L (unsupported)

• Platelets greater than or equal to 100,000/ L (unsupported)

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

• Total bilirubin < 1.5 times upper limit of normal for age

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

• 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:

• Age(years) less than or equal to 5, Maximum Serum Creatinine (mg/dL) 0.8

• Age(years) > 5 but less than or equal to 10, Maximum Serum Creatinine (mg/dL) 1

• Age(years) > 10 but less than or equal to 15, Maximum Serum Creatinine (mg/dL) 1.2

• Age(years) > 15, Maximum Serum Creatinine (mg/dL) 1.5

• Sodium, Potassium within the institutional limits of normal

• Calcium and Magnesium above the institutional lower limit of normal

• Albumin greater than or equal to 3g/dL

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

3.1.10 Hypertension

• 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.

EXCLUSION CRITERIA

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

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)

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.

Study Design

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

Related Conditions & MeSH terms

• Astrocytoma
• Fibriullary Astrocytoma
• Glioma
• Low Grade Glioma
• Optic Glioma
• Pilocytic Astrocytoma

Intervention

Drug:
• AZD6244
BID until toxicity or progression of disease.

Locations

Country	Name	City	State
United States	National Institutes of Health Clinical Center, 9000 Rockville Pike	Bethesda	Maryland

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

References & Publications (3)

Listernick R, Ferner RE, Liu GT, Gutmann DH. Optic pathway gliomas in neurofibromatosis-1: controversies and recommendations. Ann Neurol. 2007 Mar;61(3):189-98. Review. — View Citation

Roberts PJ, Der CJ. Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene. 2007 May 14;26(22):3291-310. Review. — View Citation

Yunoue S, Tokuo H, Fukunaga K, Feng L, Ozawa T, Nishi T, Kikuchi A, Hattori S, Kuratsu J, Saya H, Araki N. Neurofibromatosis type I tumor suppressor neurofibromin regulates neuronal differentiation via its GTPase-activating protein function toward Ras. J Biol Chem. 2003 Jul 18;278(29):26958-69. Epub 2003 May 2. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Assess sutained response rate in 6 strata		At time of recurrence	No
Primary	Estimate MTD or RP2D and describe the toxicity profile		After 1 course	Yes
Primary	Study Safety of MTD		After 1 course	Yes
Secondary	Characterize PK		First course	No
Secondary	Describe MRI characteristics		At each response evaluation
Secondary	Explore Pharmacogenetic polymorphisms		Prior to first dose	No

External Links

•   NIH Clinical Center Detailed Web Page