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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



Florida Hospital Cancer Institute Orlando, Florida  32804
Florida Cancer Specialists Fort Myers, Florida  33901
Nebraska Methodist Hospital Omaha, Nebraska  68114
Virginia Cancer Institute Richmond, Virginia  23230
Peninsula Cancer Institute Newport News, Virginia  23601
Center for Cancer and Blood Disorders Bethesda, Maryland  20817
St. Louis Cancer Care Chesterfield, Missouri  63017
Tennessee Oncology Nashville, Tennessee  37203
Yale School of Medicine New Haven, Connecticut  06510
Woodlands Medical Specialists Pensacola, Florida  32503