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EXEL 2310   |   CC879
A Phase I Dose - Escalation Study of XL765 in Combination with Temozolomide in Subjects with Malignant Gliomas

Main Campus
Phase 1
Temozolomide (SCH 52365)

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  1. The primary objectives of this study are:
    • To evaluate the safety and tolerability of daily oral administration of XL765 in combination with TMZ in subjects with AG or glioblastoma currently stable on a maintenance TMZ dose of 200 mg/m2/day given on Days 1-5 on a 28-Day cycle
    • To determine the maximum tolerated dose (MTD) of XL765 in combination with TMZ in subjects with AG or glioblastoma currently stable on a maintenance TMZ dose

Inclusion Criteria
  1. The subject has a histologically confirmed intracranial Grade 3 or Grade 4 astrocytic tumor (WHO criteria 2007, Louis et al. 2007), anaplastic oligodendroglioma, or anaplastic oligoastrocytoma. Only subjects with Grade 4 astrocytic tumors are allowed into the MTD expansion cohorts.
  2. The subject has received at least one cycle of TMZ at a dose of 200 mg/m2/day administered on Days 1-5 of a 28-day cycle, without unacceptable (ie, requiring a dose interruption or reduction) toxicity and without clinical or radiologic progression of their disease. This may be decreased to 175 mg/m2/day if the combinations of TMZ 200 mg/m2/day with XL765 are not well tolerated (see Section 3.4.2 and Table 3-2).
  3. The subject is expected to receive at least 3 more cycles of maintenance TMZ treatment to be given in combination with XL765.
  4. The subject has had no previous treatment except partial or complete resection surgery for current diagnosis of Grade 3 (Group 2 only) or Grade 4 astrocytic tumors (ie, no previous RT, local chemotherapy, or systemic therapy). Subjects with secondary high grade astrocytic tumors are eligible if they have received prior treatment for lower grade astrocytic tumors. Note: subjects who have had only a biopsy for current diagnosis of the tumor are not eligible.
  5. The subject must be able to initiate RT within 49 days after surgery with adequate wound healing prior to starting study treatment.
  6. The subject has a Karnofsky performance status of 70 or more.
  7. The subject has organ and marrow function as follows:
    1. Absolute neutrophil count ≥ 1500/mm3
    2. Platelets ≥ 100,000/mm3
    3. Hemoglobin ≥ 9 g/dL
    4. Bilirubin ≤ 1.5 x the upper limit of normal
    5. Serum creatinine ≤1.5 x the upper limit of normal or calculated creatinine clearance ≥ 60 mL/min
    6. Alanine aminotransferase and aspartate aminotransferase ≤ 1.5 x the upper limit of normal.
    7. Prothrombin time/ International Normalized Ratio (PT/ INR) or partial thromboplastin time (PTT) ≤ 1.3 x the laboratory upper limit of normal
  8. The subject has a fasting plasma glucose (FPG) ≤ 160 mg/dL at screening.
  9. At least 15 unstained 4-10 micron tissue sections (≥ 15 slides, without coverslips), archival or fresh, or a tissue block, of the subject's tumor are identified and designated for central laboratory analysis where allowed by local regulatory bodies (including Institutional Review Board [IRB]/ Ethics Committee [EC] policies).
  10. Sexually active subjects (male and female) must use accepted methods of contraception during the course of the study and for 3 months after the last dose of XL765.
  11. Female subjects of childbearing potential must have a negative serum pregnancy test at screening. Females of childbearing potential are defined as sexually mature women without prior hysterectomy or who have had any evidence of menses in the past 12 months. Women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior therapy such as chemotherapy, anti-estrogens, or ovarian suppression.
  12. The subject has not had a diagnosis of non-glioma malignancy other than:
    1. Surgically excised non-melanoma skin cancer or in situ carcinoma of the cervix
    2. A malignancy diagnosed 2 or more years ago if the subject has had no evidence of disease for 2 years prior to screening for this study.
  13. A brain magnetic resonance imaging (MRI) must be performed within 14 days prior to the first dose of XL765 and with the subject on a glucocorticoid dose that has been stable for at least 5 days. If the glucocorticoid dose is changed between the date of imaging and the first dose of XL765, a new baseline MRI is required.
  14. The subject is ≥18 years old.
  15. The subject is capable of understanding and complying with the protocol and has signed the informed consent document.

Exclusion Criteria
  1. Subjects who have progressed on TMZ.
  2. Subject has evidence of acute intracranial or intratumoral hemorrhage > Grade 1 either by MRI or CT scan. Subjects with resolving hemorrhage changes, punctate hemorrhage, or hemosiderin may enter the study.
  3. Group 1 subjects who have received any of the following:
    • Cytotoxic chemotherapy other than TMZ ( including investigational cytotoxic agents) or biologic agents (antibodies, immune modulators, cytokines) within 4 weeks or has received nitrosoureas or mitomycin C within 6 weeks before the first dose of XL765
    • A small-molecule kinase inhibitor (including investigational small-molecule kinase inhibitors) or non-cytotoxic hormonal agent within 7 days or 5 half-lives of the drug or active metabolites prior to the first dose of XL765, whichever is longer
    • Radiation therapy within 28 days before the first dose of XL765

    Group 2 and MTD expansion cohort subjects who have received any of the following for the current diagnosis of Grade 3 or Grad 4 astrocytic tumors:
    • Cytotoxic chemotherapy including investigational cytotoxic agents, biologic agents (antibodies, immune modulators, cytokines), a small-molecule kinase inhibitor (including investigational small-molecule kinase inhibitors) or noncytotoxic hormonal agent
    • Radiation Therapy

    For all subjects:
    • Any prior therapy with a PI3K inhibitor
    • Any prior therapy with a PI3K inhibitor

    NOTE: Any questions related to the timing from prior therapies should be discussed and resolved by the investigator and the sponsor prior to the subject entering the study.
  4. The subject has not recovered to baseline or CTCAE Grade ≤1 (except alopecia) due to any prior treatment. Subjects with Grade 2 toxicities from prior therapy deemed irreversible may be eligible if agreed to by the sponsor and investigator.
  5. The subject is taking enzyme-inducing anti-convulsants (see Appendix F) within 14 days before the first dose of XL765.
  6. The subject is taking valproic acid within 14 days before the first dose of XL765.
  7. The subject is receiving anticoagulation with therapeutic doses of warfarin or other coumarin derivatives. NOTE: low-dose warfarin (≤ 1 mg/day), heparin, and low-molecular-weight heparin are permitted.
  8. The subject has a major ongoing or active infection (eg, including but not limited to cytomegalovirus, Epstein-Barr virus, toxoplasmosis, or bacterial pneumonia) requiring hospitalization or parenteral anti-infective therapy within 4 weeks before the first dose of XL765. The subject has had an uncontrolled intercurrent illness including but not limited to congestive heart failure, unstable angina, a myocardial infarction within 3 months of entering the study, or hypertension that would limit compliance with study requirements.
  9. The subject has a corrected QT interval (QTc) > 460 ms at screening.
  10. The subject is pregnant or breastfeeding.
  11. The subject is known to be positive for the human immunodeficiency virus. (HIV testing is not required for eligibility.)
  12. The subject has a previously identified allergy or hypersensitivity to components of the XL765 formulation or TMZ, including the active metabolite 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC).
  13. The subject is unable or unwilling to abide by the study protocol or cooperate fully with the investigator or designee.

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