Everolimus With and Without Temozolomide in Adult Low Grade Glioma

Study Description

Go to 

Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

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

Go to 

Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	159 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
Study Start Date :	February 2014
Estimated Primary Completion Date :	January 2019
Estimated Study Completion Date :	January 2019

Arms and Interventions

Go to 

Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

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; 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; Other Name: RAD001, Afinitor Drug: Temozolomide; 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; Other Name: RAD001, Afinitor

Outcome Measures

Go to 

Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Primary Outcome Measures :

1. Arm 1 & 2 Progression-free survival [ Time Frame: 33 Months ]
2. Arm 3 progression-free survival [ Time Frame: 38 Months ]

Secondary Outcome Measures :

1. Median and distribution of overall survival (OS) and PFS [ Time Frame: 36 Months ]
2. Objective Response Rate (ORR) [ Time Frame: 36 Months ]
3. Number of adverse events related to combination treatment [ Time Frame: 36 Months ]
4. Rate of Reduction in Seizures [ Time Frame: 36 Months ]

Eligibility Criteria

Go to 

Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Ages Eligible for Study:	18 Years and older (Adult, Senior)
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

Go to 

Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Contacts

Contact: Jennifer Clarke, MD, MPH	415-353-2966	Jennifer.Clarke@ucsf.edu
Contact: Tiffany Jones, MPH	415-353-9641	Tiffany.Jones@ucsf.edu

Locations

United States, California
University of California, San Francisco	Recruiting
San Francisco, California, United States, 94143-0372
Contact: Jennifer Clarke, MD, MPH 415-353-2966 Jennifer.Clarke@ucsf.edu
Contact: Tiffany Jones 415-353-9641 Tiffany.Jones@ucsf.edu
Principal Investigator: Jennifer Clarke, MD

Sponsors and Collaborators

University of California, San Francisco

Investigators

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

More Information

Go to 

Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Additional Information:

UCSF Neurosurgery 

Responsible Party:	University of California, San Francisco
ClinicalTrials.gov Identifier:	NCT02023905 History of Changes
Other Study ID Numbers:	Novartis- CRAD001CUS225T; Cancer Center # 131012 ( Other Identifier: UCSF )
First Posted:	December 30, 2013
Last Update Posted:	January 17, 2018
Last Verified:	January 2018

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; Temozolomide; Everolimus; Sirolimus	Dacarbazine; 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