Phase II Trial of Chemotherapy in Sporadic and Neurofibromatosis Type 1 Associated High Grade

Malignant Peripheral Nerve Sheath Tumors

Brigitte Widemann, NCI, POB

SARC 006

SARC006 Study Objectives

Primary Objective Determine clinical response rate (WHO)

High grade, unresectable, or metastatic, potentially resectable sporadic and NFI associated MPNST for which neoadjuvant chemotherapy is determined to be the best treatment option by institutional PI

Secondary Objectives Imaging (PET/Volumetric MRI analysis) Pathology (Percent necrosis; tissue microarray) Biomarker Improve knowledge of NF1 epidemiology

*Eight chemotherapy courses total

MPNST

NF1

Sporadic

IE x2IA x2

IA x 2

Response Evaluation

Local Control Chemotherapy

IE x2

PET3D MRI

SurgeryXRTMRI

PET3D MRI

Trial Schema

Patient Eligibility

Sporadic or NF1 associated MPNST Unresectable; metastatic; potentially resectable but neoadjuvant

chemotherapy is determined to be in the best patient interest Not previously treated with chemotherapy; prior radiation permitted No upper or lower age limit ECOG 0-2 Normal organ function

Cardiac (MUGA or Echo) Renal, liver and bone marrow

Prior treatment with biologic agents or chemotherapy for other NF1 associated tumors permitted No prior ifosfamide, etoposide or doxorubicin

Trial Status

Patients enrolled: 12 NF1 associated MPNST 8 pts; sporadic MPNST 3 pts

Median age 29.5 years (range 21-67 years) Disease status:

Localized 7 pts; metastatic: 5 pts On study 7 pts, off study 5 pts SAEs (possibly, probably, or definitely related):

One pt: Ifosfamide related aphasia (gr. 4), somnolence (gr. 4) One pt: Anemia, dyspnea, and fatigue (gr. 3), orthostatic

hypotension (gr. 2) One pt: Urinary tract infection (gr. 3) One pt: Leukopenia (gr. 4) and fever (gr. 1)

Response Evaluation NF1 MPNST

PTLocalized / Metastatic

Post cycle 2 (SD, PD, PR)

% Change from

BaselinePost cycle 4 (SD, PD, PR)

% Change from

Baseline

1 Metastatic SD 0.4 SD 22.3

3 Metastatic SD 26 SD 31

4 Localized PD 26 PD 27from cy 2

5 Localized SD 5 SD 4

6 Localized SD 23 SD 5

8 Localized NE - NE -

9 Metastatic Too early - Too early -

10 Localized SD 10 SD 19

12 Localized Too early - Too early -

Nine patients enrolled

Response Evaluation Sporadic MPNST

PTLocalized / Metastatic

Post cycle 2 (SD, PD, PR)

% Change from

BaselinePost cycle 4 (SD, PD, PR)

% Change from

Baseline

2 Metastatic NE - NE -

7 Localized PD 40 SD 22

11 Metastatic SD 18.4 Too Early -

Three patients enrolled

SARC 006 Protocol Status

SARC Sites: Open for Enrollment 9 Sites

Huntsman Cancer Institute Texas Children’s Hospital

Indiana University University of Iowa

MD Anderson Cancer Center University of Michigan

National Cancer Institute University of Minnesota

Pennsylvania Oncology

Close to Approval

Carolinas Johns Hopkins

University of Alabama

SARC 006 Protocol Status

SARC Sites:In Review/Consideration

Arkansas Children’s Hospital Mayo Clinic

Cedar Sinai Stanford Cancer Center

Cleveland Clinic Vanderbilt

Emory

Not participating: City of Hope, Dana-Farber, Fox Chase, Johns Hopkins, Moffitt, MSKCC, Oregon Health and Science University, Sarcoma Oncology Center, Stanford, Seattle Care Alliance, UCLA, University of Florida, Washington Cancer Institute

SARC 006 Protocol Status

NF1 Sites:Open for Enrollment 5 Sites

Children’s Hospital and Clinics of Minnesota

Children’s Memorial Hospital Chicago

Children’s Hospital of Philadelphia St. Louis Children’s Wash. Univ.

Cincinnati Children’s Hospital

Close to Approval

University of Alabama

In Review/Consideration

Children’s Hospital of Pittsburg Children’s National Medical Center

SARC 006 Approval Process Contract with SARC Institutional protocol review US Army IRB review:

Informed consent form, assent (ages 13-17 years) form, and information page (ages 7-12 years old), site specific protocol appendices

CV for all investigators Facility safety plan PI assurance plan GCP training for PI

US Army will perform pre-review of documents prior to local IRB submission

All communication with US Army IRB through SARC