Tandutinib in Treating Patients With Recurrent or Progressive Glioblastoma

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Feasibility Assessment and a Phase I/II Trial of MLN518 for Treatment of Patients With Recurrent Glioblastoma

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

Intervention / Treatment
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* Procedure: conventional surgery
* Drug: tandutinib
* Other: pharmacological study
* Other: Tissue samples


Participation Criteria
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Eligibility Criteria
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Criteria: Histologically confirmed glioblastoma: Progressive or recurrent disease after prior radiotherapy (with or without chemotherapy) Patients with a previous low-grade glioma that progressed after prior radiotherapy (with or without chemotherapy) and are found to have glioblastoma by biopsy are eligible Measurable disease, defined as contrast-enhancing progressive or recurrent glioblastoma by MRI or CT imaging within the past 2 weeks Must be maintained on a stable corticosteroid regimen from the time of baseline scan to the start of study treatment Feasibility study only: Planning to undergo surgical resection or biopsy Stereotactic biopsy for confirmation of tumor progression or differentiation of tumor progression from treatment-induced effects allowed Corticosteroids must be tapered to the lowest required steroid dose and patient must be maintained on a stable dose after surgery or biopsy Karnofsky performance status 60-100% Absolute neutrophil count >= 1,500/mm^3 Hemoglobin >= 10 mg/dL Bilirubin =< 1.5 mg/dL AST and ALT =< 4 times upper limit of normal Not pregnant or nursing Negative pregnancy test Fertile patients must use effective barrier method contraception during and for 3 months after completion of study treatment Mini Mental State Exam score >= 15 Mean QTc =< 500 msec (with Bazett's correction) by screening electrocardiogram LVEF >= 40% No history of familial long QT syndrome No myocardial infarction within the past 6 months No severe uncontrolled ventricular arrhythmias No uncontrolled angina No electrocardiographic evidence of acute ischemia or active conduction system abnormalities No ongoing vomiting or nausea >= grade 2 No gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for intravenous alimentation No active peptic ulcer disease No other condition that would impair ability to swallow pills or absorb oral medications No muscular dystrophy No myasthenia gravis No other known or suspected primary muscular or neuromuscular disease No history of allergic reactions attributed to compounds of similar chemical or biologic composition to tandutinib (e.g., erlotinib hydrochloride, gefetinib, or doxazosin mesylate) Patients who developed an acneiform/maculopustular rash while receiving either gefitinib or erlotinib hydrochloride are eligible unless the rash is considered an allergic reaction (angioedema/urticaria) or Stevens-Johnson syndrome No ongoing or active infections No psychiatric illness or social situations that would preclude study compliance No other serious infection or medical illness At least 3 weeks since prior chemotherapy (6 weeks for nitrosoureas) No other uncontrolled illness No other malignancy within the past 5 years except for basal cell or squamous cell skin cancer or carcinoma in situ of the cervix or breast Recovered from prior therapy At least 3 months since prior radiotherapy No prior surgical procedures affecting absorption No concurrent combination antiretroviral therapy for HIV-positive patients No other concurrent investigational agents No concurrent agent that would cause QTc prolongation No concurrent prophylactic growth factors (e.g., filgrastim [G-CSF] or sargramostim [GM-CSF]) At least 10 days since prior and no concurrent anticonvulsant drugs that induce hepatic metabolic enzymes (e.g., primidone, oxcarbazepine, phenytoin, carbamazepine, or phenobarbital) No prior treatment with small molecule inhibitors of platelet-derived growth factor receptor (e.g., sunitinib malate, sorafenib, or imatinib mesylate) Platelet count >= 100,000/mm^3 No New York Heart Association class III or IV heart failure Creatinine =< 1.5 mg/dL OR creatinine clearance >= 60mL/min

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I - Feasibility<br>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 | Procedure: conventional surgery<br>* Undergo surgery<br>* Other names: MLN518;Drug: tandutinib<br>* Given orally<br>* Other names: CT53518;Other: pharmacological study<br>* Correlative studies<br>Other: Tissue samples<br>* Correlative studies<br>|
| Experimental: Arm 2 - Dose Escalation (Phase 1)<br>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 | Drug: tandutinib<br>* Given orally<br>* Other names: CT53518;Other: pharmacological study<br>* Correlative studies<br>Other: Tissue samples<br>* Correlative studies<br>|
| Experimental: Arm 3 - Phase 2<br>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 | Drug: tandutinib<br>* Given orally<br>* Other names: CT53518;Other: pharmacological study<br>* Correlative studies<br>Other: Tissue samples<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 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. | 7 days prior to surgery including surgery | 
| Number of Dose Limiting Toxicities Per Dose Level | 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 | 28 days | 
| Tumor Response (Complete Response and Partial Response) Rate (Phase II) | 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 | Up to 4 years | 
| Pharmacokinetics (Max Concentration of Plasma) for Tandutinib in Phase 1 and Phase 2 | 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 | 28 days | 
| Pharmacokinetics (Apparent Terminal Phase Half-life) for Tandutinib in Phase 1 and Phase 2 | 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 | 28 days | 
| Pharmacokinetics (Area Under the Plasma Concentration Time Profile From Zero to Infinity (AUC)) for Tandutinib in Phase 1 and Phase 2 | 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 | 28 days | 
| Pharmacokinetics; Apparent Oral Clearance for Tandutinib in Phase 1 and Phase 2 | 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 | 28 days | 
| Pharmacokinetics; Apparent Oral Total Body Volume of Distribution for Tandutinib in Phase 1 and Phase 2 | 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 | 28 days | 
| Pharmacokinetics; Steady-state Trough Concentration for Tandutinib in Phase 1 and Phase 2 | 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 | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (Phase II) | 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. | Up to 4 years | 
| Six-month Progression-free Survival Rate (Phase II) | 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. | At 6 months | 
| Overall Failure Rate (Phase II) | The overall failure rate is expressed as hazard of failure per person-year of follow-up. | up to 4 years | 
| Proportion of Patients With Serious or Life Threatening Toxicities | Grade 3 or 4 toxicities related to treatment as determined by the CTCAE | 2 year period | 
| Protein Expression Patterns Post Treatment - Loss or Gain | 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 | baseline - cycle 2 (28 days) |