clinical trials for meningiomas andrew norden, m.d

Clinical Trials for MeningiomasClinical Trials for Meningiomas

Andrew Norden, M.D.

Division of Cancer Neurology, Department of Neurology Brigham and Women’s Hospital

Center For Neuro-Oncology

Dana-Farber Cancer Institute

When to Consider Clinical Trials

• Surgery or radiation cannot be given safely• The tumor begins to grow after maximal

surgery and radiation• You and your treatment team think that

clinical trials may be appropriate

Cytotoxic Chemotherapy

• Adriamycin and dacarbazine

• Cyclophosphamide, adriamycin, and vincristine (CAV)

• Hydroxyurea• Ifosfamide• Interferon-alpha

• Irinotecan

• Temozolomide

Hormonal Therapy:Progesterone Receptor Blockers

• Phase III Trial - Grunberg et al (ASCO 2001):– Unresectable benign and

atypical meningiomas (193 patients)

– Randomized to RU-486 200 mg daily or placebo

– Well tolerated: common toxicities were fatigue, headache, and hot flashes

– No benefit from RU-486 Kubo et al. Jpn J Clin Oncol 2001;31:510-3

Hormonal Therapy:Somatostatin Analogs

Schulz et al. Clin Cancer Res 2000;6:1865-74.

Octreotide Scans

Depot Octreotide Acetate (Sandostatin LAR)

• Chamberlain et al (Neurology 2007) – 16 patients (8 benign, 3 atypical, 5 malignant)– Positive octreotide scans – Sandostatin LAR 20-40 mg IM monthly– Few side effects– After 3 months, 31% partial responses and 31% stable

tumors– 44% six-month progression-free survival

Pasireotide (SOM230)

• More potent than octreotide• Acts on a wider range of somatostatin

receptors (especially sst1, 3, 5)• Ongoing trial

Phase 2 SOM230 LAR Trial

• Dosing: 60 mg IM every 28 days• Eligibility criteria: recurrent or inoperable meningioma, KPS 601,

no limit to prior therapy• Very well tolerated • 6/40 patients enrolled• Sites: DF/HCC, Memorial Sloan-Kettering, Wake-Forest, Duke,

Northwestern, Univ. of Washington, Cedars-Sinai

1Requires occasional assistance, but cares for most personal needs

Targeted Molecular Therapies

Perry et al. J Neurooncol 2004;70:183-202

Molecular Targets

Drappatz J, Wen PY. Expert Rev Neurother 2006;6:1465-79.

TumorVEGF

Bevacizumab

VEGFR Inhibitors

Blood vesselendothelial cell

VEGFR

Angiogenesis

X

DRUG

Phosphorylated receptor

Examples• Sunitinib

• Sorafenib• Cediranib

Angiogenesis and Meningiomas

Peri-Tumoral Edema

Phase 2 Sunitinib Trial

• Dosing: 50 mg daily for 4 weeks, 2 weeks off

• Eligibility criteria: recurrent or inoperable meningioma, KPS 60, no limit to prior therapy

• Side effects: fatigue, rash, diarrhea

• Sites: DF/HCC, Memorial Sloan-Kettering, UVA

• Results in first 10 patients (Kaley et al., SNO 2008): 1 partial response, 8 stable tumors, 50% six-month progression-free survival rate

Dynamic Contrast-Enhanced MRI

Pre-treatmentPerfusion ratio = 7.4

Post-treatmentPerfusion ratio = 3.9

Summary and Conclusions

• Clinical trial options may be considered if surgery and radiation are unsafe or ineffective

• Promising approaches include:– Somatostatin analogs– Targeted molecular drugs in various combination– Anti-angiogenic agents

• Advances in meningioma biology will continue to drive progress in therapeutics