UCSF BTC Clinical Trials

Everolimus With and Without Temozolomide in Adult Low Grade Glioma

 

Summary

The purpose of this study is to investigate the effect of a drug called everolimus (RAD001, or Afinitor) alone or in combination with temozolomide (a chemotherapy drug) in treating patients with newly diagnosed low-grade glioma. 

Everolimus is an approved anti-cancer agent for other tumor types, and is currently being investigated for use in treating low-grade glioma. Everolimus blocks the effect of mTOR, a protein that we think helps many tumors to grow.

Temozolomide is a chemotherapy drug that prevents tumor cells from growing and multiplying. It works by interfering with the cell’s DNA, which eventually triggers death of the cancer cell.

In this Phase II clinical trial, patients will be assigned to a particular treatment group based on the genetic features of their tumor. Oligodendrogliomas are missing sections of the 1p and 19q chromosomes; these are called “1p/19q co-deleted”, and is a common genetic feature. Another tumor feature that is relevant to this study involves PRAS40, a protein that is involved in the mTOR pathway–the same signaling pathway that everolimus inhibits.  When phosphorylated (“p-PRAS40 positive”) it is thought to be indicative of overactivity of the mTOR pathway. 

Accordingly, participants in this study will be assigned to the following treatment groups:

  • Group 1 (ATRX lost and/or 1p/19q intact, p-PRAS40 positive): everolimus alone
  • Group 2 (ATRX lost and/or 1p/19q intact, p-PRAS40 negative): everolimus + temozolomide
  • Group 3 (1p/19q co-deleted): everolimus alone

 

Inclusion Criteria
  1. Age ≥ 18 years
  2. KPS ≥ 60
  3. 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;
  4. Adequate liver function as shown by: Total serum bilirubin ≤ 2.0 mg/dL, ALT and AST ≤ 2.5x ULN, INR ≤ 2;
  5. Adequate renal function: serum creatinine ≤1.5 x ULN;
  6. 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;
  7. Signed informed consent prior to any screening procedures
  8. 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.
  9. Patient's tumor must have documentation of the presence of an IDH-1 and/or IDH-2 mutation of any type.
  10. Results of ATRX and/or 1p/19q chromosomal status: if ATRX is lost, 1p/19q status is not required.  if ATRX is intact, 1p/19q chromosomal status must be available to permit treatment selection.
  11. Results of pRAS40 testing.
  12. Evaluable disease
  13. Must begin treatment within 120 days of surgical procedure

For a full description of criteria, please visit clinicaltrials.gov.

Exclusion Criteria
  1. No prior tumor treatment except for surgery, and must have adequately recovered from surgery
  2. Known impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral everolimus or temozolomide
  3. 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;
  4. 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;
  5. Chronic treatment with corticosteroids or other immunosuppressive agents. Topical or inhaled corticosteroids are allowed, and treatment with low dose Decadron (≤ 3mg daily) is allowed;
  6. Known history of HIV seropositivity;
  7. Positive serological test results for hepatitis B
  8. Positive serological test result for hepatitis C
  9. 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;
  10. 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;

For a full description of criteria, please visit clinicaltrials.gov.

Investigator(s)

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