Clinical trial NCT00499473: Sunitinib in Treating Patients With Recurrent Malignant Gliomas
Official title: A Pharmacokinetic and Phase 2 Study of Sunitinib Malate in Recurrent Malignant Gliomas
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Adult Anaplastic Astrocytoma
Adult Diffuse Astrocytoma
Adult Giant Cell Glioblastoma
Adult Glioblastoma
Adult Gliosarcoma
Adult Mixed Glioma
Adult Oligodendroglioma
Adult Pineal Gland Astrocytoma
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2007-07-11
Enrollment: 31
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This phase II trial is studying how well sunitinib works in treating patients with recurrent malignant gliomas. Sunitinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor.

Detailed description: PRIMARY OBJECTIVES:

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.

SECONDARY OBJECTIVES:

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

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.

Eligibility criteria: 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 system
* 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 tamoxifen
* 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

Primary outcomes:
measure: Progression-free Survival at 6 Months (Stratum 1)
timeFrame: From time to registration to up to 6 months
measure: Maximum Tolerable Dose Based on Dose-limiting Toxicity of Sunitinib in Patients Receiving EIAC (Stratum 2)
timeFrame: From the time of first treatment with sunitinib until completion of treatment, assessed up to 30 days
measure: Dose Resulting in Steady-state Trough
timeFrame: At baseline (day 8) and days 15, 22, and 23
Secondary outcomes:
measure: Confirmed Objective Response (Complete Response[CR] or Partial Response [PR])
timeFrame: up to 12 weeks
measure: Percentage of Patients Progression Free at 12 Months
timeFrame: At 12 months after the start of treatment
measure: Overall Survival
timeFrame: up to 12 months
Other outcomes:
Locations:
city: Columbus
country: United States
facility: Ohio State University Medical Center
state: Ohio
Study officials:
affiliation: Ohio State University
name: Robert Cavaliere
role: PRINCIPAL_INVESTIGATOR
References: