Effect of Tumor Treating Fields (TTFields, 200 kHz) Concomitant With Weekly Paclitaxel for the Treatment of Recurrent Ovarian Cancer (ENGOT-ov50 / GOG-3029 / INNOVATE-3)

PAST PRE-CLINICAL AND CLINICAL EXPERIENCE:

The effect of the electric fields (TTFields, TTF) has demonstrated significant activity

in in vitro and in vivo ovarian carcinoma 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. In addition, TTFields have shown to inhibit metastatic spread of

malignant melanoma in in vivo experiment.

In a pilot study, 31 patients with recurrent platinum-resistant ovarian carcinoma

received paclitaxel together with TTFields (200 kHz) applied to the abdomen/pelvis 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). 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.

DESCRIPTION OF THE TRIAL:

All patients included in this trial are patients with platinum-resistant ovarian

carcinoma. In addition, all patients must meet all eligibility criteria.

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

1. Patients receive TTFields at 200 kHz to the abdomen and pelvis using the

NovoTTF-100L(O) System together with weekly paclitaxel.

2. Patients receive weekly paclitaxel alone.

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-100L(O) group, the patients will be

treated continuously with the device until progression in the abdomen/pelvis. On both

arms, patients who have progression outside the abdomen/pelvis 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 (200 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 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 could potentially become treatment for ovarian cancer with very

few side effects.