The purpose of this study is to find out what effects, good and/or bad, everolimus (RAD001, also known as Afinitor®) alone or with temozolomide has on the patient and the patient's low-grade glioma. Everolimus is being investigated as an anticancer agent based on its potential to prevent tumor cells from growing and multiplying. Specifically, there is a protein called mTOR that we think helps many tumors to grow, and everolimus blocks the effect of mTOR. Temozolomide is also an anticancer agent that prevents tumor cells from growing and multiplying.
PRIMARY OBJECTIVES: Arm 1: To assess progression-free survival in patients with previously untreated alpha-thalassemia/mental retardation, X-linked (ATRX) lost and/or 1p/19q intact, phosphatidylinositol 3-kinase (PI3K)/Mechanistic target of rapamycin (mTOR) pathway-activated low grade-glioma (LGG) treated with everolimus. Arm 2: To assess progression-free survival in patients with previously untreated ATRX lost and/or 1p/19q intact, PI3K/mTOR pathway-non-activated LGG treated with everolimus and TMZ. Arm 3: To assess progression-free survival in patients with previously untreated ATRX intact and/or 1p/19q co-deleted LGG treated with everolimus. SECONDARY OBJECTIVES: 1. To assess overall and progression-free survival distributions (Arms 1, 2 \& 3). 2. To assess the objective response rate to treatment (Arms 1, 2 \& 3). 3. To further delineate the safety profile of the combination of everolimus and TMZ (Arm 2) 4. To assess whether treatment (Arms 1, 2 \& 3) provides clinical benefit by reducing seizure frequency EXPLORATORY OBJECTIVES 1. Pending adequate funding, to assess the ability of metabolic and physiologic imaging parameters such as magnetic resonance (MR) spectroscopy, perfusion-weighted imaging, and diffusion-weighted imaging to predict clinically relevant endpoints such as time to progression and survival. 2. To assess for an association between the presence/absence of clonal or subclonal genetic mutations in the PI3K pathway and Median progression-free survival (PFS), Objective Response Rate (ORR), phosphatase and tensin homolog (PTEN) gene methylation, and the immunohistochemical measurements of the PI3K pathway activation in patients treated with everolimus or TMZ and everolimus. 3. To longitudinally assess quality of life (QoL) in low-grade glioma patients over the course of treatment with everolimus (Arms 1 \& 3). OUTLINE: Patients will be assigned to one of 3 treatment arms based on two characteristics of their tumor, called "1p/19q" (this is a test of the tumor chromosomes) and "p-PRAS40" (this is a test of a pathway in the tumor called mTOR). If the patient's tumor is 1p/19q intact and the phosphorylation of proline-rich Ak strain transforming (AKT) substrate of 40 kDa, encoded by the gene AKT1S1 (p-PRAS40) positive, the patient will be assigned to Treatment Arm 1. If the patient's tumor is 1p/19q intact and p-PRAS40 negative, the patient will be assigned to Treatment Arm 2. If the patient's tumor is 1p/19q co-deleted, regardless of the p-PRAS40 result, the patient will be assigned to Treatment Arm 3. All patients will be observed for safety for 30 days following the last dose of everolimus. After completion of study treatment, patients whose tumors have not progressed will be followed with interval MRIs for an additional 2 years, and thereafter as per the discretion of the managing physician. Patients off protocol therapy will continue to be followed for survival only.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
27
everolimus at 10 mg daily continuously
Temozolomide will be dosed initially at 150 mg/m2/day for 5 days out of a 28-day cycle. TMZ will be stopped after 12 cycles
University of California, San Francisco
San Francisco, California, United States
Progression-Free Survival Rate (PFS) (Arms 1 and 2)
Participants will be analyzed based on intention to treat using the Response Assessment in Neuro-Oncology (RANO) criteria for progression. Based on RANO criteria, a responder is defined using both radiographic and clinical criteria. Complete response (CR) or Partial Response (PR) will be first assessed by radiographic changes as determined by an improvement of the bi-dimensional evaluation of the tumor size. In addition, changes in neurologic function and steroid use will be considered. Analyses will be performed after all enrolled participants in arm 1 or arm 2 have completed 33 months on study, or whenever the progression status of all participants has been established, whichever comes first. Kaplan-Meier estimates and the associated 95% confidence intervals (CI) will be calculated for the 33-month PFS separately for the two arms.
Time frame: Up to 33 Months
Progression-Free Survival Rate (PFS) (Arm 3)
Participants will be analyzed based on intention to treat using the Response Assessment in Neuro-Oncology (RANO) criteria for progression. Based on RANO criteria, a responder is defined using both radiographic and clinical criteria. Complete response (CR) or Partial Response (PR) will be first assessed by radiographic changes as determined by an improvement of the bi-dimensional evaluation of the tumor size. In addition, changes in neurologic function and steroid use will be considered. Analyses will be performed after all participants enrolled in arm 3 have completed 38 months on study, or whenever the progression status of all participants has been established, whichever comes first. Kaplan-Meier estimates and the associated 95% CIs will be calculated for the 38-month PFS.
Time frame: Up to 38 Months
Median Progression Free Survival (PFS)
Participants will be analyzed based on an intention to treat model. PFS is defined as the time from first objective response to the time of disease progression or death using the Response Assessment in Neuro-Oncology (RANO) criteria to determine progression. If the participant does not have an event of disease progression or recurrence nor has the patient died, the participant's data will be censored at the date of last contact with the patient. Kaplan-Meier estimates and the associated 95% CIs will be calculated.
Time frame: Up to 84 Months
Overall Survival Rate (OS)
Participants will be analyzed based on an intention to treat model. Overall survival is defined as the first day of treatment until death or study completion, whichever comes first. Kaplan-Meier estimates and the associated 95% CIs will be calculated by treatment arm.
Time frame: Up to 84 Months
Objective Response Rate (ORR)
Overall response rate (ORR) is the percentage of patients who achieved a best response of complete response (CR) or partial response (PR) out of all assigned patients. Based on the best objective status as assessed by the Response Assessment in Neuro-Oncology (RANO) criteria. Using RANO criteria, a responder is defined by radiographic and clinical criteria. Complete response or PR will be first assessed by radiographic changes as determined by an improvement of the bi-dimensional evaluation of the tumor size. In addition, changes in neurologic function and steroid use will be considered. The point estimate and the associated 2-sided 95% CI for the response rate separately for the three arms.
Time frame: Up to 36 Months
Rate of Reduction in Seizures
To assess the reduction in seizure rate the investigator will compare the seizure rate on study to that experienced one month prior to enrolling in the study. The RANO low grade gliomas (LGG) guideline will be used to assess reduction of seizures, which calls a 50% or more reduction number of monthly seizures an 'improvement'; a 50% or more increase a worsening'; and anything less than 50% in either direction a 'stable seizure rate'.
Time frame: Up to 36 Months
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