Clinical trial NCT00379080: Tandutinib in Treating Patients With Recurrent or Progressive Glioblastoma
Official title: A Feasibility Assessment and a Phase I/II Trial of MLN518 for Treatment of Patients With Recurrent Glioblastoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Adult Brain Tumor
Adult Giant Cell Glioblastoma
Adult Glioblastoma
Adult Gliosarcoma
Recurrent Adult Brain Tumor
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2006-09-21
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Maximum Tolerated Dose of Tandutinib Defined by Dose Limiting Toxicities (Phase 1)
timeFrame: cycle 1 - 28 days
measure: To Determine the Tumor/Plasma Ratio of in Subjects With Recurrent GBM Undergoing Resections (Phase 0)
timeFrame: 7 days prior to surgery including surgery
measure: Number of Dose Limiting Toxicities Per Dose Level
timeFrame: 28 days
measure: Tumor Response (Complete Response and Partial Response) Rate (Phase II)
timeFrame: Up to 4 years
measure: Pharmacokinetics (Max Concentration of Plasma) for Tandutinib in Phase 1 and Phase 2
timeFrame: 28 days
measure: Pharmacokinetics (Apparent Terminal Phase Half-life) for Tandutinib in Phase 1 and Phase 2
timeFrame: 28 days
measure: Pharmacokinetics (Area Under the Plasma Concentration Time Profile From Zero to Infinity (AUC)) for Tandutinib in Phase 1 and Phase 2
timeFrame: 28 days
measure: Pharmacokinetics; Apparent Oral Clearance for Tandutinib in Phase 1 and Phase 2
timeFrame: 28 days
measure: Pharmacokinetics; Apparent Oral Total Body Volume of Distribution for Tandutinib in Phase 1 and Phase 2
timeFrame: 28 days
measure: Pharmacokinetics; Steady-state Trough Concentration for Tandutinib in Phase 1 and Phase 2
timeFrame: 28 days
Secondary outcomes:
measure: Overall Survival (Phase II)
timeFrame: Up to 4 years
measure: Six-month Progression-free Survival Rate (Phase II)
timeFrame: At 6 months
measure: Overall Failure Rate (Phase II)
timeFrame: up to 4 years
measure: Proportion of Patients With Serious or Life Threatening Toxicities
timeFrame: 2 year period
measure: Protein Expression Patterns Post Treatment - Loss or Gain
timeFrame: baseline - cycle 2 (28 days)
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center and Research Institute
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital Cancer Center
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Winston-Salem
country: United States
facility: Wake Forest University Health Sciences
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
Study officials:
affiliation: National Cancer Institute (NCI)
name: Tracy Batchelor, MD
role: PRINCIPAL_INVESTIGATOR
References: