The study is a prospective, randomized controlled phase III trial aimed to test the efficacy and safety of Tumor Treating Fields (TTFields) concomitant with weekly paclitaxel for the treatment of recurrent ovarian cancer . 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.

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.

Inclusion Criteria:

1. 18 years of age and older
2. Epithelial histology of ovarian/primary peritoneal or fallopian tube carcinoma at the time of diagnosis
3. Life expectancy of ≥ 12 weeks
4. Maximum two prior lines of systemic therapy following diagnosis of platinum-resistance
5. Maximum total of 5 prior lines of systemic therapy
6. Amenable to receive weekly paclitaxel and able to operate the NovoTTF-100L(O) System
7. ECOG 0-1
8. Evaluable (measurable or non-measurable) disease in the abdominal/pelvic region per RECIST V1.
9. Signed informed consent form for the study protocol

Exclusion Criteria:

1. Primary platinum-refractory disease (progression per RECIST V1.1 during or within 1 month after first line therapy), while secondary platinum-refractory disease is allowed
2. Prior disease progression on a weekly paclitaxel for recurrent disease
3. Brain metastasis or leptomeningeal spread of the tumor
4. Albumin level <25 gram/liter (subjects should not receive total parenteral nutrition or albumin within 2 weeks of the test)
5. CTCAE V5.0 Grade 3 or higher peripheral neuropathy
6. Implantable electrical medical devices
7. Known allergies to medical adhesives or hydrogel
8. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to paclitaxel or drugs similar or related to paclitaxel, except for cases that were able to undergo desensitization per investigator
9. Prior malignancies treated primarily or for recurrence within 2 years prior to inclusion in this study, except for completely resected non-melanomatous skin carcinoma, or successfully treated in situ carcinoma of the skin, breast or cervix of the uterus
10. Serious co-morbidities
11. Concurrent anti-tumor therapy beyond weekly paclitaxel, excluding hormonal therapy for breast cancer
12. Concurrent active treatment in another clinical trial. However prior participation in clinical trials is allowed as well as participation during survival follow-up
13. Pregnancy or breast-feeding (female patients with reproductive potential and their partners must accept to use effective contraception throughout the entire study period and for 3 months after the end of treatment). All patients who are capable of becoming pregnant must take a pregnancy test which is negative within 72 hours before beginning treatment. The definition of effective contraception is left up to the decision of the investigator
14. Admitted to an institution by administrative or court order