ATN-161 and Carboplatin in Treating Patients With Recurrent Malignant Glioma
ATN-161 and Carboplatin in Treating Patients With Recurrent Malignant Glioma
RATIONALE: ATN-161 may stop the growth of tumor cells by blocking blood flow to the tumor.
 Drugs used in chemotherapy, such as carboplatin, work in different ways to stop the growth of
 tumor cells, either by killing the cells or by stopping them from dividing. Giving ATN-161
 together with carboplatin may kill more tumor cells.

 PURPOSE: This phase I/II trial is studying the side effects and best dose of ATN-161 when
 given together with carboplatin and to see how well they work in treating patients with
 recurrent malignant glioma.
OBJECTIVES:

 Primary

 -  Establish the safety of ATN-161 and carboplatin in patients with recurrent intracranial
 malignant glioma.

 -  Determine the maximum tolerated dose of ATN-161 when administered with carboplatin in
 these patients. (phase I)

 -  Determine the antitumor activity of ATN-161 when administered with carboplatin in these
 patients. (phase II)

 Secondary

 -  Describe the effects of this regimen on potential biomarkers of activity, including
 functional imaging with brain perfusion scans and circulating endothelial progenitor
 cells.

 -  Obtain preliminary evidence of efficacy of this regimen in these patients. (phase I)

 -  Characterize the plasma concentrations of this regimen in these patients. (phase I)

 OUTLINE: This is an open-label, phase I dose-escalation study of ATN-161 followed by a phase
 II study. Patients in the phase II portion of the study are stratified according to tumor
 type (glioblastoma multiforme vs anaplastic glioma).

 -  Phase I: Patients receive ATN-161 IV over 10 minutes 3 times weekly in weeks 1-6 and
 carboplatin IV over 20 minutes in week 3 during course 1. Beginning in course 2,
 patients receive carboplatin IV over 20 minutes in week 1 and ATN-161 IV over 10 minutes
 3 times weekly in weeks 1-4. Treatment repeats every 4 weeks in the absence of disease
 progression or unacceptable toxicity.

 Cohorts of 3-6 patients receive escalating doses of ATN-161 until the maximum tolerated dose
 (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients
 experience dose-limiting toxicity during the first 6 weeks of treatment.

 -  Phase II: Patients receive carboplatin IV in week 1 and ATN-161 IV, at the MTD
 determined in phase I, 3 times weekly in weeks 1-4. Treatment repeats every 4 weeks for
 up to 12 courses in the absence of disease progression or unacceptable toxicity.

 Patients undergo blood collection at baseline and then periodically during phase I course 1
 for pharmacokinetic and pharmacodynamic analysis and at baseline and then periodically during
 study for biomarker (e.g., circulating endothelial progenitor cells) correlative studies.

 After completion of study treatment, patients are followed for 28 days.

 PROJECTED ACCRUAL: A total of 82 patients will be accrued for this study.
DISEASE CHARACTERISTICS:

 -  Histologically confirmed intracranial malignant glioma

 -  Original low-grade glioma histology allowed provided there is subsequent
 histologic confirmation of malignant glioma

 -  Any of the following diagnoses:

 -  Glioblastoma multiforme

 -  Gliosarcoma

 -  Anaplastic astrocytoma

 -  Anaplastic oligodendroglioma

 -  Anaplastic mixed oligoastrocytoma

 -  Malignant astrocytoma not otherwise specified

 -  Recurrent disease

 -  Must have failed prior radiotherapy

 -  Must have confirmation of true progressive disease (rather than radiation
 necrosis) based upon either positron emission tomography or thallium
 scanning, MR spectroscopy, or surgical documentation of disease if
 radiographic recurrence is within the high-dose radiation field (for
 patients who underwent prior interstitial brachytherapy or stereotactic
 radiosurgery)

 -  Prior recent resection of recurrent or progressive tumors allowed if all of the
 following criteria are met:

 -  Recovered from prior surgery

 -  Evaluable disease after resection

 -  Unequivocal evidence of tumor progression by MRI

 -  Steroid dose must be stable for ≥ 5 days prior to MRI

 PATIENT CHARACTERISTICS:

 -  Karnofsky performance status 60-100%

 -  Life expectancy > 8 weeks

 -  WBC ≥ 3,000/mm³

 -  Absolute neutrophil count ≥ 1,500/mm³

 -  Platelet count ≥ 100,000/mm³

 -  Hemoglobin ≥ 10 g/dL (transfusion allowed)

 -  AST < 2.5 times upper limit of normal (ULN)

 -  Bilirubin < 2.5 times ULN

 -  Creatinine < 1.5 mg/dL OR creatinine clearance ≥ 60 mL/min

 -  Not pregnant or nursing

 -  Negative pregnancy test

 -  Fertile patients must use effective contraception during and for 1 month after
 completion of study treatment

 -  No significant medical illness that would preclude study treatment

 -  No history of other cancer (except nonmelanoma skin cancer or carcinoma in situ of the
 cervix) unless disease is in complete remission and off all therapy for ≥ 1 year

 -  No active infection or serious intercurrent medical illness

 -  No disease that will obscure toxicity or dangerously alter drug metabolism

 -  Able to undergo MRI scan and receive contrast agents for perfusion scanning

 PRIOR CONCURRENT THERAPY:

 -  See Disease Characteristics

 -  Recovered from prior therapy

 -  At least 28 days since prior cytotoxic therapy

 -  At least 14 days since prior vincristine

 -  At least 42 days since prior nitrosoureas

 -  At least 21 days since prior procarbazine

 -  At least 7 days since prior interferon, tamoxifen, thalidomide, isotretinoin, or other
 noncytotoxic agents (radiosensitizer does not count)

 -  At least 14 days since prior noncytotoxic investigational agents

 -  At least 42 days since prior radiotherapy

 -  No prior cisplatin, carboplatin, oxaliplatin, or platinum-containing analogue

 -  No concurrent prophylactic filgrastim (G-CSF) or sargramostim (GM-CSF)

 -  No other concurrent anticancer therapy (including chemotherapy, radiotherapy, hormonal
 therapy, or immunotherapy)

 -  No other concurrent investigational drugs