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A Pharmacokinetic and Phase 2 Study of Sunitinib Malate in Recurrent Malignant Gliomas

Phase 2
18 Years
Open (Enrolling)
Adult Anaplastic Astrocytoma, Adult Diffuse Astrocytoma, Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma, Adult Mixed Glioma, Adult Oligodendroglioma, Adult Pineal Gland Astrocytoma

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Trial Information

A Pharmacokinetic and Phase 2 Study of Sunitinib Malate in Recurrent Malignant Gliomas


I. To assess the efficacy of sunitinib malate in patients with recurrent malignant gliomas
as measured by 6-month progression-free survival.

II. To determine the lower of the dose of sunitinib malate in patients receiving
enzyme-inducing anti-convulsants that would achieve similar serum drug and metabolite
concentrations as that in patients not receiving enzyme-inducing anticonvulsants or the
maximum tolerated dose in the same population.


I. To examine the toxicity and safety of sunitinib malate in patients with the above noted

II. To evaluate tumor responses in the stated patients. III. To evaluate progression-free
and overall survival in the stated patients.

OUTLINE: This is a multicenter study. Patients are stratified according to use of
enzyme-inducing anticonvulsants (EIAC) (yes vs no).

STRATUM 1 (non-EIAC): Patients receive oral sunitinib malate once daily for 4 consecutive
weeks followed by 2 weeks of rest.

STRATUM 2 (EIAC & OSU patients only): Patients receive oral sunitinib malate as in stratum
1. Patients receive escalating doses of oral sunitinib malate until the maximum tolerated
dose (MTD) is determined.

Patients undergo blood sample collection periodically for pharmacokinetic studies. Samples
are analyzed for plasma concentrations of sunitinib malate via LC/MS/MS method.

In both strata, treatment repeats every 6 weeks in the absence of disease progression or
unacceptable toxicity.

Inclusion Criteria:

- Stratum 1:

- Currently not receiving an enzyme-inducing anticonvulsant

- Patients receiving non-enzyme inducing anticonvulsants are eligible for
this stratum

- Histologically confirmed WHO grade IV astrocytoma (glioblastoma multiforme
[GBM]) including gliosarcoma

- Stratum 2 (USA patients only):

- Currently on stable dose of an enzyme-inducing anticonvulsant (with confirmed
therapeutic serum levels) for at least 2 weeks prior to study registration
including any of the following:

- Phenytoin

- Carbamazepine

- Phenobarbital

- Histologically confirmed grade IV astrocytoma (GBM), gliosarcoma, grade III
astrocytoma, oligodendroglioma, or mixed oligoastrocytoma

- All patients must have unequivocal evidence of tumor progression by MRI or CT scan
performed no longer than 14 days prior to study registration

- Patients undergoing surgery for progressive disease with nonmeasurable disease
on post-operative MRI, ideally obtained within 48 hours of surgery, (i.e.,
macroscopic gross total resection) are eligible

- ECOG performance status 0-2 (Karnofsky ≥ 60%)

- Life expectancy > 3 months

- Leukocytes ≥ 3,000/μL

- Absolute neutrophil count ≥ 1,500/μL

- Platelet count ≥ 100,000/μL

- Hemoglobin ≥ 9 g/dL

- Serum calcium ≤ 12.0 mg/dL

- Total bilirubin within normal institutional limits (ULN)

- AST(SGOT)/ALT(SGPT) ≤ 2.5 X institutional ULN

- Creatinine < 1.5 X institutional ULN

- Patients must have QTc < 500 msec

- The following groups of patients are eligible provided they have New York Heart
Association class II cardiac function on baseline ECHO or MUGA:

- Those with a history of class II heart failure who are asymptomatic on treatment

- Those with prior anthracycline exposure

- Those who have received central thoracic radiation that included the heart in
the radiotherapy port

- Women of childbearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control or abstinence) prior to study entry and
for the duration of study participation

- All women of childbearing potential must have a negative pregnancy test prior to
receiving sunitinib malate

- Patients with a history of QTc prolongation (defined as a QTc interval >= 500 msec),
serious ventricular arrhythmia (VT or VF > 3 beats in a row) or other significant ECG
abnormalities are excluded

- Patients with poorly controlled hypertension (systolic BP ≥ 140 mm Hg or diastolic BP
≥ 90 mm Hg) are ineligible

- Patients with any condition (e.g., gastrointestinal tract disease resulting in an
inability to take oral medication or a requirement for IV alimentation, prior
surgical procedures affecting absorption, or active peptic ulcer disease) that
impairs their ability to swallow and retain sunitinib malate tablets are excluded

- Patients with any of the following conditions are excluded:

- Serious or non-healing wound, ulcer, or bone fracture

- History of abdominal fistula, gastrointestinal perforation, or intra-abdominal
abscess within 28 days of treatment

- History of myocardial infarction, cardiac arrhythmia, stable or unstable angina,
symptomatic congestive heart failure, or coronary or peripheral artery bypass
graft or stenting within 12 months prior to study entry

- Class III or IV heart failure as defined by the NYHA functional classification

- Patients with a pre-existing thyroid abnormality who are unable to maintain thyroid
function in the normal range with medication are ineligible

- Patients with uncontrolled intercurrent illness including, but not limited to,
ongoing or active infections requiring antibiotics or psychiatric illness/social
situations that would limit compliance with study requirements are ineligible

- Pregnant women are excluded from this study

- Breastfeeding should be discontinued if the mother is treated with sunitinib malate

- Patients are eligible if they received up to 1 previous chemotherapy regimen

- ≥ 12 weeks must have elapsed from the completion of radiation therapy

- ≥ 4 weeks from previous non-nitrosoureas-based cytotoxic chemotherapy

- ≥ 6 weeks from any nitrosoureas

- ≥ 2 weeks from last cytostatic chemotherapy such as erlotinib hydrochloride or

- Patients who have undergone previous stereotactic radiosurgery, intratumoral
chemotherapy, or brachytherapy are eligible if functional imaging (PET or SPECT scan,
MR spectroscopy, or dynamic MRI) supports the diagnosis of recurrent tumor or
recurrent disease is confirmed histologically

- Concurrent steroids allowed provided the patients is on a stable or decreasing dose
for at least 7 days prior to baseline tumor assessment (MRI and/or CT scan)

- Patients who have received prior treatment with any other antiangiogenic agent (e.g.,
bevacizumab, sorafenib, pazopanib, AZD2171, PTK787, or VEGF Trap) are ineligible

- Patients who require use of therapeutic doses of coumarin-derivative anticoagulants
such as warfarin or enoxaparin are excluded, although warfarin doses of up to 2 mg
daily are permitted for prophylaxis of thrombosis

- Low molecular weight heparin is permitted provided the patient's PT INR is < 1.5

- Use of agents with proarrhythmic potential (e.g., terfenadine, quinidine,
procainamide, disopyramide, sotalol, probucol, bepridil, haloperidol, risperidone,
indapamide, or flecainide) is not permitted during the study

- No other investigational or commercial agents or non-investigational therapy designed
to treat the brain malignancy (i.e., radiation therapy, systemic or intratumoral
chemotherapy, biological agents, immunotherapy, or hormonal therapy) is allowed
during the study period

- HIV-positive patients on combination antiretroviral therapy are ineligible

Exclusion Criteria:

- History of allergic reactions attributed to compounds of similar chemical or
biological composition to sunitinib malate

- Patients who have had chemotherapy within 4 weeks (6 weeks for nitrosoureas or
mitomycin C) or radiation therapy within 12 weeks prior to entering the study or
those who have not recovered from adverse events due to agents administered more than
4 weeks earlier

- At least 4 weeks must have elapsed since any major surgery

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Progression-free survival at 6 months (Stratum 1)

Outcome Description:

Progression-free survival is defined as the length of time from date of registration to date of progression or last follow-up. Analysis will be conducted using an intent-to-treat approach with all enrolled patients beginning treatment included in the analysis.

Outcome Time Frame:

From time to registration to up to 6 months

Safety Issue:


Principal Investigator

Robert Cavaliere

Investigator Role:

Principal Investigator

Investigator Affiliation:

Ohio State University


United States: Food and Drug Administration

Study ID:




Start Date:

June 2007

Completion Date:

Related Keywords:

  • Adult Anaplastic Astrocytoma
  • Adult Diffuse Astrocytoma
  • Adult Giant Cell Glioblastoma
  • Adult Glioblastoma
  • Adult Gliosarcoma
  • Adult Mixed Glioma
  • Adult Oligodendroglioma
  • Adult Pineal Gland Astrocytoma
  • Astrocytoma
  • Glioblastoma
  • Glioma
  • Oligodendroglioma
  • Gliosarcoma



Ohio State University Medical Center Columbus, Ohio  43210