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Phase I/II Study of the Combination of BKM120 and Bevacizumab in Patients With Refractory Solid Tumors (Phase I) and Relapsed/Refractory Glioblastoma Multiforme (Phase II)

Phase 1/Phase 2
18 Years
Open (Enrolling)
Glioblastoma Multiforme

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Trial Information

Phase I/II Study of the Combination of BKM120 and Bevacizumab in Patients With Refractory Solid Tumors (Phase I) and Relapsed/Refractory Glioblastoma Multiforme (Phase II)

This is an open-label, non-randomized Phase I study of patients with advanced refractory
solid tumors followed by a Phase II study for the second-line treatment of patients with
relapsed/refractory glioblastoma multiforme.

The phase I study will determine the MTD of BKM120 when combined with bevacizumab. The
Phase I portion will follow a standard dose escalation design, beginning with dose level 1.
The sequence of dose escalation for BKM120 and bevacizumab is based on a starting dose of 60
mg/day for BKM120 (i.e. 50% of the MTD of BKM120 when administered as a single agent). A
maximum of three BKM120 dose levels will be evaluated. Bevacizumab will be fixed at 10
mg/kg IV and will be administered every two weeks. Approximately 18 patients will be
enrolled during the Phase I portion to establish the MTD.

In the Phase II portion of this study, patients with relapsed/refractory GBM following first
line therapy will receive treatment with the BKM120/bevacizumab combination. Limited BKM120
pharmacokinetic evaluation will be performed on all patients treated during the Phase II
portion of the study. Patients will be reevaluated for response to treatment after 2 cycles
(8 weeks). Patients with objective response or stable disease will continue treatment, with
subsequent reevaluations every 8 weeks, until disease progression or unacceptable toxicity

Two populations of patients with relapsed/refractory GBM will be treated in the Phase II
trial: 1) patients with no previous exposure to bevacizumab (N= 55) and 2) patients who
received bevacizumab as part of first-line combined modality treatment (N= 20).

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


- Progressive GBM after treatment with surgical resection (if possible) and 1st line

- 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.


- 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

- Major surgical procedure, open biopsy, intracranial biopsy, ventriculoperitoneal
shunt or significant traumatic injury ≤ 28 days prior to entry.

Type of Study:


Study Design:

Endpoint Classification: Pharmacokinetics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To establish the optimal dose of BKM120 that can be administered in combination with a standard dose of bevacizumab. (Phase I)

Outcome Time Frame:

18 months

Safety Issue:


Principal Investigator

John Hainsworth, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Sarah Cannon Research Institute


United States: Food and Drug Administration

Study ID:




Start Date:

December 2011

Completion Date:

August 2014

Related Keywords:

  • Glioblastoma Multiforme
  • Glioblastoma multiforme
  • GBM
  • Bevacizumab
  • PI3K Pathway
  • BKM120
  • Glioblastoma



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