Tandutinib in Treating Patients With Recurrent or Progressive Glioblastoma

Phase 1

Completed

Conditions: Adult Giant Cell Glioblastoma
Adult Glioblastoma
Adult Brain Tumor
Adult Gliosarcoma
Recurrent Adult Brain Tumor

Interventions: Drug: tandutinib
Procedure: conventional surgery
Other: pharmacological study
Other: Tissue samples

Registration Number: NCT00379080

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: This phase I/II trial is studying the side effects and best dose of tandutinib and to see how well it works in treating patients with recurrent or progressive glioblastoma.Tandutinib 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. Assess the ability of tandutinib to achieve a target tumor/plasma ratio ≥ 0.33 in patients with recurrent glioblastoma undergoing resection. (Feasibility study) II. Detect potential biological effects of tandutinib by measuring platelet-derived growth factor receptor phosphorylation status and downstream activation of Akt and Erk. (Feasibility study) III. Determine the maximum tolerated dose of tandutinib in patients with recurrent or progressive glioblastoma. (Phase I) IV. Estimate the frequency of toxicities associated with tandutinib in patients with recurrent or progressive glioblastoma. (Phase I) V. Describe the pharmacokinetics of this route of administration in patients with recurrent or progressive glioblastoma. (Phase I) VI. Assess tumor response rate in patients with recurrent or progressive glioblastoma. (Phase II)

SECONDARY OBJECTIVES:

I. Estimate overall survival of patients with recurrent or progressive glioblastoma. (Phase II) II. Estimate the 6-month progression-free survival rate in these patients. (Phase II) III. Assess the toxicities associated with tandutinib in these patients. (Phase II) IV. Assess the pharmacokinetic profile of this route of administration in these patients. (Phase II) V. Explore protein-expression patterns that distinguish patients who respond to therapy from those who do not. (Phase II)

OUTLINE: This is a multicenter, prospective, nonrandomized, feasibility study and phase I study (in parallel) followed by an open label phase II study.

FEASIBILITY STUDY: Patients receive oral tandutinib twice daily for 7 days. Patients then undergo biopsy or surgery to remove the tumor. Within 2 weeks after biopsy or surgery, patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

PHASE I: Patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of tandutinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD.

\[Note: \*On day 1 of course 1, patients receive only 1 dose of tandutinib.\]

PHASE II: Patients receive tandutinib as in phase I at the MTD determined in phase I.

Patients undergo blood sample collection for pharmacokinetic studies. Patients in the feasibility portion of the study also undergo blood and tissue sample collection for correlative studies by mass spectrometry for tandutinib concentration. Samples are also examined for circulating endothelial cells and plasma proteins (vascular endothelial growth factor \[VEGF\]-A, -B, -C, and -D, soluble VEGF receptors \[sVEGFR's\], placental growth factor \[P1GF\], platelet-derived growth factor \[PDGF\]-AA, PDGF-AB, PDGF-BB, angiopoietin-1 and -2, tumstatin, thrombospondin-1, and IL-8) as potential markers of the antiangiogenic effect of tandutinib.

After completion of study treatment, patients are followed every 2 months.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 60

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Arm 2 - Dose Escalation (Phase 1)	tandutinib	Phase I: Patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tandutinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD. the starting dose for tandtinib is 500mg BID oral tandutinib Pharmacological study Tissue samples
Arm I - Feasibility	conventional surgery	Patients receive oral tandutinib twice daily for 7 days. Patients then undergo biopsy or surgery to remove the tumor. Within 2 weeks after biopsy or surgery, patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. conventional surgery oral tandutinib Pharmacological study Tissue samples
Arm I - Feasibility	tandutinib	Patients receive oral tandutinib twice daily for 7 days. Patients then undergo biopsy or surgery to remove the tumor. Within 2 weeks after biopsy or surgery, patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. conventional surgery oral tandutinib Pharmacological study Tissue samples
Arm I - Feasibility	pharmacological study	Patients receive oral tandutinib twice daily for 7 days. Patients then undergo biopsy or surgery to remove the tumor. Within 2 weeks after biopsy or surgery, patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. conventional surgery oral tandutinib Pharmacological study Tissue samples
Arm I - Feasibility	Tissue samples	Patients receive oral tandutinib twice daily for 7 days. Patients then undergo biopsy or surgery to remove the tumor. Within 2 weeks after biopsy or surgery, patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. conventional surgery oral tandutinib Pharmacological study Tissue samples
Arm 2 - Dose Escalation (Phase 1)	pharmacological study	Phase I: Patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tandutinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD. the starting dose for tandtinib is 500mg BID oral tandutinib Pharmacological study Tissue samples
Arm 2 - Dose Escalation (Phase 1)	Tissue samples	Phase I: Patients receive oral tandutinib twice daily\* on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tandutinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD. the starting dose for tandtinib is 500mg BID oral tandutinib Pharmacological study Tissue samples
Arm 3 - Phase 2	tandutinib	Patients receive tandutinib as in phase I at the MTD determined in phase I. 600mg was the determined MTD in Dose Escalation oral tandutinib Pharmacological study Tissue samples
Arm 3 - Phase 2	pharmacological study	Patients receive tandutinib as in phase I at the MTD determined in phase I. 600mg was the determined MTD in Dose Escalation oral tandutinib Pharmacological study Tissue samples
Arm 3 - Phase 2	Tissue samples	Patients receive tandutinib as in phase I at the MTD determined in phase I. 600mg was the determined MTD in Dose Escalation oral tandutinib Pharmacological study Tissue samples

Primary Outcome Measures

Name	Time	Method
Maximum Tolerated Dose of Tandutinib Defined by Dose Limiting Toxicities (Phase 1)	cycle 1 - 28 days
To Determine the Tumor/Plasma Ratio of in Subjects With Recurrent GBM Undergoing Resections (Phase 0)	7 days prior to surgery including surgery	participants are administered tandutinib (500mg BID) for 7 days prior to surgery and then undergo resection for recurrent glioblastoma. Tissue samples will be collected for correlative studies - determine tumor/plasma ratio.
Number of Dose Limiting Toxicities Per Dose Level	28 days	cohorts of 3-6 pts will recieve oral tandutinib starting at 500mg BID with a dose escalation in each cohort. Each treatment cycle is 28 days. Evaluation period for MTD is 1st cycle - 28 days. dose limiting toxicity defined as: grades 3-4 severity (except vomiting and diarrhea without sufficient prophylaxis delay of treatment \> 14 days. ANC less/equal 500m/mm3; Plts less/equal 25,000/mm3; febrile neutropenia or delay of treatment \> 14 days
Tumor Response (Complete Response and Partial Response) Rate (Phase II)	Up to 4 years	pts receive a scan baseline and prior to every odd cycle. All responses are centrally reviewed Complete response Complete disappearance of all tumor on MRI scan, off all glucocorticoids with stable or improving neurological exam minimum of 4 wks Partial response Greater than or equal 50% reduction in tumor size on MRI, on sable or decreasing glucocorticoids with stable or improving neurological exam for a minimum of 4 wks. Progressive disease Progressive neurological abnormalities not explained by other causes or greater than 25% increase in size of tumor or if new lesion. Stable disease Clinical status and MRI does not qualify for complete response, partial response or progression
Pharmacokinetics (Max Concentration of Plasma) for Tandutinib in Phase 1 and Phase 2	28 days	pre-dose, 1,2,4,6,8 and 24 hrs post dose and days 8,15, 21 of cycle 1 and day one of cycle 2
Pharmacokinetics (Apparent Terminal Phase Half-life) for Tandutinib in Phase 1 and Phase 2	28 days	pre-dose, 1,2,4,6,8 and 24 hrs post dose and days 8,15, 21 of cycle 1 and day one of cycle 2
Pharmacokinetics (Area Under the Plasma Concentration Time Profile From Zero to Infinity (AUC)) for Tandutinib in Phase 1 and Phase 2	28 days	pre-dose, 1,2,4,6,8 and 24 hrs post dose and days 8,15, 21 of cycle 1 and day one of cycle 2
Pharmacokinetics; Apparent Oral Clearance for Tandutinib in Phase 1 and Phase 2	28 days	pre-dose, 1,2,4,6,8 and 24 hrs post dose and days 8,15, 21 of cycle 1 and day one of cycle 2
Pharmacokinetics; Apparent Oral Total Body Volume of Distribution for Tandutinib in Phase 1 and Phase 2	28 days	pre-dose, 1,2,4,6,8 and 24 hrs post dose and days 8,15, 21 of cycle 1 and day one of cycle 2
Pharmacokinetics; Steady-state Trough Concentration for Tandutinib in Phase 1 and Phase 2	28 days	pre-dose, 1,2,4,6,8 and 24 hrs post dose and days 8,15, 21 of cycle 1 and day one of cycle 2

Secondary Outcome Measures

Name	Time	Method
Overall Survival (Phase II)	Up to 4 years	Median time of survival along with 95% confidence interval will be estimated using Kaplan-Meier method. An overall failure rate will be estimated with 95% CI.
Six-month Progression-free Survival Rate (Phase II)	At 6 months	The probability of 6-momth progression-free survival will be estimated using binomial distribution. Progression defined as: Progressive neurological abnormalities not explained by other causes or greater than 25% increase in size of tumor or if new lesion.
Overall Failure Rate (Phase II)	up to 4 years	The overall failure rate is expressed as hazard of failure per person-year of follow-up.
Proportion of Patients With Serious or Life Threatening Toxicities	2 year period	Grade 3 or 4 toxicities related to treatment as determined by the CTCAE
Protein Expression Patterns Post Treatment - Loss or Gain	baseline - cycle 2 (28 days)	serial blood samples over multiple time points (prior to treatment, 2 days post treatment, 8 days post treatment, 10 days post treatment and 28 days post treatment. statistical analyses presented for the comparisons that yielded a p-value \<=0.05

Trial Locations

Locations (9): Cleveland Clinic Foundation
🇺🇸
Cleveland, Ohio, United States
University of Alabama at Birmingham
🇺🇸
Birmingham, Alabama, United States
H. Lee Moffitt Cancer Center and Research Institute
🇺🇸
Tampa, Florida, United States
Massachusetts General Hospital Cancer Center
🇺🇸
Boston, Massachusetts, United States
Wake Forest University Health Sciences
🇺🇸
Winston-Salem, North Carolina, United States
Dana-Farber Cancer Institute
🇺🇸
Boston, Massachusetts, United States
Henry Ford Hospital
🇺🇸
Detroit, Michigan, United States
Johns Hopkins University
🇺🇸
Baltimore, Maryland, United States
Emory University
🇺🇸
Atlanta, Georgia, United States