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Phase II Study of TKI258 (Dovitinib) in Patients With Recurrent or Progressive Glioblastoma Who Have Progressed on Anti-Angiogenic Therapy (Including Anti-VEGF Therapy)

Phase 2
18 Years
Open (Enrolling)
Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma, Recurrent Adult Brain Tumor

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Trial Information

Phase II Study of TKI258 (Dovitinib) in Patients With Recurrent or Progressive Glioblastoma Who Have Progressed on Anti-Angiogenic Therapy (Including Anti-VEGF Therapy)


I. To estimate time to progression in this patient population in patients with recurrent or
progressive glioblastoma who have progressed on anti-angiogenic therapy (including
anti-vascular endothelial growth factor [VEGF] therapy).


I. To evaluate the side effect profile of dovitinib in this patient population. II. To
evaluate the efficacy of dovitinib as measured by objective response rate (ORR) in this
patient population.

III. To estimate time to percentage of patients free from progression at 6 months (PFS-6).

IV. To evaluate the overall survival (OS) in this patient population.


I. To explore association between clinical outcome and potential biomarkers that may include
microparticles, placental growth factor (PlGF), platelet-derived growth factor (PDGF)-AA,
PDGF-AB, PDGF-BB, stromal cell-derived factor 1 alpha (SDF-1a), thrombospondin-1,
angiopoietin 1 (Ang1), and interleukin 6 (IL-6), interleukin 8 (IL-8) and fibroblast growth
factor (FGF).

II. To assess on archival tumor/fresh biopsy samples, if available, the expression of
biomarkers and mutations related dovitinib mechanism of action.


Patients receive dovitinib orally (PO) 5 days a week. Courses repeat every 4 weeks in the
absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

Inclusion Criteria:

- Histologically confirmed glioblastoma, recurrent after standard external-beam
fractionated radiotherapy and temozolomide chemotherapy

- Patients who have received any anti-angiogenic therapy (anti-VEGF, including avastin,
cediranib, or other anti-angiogenic therapies like cilengitide)

- Karnofsky performance status >= 60%

- Absolute neutrophil count (ANC) >= 1.5 x 10^9/L

- Platelets >= 100 x 10^9/L

- Hemoglobin (Hgb) > 9 g/dL

- Serum total bilirubin =< 1.5 x upper limit of normal (ULN)

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3.0 x ULN

- Serum creatinine =< 1.5 x ULN

- Minimum interval since completion of radiation treatment is 12 weeks

- Minimum interval since last drug therapy 2 weeks since last non-cytotoxic therapy 3
weeks must have elapsed since the completion of a non-nitrosourea containing
chemotherapy regimen 6 weeks since the completion of a nitrosourea containing
chemotherapy regimen

- Patients must be able to provide written informed consent

- Patients with the potential for pregnancy or impregnating their partner must agree to
follow acceptable birth control methods to avoid conception; the anti-proliferative
activity of this experimental drug may be harmful to the developing fetus or nursing
infant; female patients of child-bearing potential must have a negative pregnancy

- Patients must have no concurrent malignancy except curatively treated basal or
squamous cell carcinoma of the skin or carcinoma in situ of the cervix and breast,
adequately treated stage I or II cancer from which the patient is in complete
remission; patients with other prior malignancies must be disease-free for >= three

- Patients must be maintained on a stable corticosteroid regimen from the time of their
baseline scan until the start of treatment and/or for at least 5 days before starting

- Patients must have a Mini Mental State Exam score >= 15

Exclusion Criteria:

- Patients who have undergone major surgery (e.g. intra-thoracic, intra-abdominal or
intra-pelvic), open biopsy or significant traumatic injury =< 4 weeks prior to
starting study drug, or patients who have had minor procedures, percutaneous biopsies
or placement of vascular access device =< 1 week prior to starting study drug, or who
have not recovered from side effects of such procedure or injury

- Patients with a history of pulmonary embolism (PE), or untreated deep venous
thrombosis (DVT) within the past 6 months

- Patients with any of the following concurrent severe and/or uncontrolled medical
conditions which could compromise participation in the study:

- Impaired cardiac function or clinically significant cardiac diseases, including
any of the following:

- History or presence of serious uncontrolled ventricular arrhythmias

- Clinically significant resting bradycardia

- Left ventricular ejection fraction (LVEF) assessed by 2-dimensional (2-D)
echocardiogram (ECHO) < 50% or lower limit of normal (whichever is higher)
or multi gated acquisition scan (MUGA) < 45% or lower limit of normal
(whichever is higher)

- Any of the following within 6 months prior to starting study drug:
myocardial infarction (MI), severe/unstable angina, coronary artery bypass
graft (CABG), congestive heart failure (CHF), cerebrovascular accident
(CVA), and transient ischemic attack (TIA)

- Uncontrolled hypertension defined by a systolic blood pressure (SBP) >= 160
mm Hg and/or diastolic blood pressure (DBP) >= 100 mm Hg, with or without
anti-hypertensive medication(s)

- Impairment of gastrointestinal (GI) function or GI disease that may
significantly alter the absorption of dovitinib (e.g. ulcerative diseases,
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel

- Cirrhosis, chronic active hepatitis or chronic persistent hepatitis

- Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is
not mandatory)

- Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g.
active or uncontrolled infection, uncontrolled diabetes) that could cause
unacceptable safety risks or compromise compliance with the protocol

- Women of child-bearing potential, who are biologically able to conceive, not
employing two forms of highly effective contraception; highly effective
contraception (e.g. male condom with spermicide, diaphragm with spermicide,
intra-uterine device) must be used by both sexes during the study and must be
continued for 8 weeks after the end of study treatment; oral, implantable, or
injectable contraceptives may be affected by cytochrome P450 interactions, and
are therefore not considered effective for this study; women of child-bearing
potential, defined as sexually mature women who have not undergone a
hysterectomy or who have not been naturally postmenopausal for at least 12
consecutive months (e.g., who has had menses any time in the preceding 12
consecutive months), must have a negative serum pregnancy test =< 14 days prior
to starting study treatment

- Fertile males not willing to use contraception, as stated above

- Patients who are currently receiving full dose anticoagulation treatment with
therapeutic doses of warfarin or anti-platelet therapy (e.g., Plavix
[clopidogrel bisulfate]); treatment with locally accepted low molecular weight
heparin and low dose of acetylsalicylic acid (i.e., 81mg or 100 mg daily) to
prevent cardiovascular events or strokes is allowed

- Patients unwilling or unable to comply with the protocol

Type of Study:


Study Design:

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

Outcome Measure:

Determine median time to progression

Outcome Description:

The Kaplan-Meier method will be used. Time to tumor progression (TTP), is defined as the time from randomization to time of progressive disease. So it is ongoing and will be assessed every 8 weeks …8, 16, 24, 32 …week.

Outcome Time Frame:

at 8 weeks (2 cycles of treatment)

Safety Issue:


Principal Investigator

Manmeet Ahluwalia

Investigator Role:

Principal Investigator

Investigator Affiliation:

Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

December 2012

Completion Date:

Related Keywords:

  • Adult Giant Cell Glioblastoma
  • Adult Glioblastoma
  • Adult Gliosarcoma
  • Recurrent Adult Brain Tumor
  • Brain Neoplasms
  • Glioblastoma
  • Gliosarcoma



Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer CenterCleveland, Ohio  44195