Primary objective:- To determine if TTFields at 200 kHz to the abdomen and pelvis with weekly paclitaxel in the treatment of recurrent ovarian cancer patients prolongs the overall survival of patients, compared to weekly paclitaxel treatment alone.…
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Source
Brief title
Condition
- Reproductive neoplasms female malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoint:
- Overall survival (OS) of patients treated with TTFields at 200 kHz to the
abdomen and pelvis with weekly paclitaxel for recurrent ovarian cancer,
compared to overall survival of patients treated with weekly paclitaxel alone,
measured from randomization.
Secondary outcome
Secondary endpoint:
- Progression-free survival (PFS) of patients treated with TTFields at 200 kHz
to the abdomen and pelvis with weekly paclitaxel for recurrent ovarian cancer,
compared to progression-free survival of patients treated with weekly
paclitaxel alone, measured as the time interval between randomization and the
date of disease progression (based on CT or MRI scans collected during the
study, using the RECIST V1.1 Criteria1 and the GCIG guidelines2).
- Objective response rate (ORR) of patients treated with TTFields at 200 kHz to
the abdomen and pelvis with weekly paclitaxel for recurrent ovarian cancer,
compared to the objective response rate of patients treated with weekly
paclitaxel alone, based on CT or MRI scans collected during the study, using
the RECIST V1.1 Criteria, and the GCIG guidelines2.
- Next progression-free survival (PFS2) of patients treated with TTFields at
200 kHz to the abdomen and pelvis with weekly paclitaxel for recurrent ovarian
cancer, compared to the next progression-free survival of patients treated with
weekly paclitaxel alone, measured from the time of randomization to tumor
progression based on investigator*s assessment, and preferrably based on RECIST
V1.1 Criteria1 (as long as radiological data are available at this stage of the
study follow up), on next-line treatment46.
- Toxicity profile in patients treated with TTFields at 200 kHz to the abdomen
and pelvis with weekly
paclitaxel for recurrent ovarian cancer, compared to the toxicity profile of
patients treated with weekly paclitaxel alone, measured by the rate of patients
with treatment-emergent toxicities in both arms based on the Common Terminology
Criteria for Adverse Events (CTCAE) V5.0
(https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_
v5_Quick_Reference_5x7.pdf).
- Time until definitive deterioration in HRQoL (TUDD) or death of patients
treated with TTFields at 200 kHz to the abdomen and pelvis with weekly
paclitaxel for recurrent ovarian cancer, compared to the TUDD of patients
treated with weekly paclitaxel alone, measured as the time interval between
randomization and the first decrease in HRQoL score >= 10-point with no further
improvement in HRQoL score >= 10 points or any further HRQoL data, based on the
EORTC QLQ-C30 questionnaire47,48.
- Time to first and second subsequent therapy or death (TFST & TSST) of
patients treated with TTFields at 200 kHz to the abdomen and pelvis with weekly
paclitaxel for recurrent ovarian cancer, compared to the TFST & TSST of
patients treated with weekly paclitaxel alone, measured as the time from the
date of randomization to the clinical decision made by the investigator to
initiate a first and second subsequent lines of treatment, respectively, or
death date49.
- Quality of life of patients treated with TTFields at 200 kHz to the abdomen
and pelvis with weekly
paclitaxel for recurrent ovarian cancer, compared to the quality of life of
patients treated with weekly paclitaxel alone, assessed using the EORTC QLQ C30
quality of life questionnaire with the ovarian cancer symptom OV28 module.
Background summary
Novocure, sponsor of this clinical study, has previously developed the
experimental device NovoTTF-100A for use in treating glioblastoma multiform, a
type of brain cancer. A randomized study that included 695 patients with
glioblastoma which has been recently diagnosed has been conducted to evaluate
TTFields in this disease. It was shown that adding TTFields at a specific
frequency to the standard chemotherapy used to treat patients after their
initial therapy led to a longer survival time in these patients.
The effect of TTFields on ovarian cancer has been tested in the laboratory in
cell cultures and animal studies. In these studies, TTFields treatment resulted
in decreased ovarian cancer cell growth. When combined with chemotherapy there
was an even greater decrease in ovarian cancer cell growth.
TTFields have also been evaluated in a clinical study in ovarian cancer
patients. In this pilot study, 31 patients suffering from recurrent
platinum-resistant ovarian cancer applied the NovoTTF-100L(O) System to the
abdomen and pelvis. At the same time, subjects received weekly drug called
paclitaxel. Paclitaxel is a chemotherapy used in subjects with platinum
resistant ovarian cancer. This NovoTTF-100L(O) system, used also in the current
trial, delivers TTFields at a specific frequency. This frequency was
demonstrated to kill ovarian cancer cells in the lab more effectively.
Patients treated with TTFields using the NovoTTF-100L(O) combined with weekly
paclitaxel as part of this trial tolerated the treatment well. Mild to moderate
skin irritation was the most common adverse event related to the device. In
most cases, creams or ointments applied to the skin improved the skin
irritation. If case skin irritation occurs, study doctor will provide you with
appropriate treatment.
Ovarian cancer is the second most common gynecologic malignancy and the most
common cause of gynecologic cancer death in the United States. Most patients
are diagnosed at an advanced, unresectable stage and receive palliative
therapy. PROC, developed ultimately in almost all patients, remains a condition
with poor prognosis and little advancement in prolonging survival over the last
decade.
TTFields have been demonstrated to reduce the proliferative capacity of
multiple cancers in preclinical models, predominantly by inhibiting the normal
polymerization process of the mitotic spindle at metaphase. TTFields increased
survival when added to temozolomide in a phase 3 in newly diagnosed
glioblastoma. It also showed to have a mild safety profile with preliminary
promising efficacy in pilot studies in NSCLC, mesothelioma and pancreatic
cancer. TTFields is a loco-regional anti-mitotic therapy, which can be applied
to the abdominal and pelvic regions. Simulations have demonstrated that
therapeutic level TTFields could be delivered to common sites of disease in
ovarian cancer, including malignant ascites.
The efficacy of TTFields in ovarian cancer has been shown using in vitro and in
vivo models. The addition of taxanes to TTFields was synergistic in preclinical
ovarian models, potentially resulting from the mitotic spindle being a common
target for both treatments. In the INNOVATE pilot clinical study, TTFields at
200 kHz to the abdomen and pelvis were used in combination of weekly paclitaxel
for the treatment of 31 PROC patients, who had good compliance on TTFields and
promising PFS outcomes. The only TTFields-related adverse event was dermatitis
underneath the transducer arrays in most patients, which was CTCAE grade 1-2 in
the vast majority of cases.
Taken together, there is a strong rationale for testing TTFields at 200 kHz to
the abdomen and pelvis in combination with weekly paclitaxel as a potentially
safe and effective treatment in PROC.
The hypothesis of this study is that the use of TTFields concommitant to weekly
paclitaxel in subjects with recurrent ovarian cancer will increase overall
survival compared to subjects treated with weekly paclitaxel alone.
Study objective
Primary objective:
- To determine if TTFields at 200 kHz to the abdomen and pelvis with weekly
paclitaxel in the treatment of recurrent ovarian cancer patients prolongs the
overall survival of patients, compared to weekly paclitaxel treatment alone.
Secondary objectives:
- To determine if TTFields at 200 kHz to the abdomen and pelvis with weekly
paclitaxel in the treatment of recurrent ovarian cancer patients prolongs the
progression-free survival (PFS) of patients, compared to weekly paclitaxel
treatment alone.
- To determine if TTFields at 200 kHz to the abdomen and pelvis with weekly
paclitaxel in the treatment of recurrent ovarian cancer patients increases the
rate of objective response rate (ORR) of patients, compared to weekly
paclitaxel treatment alone.
- To determine if TTFields at 200 kHz to the abdomen and pelvis with weekly
paclitaxel in the treatment of recurrent ovarian cancer patients prolongs the
next progression-free survival (PFS2) of patients, compared to weekly
paclitaxel treatment alone.
- To determine if TTFields at 200 kHz to the abdomen and pelvis with weekly
paclitaxel in the treatment of recurrent ovarian cancer patients is a safe
treatment compared to weekly paclitaxel treatment alone.
- To determine if TTFields at 200 kHz to the abdomen and pelvis with weekly
paclitaxel in the treatment of recurrent ovarian cancer patients prolongs the
time until definitive deterioration in HRQoL (TUDD) or death of patients,
compared to weekly paclitaxel treatment alone.
Study design
Pivotal, randomized (1:1), open-label, two-arm, multi-center study of the
NovoTTF-100L(O) system.
Stratification factors:
1. Prior Therapy - 1) No prior systemic therapy following platinum resistance
2) One prior line of systemic therapy following platinum resistance 3) Two
prior lines of systemic therapies following platinum resistance
2. Prior bevacizumab use - 1) bevacizumab was used prior to enrollment in the
study 2) bevacizumab was not used prior to enrollment in the study
3. BRCA Status - 1) mutated BRCA 2) wild type BRCA / unknown
Intervention
Patients will be centrally randomized using an IxRS system at a 1:1 ratio to 2
treatment arms within 28 days of signing the ICF, using variable blocked
randomization:
1. Treatment arm I: Patients receive TTFields at 200 kHz to the abdomen and
pelvis using the
NovoTTF-100L(O) System together with weekly paclitaxel.
2. Treatment arm II: Patients receive weekly paclitaxel alone.
The NovoTTF-100L(O) System is an investigational medical device delivering 200
kHz TTFields to the abdomen and pelvis for the treatment of patients at the age
of 18 years or older with platinum-resistant ovarian, primary peritoneal or
fallopian tube carcinomas, in combination with weekly paclitaxel. It is
intended to be used for at least 18 hours per day on a monthly average and
exclusively by patients in a clinical trial.
The device is a portable, battery operated system which delivers TTFields at
200 kHz to the abdomen and pelvis by means of insulated Transducer Arrays. The
NovoTTF-100L(O) produces electric forces intended to disrupt cancer cell
division.
Paclitaxel will be administered per institutional practice with appropriate
pre-medications and will be supplied from commercial sources as concentrate for
reconstitution and administered weekly intravenously over 1 hour. The starting
dose for all patients will be 80 mg/m2. Paclitaxel will be administered via
intravenous infusion weekly for 8 weeks and then for all subsequent cycles on
days 1, 8 and 15 of each subsequent 28 day cycle. Paclitaxel will be
administered until radiological progression per RECIST V1.1 and the GCIG
guidelines2, clear clinical disease progression per study investigator or
unacceptable toxicity based on investigator assessment. Hematologic toxicities
will be assessed prior to each paclitaxel dose with a complete blood count
(CBC) including differential and platelet count.
Study burden and risks
Patients will come to the study site two times for baseline evaluation /
screening and then every 4 weeks for until disease progression. If the study
treatment is discontinued, another visit will be scheduled for approximately
one month after discontinuation. Following local disease progression, patients
will be followed monthly for survival by telephone call to the patient or
caregiver appointed in the informed consent process (unless a clinical visit is
performed). Information on survival status, treatment for ovarian cancer and
disease progression therapy will be collected.
Additionally, patients will receive weekly paclitaxel infusion as per
institutional practice.
A CT scan or MRI scan of chest, abdomen and pelvis is performed 28 days prior
to randomization. Additionally bone scan, another MRI or the CT scan of the
brain can be performed if clinically indicated. Within 14 days prior to
randomization following examinations will be performed: Medical history,
physical examinations, vital signs (blood pressure, heart rate, respiratory
rate, temperature, size and weight), concomitant medication recording,
performance status (ECOG Score), serum pregnancy test (if applicable), blood
draws (for complete blood count, serum chemistry panel including CA-125,
coagulation tests), EORT QLQ C30 questionnaire + OV28 module questionnaire.
All patients will come to the hospital every 4 weeks after randomization for
physical examination including vital signs assessment and performance status
determination, blood draws (serum chemistry, complete blood count, ).
Additionally every other visit, a CT Scan and/or MRI Scan is performed to
evaluate the tumour assessment (same modality through entire follow-up period).
CT/MRI of the brain and a bone scan can be performed if indicated. A
paper-based Quality of Life Questionnaire (total of 4 pages) is to be completed
by the patient every other visit (every 8 weeks).
Patients assigned to the treatment arm with TTFields together with weekly
paclitaxel will be trained on the use of the NovoTTF-100L(O) device and the
array placement onto the skin.
The NovoTTF-100L(O) System is comprised of two main components: The
NovoTTF-100L(O) device which generates TTFields and the transducer arrays -
sticky pads- which attach around the abdominal region and deliver TTFields to
the ovary/ovaries. The device can be used with minimal change to the daily
routine. The device is designed to allow normal social life with minimal
discomfort:
Patients are able to carry the portable, battery operated device in a dedicated
backpack. .For sleeping or times where the patient stays in the same place, the
device is plugged into a standard wall outlet.
Patients will replace the transducer arrays twice to three times per week with
the help of a caregiver. A device technician (Novocure Device Support
Specialist) is assisting the patient in the functionality of the device and
re-training of the transducer array placement.
Patients assigned to NovoTTF arm will have to use NovoTTF-100L(O) for at least
18 hours a day on average. Patients may take breaks for personal needs (e.g.
showering, array exchange) as long as the average treatment remains 18 hours
per day (monthly average). TTFields may be continued as long as there is no
progression in the abdominal or pelvic regions (*local disease progression*)
per RECIST V1.11 or any of the treatment discontinuation conditions.
Risks:
Paclitaxel:
The most common side effects are:
Low number of blood cells, including white (leucocytes) and red (erythrocytes)
blood cells and platelets, infections and fever; bleeding; hypersensitivity
reactions, including an itchy skin rash, swelling of the throat and tongue;
shortness of breath, swelling of the hands, face or feet; hives; slow
heartbeat; low blood pressure; injury to the peripheral nervous system (the
part of the nervous system outside the brain and spinal cord), leading to
weakness, numbness, pain and changes in the sensitivity of the hands and feet
(the hands and feet are less sensitive or completely insensitive to the effects
of stimulants such as temperature, touch, vibrations, pain, changes in
position, and pressure). This is frequently associated with the sensation of
tingling or a feeling of numbness); joint and muscle pain; nausea; vomiting;
diarrhea; intestinal inflammation; hair loss; reduced liver function; skin
reactions at the paclitaxel injection site, such as increased skin
pigmentation, redness, tenderness, swelling, heat or dryness of the skin; a
feeling of weakness or fatigue.
TTFields:
We do not expect treatment with the NovoTTF-100L(O) to cause any severe adverse
reactions. However, it is possible that treatment may cause localized skin
irritation, skin issues, or infection where the electrodes come into contact
with your skin, as well as pain. If these symptoms occur, however, they shall
be assessed and treated by the investigator, and should be completely healed as
soon treatment with the device ends. The device may also cause a local
sensation of heat and tingling, as well as falls and fatigue (tiredness and
exhaustion). The treatment may also have no effect on tumor progression or
regression.
Apart from the expected skin irritation, it has not been reported in animal
studies nor in the pilot study in ovarian cancer patients described above that
the use of TTFields was associated with damage to healthy tissues, which are
not related to the tumor. Nevertheless, since the NovoTTF-100L(O) intends to
interfere with the cell division process, there is a potential risk of such
damage to healthy tissues in the region of the tumor.
The other possible risks of any electrical device, including the
NovoTTF-100L(O), are the risk of a power cut or mechanical problems, an
electric shock and electromagnetic interference. However, the device
manufacturer has taken appropriate measures to minimize the probability of
these risks appearing.
Taking blood:
The risks associated with taking a blood sample include mild pain when the
needle is inserted into the arm, the formation of hematoma at the injection
site, a low risk of venous inflammation, nerve lesions (nerve injuries) and a
risk of fainting. There is also a risk of infection. Up to 10 ml of blood (2
teaspoons) may be taken for each scheduled laboratory test. Approximately 220
mL of blood (1 cup) will be drawn during the entire duration of the study. If
necessary, the investigator may test blood more frequently.
The blood samples will be examined at the hospital. Blood samples will not be
sent outside the hospital for examination.
Computed tomography (CT):
CT imaging is a painless procedure that is safe for most people. People with
fear of confined spaces may feel anxious during the procedure. Nausea,
headaches, hot flushes, palpitations and allergic reactions (anaphylactic shock
included) may happen as a reaction to the contrast agent. The increased dose of
radiation may lead to cancer and other diseases.
Magnetic Resonance Imaging (MRI):
Some people feel anxious or are fearful in small spaces (claustrophobia). The
MRI scanner makes loud knocking noises during measurements, which may be
uncomfortable.
Gadolinium-based contrast agents in patients with pre-existing, severe hepatic
dysfunction, or who have recently (within the last 4 weeks) had a kidney or
liver transplant, is associated with a rare occurrence of nephrogenic systemic
fibrosis (NSF), however kidney function will be checked for in medical history.
Intravenous infusion:
The risks associated with the intravenous cannulas are similar to those
associated with taking a blood sample (see above).
Park 6
Root D4 6039
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Park 6
Root D4 6039
CH
Listed location countries
Age
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
a. Platinum resistance is defined as tumor progression per RECIST V1.1 within 6
months of the last administration of a platinum agent
b. *Line of systemic therapy* includes the following:
(i) Any targeted therapy
(ii) Any change to a new family of systemic therapy following toxicity
(regardless of radiological status)
c. *Line of systemic therapy* does NOT include the following:
(i) Maintenance therapy (started prior to progressive disease per RECIST V1.1)
(ii) Therapy replaced with another agent of the same family (i.e. due to
toxicity)
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
V1.1
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:
a. Hematological, hepatic and renal dysfunction, defined as: Neutrophil count <
1.5 x 10^9/L and platelet count < 100 x 10^9/L; bilirubin > 1.5 x Upper Limit
of Normal (ULN); AST and/or ALT >
2.5 x ULN; and serum creatinine > 1.5 x ULN, as long as they are determined
clinically significant by the investigator.
b. History of significant cardiovascular disease unless the disease is well
controlled; significant cardiac disease includes second/third degree heart
block; significant ischemic heart disease; poorly controlled hypertension;
congestive heart failure of the New York Heart Association (NYHA) Class II or
worse (slight limitation of physical activity; comfortable at rest, but
ordinary activity results in fatigue, palpitation or dyspnea).
c. History of arrhythmia that is symptomatic or not adequately controlled.
Specifically, patients with atrial fibrillation or flutter controlled by
medication are not excluded from participation in the trial.
d. History of cerebrovascular accident (CVA) within 6 months prior to
randomization or that is not stable.
e. Active infection or serious underlying medical condition that would impair
the ability of the patient to receive protocol therapy.
f. Unable to follow the protocol for medical, psychological, familial,
geographic or other reasons, or comply with the requirements of the study or to
provide consent.
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.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| ClinicalTrials.gov | NCT03940196 |
| CCMO | NL74118.041.20 |