A phase II trial of TTFields in addition to pemetrexed and cisplatin or carboplatin as first-line
treatment in malignant pleural mesothelioma

Most patients with malignant pleural mesothelioma are candidates for
chemotherapy during the course of the disease, and the combination of platinum
(cisplatin or carboplatin) with pemetrexed is currently considered the standard
first-line approach for patients with disease that is not amenable to surgical
intervention. Unfortunately, invariably all patients progress during or after
front-line chemotherapy and no standard second-line options are available, with
single-agent vinorelbine or gemcitabine considered as a reasonable options for
palliation (NCCN guidelines version 1.2015).

Malignant Pleural Mesothelioma (MPM) Treatment:
MPM is an aggressive but rare thoracic malignancy that occurs in approximately
3000 people in the United States annually [1]. Its incidence peaked in between
2005 and 2010 and declined thereafter [2]. This is mainly due to restrictions
in exposure to absestos, which has been strongly associated with the
development of mesothelioma and the disease*s latent nature [3].However, MPM
remains a serious problem with its incidence rising worldwide. The treatment of
MPM is very challenging with median survival (MS) of less than 20 months
reported in most series [1]. Local therapy is the primary treatment modality
because MPM is known to remain localized in the ipsilateral hemithorax early in
its clinical course. The initial approach is usually surgical resection, such
as pleurectomy and decortication (P/D), or extrapleural pneumonectomy (EPP). In
general,
surgery alone is associated with high local recurrence rates. Radiotherapy (RT)
alone is not the treatment of choice for this disease because of the inability
to deliver a therapeutic dose of radiation (approximately 60 Gy in 30
fractions) to the pleura without overdosing the ipsilateral lung parenchyma and
causing severe pulmonary toxicity [4]. Because of the high local recurrence
rate after surgery and the radiosensitivity of lung tissue, adjuvant RT has
been attempted after P/D or EPP. Without significant improvement in local
control after P/D, RT has been shown to decrease local recurrence after EPP
[5-8]. With the significantly improved response rate, progression-free
survival, and overall survival associated with the cisplatin/pemetrexed doublet
regimen in unresectable MPM over cisplatin alone, trimodality therapy
(neoadjuvant or adjuvant doublet
chemotherapy, EPP, and adjuvant RT) has emerged to become the most common
treatment approach for resectable MPM [710].
The trimodality therapy permitted to register an improved survival of more than
20 months [10-12]. To date, no drugs have been approved for second-line
treatment of mesothelioma, when the disease continues to progress after first
line chemotherapy [13-14]. Unfortunately, nearly all MPM patients progress
during or after first-line treatment. Second-line chemotherapy is being
increasingly used in clinical practice, because patients frequently still have
a good performance status at the time of disease progression [15]. In
pemetrexed-naïve patients, data from a large randomized trial versus best
supportive care and from the Expanded Access Programs support the use of single
agent pemetrexed as a standard second-line treatment [16-17]. In
pemetrexed-pretreated patients, there is no approved drug or drug combination
for second-line therapy, and this
remains an ideal field in which to test new agents. Vinorelbine or gemcitabine
are considered as a potential option for palliation. A number of phase II
trials have exploited different chemotherapeutic, such as topotecan and
docetaxel, and targeted agents, but results have been generally disappointing.

Tumor Treating Fields (TTFields) Overview:
Recently, low intensity, intermediate frequency (100-300 kHz) alternating
electric fields, also known as Tumor Treating Fields (TTFields) were found to
have a profound inhibitory effect on the growth rate of a variety of human
cancer cells. Preclinical studies on tumor cells lines have shown that TTFields
targets two stages of the cell cycle leading to apoptosis: metaphase and
microtubule spindle assembly and telophase/anaphase by causing intracellular
dielectrophoresis of macromolecules and organelles. Pre-clinical data
demonstrates disruption of the microtubules of the mitotic spindle and abnormal
microtubule formation and physical disruption of cell integrity at the cleavage
plane during telophase, both of which lead to apoptosis [18]. In vitro study
showed anti-tumor activity in respect of melanoma, glioblastoma (GBM), breast
carcinoma and non-small cell
lung cancer (NSCLC) cell lines [19]. At intensities of approximately 1 V/cm,
TTFields can be frequency-tuned to effectively inhibit different cancer cell
types (i.e., the smaller the cell, the higher the frequency needed), due to
disruption of microtubule polymerization and physical disruption of cell
integrity at the cleavage plane during telophase [18]. TTFields have been shown
in vivo to effectively inhibit cancer cell replication during mitosis without
any systemic side effects. Specifically, TTFields have been shown to inhibit
GBM cells in vitro and in vivo at a frequency of 200 kHz and an intensity of
0.7 V/cm. Based on realistic finite element mesh simulations and direct
measurements of TTFields intensity in experimental animals, and in the human
brain, Novocure has concluded that effective TTFields intensities can be
generated in the brains of large animals and humans
and the effect does not attenuate over distance. Extensive safety studies in
healthy animals (mice, rats and rabbits) have shown that TTFields are not
associated with significant systemic toxicities. Neither acute, nor chronic
systemic toxicities were seen when TTFields were applied to the torso or head,
at different frequencies (100-200 kHz), different intensities and for different
periods of time [19]. These finely tuned electric fields can be generated in
vivo by a novel device with a portable battery (NovoTTF-100A System and
NovoTTF-100L System; Novocure Ltd., Haifa, Israel) through insulated surface
transducer arrays. Moreover, due to their relatively high frequency range and
very low intensity, TTFields do not stimulate nerves and muscles, do not
generate meaningful temperature elevation or puncture the cell membrane (as the
strong electroporation
fields do) [20]. Thus, TTFields are not associated with significant toxicity in
contrast to most anti-cancer agents currently in use [21].

Primary Objective:
* To determine if TTFields in combination with pemetrexed/platinum improves
overall survival (OS) compared to historical control in patients with
unresectable mesothelioma.

Secondary Objectives:
* To evaluate the overall response rate of TTields in combination with
pemetrexed/platinum in patients with unresectable mesothelioma.
* To evaluate the progression free survival (PFS) of TTFields in combination
with pemetrexed/platinum in patients with unresectable mesothelioma.
* To evaluate the safety of TTFields in combination with pemetrexed/platinum in
patients with unresectable mesothelioma.

This is a prospective phase II, single arm, historical control study evaluating
pemetrexed and platinum (cisplatin or carboplatin) in combination with TTFields
in patients with untreated mesothelioma.

1) Patients will receive pemetrexed based doublet in combination with
TTFields. For the purpose of this study 3 weeks (21 days) will constitute one
treatment cycle.

Chemotherapy: Treating investigators may choose one of the following
regimens: pemetrexed/cisplatin, or pemetrexed/carboplatin.

Pemetrexed administered intravenously at a dose of 500 mg/m2 day 1 together
with cisplatin 75 mg/m2 day 1 or carboplatin AUC 5 day 1. Cycles will be
repeated every 21 days for up to 6 cycles in the absence of progression or
unacceptable toxicity .In the event of chemotherapy toxicities, dose
modifications may be employed and guidance for modifications will be outlined
in the protocol.

2) NovoTTF-100L-systeem: Continuous TTFields for at least 18 hours/day
applied to the thorax. This means that the device (3 kg) will be carried on
by the subject either in a backpack or in a trolley. TTFields will be
administered until radiological disease progression, or unacceptable
toxicity based on investigator assessment. There will be no dose modifications
for TTFields but treatment interruptions may occur if recommended by
investigator.

In the case of chemotherapy discontinuation due to toxicity, TTFields therapy
may continue.

During the patient first study visit he/she will be trained on how to operate
the device, replace batteries that have lost *charge*, recharge batteries and
connect the device to an external power supply (electrical plug) overnight. The
patient will also learn how to place the transducer arrays on their thorax.
After this first visit the patient will continue treatment at home where he/she
can maintain their regular daily routine. The patient will be required to use
the device for at least 18 hours per day in average. The transducer arrays will
need to be replaced 2 or 3 times a week. A family member/caregiver can be
trained to help the patient replace transducer arrays. For sleeping or when the
patient plans to stay in the same place for a while, he/she can plug the device
into a standard electrical wall outlet. He/She will be required to keep
treatment breaks to a minimum and interrupt it only for personal needs.

3) VAS questionnaire completion is requested at baseline and day 1 of each
treatment cycle

Risks and benefits of the investigational device and clinical investigation are
described in the document Risk Analysis for
Participation in the EF-23 clinical trial attached to the protocol (Appendix F)

Anticipated Benefits:
Chemotherapy treatment is the most common mesothelioma treatments which is used
to improve symptoms and prolong survival, athough there is no guarantee that
this treatment will work for the patient.
Because the NovoTTF-100L is an experimental device, its safety and
effectiveness have not yet been demonstrated fully. Therefore, there may be no
direct benefit to patients from participating in this study. Animal testing of
the device indicates that treatment with TTFields could disrupt cancer cell
division. However, there is no guarantee that NovoTTF-100L can relieve symptoms
of the patient or stop progression of their cancer, and their symptoms could
remain unchanged. There will be no other direct benefit to patients because of
their participation in the study above and beyond the potential benefit of the
NovoTTF-100L treatment and frequent visits to their physician.

Data collected in this study will help the medical and scientific field gain
knowledge as to whether TTFields improves the outcome for people with newly
diagnosed malignant pleural mesothelioma.

Anticipated Risks:
There are side effects associated with chemotherapy and TTFields, as mentioned
below. Your doctor will monitor you for side effects and may give you
medication to help make these side effects more tolerable or go away completely.
Common side effects are:

* Cisplatin:
kidney damage; decreased blood levels of magnesium, potassium, and calcium;
nausea; vomiting; low white blood cell count with increased risk of infection;
low platelet count with increased risk of bleeding; low red blood cell count
(anemia), which can make the patient tired, dizzy, or easily out of breath;
taste changes, including metallic taste of foods and rarely loss of taste;
sensation of pins and needles or numbness in hands and/or feet caused by
irritation of nerves, which usually goes away when treatment is stopped;
swelling in hands, feet or legs; fetal changes if pregnant during treatment.

* Carboplatin:
low white blood cell count with increased risk of infection; low platelet count
with increased risk of bleeding; low red blood cell count (anemia) which can
make the patient tired, dizzy, or easily out of breath; brittle hair; kidney
function can be altered at high doses; fetal abnormalities if patient get
pregnant while taking this drug.

* Pemetrexed:
low white blood cell count with increased risk of infection; low platelet count
with increased risk of bleeding; low red blood cell count (anemia) with
increased risk of fatigue and shortness of breath; nausea; vomiting;
constipation; sores in mouth or on the lips or in the esophagus (swallowing
tube)

* TTFields:
Treatment with the NovoTTF-100L is not expected to cause any serious side
effects. It is possible that treatment may cause local irritation, skin
breakdown, or infection at the sites of electrode contact to the patient skin;
however, these conditions, if they occur, will be evaluated and treated by the
physician and should heal completely after treatment is stopped. In addition
the patient may suffer headaches and fatigue. In addition, it is possible that
the treatment will not be effective in delaying tumor progression or causing
regression.
Other potential risks of any electrical device, including the NovoTTF-100L,
involve risk of electrical or mechanical failure, electrical shock, and
electromagnetic interference. However, the company has taken appropriate
actions to minimize the likelihood of these risks.

* Blood Draws
The risks associated with drawing blood include slight pain when the arm is
stuck with a needle, bruising at the spot where the arm is stuck, a slight
chance of inflammation of the vein and a risk of fainting. It is also possible
that the patient could get an infection. Up to 30 ml of blood (approximately 2
tablespoons) will be taken at each scheduled laboratory visit. If needed, the
study doctor may test the patient blood more frequently.

* Computerized Tomography (CT) Imaging
CT imaging is a painless procedure that is safe for most people. During the
imaging, the patient will lie flat with your body in a metal ring. Some people
who fear closed spaces may be frightened during the procedure. The patient will
be observed by the operator(s) at all times during the procedure and can be
assisted if necessary. If the patient request, he/she can be moved out of the
machine. A small proportion of people develop short-lived reactions during the
contrast medium administration, including nausea, headache, hot flashes, and
heart palpitations. These symptoms usually resolve on their own within minutes.
The patient will be closely monitored during the procedure and if any allergic
reaction develops, he/she will be treated immediately. CT scans do use low
levels of ionizing radiation, which has the potential to cause cancer and other
defects. However, the risk associated with any individual scan is small. The
most common type of contrast given into a vein contains iodine. If a person
with an iodine allergy is given this type of contrast, nausea, sneezing,
vomiting, itching, or hives may occur. Rarely, the contrast medium may cause a
life-threatening allergic response called anaphylaxis. If the patient have any
trouble breathing during the test, he/she should notify the scanner operator
immediately.

* PET, if performed (positron emission tomography scan)
A standard imaging procedure in which a small amount of radioactive material is
injected into a vein, and a scanner is used to make detailed, computerized
pictures of areas inside the body where the glucose is taken up. Because cancer
cells often take up more of the radioactive material than normal cells, the
pictures can be used to find cancer cells in the body.
While the scan does involve radioactive tracers, the exposure to harmful
radiation is minimal.
Combining CT and PET may provide a more complete picture of a tumor*s location
and growth or spread than either test alone. The combined procedure may improve
the ability to diagnose cancer, to determine how far a tumor has spread, to
plan treatment, and to monitor response to treatment.

* Bone Scan , if performed
This exam is performed to detect bone metastases. The patient will receive an
injection of a radioactive material with very low radioactivity. The
radioactive material does not cause any side effects and is attracted to
diseased bone cells throughout the body. A special camera takes the image and
shows the diseased bone.

* Intravenous Infusion
Risks associated with placement of the intravenous line are similar to those
associated with blood draw (see above).

* Pregnancy
Pregnant women cannot participate in the trial and will be withdrawn from the
study if they become pregnant because the risks to the unborn baby from the
device or chemotherapy are not known. Women at childbearing age must use
effective contraception in order to ensure that conception is avoided. If
relevant, the treating physician will be consulted about effective
contraceptives that should be used during the trial. It is also possible that
site effects, not yet observed, may occur.