Current Ther Neuro Klesse

7/31/2019 Current Ther Neuro Klesse

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Current Therapies for

, Assistant Professor of PediatricsUT Southwestern Medical Center

ren s e ca enter o a as


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What is a Clinical Trial? Test of a new treatment in humans.

Test the effectiveness of a therapy in treating thedisease process.

es ng e sa e y o e erapy. Comes out of both clinical observations and

research in the laborator . Approved by local or national Institutional

Review Boards (IRB) for safety, potentialene s.


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Phases of Clinical Trials Early St ages

Preclinical Trials: work done in the laboratory .

Often critical in identifying promising agents.

Phase 0 : Exploratory, first in human trials. Designed to speed development of promising drugs. Smaller doses, usually small numbers of subjects. No real safet or efficac information.

Phase I: First stage of testing in humans goal isto test safety and tolerability.

ma num ers, usua y 20- 0 pa en s.


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Phases of Clinical Trials Later Phases

Phase II: First real test of the drugs efficacy in.

Larger numbers of patients 100-300.

Phase III: Large group, randomized andcontrolled to fully assess efficacy.

Often multi-center.

- . Phase IV: Continued safety monitoring. Drug is now marketed for the disease.


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Clinical Trials Development Based on preclinical testing biology.

. Based on clinical observations.

.


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NF1 a classic tumor

suppressor. Found on Chromosome

. Very mutable. Mutation does not predict

outcome. Negatively regulates Ras

signaling. Tumor formation

requires a second hit.


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Clinical Trials in Neurofibromatosis Often done at local institutions. en w m e num ers o pa en s. More patients is always better!!

. CTF clinical consortium

De artment of Defense Phase II 9 centers. Started in 2007.


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25% of patients with NF-1.

Masses of Schwann cells, fibroblasts, mast cells andendothelial cells around nerves. Potentially life threatening

No known effective medical therapy!! urg ca resect on cont nues to e t e stan artreatment.

Com lete resection is often difficult. 44% grow back if subtotally resected.Often have major sequelae.

.

Radiation therapy not effective.


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developed as anantifungal agent.

Inhibits mTOR

signaling. Promising in

preclinical work.


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Sirolimus (Rapamycin)

Clinical Consortium Centers. Enrolling patients older than 3 years of age. ra um 1: nopera e, progress ng Stratum 2: High risk

Preliminary evidence: Time to progression around 10 months.

Stratum 1: 36 of 46 enrolled.Stratum 2: 1 enrolled all removed after 6 c cles.

11 without response, 1 with progression. Toxicity noted.

Decreases in doses removed for toxicit .


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- n er eron Inhibits growth.

In ts oo vesse s. Immune modulation. Not specific.

- 5/27 patients reported clinical improvement.

26/27 had stable plexiforms on MRI scan. . Get rebound growth after stopping.

Administered under the skin once per week. .

Plexiforms increasing in size or in dangerouslocations.

Currentl o en in Pittsbur NCI Chica o andSeatt e.


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eevac

Inhibits cell surface receptors which are involvedin the develo ment of lexiform neurofibromas.

Work done in Luis Paradas lab at UT Southwestern

the basis for this trial. n s , c- an c-a . 1 patient had >50% reduction in tumor size.

Robertson at Indiana University.

Recentl closed, awaitin results.


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Phase I stud .

Given by mouth twiceper day for 28 days

Inoperable, growing

or in dangerous area. . Ages 3-18. Has toxicity

s gn cant ncrease npain, hand/footsyndrome.


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Studies which demonstrated no effect

Pifenidone .

Tested as a Phase II.

Time to progression was 13.2 mths versus 10.6 forplacebo.

Tipfarnib Inhibited the activation of ras.

o mprovemen over con ro s.


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Difficult ies of Plexiform Trials Erratic growth:

. Likely have growth throughout lifetime.

Difficulty with accurate measurements.

Difficult measurin rowth: Improved with 3D measurements


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Pilocyt ic Ast rocytomas Low grade, benign tumors of the central nervous

. Derived from glia, the support cells of CNS.

- . Overall survival very good - >90% at 5 years. Neurofibromatosis type 1 patients at increased

risk.


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Low-Grade Gliomas: Influence of-


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Treatment for low grade gliomas If treatment is required discussion is often

. Based on the ability to resect without significant

conse uences. Radiation is avoided.


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Optic Gliomas Affects 15- 25 % of patients with NF-1.

than 10 years of age.

Can cause significant morbidity. Proptosis, vision loss, endocrine abnormalities.

Are low grade tumors .

Often have limited growth. Only 25% require treatment.


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Optic Gliomas Screening:

Yearly ophthalmology exam na on un age ,then every 2 years.

Limited evidence inchildren less than 1 earof age.

Changes in visual acuity or visual fields need

. Role of MRI?

Screening MRIs notrecommended.


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Current Therapy for OPG When to treat:

. Loss of vision.

patient age. Often watchful waiting. First line treatment: Chemotherapy.

Carboplatin and vincristine. Second line vinblastine, avastin/irinotecan.


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OPG t reatment Surgery:

Biopsy not necessary for diagnosis. Often used for atients with si nificant ro tosis when

vision is lost. Chiasmal tumors may require surgical debulking .

Felt to have unacceptable sequelae. 9 of 18 NF pts with progressive OG treated with

radiotherapy had 12 secondary malignancies. (Sharif et al.,JCO 2006).

Also at risk for si nificant cerebral occlusive vasculo ath(Grill et al., Ann Neurol 1999).


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New Therapies: Tarceva and Rapamycin

Blocks mTOR signaling and EGFR signaling.

8 of low rade liomas have increased ex ressionof EGFR.77% of LGGs have increased mTOR.

ynergy note n an ma mo e s.


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New Therapies 7 patients with NF treated.

. Eight patients in remission from 1 to 18 months.

6 patients off therapy secondary to progression. All patients with NF1 had stable disease or

response.

one year.

Pac er, RJ.


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Malignant Peripheral Nerve Sheath

Account for 10% of soft tissue sarcomas. Rare in pediatrics:

n y 20 o s are agnose n e rs 2 eca es o e. Strong association with NF1 50% are in patients with

NF1. , -neurofibromas.

Both have loss of NF1, but MPNST associated with loss of secondtumor suppressors including p53, p16.

Present with persistent pain, rapid growth, change in consistency or new neurologic finding. Patients with NF1 have a 10% risk of developing MPNST

.


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MPNSTs and NF1

Patients with NF1 present with MPNSTs at a youngerage.- .

Patients with NF1 and MPNSTS have less response to

chemotherapy. 126 patients over 25 yearsResponse to chemotherapy was 55% without NF1; 18% in patients with NF1

Overall survival at 5 years was 55% vs 32%. Patients with NF1 are more likely to present with large,

unresectable tumors or distant metastates.


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MPNSTs therapy

Surgery is the corner stone of therapy. For high grade lesions, even with surgery have ahigh local recurrence rate (32-65%).

Radiotherapy after surgery improves controlrates an s recommen e or g gra e es onsand intermediate lesions >5 cm.

control rates of 30-40% reported. Gupta et al., 2008


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Fut ure Direct ions for MPNST. ear y nee e er erap es. New chemotherapy approaches:

Currentl NCI o en Phase II for chemotheranave, unresectable MPNSTs using doxorubicin,ifosfamide and etoposide.

Epidermal Growth Factor?

EGFR is expressed on a substantial percentage of human

s an ts express on s assoc ate w t a worseprognosis. Keizman, et al, 2009Preclinical studies demonstrate a potential role.

ng et a ., 2005.


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Role of PET scans Significant difficulty in distinguishing

MPNSTs.

error. Earl detection ma benefit NF atients. PET has 95% sensitivity and 87% specificity in

detecting MPNSTs.


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PET scans and NF1

Tucker et al., 2009


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Learning Disabilities euro- eve opmen a pro ems oun n over

50% of NF patients. Only a very small proportion have severe mental

re ar a on Learning Disabilities overall 5 times more

common in NF patients than the generalpopu at on. Speech abnormalities (esp. articulation issues). ttention deficient disorders.

Impaired performance in at least 1 area of academicachievement. Visual-spatial-perceptual problems. Motor disorders.


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Commonly utilized forcholesterol control.

Well tolerated. Inhibits ras activation. Currently in phase II study for

patients 10-16 years of age,open at CTF organizations.

In initial study in Netherlands: measure.

Larger US study is plannedto o en.

In animal models,demonstrated improvementsin spatial learning andmemory.


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Further information

Childrens Tumor Foundation website. . . Also listings for tissue donation, etc.

Institute.

www.clinicaltrials.gov


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Quest ions?

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Current Ther Neuro Klesse