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Central Lab ProcedureEF-14 Clinical Trial ● Novocure

A Prospective, Multi-center Trial of NovoTTF-100A Together With Temozolomide Compared to Temozolomide Alone in

Patients With Newly Diagnosed GBM

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Tumor Genetic Assessments – Rationale

What is the importance of genetic variations in cancer?

• Certain genetic traits can predict response to treatment, or prognosis:• Erlotinib (Tarceva) in EGFR overexpression (NSCLC patients)• Crizotinib in ALK-positive tumors (NSCLC patients)• Temozolomide in MGMT promoter methylated tumors (GBM patients)

• The effect of MGMT promoter status on the response of newly diagnosed GBM patients to temozolomide treatment is known

• TTFields therapy is an experimental treatment in GBM• It is unknown whether certain genetic traits may or may not affect

response to TTFields (alone or in combination with temozolomide)• There is a number of known, major genetic variations in GBM tumors

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Tumor Genetic Assessments – Rationale

How are genetic variations analyzed?

• a number of different methods and protocols have been used for MGMT analysis

• DNA-, RNA- and protein-level analysis is available• DNA-based methods for MGMT analysis seem more promising for

translation into the clinical setting• at present there is lack of data to base recommendations for a specific

method or protocol for MGMT testing on

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Tumor Genetic Assessments – Rationale

Why can’t we use site-based testing?

• There are a number of methods for MGMT promoter testing• Each method has different cutoff for determining “positive”/”negative”

when used by different laboratories• Many sites do not perform MGMT testing on a routine basis• We need to have a uniform test and standardized scale for results in order

to have a meaningful interpretation

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Tumor Genetic Assessments – Rationale

Why are we utilizing MDxHealth as our central lab for MGMT testing?

• MDxHealth validated a Real-Time Methylation-Specific PCR to Determine O6-Methylguanine-DNA Methyltransferase gene promoter methylation in gliomas

• The method was used in the validation of the effect MGMT promoter status has on response to temozolomide in GBM

• The method has been used on thousands of samples and in large clinical trials conducted by Merck Serono, Roche, and Merck/Schering-Plough

• The method is patented

Monika E. Hegi et al, MGMT Gene Silencing and Benefit from Temozolomide in Glioblastoma., N Engl J Med. 2005; 352:997-1003

Ilse Vlassenbroeck et al, Validation of Real-Time Methylation-Specific PCR to Determine O6-Methylguanine-DNA Methyltransferase Gene Promoter Methylation in Glioma. J Mol Diagn. 2008; 10(4): 332–337 Confidential1_29_13_Protv2.0

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Tumor Genetic Assessments – Rationale

Why is the test performed prospectively (prior to randomization)?

• MGMT promoter status affects patients’ response to an experimental treatment (temozolomide / temozolomide + TTF)

• We need to make sure there is no imbalance between the two arms of the study that will interfere with our ability to compare between the two experimental treatments

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Tumor Genetic Assessments – Analysis

How will genetic tests results be analyzed on the EF-14 trial?

A Cox proportional hazards model will be used to evaluate covariates. The effect of the following covariates will be compared and adjusted for between the treatment and control groups:

1. Age 2. Extent of surgery (biopsy, partial, or total resection) 3. MGMT methylation status (positive, negative, unknown) 4. Additional genetic markers: a. EGFR amplification, over expression or rearrangement b. Chromosomes 1p/19q deletion status c. IDH1 mutation

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Tumor Genetic Assessments (V2.0)

• MGMT• EGFR amplification, over expression or rearrangement• Chromosomes 1p/19q deletion status• IDH1 mutation

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Central lab contact information

All samples will be sent to the Central Laboratory at CHUV (Dr. Monika Hegi) Experimental and Translational Neuro-Oncology Lab of Brain Tumor Biology and Genetics Neurosurgery Department of Clinical Neurosciences rue du Bugnon 46 University Hospital (CHUV BH19-110) 1011 Lausanne Switzerland

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Central lab contact information

Pathology technical requirements:

• All patients enrolled in the study must have paraffin embedded brain tissue available for central pathology review.

• Biopsy-only patients will need to have an H&E-stained slide showing all criteria of glioblastoma as a minimal requirement, allowing confirmation of GBM diagnosis.

- All samples will be Formalin-Fixed Paraffin-Embedded (FFPE) tissue samples. - All samples should preferably be fixed in 10% v/v neutral buffered formalin. acidic

formalin, zinc or mercuric chloride should be avoided. - All samples should be fixed in formalin less than 18 hours, to avoid overfixation

yielding low quality DNA. - Samples will be shipped in the designated kit provided by Novocure and in ambient

temperature. - An accompanying H&E slide is encouraged for rapid diagnosis.

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Central lab contact information

Pathology technical requirements (sites that cannot ship tissue block only!):

• MGMT testing: Four slides of 5μm sections with a minimal area of 0.5cm^2 viable tumor tissue, *for smaller tumors the number of slides provided has to be increased accordingly.

• GBM diagnosis (H&E, IHCs): Six unstained slides. • IDH1-R132H and EGFR test (IHC): Two superfrost glass slides with

sufficient viable tumor tissue. • EGFR and co-deletion of 1p/19q test on TMA: when a paraffin block with

sufficient amount of tissue is available • EGFR and co-deletion of 1p/19q test (FISH): Three superfrost glass slides

of 5μm sections with sufficient viable tumor tissue. • Total number of slides: 15. Additional sections are required if the viable

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Offer the EF-14 Trial to any potential study patient

Sign patient on applicable ICF

Ship tissue block using kits supplied by CRO

Receive, identify, register and QC Tissue

Prepare slides for MGMT Analysis

Ship slides for MGMT testing

Test MGMT Promoter status

Send MGMT test results to site

Randomize patient 4-7 weeks after last dose of RT/TMZ using

MGMT test results

Analyze EGFR, IDH1, Chr. 1p/19q

Send test results to site

Ship remaining block back to site

Site

CHUV

MDxHealth

Initial GBM

Dx to 1

week before last

dose of RT/TMZ

Completed prior to

7 weeks out of RT/TM

Z

EF-14 Genetic Assessments Procedure

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Randomization on the EF-14 trial takes place between 4 to 7 weeks from last dose of the concomitant (temozolomide & radiotherapy) treatment. To allow randomization of the patient, please ship tumor block no later than 5

weeks prior to the planned time of randomization. The latest time for shipping tissue sample from the site is 1 week prior to the last

dose of the concomitant therapy. Please contact CRO / Novocure whenever you cannot comply with the central

lab timelines, in order to check the option of an exceptional expedited delivery of tumor sample to the central lab. This must be checked on a case-by-case basis. CRO and Novocure will make every effort to allow the inclusion of patients whose tissue samples are sent outside of the required time window.

Except for MGMT status, genetic test results will be sent to site when they are available and will not be used for stratification.

Remaining tissue will be sent to the site by the central lab 2 months after the completion of all genetic tests. Sites may request to receive the tissue earlier for any purpose.

Timelines for Sending tissue

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Each kit box contains the following items:Properly labeled box for shipping kit1 specimen transport bag Bubble wrapBlue content cardLocal pathology form and shipment alert form (see Appendix A)Packaging and shipping instructions4 slide mailers

Sites should have 2 kits at all timesWhen a site is in need of kits, please contact Seoul CRO contact person (see contact information in this manual)

Pathology shipment kit

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1. Assign a sequential 6 digit patient ID to every subject who signs consent. • Consists of 3-digit site ID (0XX) and 3-digit patient ID (001,

002, and so on). Example: 099-001, 099-002, 099-003 and so on.

2. Use this patient ID to send tissue samples to the central lab. The same patient ID should be used during randomization in EDC. • Example: Screened patient # 003 will have the patient ID #

099-003. Note 099-003 on the tissue samples sent to central lab. This patient might be the first patient to randomize in EDC. In the EDC use the same ID (099-003) to randomize the subject.

Patient ID Assignment

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Instructions for shipping EF-14 Genetic Testing Kits

• Kits will be delivered to sites with plastic shipping pouches containing a shipping label and 3 copies of customs documentation.

• Before shipping tissue samples, sites must print & sign all three copies of the customs documents as well as filling in the date of shipment

• Kits can be dropped of at a UPS drop box or at the UPS pickup location at the site. If neither of these are available UPS can be called to pick up the shipment.

• If there is need for an overnighted/urgent shipment sites should contact the local CRO to send a new, overnight, shipping label. This label will be sent via email to the site. New customs forms will also need to be printed to match the new tracking number. This also will be provided by CROs as they have the customs template.

• If labels are sent electronically please only print and use one copy of this label as each package needs a separate tracking number.

• Tracking on labels will expire in 120 days from creation. CROs will be marking kits with expiration dates according to this date. If a kit has past its expiration date please discard label and customs documents, inform your CRO of this issue and a new label and customs forms will be sent.

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Instructions for shipping EF-14 Genetic Testing Kits

If you already have a kit in your possession without attached shipping pouch:• PLEASE DISCARD THE SHIPPING LABEL THAT WAS ORGIONALLY SENT INSIDE THE KIT

(US sites only)• Print out the electronic label that was emailed to the study coordinator. Please

note that each label sent via email can only be used for one kit. Do not print out this label multiple times to ship multiple kits.

• Fill in the appropriate information on the customs template sent to the site by your CRO

• Site Address, shipper telephone number and email• Date• Tracking number from electronic label (all UPS tracking numbers start

with “1Z”• Print out three copies of the customs document and sign each copy• Place shipping label and the 3 copies of the customs forms in UPS shipping pouch

and adhere to the back of kit (this may wrap around the bottom of the kit it necessary). Be careful not to cover any labeling already on kit.

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EF-14 Local Pathology and Shipment Alert Form E-mail shipment notification to genetictesting@novocure.com.

EF-14: A Prospective, Multi-center Trial of NovoTTF-100A Together With Temozolomide Compared to Temozolomide Alone in Patients with Newly Diagnosed GBM

To be completed by the local pathologist or delegate

Institution name: ……………………………………………… PI Name: ...................................................... Name of local pathologist: ............................................................... Name of site contact: ……………………………………………… Contact Email: ……………………………………………… Tel:………………………………………………Fax: ………………………………………………

Patient ID (0XX-XXX): ………………………………………… (Use same ID for randomization) Patient Initials (where applicable): ……………………………………………… Patient birthdate (DD/MM/YYY): …………………………Date of surgery: ……………………………………… Date of (planned or actual) last dose of concomitant RT/Temodar _______________________ Diagnosis local pathologist: ………………………………………………………………….…… ………………………………………………………………………………………………………………………………………………………………………………………………………………………… Location:

Supratentorial Left Hemispheric Right Basal ganglia Ventricles

Tissue block needs to be returned to the site: Yes / No Name and signature of local pathologist/designee: _________________Date:____________ Courier TRACKING NUMBER: ___________________________________________________ Include the following with the shipment:

□ Tissue blocks or slides (only if block is not available)- please see the lab manual for details

□ Copy of the completed and signed “Local Pathology and Shipment Form” □ E-mail the completed “Local Pathology and Shipment Form” to

genetictesting@novocure.com. If unable to scan the form please fax to 212-767-7554 as soon as shipment is prepared so we can look out for the package.

□ Keep original Local Pathology and Shipment Form for your study files. Please send the shipment to Dr Monika Hegi, Lausanne, Switzerland using the shipping supplies and airway bills provided. Lab of Brain Tumor Biology and Genetics (Prof. Monika Hegi) Neurosurgery, University Hospital (CHUV BH19-110) Rue du Bugnon 46, Lausanne 1011, Switzerland, Phone: +41-21 314 25 81