Everolimus With and Without Temozolomide in Adult Low Grade Glioma

• ClinicalTrials.gov Identifier: NCT02023905
• Recruitment Status: Active, not recruiting
• First Posted: December 30, 2013
• Last Update Posted: March 11, 2020
• Sponsor: University of California, San Francisco
• Collaborator: Novartis
• Information provided by (Responsible Party): University of California, San Francisco

Study Description

Brief Summary:

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. About 159 people total will take part in this study. Patients will be assigned to one of three treatment groups depending on the results of some tests done on their tumor. Each group will have 53 patients in it. 2 groups will receive treatment with everolimus alone, while the third group will receive treatment with both everolimus and temozolomide. In this study, 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 p-PRAS40 positive, the patient will be assigned to Treatment Arm 1, and the patient will receive everolimus alone. If the patient's tumor is 1p/19q intact and p-PRAS40 negative, the patient will be assigned to Treatment Arm 2 and the patient will receive everolimus and temozolomide. 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, and the patient will receive everolimus alone.

Condition or disease	Intervention/treatment	Phase
Low Grade Glioma; WHO Grade II Astrocytomas; Oligodendrogliomas; Mixed Oligoastrocytomas	Drug: Everolimus; Drug: Temozolomide	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 27 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: PI3K/mTOR Pathway Activation Selected Phase II Study of Everolimus (RAD001) With and Without Temozolomide in the Treatment of Adult Patients With Supratentorial Low-Grade Glioma
• Actual Study Start Date: February 18, 2018
• Estimated Primary Completion Date: July 31, 2021
• Estimated Study Completion Date: September 30, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Arm 1; If the tumor is 1p/19q intact, then patients will be further selected by whether or not their tumor demonstrates activation of the PI3K/mTOR pathway. If activation is present, patients will be treated in Arm 1 with single-agent everolimus at 10 mg daily continuously. In all arms, treatment with everolimus will continue for up to 24 cycles, after which patients will be followed with interval MRIs until progression.	Drug: Everolimus; everolimus at 10 mg daily continuously; Other Name: RAD001, Afinitor
Experimental: Arm 2; If the tumor is 1p/19q intact, then patients will be further selected by whether or not their tumor demonstrates activation of the PI3K/mTOR pathway. If activation is not present, patients will be treated in Arm 2 with combined everolimus and Temozolomide. Everolimus will be given at 10 mg daily continuously, and Temozolomide will be dosed initially at 150 mg/m2/day for 5 days out of a 28-day cycle. In all arms, treatment with everolimus will continue for up to 24 cycles, after which patients will be followed with interval MRIs until progression. In Arm 2, TMZ will be stopped after 12 cycles.	Drug: Everolimus; everolimus at 10 mg daily continuously; Other Name: RAD001, Afinitor; Drug: Temozolomide; 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; Other Name: Temodar, TMZ
Experimental: Arm 3; If the tumor is 1p/19q intact, then patients will be further selected by whether or not their tumor demonstrates activation of the PI3K/mTOR pathway. If 1p/19q co-deletion is present, patients will be treated in Arm 3 with single-agent everolimus at 10 mg daily continuously. In all arms, treatment with everolimus will continue for up to 24 cycles, after which patients will be followed with interval MRIs until progression.	Drug: Everolimus; everolimus at 10 mg daily continuously; Other Name: RAD001, Afinitor

Outcome Measures

Primary Outcome Measures :

1. Progression-free survival (PFS) (Arms 1 and 2) [ Time Frame: Up to 33 Months ]
   Participants will be analyzed based on intention to treat using the Response Assessment in Neuro-Oncology (RANO) criteria for progression. 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% CIs will be calculated for the 33-month PFS separately for the two arms. The Cox proportional hazards model will also be used to allow for adjustment of the prognostic factors including age, KPS, and extent of resection
2. Progression-free survival (PFS) (Arm 3) [ Time Frame: Up to 38 Months ]
   Participants will be analyzed based on intention to treat using the Response Assessment in Neuro-Oncology (RANO) criteria for progression. 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. The Cox proportional hazards model will also be used to allow for adjustment of the prognostic factors including age, KPS, and extent of resection

Secondary Outcome Measures :

1. Median and distribution of overall survival (OS) [ Time Frame: Up to 36 Months ]
   Participants will be analyzed based on intention to treat. Overall survival is defined as the first day of treatment until death, or completion of 36 months on study whichever comes first. Kaplan-Meier estimates and the associated 95% CIs will be calculated for the 36-month survival rate by treatment arm. The Cox proportional hazards model will also be used to allow for adjustment of the prognostic factors including age, KPS, and extent of resection
2. Median and distribution of Overall PFS [ Time Frame: Up to 36 Months ]
   Participants will be analyzed based on intention to treat using the Response Assessment in Neuro-Oncology (RANO) criteria for progression. Overall PFS will be performed after all participants enrolled have completed 36 months on study, or whenever the progression status of all patients has been established, whichever comes first. Kaplan-Meier estimates and the associated 95% CIs will be calculated for the 36-month PFS. The Cox proportional hazards model will also be used to allow for adjustment of the prognostic factors including age, KPS, and extent of resection
3. Objective Response Rate (ORR) [ Time Frame: Up to 36 Months ]
   Response is based on the best response, defined as the best objective status as assessed by the Response Assessment in Neuro-Oncology (RANO) criteria. The point estimate and the associated 2-sided 95% CI for the response rate separately for the three arms.
4. Frequency of treatment-related adverse events related to combination treatment [ Time Frame: Up to 36 Months ]
   The frequency of treatment-related toxicities will be reported and classified by the investigator according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.0.
5. Rate of Reduction in Seizures [ Time Frame: Up to 36 Months ]
   To assess the reduction in seizure rate we will compare the seizure rate on study to that experienced one month prior to enrolling in the study. We will follow the RANO low grade gliomas (LGG) guideline 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'.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Age ≥ 18 years
• KPS ≥ 60
• Adequate bone marrow function as shown by: ANC ≥ 1.5 x 10^9/L, Platelets ≥ 100 x 10^9/L, Hb ≥ 9.0 g/dL;
• Adequate liver function as shown by: Total serum bilirubin ≤ 2.0 mg/dL, ALT and AST ≤ 2.5x ULN, INR ≤ 2;
• Adequate renal function: serum creatinine ≤1.5 x ULN;
• Fasting serum cholesterol ≤ 300 mg/dL OR ≤ 7.75 mmol/L AND fasting triglycerides ≤ 2.5x ULN. NOTE: In case one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication with confirmed reduction of lab values to within eligibility parameters;
• Signed informed consent prior to any screening procedures
• Histologically proven supratentorial low-grade glioma at initial diagnosis; pathology must have been reviewed by UCSF neuropathology. Eligible low-grade gliomas include: astrocytoma, oligodendroglioma and mixed oligoastrocytoma. Pilocytic astrocytomas are excluded.
• Patient's tumor must have documentation of the presence of an IDH-1 and/or IDH-2 mutation of any type.
• Results of 1p/19q chromosomal status and pPRAS40 testing must be available to permit treatment selection.
• Evaluable disease
• Must begin treatment within 120 days of surgical procedure

Exclusion Criteria:

• No prior tumor treatment except for surgery at diagnosis, and must have adequately recovered from surgery
• Known intolerance or hypersensitivity to everolimus or other rapamycin analogs (e.g. sirolimus, temsirolimus) or to temozolomide
• Known impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral everolimus or temozolomide
• Uncontrolled diabetes mellitus as defined by HbA1c > 8.0% despite adequate therapy. Patients with a known history of impaired fasting glucose or diabetes mellitus (DM) may be included, however blood glucose and antidiabetic treatment must be monitored closely throughout the trial and adjusted as necessary;
• Any severe and/or uncontrolled medical conditions such as: unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction ≤6 months prior to start of everolimus, serious uncontrolled cardiac arrhythmia, or any other clinically significant cardiac disease; symptomatic congestive heart failure of New York heart Association Class III or IV; active (acute or chronic) or uncontrolled severe infection, liver disease such as cirrhosis, decompensated liver disease, and chronic hepatitis (i.e. quantifiable HBV-DNA and/or positive HbsAg, quantifiable HCV-RNA); known severely impaired lung function (spirometry and DLCO 50% or less of normal and O2 saturation 88% or less at rest on room air); active, bleeding diathesis;
• Chronic treatment with corticosteroids or other immunosuppressive agents. Topical or inhaled corticosteroids are allowed, and treatment with low dose Decadron (≤ 3mg daily) is allowed;
• Known history of HIV seropositivity;
• Positive serological test results for hepatitis B
• Positive serological test result for hepatitis C
• Recipients of live attenuated vaccines within 1 week of start of treatment and during the study. Avoid close contact with others who have received live attenuated vaccines. Examples of live attenuated vaccines include intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella and TY21a typhoid vaccines;
• History of another primary malignancy, with the exceptions of: non-melanoma skin cancer, and carcinoma in situ of the cervix, uterus, or breast, unless the patient has been disease free for ≥ 3 years;
• History of non-compliance to medical regimens or who are considered potentially unreliable or will not be able to complete the entire study;
• Currently part of or have participated in any clinical investigation with an investigational therapeutic drug within 1 month prior to dosing;
• Pregnant or nursing (lactating) women;
• Women of child-bearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant, who are not willing to use adequate methods of contraception during the study and for 8 weeks after the end of treatment.
• Women are considered post-menopausal and not of child-bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks prior to randomization. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child-bearing potential.
• Male patients whose sexual partner(s) are WOCBP who are not willing to use adequate contraception, during the study and for 8 weeks after the end of treatment

Contacts and Locations

Locations

United States, California

University of California, San Francisco

San Francisco, California, United States, 94143-0372

Sponsors and Collaborators

University of California, San Francisco

Novartis

Investigators

• Principal Investigator: Jennifer Clarke, MD, MPH; University of California, San Francisco

More Information

Additional Information:

UCSF Neurosurgery 

• Responsible Party: University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT02023905
• Other Study ID Numbers: Novartis-CRAD001CUS225T; Cancer Center # 131012 ( Other Identifier: UCSF ); NCI-2014-00749 ( Registry Identifier: NCI Clinical Trials Reporting Program (CTRP) )
• First Posted: December 30, 2013
• Last Update Posted: March 11, 2020
• Last Verified: March 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:

Glioma; Astrocytoma; Oligodendroglioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Sirolimus; Everolimus; Temozolomide; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotics, Antineoplastic; Antifungal Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action