Combination of BKM120 and Bevacizumab in Refractory Solid Tumors and Relapsed/Refractory Glioblastoma Multiforme

Inclusion Criteria:

Phase I ONLY

• Advanced, metastatic solid tumor that has progressed after standard therapy, or is a tumor type resistant to therapy, and for which bevacizumab is clinically appropriate.
• Patient may have measurable disease or non-measureable disease as defined by RECIST v1.1 criteria

Phase II ONLY

• Progressive GBM after treatment with surgical resection (if possible) and 1st line radiation/chemotherapy.
• No previous treatment with a PI3K inhibitor. Previous treatment with bevacizumab as a component of first-line therapy is allowed.
• At least one measurable or evaluable lesion definable by MRI scan. Disease must be measurable per adapted MacDonald criteria
• Archival tumor tissue available for correlative testing for identification of PI3K pathway activation.

ALL PATIENTS

• Patient must be ≥ 4 weeks from administration of last dose of cancer therapy (including radiation therapy, biologic therapy, hormonal therapy, or chemotherapy). Patients who receive a small molecule targeted therapy as part of their first line treatment regimen must be ≥ 4 weeks or ≥ 5 half lives from administration of last dose, whichever is shorter. The patient must have recovered from or come to a new chronic or stable baseline from all treatment-related toxicities.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
• Life expectancy of ≥ 3 months.

• Adequate hematologic function defined by:

  • Absolute neutrophil count (ANC) ≥1500/μL
  • Hemoglobin (Hgb) ≥ 9 g/dL
  • Platelets ≥ 100,000/µL

• Adequate liver function defined by:

  • Alanine aminotransferase (AST) or aspartate aminotransferase (ALT) within normal limits (WNL) (or ≤ 3.0 x upper limit of normal (ULN) in patients with liver metastases
  • Serum bilirubin WNL (or ≤ 1.5 x the institutional ULN in patients with liver metastases; or total bilirubin ≤ 3.0 x ULN with direct bilirubin WNL in patients with well documented Gilbert Syndrome).

• Adequate renal function, defined by:

  •Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 50 mL/min

• Urine dipstick for proteinuria < 2+ at screening. Patients with dipstick urinalysis ≥2+ proteinuria at baseline should undergo a 24 hour urine collection, and must demonstrate ≤ 1 g of protein/24 hours to be eligible.

Exclusion Criteria:

• Patients with diarrhea ≥ grade 2.
• Patients with uncontrolled type I or type II diabetes mellitus, defined as a fasting plasma glucose ≥120 mg/dL.
• Treatment with therapeutic doses of coumarin-type anticoagulants (maximum daily dose of 1 mg allowed for port line patency permitted).

• Patient has active cardiac disease including any of the following:

  • Left ventricular ejection fraction (LVEF) < 50% as determined by Multiple Grated acquisition (MUGA) scan or echocardiogram (ECHO)
  • QTc > 480 msec on screening ECG (using the QTcF formula)
  • Angina pectoris that requires the use of anti-anginal medication
  • Ventricular arrhythmias except for benign premature ventricular contractions
  • Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication
  • Conduction abnormality requiring a pacemaker
  • Valvular disease with documented compromise in cardiac function
  • Symptomatic pericarditis
• Patients with clinical history of hemoptysis or hematemesis (defined as having bright red blood of ½ teaspoon or more per episode) ≤1 month prior to study enrollment.
• Patients with any history of a bleeding diathesis or coagulopathy (in the absence of therapeutic anticoagulation)
• Patients who have received chemotherapy or targeted anticancer therapy ≤ 4 weeks (6 weeks for nitrosourea, antibodies or mitomycin-C) prior to starting study drug must recover to a grade 1 before starting the trial.
• Patients who have received any continuous or intermittent small molecule therapeutics (excluding monoclonal antibodies) ≤ 5 effective half lives prior to starting study drug or who have not recovered from side effects of such therapy.
• Patients who have been treated with any hematopoietic colony-stimulating factors (e.g. G-CSF, GM-CSF) ≤ 2 weeks prior to starting study drug. Erythropoietin or darbepoetin therapy, if initiated at least 2 weeks prior to enrollment may be continued.
• Major surgical procedure, open biopsy, intracranial biopsy, ventriculoperitoneal shunt or significant traumatic injury ≤ 28 days prior to entry.