Sunitinib in Treating Patients With Recurrent Malignant Gliomas

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00499473
• Collaborator: (none)
• Enrollment: 31
• Location: 1
• Arms: 2
• Duration (Months): 88
• Patients Per Site Per Month: 0.4

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Adult Anaplastic Astrocytoma; Adult Diffuse Astrocytoma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Mixed Glioma; Adult Oligodendroglioma; Adult Pineal Gland Astrocytoma	Drug: sunitinib malate; Other: pharmacological study	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

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

2. 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:

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

2. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 31 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Pharmacokinetic and Phase 2 Study of Sunitinib Malate in Recurrent Malignant Gliomas
• Study Start Date: Jun 1, 2007
• Actual Primary Completion Date: Jun 1, 2009
• Actual Study Completion Date: Oct 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Stratum 1 (kinase inhibitor therapy) Non-EIAC patients receive oral sunitinib malate once daily for 4 consecutive weeks followed by 2 weeks of rest.	Drug: sunitinib malate; Given orally; Other Names: SU11248 sunitinib Sutent ; Other: pharmacological study; Correlative studies; Other Names: pharmacological studies
Experimental: Stratum 2 (kinase inhibitor therapy) EIAC & OSU 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.	Drug: sunitinib malate; Given orally; Other Names: SU11248 sunitinib Sutent ; Other: pharmacological study; Correlative studies; Other Names: pharmacological studies

Outcome Measures

Primary Outcome Measures

1. Progression-free Survival at 6 Months (Stratum 1) [From time to registration to up to 6 months]

   Number of patients with Progression-free Survival at 6 months for Stratum 1

2. Maximum Tolerable Dose Based on Dose-limiting Toxicity of Sunitinib in Patients Receiving EIAC (Stratum 2) [From the time of first treatment with sunitinib until completion of treatment, assessed up to 30 days]

   Maximum tolerable dose of sunitinib in patients receiving treatment with EIAC agents using dose escalation based on the steady-state trough sunitinib + SU12662 plasma concentrations on day 14 observed in patients treated in stratum 1. Six patients will be treated in each dose cohort with up to 12 patients being treated at the maximum tolerable dose for a total of 18-24 patients with gliomas receiving EIAC.

3. Dose Resulting in Steady-state Trough [At baseline (day 8) and days 15, 22, and 23]

   Average of pre-dose values of sunitinib + SU12662 plasma concentrations equivalent to that observed in patients not receiving EIAC based on pharmacokinetic modeling.

Secondary Outcome Measures

1. Confirmed Objective Response (Complete Response[CR] or Partial Response [PR]) [up to 12 weeks]

   Confirmatory scans should also be obtained within 4 to 6 weeks following initial documentation of objective response. Confidence intervals for the true proportion will be calculated using the exact binomial method. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

2. Percentage of Patients Progression Free at 12 Months [At 12 months after the start of treatment]

3. Overall Survival [up to 12 months]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Ohio State University Medical Center	Columbus	Ohio	United States	43210

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Robert Cavaliere, Ohio State University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00499473
• Other Study ID Numbers: NCI-2009-00215; NCI-2009-00215; OSU-IRB-2006C0098; CDR0000554443; OSU-06060; OSU 06060; 7745; N01CM62207; N01CM62203; P30CA016058; N01CM62206
• First Posted: Jul 11, 2007
• Last Update Posted: Feb 29, 2016
• Last Verified: Jan 1, 2016

• Additional relevant MeSH terms: Glioblastoma; Glioma; Astrocytoma; Gliosarcoma; Oligodendroglioma; Sunitinib

Study Results

Participant Flow

Arm/Group Title	Stratum I: Non-EIAC	Stratum 2: EIAC
Arm/Group Description	Patients will take one 50-mg capsule of sunitinib orally once daily for 4 consecutive weeks followed by 2 weeks of rest (drug holiday) with no sunitinib.	The first six patients enrolled on stratum 2 will be dosed identical to those patients on stratum 1.The dosage of the next 6-patient cohort in stratum 2 will be adjusted to that predicted by pharmacokinetic modeling to provide the same concentrations seen in first six non-enzyme inducing patients.
Period Title: Overall Study
STARTED	27	4
COMPLETED	21	4
NOT COMPLETED	6	0

Baseline Characteristics

Arm/Group Title	Stratum I: Patients Not on EIAC	Stratum 2: Patients on EIAC	Total
Arm/Group Description	Patients will take one 50-mg capsule of sunitinib orally once daily for 4 consecutive weeks followed by 2 weeks of rest (drug holiday) with no sunitinib.	The first six patients enrolled on stratum 2 will be dosed identical to those patients on stratum 1.The dosage of the next 6-patient cohort in stratum 2 will be adjusted to that predicted by pharmacokinetic modeling to provide the same concentrations seen in first six non-enzyme inducing patients.	Total of all reporting groups
Overall Participants	27	4	31
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	21 77.8%	4 100%	25 80.6%
>=65 years	6 22.2%	0 0%	6 19.4%
Sex: Female, Male (Count of Participants)
Female	11 40.7%	0 0%	11 35.5%
Male	16 59.3%	4 100%	20 64.5%
Region of Enrollment (participants) [Number]
United States	27 100%	4 100%	31 100%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival at 6 Months (Stratum 1)
Description	Number of patients with Progression-free Survival at 6 months for Stratum 1
Time Frame	From time to registration to up to 6 months

Outcome Measure Data

Analysis Population Description

Only 21 patients were evaluable for PFS

Arm/Group Title	Stratum I: Non-EIAC	Stratum 2: EIAC
Arm/Group Description	Patients will take one 50-mg capsule of sunitinib orally once daily for 4 consecutive weeks followed by 2 weeks of rest (drug holiday) with no sunitinib.	The first six patients enrolled on stratum 2 will be dosed identical to those patients on stratum 1.The dosage of the next 6-patient cohort in stratum 2 will be adjusted to that predicted by pharmacokinetic modeling to provide the same concentrations seen in first six non-enzyme inducing patients.
Measure Participants	21	0
Number [patients]	1

2. Primary Outcome

Title	Maximum Tolerable Dose Based on Dose-limiting Toxicity of Sunitinib in Patients Receiving EIAC (Stratum 2)
Description	Maximum tolerable dose of sunitinib in patients receiving treatment with EIAC agents using dose escalation based on the steady-state trough sunitinib + SU12662 plasma concentrations on day 14 observed in patients treated in stratum 1. Six patients will be treated in each dose cohort with up to 12 patients being treated at the maximum tolerable dose for a total of 18-24 patients with gliomas receiving EIAC.
Time Frame	From the time of first treatment with sunitinib until completion of treatment, assessed up to 30 days

Outcome Measure Data

Analysis Population Description

MTD in Stratum 2 not determined due to lack of efficacy in Stratum 1

Arm/Group Title	Stratum I: Non-EIAC	Stratum 2: EIAC
Arm/Group Description	Patients will take one 50-mg capsule of sunitinib orally once daily for 4 consecutive weeks followed by 2 weeks of rest (drug holiday) with no sunitinib.	The first six patients enrolled on stratum 2 will be dosed identical to those patients on stratum 1.The dosage of the next 6-patient cohort in stratum 2 will be adjusted to that predicted by pharmacokinetic modeling to provide the same concentrations seen in first six non-enzyme inducing patients.
Measure Participants	0	0

3. Primary Outcome

Title	Dose Resulting in Steady-state Trough
Description	Average of pre-dose values of sunitinib + SU12662 plasma concentrations equivalent to that observed in patients not receiving EIAC based on pharmacokinetic modeling.
Time Frame	At baseline (day 8) and days 15, 22, and 23

Outcome Measure Data

Analysis Population Description

Not determined due to early termination of the study due to lack of efficacy

Arm/Group Title	Stratum I: Non-EIAC	Stratum 2: EIAC
Arm/Group Description	Patients will take one 50-mg capsule of sunitinib orally once daily for 4 consecutive weeks followed by 2 weeks of rest (drug holiday) with no sunitinib.	The first six patients enrolled on stratum 2 will be dosed identical to those patients on stratum 1.The dosage of the next 6-patient cohort in stratum 2 will be adjusted to that predicted by pharmacokinetic modeling to provide the same concentrations seen in first six non-enzyme inducing patients.
Measure Participants	0	0

4. Secondary Outcome

Title	Confirmed Objective Response (Complete Response[CR] or Partial Response [PR])
Description	Confirmatory scans should also be obtained within 4 to 6 weeks following initial documentation of objective response. Confidence intervals for the true proportion will be calculated using the exact binomial method. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time Frame	up to 12 weeks

Outcome Measure Data

Analysis Population Description

Only 21 patients were evaluable for response

Arm/Group Title	Stratum I: Non-EIAC	Stratum 2: EIAC
Arm/Group Description	Patients will take one 50-mg capsule of sunitinib orally once daily for 4 consecutive weeks followed by 2 weeks of rest (drug holiday) with no sunitinib.	The first six patients enrolled on stratum 2 will be dosed identical to those patients on stratum 1.The dosage of the next 6-patient cohort in stratum 2 will be adjusted to that predicted by pharmacokinetic modeling to provide the same concentrations seen in first six non-enzyme inducing patients.
Measure Participants	21	4
Complete Response Rate	0	0
Partial Response Rate	0	0

5. Secondary Outcome

Title	Percentage of Patients Progression Free at 12 Months
Time Frame	At 12 months after the start of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Stratum I: Non-EIAC	Stratum 2: EIAC
Arm/Group Description	Patients will take one 50-mg capsule of sunitinib orally once daily for 4 consecutive weeks followed by 2 weeks of rest (drug holiday) with no sunitinib.	The first six patients enrolled on stratum 2 will be dosed identical to those patients on stratum 1.The dosage of the next 6-patient cohort in stratum 2 will be adjusted to that predicted by pharmacokinetic modeling to provide the same concentrations seen in first six non-enzyme inducing patients.
Measure Participants	21	4
Number [percent of patients]	0	0

6. Secondary Outcome

Title	Overall Survival
Time Frame	up to 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Stratum I: Non-EIAC	Stratum 2: EIAC
Arm/Group Description	Patients will take one 50-mg capsule of sunitinib orally once daily for 4 consecutive weeks followed by 2 weeks of rest (drug holiday) with no sunitinib.	The first six patients enrolled on stratum 2 will be dosed identical to those patients on stratum 1.The dosage of the next 6-patient cohort in stratum 2 will be adjusted to that predicted by pharmacokinetic modeling to provide the same concentrations seen in first six non-enzyme inducing patients.
Measure Participants	27	4
Median (Full Range) [months]	5.7	12.3

Adverse Events

Adverse Event Reporting Description	The NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 was utilized for Adverse event reporting.
Arm/Group Title	Stratum I: Non-EIAC		Stratum 2: EIAC
Arm/Group Description	Patients will take one 50-mg capsule of sunitinib orally once daily for 4 consecutive weeks followed by 2 weeks of rest (drug holiday) with no sunitinib.		Patients will take one 50-mg capsule of sunitinib orally once daily for 4 consecutive weeks followed by 2 weeks of rest (drug holiday) with no sunitinib. In addition to EIAC (Enzyme-inducing anticonvulsant)
All Cause Mortality
	Stratum I: Non-EIAC		Stratum 2: EIAC
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Stratum I: Non-EIAC		Stratum 2: EIAC
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/27 (0%)		0/4 (0%)
Other (Not Including Serious) Adverse Events
	Stratum I: Non-EIAC		Stratum 2: EIAC
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	27/27 (100%)		4/4 (100%)
Blood and lymphatic system disorders
Anemia	2/27 (7.4%)	4	0/4 (0%)	0
Platelet count decreased	3/27 (11.1%)	5	2/4 (50%)	2
Eye disorders
Blurred vision	2/27 (7.4%)	2	1/4 (25%)	1
Gastrointestinal disorders
Anorexia	1/27 (3.7%)	1	1/4 (25%)	1
Constipation	3/27 (11.1%)	3	0/4 (0%)	0
Diarrhea	9/27 (33.3%)	10	1/4 (25%)	1
Dyspepsia	7/27 (25.9%)	11	2/4 (50%)	2
Fatigue	11/27 (40.7%)	14	2/4 (50%)	2
Flatulence	1/27 (3.7%)	1	1/4 (25%)	1
Mucositis oral	2/27 (7.4%)	2	0/4 (0%)	0
Nausea	4/27 (14.8%)	4	1/4 (25%)	1
Vomiting	3/27 (11.1%)	3	0/4 (0%)	0
General disorders
Gait disturbance	2/27 (7.4%)	6	0/4 (0%)	0
Infections and infestations
Lung infection	2/27 (7.4%)	2	0/4 (0%)	0
Investigations
Alanine aminotransferase increased	5/27 (18.5%)	6	1/4 (25%)	1
Aspartate aminotransferase increased	4/27 (14.8%)	4	1/4 (25%)	1
Neutrophil count decreased	5/27 (18.5%)	5	0/4 (0%)	0
White blood cell decreased	5/27 (18.5%)	7	1/4 (25%)	1
Metabolism and nutrition disorders
Hypoalbuminemia	2/27 (7.4%)	2	1/4 (25%)	1
Hypokalemia	1/27 (3.7%)	2	1/4 (25%)	1
Musculoskeletal and connective tissue disorders
Muscle weakness	3/27 (11.1%)	3	1/4 (25%)	1
Pain in extremity	2/27 (7.4%)	2	0/4 (0%)	0
Nervous system disorders
Dizziness	2/27 (7.4%)	2	2/4 (50%)	2
Headache	5/27 (18.5%)	5	3/4 (75%)	3
Nervous system disorder	3/27 (11.1%)	3	0/4 (0%)	0
Neuropathy	4/27 (14.8%)	4	1/4 (25%)	1
Pyramidal tract syndrome	2/27 (7.4%)	2	0/4 (0%)	0
Seizure	1/27 (3.7%)	1	2/4 (50%)	2
Psychiatric disorders
Confusion	3/27 (11.1%)	3	1/4 (25%)	1
Insomnia	2/27 (7.4%)	2	0/4 (0%)	0
Renal and urinary disorders
Urinary retention	1/27 (3.7%)	1	1/4 (25%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	3/27 (11.1%)	3	0/4 (0%)	0
Skin and subcutaneous tissue disorders
Palmar-plantar erythrodysesthesia syndrome	2/27 (7.4%)	2	0/4 (0%)	0
Rash	3/27 (11.1%)	3	1/4 (25%)	1
Skin and subcutaneous tissue disorder	0/27 (0%)	0	1/4 (25%)	2
Vascular disorders
Hypertension	4/27 (14.8%)	5	0/4 (0%)	0
Vascular disorder	0/27 (0%)	0	2/4 (50%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.