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


Phase 1/Phase 2
18 Years
N/A
Open (Enrolling)
Both
Adult Brain Tumor, Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma, Recurrent Adult Brain Tumor

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Trial Information

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


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.

Inclusion 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

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Feasibility defined as the ability of tandutinib to achieve a target tumor/plasma ratio >= 0.33 (Phase I)

Outcome Time Frame:

Up to 4 years

Safety Issue:

No

Principal Investigator

Tracy Batchelor

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2009-00681

NCT ID:

NCT00379080

Start Date:

January 2007

Completion Date:

Related Keywords:

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

Name

Location

Johns Hopkins UniversityBaltimore, Maryland  21205
Cleveland Clinic FoundationCleveland, Ohio  44195
H. Lee Moffitt Cancer Center and Research InstituteTampa, Florida  33612
Massachusetts General Hospital Cancer CenterBoston, Massachusetts  02114
Henry Ford HospitalDetroit, Michigan  48202
Dana-Farber Cancer InstituteBoston, Massachusetts  02115
Massachusetts General HospitalBoston, Massachusetts  02114-2617
University of Alabama at BirminghamBirmingham, Alabama  35294-3300
Emory UniversityAtlanta, Georgia  30322
Wake Forest University Health SciencesWinston-Salem, North Carolina  27157
Cleveland Clinic Cancer Center IndependenceIndependence, Ohio  44131
Adult Brain Tumor ConsortiumBaltimore, Maryland  21231-1000