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