Summary

Brief Summary:

The study is a prospective, randomized controlled phase III trial aimed to test the efficacy
and safety of Tumor Treating Fields (TTFields) in combination with gemcitabine and
nab-paclitaxel, for front line treatment of locally-advanced pancreatic adenocarcinoma.The
device is an experimental, portable, battery operated device for chronic administration of
alternating electric fields (termed TTFields or TTF) to the region of the malignant tumor, by
means of surface, insulated electrode arrays.

Objectives

PAST PRE-CLINICAL AND CLINICAL EXPERIENCE:

The effect of the electric fields (TTFields, TTF) has demonstrated significant activity in in
vitro and in vivo pancreatic adenocarcinoma pre-clinical models both as a single modality
treatment and in combination with chemotherapies. TTFields have been demonstrated to act
synergistically with taxanes and have been shown to be additive when combined with other
chemotherapies including gemcitabine. In addition, TTFields have shown to inhibit metastatic
spread of malignant melanoma in in vivo experiment.

In a pilot study, 40 patients with locally advanced or metastatic pancreatic adenocarcinoma
received gemcitabine together with TTFields (150 kHz) or gemcitabine and nab-paclitaxel
together with TTFields (150 kHz) applied to the abdomen until disease progression. The
combination was well tolerated and the only device-related adverse event was contact
dermatitis.

In addition, a phase III trial of Optune® (200 kHz) as monotherapy compared to active
chemotherapy in recurrent glioblastoma patients showed TTFields to be equivalent to active
chemotherapy in extending survival, associated with minimal toxicity, good quality of life,
and activity within the brain (14% response rate) (Stupp R., et al., EJC 2012). Finally, a
phase III trial of Optune® combined with maintenance temozolomide compared to maintenance
temozolomide alone has shown that combined therapy led to a significant improvement in both
progression free survival and overall survival in patients with newly diagnosed glioblastoma
without the addition of high grade toxicity and without decline in quality of life (Stupp R.,
et al., JAMA 2017).

DESCRIPTION OF THE TRIAL:

All patients included in this trial are patients with locally advanced pancreatic
adenocarcinoma. In addition, all patients must meet all eligibility criteria.

Eligible patients will be randomly assigned to one of two groups:

1. Patients receive gemcitabine and nab-paclitaxel in combination with TTFields using the
NovoTTF-200T System.

2. Patients receive gemcitabine and nab-paclitaxel without TTFields.

Patients will be randomized at a 1:1 ratio. Baseline tests will be performed in patients
enrolled in both arms. If assigned to the NovoTTF-200T group, the patients will be treated
continuously with the device until progression in the abdomen. On both arms, patients who
have progression outside the abdomen will switch to a second line treatment according to
local practice.

SCIENTIFIC BACKGROUND:

Electric fields exert forces on electric charges similar to the way a magnet exerts forces on
metallic particles within a magnetic field. These forces cause movement and rotation of
electrically charged biological building blocks, much like the alignment of metallic
particles seen along the lines of force radiating outwards from a magnet.

Electric fields can also cause muscles to twitch and if strong enough may heat tissues.
TTFields are alternating electric fields of low intensity. This means that they change their
direction repetitively many times a second. Since they change direction very rapidly (150
thousand times a second), they do not cause muscles to twitch, nor do they have any effects
on other electrically activated tissues in the body (brain, nerves and heart). Since the
intensities of TTFields in the body are very low, they do not cause heating.

The breakthrough finding made by Novocure was that finely tuned alternating fields of very
low intensity, now termed TTFields (Tumor Treating Fields), cause a significant slowing in
the growth of cancer cells. Due to the unique geometric shape of cancer cells when they are
multiplying, TTFields cause electrically-charged cellular components of these cells to change
their location within the dividing cell, disrupting their normal function and ultimately
leading to cell death. In addition, cancer cells also contain miniature building blocks which
act as tiny motors in moving essential parts of the cells from place to place. TTFields
interfere with the normal orientation of these tiny motors related to other cellular
components since they are electrically-charged as well. As a result of these two effects,
tumor cell division is slowed, results in cellular death or reverses after continuous
exposure to TTFields.

Other cells in the body (normal healthy tissues) are affected much less than cancer cells
since they multiply at a much slower rate if at all. In addition TTFields can be directed to
a certain part of the body, leaving sensitive areas out of their reach. Finally, the
frequency of TTFields applied to each type of cancer is specific and may not damage normally
dividing cells in healthy tissues.

In conclusion, TTFields hold the promise of serving as a brand new treatment for pancreatic
adenocarcinoma with very few side effects.

Eligibility

1. 18 years of age and older
2. Life expectancy of = 3 months
3. Histological/cytological diagnosis of de novo adenocarcinoma of the pancreas
4. Unresectable, locally advanced stage disease according to the following criteria:
5. Head/uncinate process:
6. Solid tumor contact with SMA>180°
7. Solid tumor contact with the CA>180°
8. Solid tumor contact with the first jejunal SMA branch
9. Unreconstructible SMV/PV due to tumor involvement or occlusion (can be d/t tumor or bland thrombus)
10. Contact with most proximal draining jejunal branch into SMV
11. Body and tail
12. Solid tumor contact of >180° with the SMA or CA
13. Solid tumor contact with the CA and aortic involvement
14. Unreconstructible SMV/PV due to tumor involvement or occlusion (can be d/t tumor or bland thrombus)
15. No distant metastasis, including non-regional lymph node metastasis
16. No borderline resectable (per Al-Hawary MM, et al., Radiology 201414)
17. ECOG score 0-2
18. Amenable and assigned by the investigator to receive therapy with gemcitabine and nab-paclitaxel
19. Able to operate the NovoTTF-200T System independently or with the help of a caregiver
20. Signed informed consent form for the study protocol

Treatment Sites in Georgia