Tandutinib in Treating Patients With Recurrent or Progressive Glioblastoma

Adult Glioblastoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00379080
• Other study ID #: NCI-2009-00681
• Secondary ID: NCI-2009-00681CD
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: September 19, 2006
• Last updated: October 7, 2013
• Start date: January 2007

Study information

• Verified date: October 2013
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 85
• Est. primary completion date: September 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Adult Brain Tumor
• Adult Giant Cell Glioblastoma
• Adult Glioblastoma
• Adult Gliosarcoma
• Brain Neoplasms
• Glioblastoma
• Gliosarcoma
• Recurrent Adult Brain Tumor

Intervention

Procedure:
• conventional surgery
Undergo surgery

Drug:
• tandutinib
Given orally

Other:
• pharmacological study
Correlative studies
• biopsy
Correlative studies

Locations

Country	Name	City	State
United States	Emory University	Atlanta	Georgia
United States	Adult Brain Tumor Consortium	Baltimore	Maryland
United States	Johns Hopkins University	Baltimore	Maryland
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital Cancer Center	Boston	Massachusetts
United States	Massachusetts General Hospital	Charlestown	Massachusetts
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	Henry Ford Hospital	Detroit	Michigan
United States	Cleveland Clinic Cancer Center Independence	Independence	Ohio
United States	H. Lee Moffitt Cancer Center and Research Institute	Tampa	Florida
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Feasibility defined as the ability of tandutinib to achieve a target tumor/plasma ratio >= 0.33 (Phase I)		Up to 4 years	No
Primary	Maximum tolerated dose of tandutinib defined by dose-limiting toxicities (Phase I)		28 days	Yes
Primary	Tumor response (complete response and partial response) rate (phase II)		Up to 4 years	No
Secondary	Proportion of patients with serious or life threatening toxicities	Will be estimated along with 95% confidence intervals.	Up to 4 years	Yes
Secondary	Pharmacokinetics of this route of administration	General descriptive statistics will be used to summarize this pharmacokinetic study.	Up to 4 years	No
Secondary	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. The overall failure rate is expressed as hazard of failure per person-year of follow-up.	Up to 4 years	No
Secondary	Six-month progression-free (complete or partial response or stable disease) survival rate (phase II)	The probability of 6-momth progression-free survival will be estimated using binomial distribution.	At 6 months	No
Secondary	Binary outcome, protein expression pattern change after the treatment (Phase II)	The Cox's proportional hazard model will be used to explore the association between the patterns and patient survival status.	Up to 4 years	No