PNOC 001: Phase II Study of Everolimus for Recurrent or Progressive Low-grade Gliomas in Children
Overview
- Phase
- Phase 2
- Intervention
- Everolimus
- Conditions
- Pediatric Recurrent Progressive Low-grade Gliomas
- Sponsor
- University of California, San Francisco
- Enrollment
- 65
- Locations
- 18
- Primary Endpoint
- Percentage of Participants With Progression Free Survival at 6 Months
- Status
- Completed
- Last Updated
- 7 months ago
Overview
Brief Summary
This is an open label study of everolimus in children with recurrent or progressive low-grade glioma.
Detailed Description
This is an open label study of everolimus in children with recurrent or progressive low-grade glioma. All patients will receive everolimus at a dose of 5 mg/m2/dose daily. An adaptive Simon two-stage design for phase 2 studies of targeted therapies will be used to assess the efficacy primary objective. The proposed treatment with everolimus will be deemed not worthy of further investigation in this patient population if the true PFS at 6-months (PFS6) is less than 50%. If in the first stage, with a combined sample size of 25, there is preliminary evidence to suggest efficacy of everolimus is restricted to patients with PI3K/AKT/mTOR activation as measured by p-S6 positivity, a total of 45 patients will be enrolled and the design will have 81% statistical power to detect a true disease stabilization rate ≥70%. If in the first stage there is preliminary evidence to suggest efficacy of everolimus is independent of PI3K/AKT/mTOR activation, a total of 65 patients will be enrolled and the design will have \>95% statistical power to detect a true disease stabilization rate ≥70%.
Investigators
Eligibility Criteria
Inclusion Criteria
- •-Patients must have radiographic progressive or recurrent confirmed world health organization (WHO) grade I or II astrocytomas, that was confirmed histologically. Progressive or recurrent disease should be based on MRI according to the definition below.
- •Eligible histologies:
- •Pilocytic Astrocytoma - 90600112
- •Astrocytoma, Low Grade (Fibrillary astrocytoma, WHO Grade 2) - 10065886
- •Astrocytoma, Low Grade (Low-grade Astrocytoma, not otherwise specified (NOS), WHO Grade 2) - 10003571
- •Tissue from the initial diagnosis or recurrence must be made available for correlative testing.
- •Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least two dimensions on MRI.
- •Patients may have had treatment (chemotherapy and/or radiotherapy) for any number of relapses prior to this recurrence.
- •Patients must have received their last dose of myelosuppressive anticancer chemotherapy at least three (3) weeks prior to study registration or at least six (6)weeks of nitrosourea.
- •Patients must have received their last dose of other investigational or biological agent \> 7 days prior to study entry.
Exclusion Criteria
- •Patients with primary spinal cord tumors
- •Patients receiving concomitant medication that may interfere with study outcome. For example, patients cannot be on enzyme inducing anticonvulsants like phenytoin.
- •Patients should not receive immunization with attenuated live vaccines within one week of study entry or during study period. Close contact with those who have received attenuated live vaccines should be avoided during treatment with everolimus. Examples of live vaccines include intranasal influenza, measles, mumps, rubella, oral polio, bacille Calmette-Guerin (BCG), yellow fever, varicella and TY21a typhoid vaccines
- •Hepatitis B/C blood test must be done at screening for all patients. Patients who test positive for Hepatitis C antibodies and the Hepatitis B antigen are ineligible.
- •A known history of HIV seropositivity. HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with everolimus. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy.
- •Patients receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent. Topical or inhaled corticosteroids are allowed.
- •Patients may not have therapy for this recurrence (including radiation).
- •Patients who do not have measurable disease on MRI.
- •Patients who have been previously treated with an mTOR inhibitor.
- •Patients with a known hypersensitivity to everolimus or other rapamycins (e.g. sirolimus, temsirolimus).
Arms & Interventions
Everolimus
Everolimus tablet will be taken daily by mouth with water. Twenty-eight days will constitute one course and subsequent courses will immediately follow with no break in the administration of the drug. Dosing is based on the body surface area (BSA) calculated at the beginning of each course of therapy. Patients will also be provided with a drug diary for everolimus. The maximum time on study is 24-months, but if there is no disease progression or adverse events, the patient may speak with a doctor about continuing the treatment off-study.
Intervention: Everolimus
Outcomes
Primary Outcomes
Percentage of Participants With Progression Free Survival at 6 Months
Time Frame: Up to 6 months
Response was be determined by bi-dimensional diameters. RECIST criteria will be collected and used for secondary evaluation. Patients will have brain MRI scans with and without gadolinium performed prior to therapy, after every second course in the first year, after every third course in the second year, and at the End of Study visit (if not done within prior 3 months). Spine MRIs should be performed prior to therapy and at the same time points as standard brain MRIs if clinically indicated.
Secondary Outcomes
- Proportion of Participants With Objective Response(Up to 6 months)
- Median Progression Free Survival in Recurrent Pediatric Low-grade Glioma (LGGs)(Up to 5 years)
- Median Overall Survival From Time of Diagnosis(Up to 5 years)
- Median Overall Survival From Time of Enrollment(Up to 5 years)