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)

Ovarian Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03940196
• Other study ID #: EF-28
• Status: Completed
• Phase: Phase 3
• Start date: March 22, 2019
• Est. completion date: May 18, 2023

Study information

• Verified date: March 2024
• Source: NovoCure Ltd.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 540
• Est. completion date: May 18, 2023
• Est. primary completion date: May 18, 2023
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Carcinoma, Ovarian Epithelial
• Ovarian Cancer
• Ovarian Neoplasms

Intervention

Device:
• NovoTTF-100L(O)
Patients receive continuous TTFields treatment using the NovoTTF-100L(O) device. TTFields treatment will consist of wearing four electrically insulated electrode arrays on the abdomen/pelvis. The treatment enables the patient to maintain regular daily routine.

Drug:
• Paclitaxel
Paclitaxel 80 mg/m^2 intravenous infusion will be administered weekly for 8 weeks and then on Days 1, 8 and 15 of each subsequent 28-day cycle.

Locations

Country	Name	City	State
Austria	KH der Barmherzigen Brüder Graz	Graz
Austria	Univ.-Klinik für Gynäkologie und Geburtshilfe	Graz
Austria	Univ.-Klinik für Gynäkologie und Geburtshilfe, Innsbruck	Innsbruck
Austria	Landesfrauenklinik Salzburg	Salzburg
Belgium	Imelda Ziekenhuis Bonheiden	Bonheiden
Belgium	Cliniques Universitaires Saint Luc, Institut Roi Albert II	Brussel
Belgium	Grand Hôpital de Charleroi, Oncologie-Hématologie	Charleroi
Belgium	AZ Maria Middelares, Clinical Trial Unit Medical Oncology - Integrated Cancer Center Ghent	Gent
Belgium	UZ Gent	Gent
Belgium	University Hospitals Leuven, Leuven Cancer Institute	Leuven
Belgium	CHU Ambroise Paré	Mons
Belgium	CHU UCL Namur - Site Ste Elisabeth	Namur
Canada	Tom Baker Cancer Center	Calgary
Canada	Centre Hospitalie	Montréal	Quebec
Canada	Jewish General Hospital	Montréal
Canada	McGill University Health Centre	Montréal
Canada	CancerCare Manitoba	Winnipeg	Manitoba
Czechia	Gynekologicko-porodnické oddelení - Nemocnice Ceské Budejovice a.s.	Ceské Budejovice
Czechia	Onkologická Klinika Fakultní nemocnice Olomouc	Olomouc
Czechia	University Hospital Ostrava	Ostrava-Poruba
Czechia	Gynekologicko-porodnická klinika, Fakultní nemocnice Královské Vinohrady	Praha 10
Czechia	Gynekologicko-porodnická klinika 1. LF UK a VFN	Praha 2
Germany	Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum, Klinik für Gynäkologie	Berlin
Germany	Universitätsklinikum Carl Gustav Carus	Dresden
Germany	Horst-Schmidt-Kliniken, Gynecology and Gynecologic, Oncology Department	Wiesbaden
Hungary	Nogyógyászati Osztály, Országos Onkológiai Intézet	Budapest
Hungary	Semmelweis University	Budapest
Hungary	Szuleszeti és Nogyogyaszati Klinika	Debrecen
Israel	Hillel Yaffe Medical Center	Hadera
Israel	Saare Zedek Medical Center - Gyneco-Oncology	Jerusalem
Israel	Oncology Institute, Galilee Medical Center	Nahariya
Israel	Gyneco-Oncology Chaim Sheba Medical Center	Ramat Gan
Italy	Policlinico S. Orsola-Malpighi, SSD Oncologia Medica Addarii	Bologna
Italy	Presidio Ospedaliero Antonio Perrino - ASL Brindisi	Brindisi
Italy	ASST Lecco - Ospedale Manzoni, Dipartimento Oncologico	Lecco
Italy	Dipartimento Medicina e Chirurgia, Università Milano-Bicocca, Direttore Programma Ginecologia Oncologica, Istituto Europeo Oncologia	Milano
Italy	IRCCS Ospedale San Raffaele, U.O. Ginecologia-Ematologia e TMO	Milano
Italy	Istituto Nazionale Tumori IRCCS Fondazione Pascale	Napoli
Italy	Fondazione Policlinico Universitario Gemelli	Roma
Italy	University Saint Anna	Torino
Netherlands	Amsterdam Universitair Medische centra	Amsterdam
Netherlands	University Medical Center Utrech	Utrecht
Poland	Szpitale Pomorskie Sp. z o.o.	Gdynia
Poland	Oddzial Kliniczny Chirurgii Ogólnej i Onkologicznej, Szpital Sw. Rafala	Kraków
Poland	Uniwersytet Medyczny w Lublinie, I Klinika Ginekologii Onkologicznej i Ginekologii	Lublin
Poland	Samodzielny Publiczny Zaklad Opieki Zdrowotnej MSWiA z Warminsko-Mazurskim Centrum Onkologii w Olsztynie, Oddzial Kliniczny Onkologii i Immunoonkologii z Osrodkiem Dziennym Terapii Onkologicznej	Olsztyn
Poland	Oddzial Ginekologii Onkologicznej Katedry i Kliniki Onkologii Uniwersytetu Medycznego w Poznaniu	Poznan
Poland	Samodzielny Publiczny Szpital Kliniczny Nr 2 PUM w Szczecinie, Klinika Ginekologii Operacyjnej i Onkologii Ginekologicznej Doroslych i Dziewczat	Szczecin
Poland	Szpital Kliniczny im. ks. Anny Mazowieckiej	Warsaw
Spain	Servicio de Oncología Médica, Hospital Universitario Quirón Dexeus	Barcelona
Spain	lnstitut Catala d'Oncologia, Hospital Universitario Dr. Josep Trueta, Servicio de Oncologia,	Girona
Spain	Clinica Universidad de Navarra en Madrid	Madrid
Spain	Hospital 12 de Octubre. Servicio Oncología Médica	Madrid
Spain	Hospital MD Anderson Cancer Center	Madrid
Spain	Hospital Universitario Ramon y Cajal, Servicio de Oncologia Médica	Madrid
Spain	Fundació Institut d'Investigació Sanitària Illes Balears - IdISBa, Hospital Universitari Son Espases	Palma De Mallorca
Switzerland	Gynecological Tumor Center, University Hospital Basel	Basel
Switzerland	IOSI Bellinzona, Oncology Institute of Southern Switzerland, Ospedale San Giovanni	Bellinzona
Switzerland	Kantonsspital Frauenfeld - Frauenklinik	Frauenfeld
Switzerland	UniversitätsSpital Zürich - Klinik für Gynäkologie	Zürich
United States	Rocky Mountain Cancer Centers	Aurora	Colorado
United States	University of Colorado Denver	Aurora	Colorado
United States	Texas Oncology Austin-Balcones	Austin	Texas
United States	Texas Oncology Austin-Midtown	Austin	Texas
United States	Texas Oncology Austin-North Austin	Austin	Texas
United States	Rocky Mountain Cancer Centers	Boulder	Colorado
United States	Lahey Hospital & Medical Center	Burlington	Massachusetts
United States	MD Anderson Cancer Center at Cooper	Camden	New Jersey
United States	Miami Valley Hospital South	Centerville	Ohio
United States	Rush University Cancer Center - Chicago and Innovation	Chicago	Illinois
United States	Rocky Mountain Cancer Centers	Colorado Springs	Colorado
United States	The Ohio State University Wexner Medical Center	Columbus	Ohio
United States	Texas Oncology	Dallas	Texas
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	Rocky Mountain Cancer Centers	Denver	Colorado
United States	Rocky Mountain Cancer Centers	Denver	Colorado
United States	Des Moines Oncology Research Association	Des Moines	Iowa
United States	Broward Health Medical Center	Fort Lauderdale	Florida
United States	Texas Oncology-Fort Worth	Fort Worth	Texas
United States	Northeast Georgia Medical Center	Gainesville	Georgia
United States	The University of Texas Medical School at Houston	Houston	Texas
United States	University of California	La Jolla	California
United States	Rocky Mountain Cancer Centers	Lakewood	Colorado
United States	Women's Cancer Center of Nevada	Las Vegas	Nevada
United States	Rocky Mountain Cancer Centers	Littleton	Colorado
United States	Rocky Mountain Cancer Centers	Lone Tree	Colorado
United States	Rocky Mountain Cancer Centers	Longmont	Colorado
United States	Norton Cancer Institute	Louisville	Kentucky
United States	Texas Oncology-McAllen	McAllen	Texas
United States	Hoag Memorial Hospital Presbyterian	Newport Beach	California
United States	Virginia Oncology Associates	Norfolk	Virginia
United States	Methodist Estabrook Cancer Center	Omaha	Nebraska
United States	AdventHealth Cancer Institute	Orlando	Florida
United States	The Valley Hospital	Paramus	New Jersey
United States	Rocky Mountain Cancer Centers	Parker	Colorado
United States	Arizona Oncology- Biltmore Cancer Center	Phoenix	Arizona
United States	UPMC Cancer Center	Pittsburgh	Pennsylvania
United States	West Penn OB/GYN	Pittsburgh	Pennsylvania
United States	Northwest Cancer Specialists, PC	Portland	Oregon
United States	Women & Infants Hospital of Rhode Island	Providence	Rhode Island
United States	Rocky Mountain Cancer Centers	Pueblo	Colorado
United States	Center of Hope at Renown Medical Center	Reno	Nevada
United States	Carilion Clinic-Gynecologic Oncology	Roanoke	Virginia
United States	Washington University School of Medicine in St. Louis	Saint Louis	Missouri
United States	Minnesota Oncology Hematology, PA	Saint Paul	Minnesota
United States	Texas Oncology San Antonio Medical Center	San Antonio	Texas
United States	California Pacific Medical Center- Pacific Campus	San Francisco	California
United States	Maryland Oncology Hematology, P.A.	Silver Spring	Maryland
United States	Sanford Gynecologic Oncology Clinic	Sioux Falls	South Dakota
United States	Texas Oncology - Sugar Land	Sugar Land	Texas
United States	Olive View - UCLA Medical Center	Sylmar	California
United States	Multicare Institute for Research and Innovation	Tacoma	Washington
United States	Texas Oncology	The Woodlands	Texas
United States	Rocky Mountain Cancer Centers	Thornton	Colorado
United States	Arizona Oncology	Tucson	Arizona
United States	Texas Oncology-Tyler	Tyler	Texas
United States	Texas Oncology-Deke Slayton Cancer Center	Webster	Texas
United States	Abington Hospital- Asplundh Cancer Pavilion	Willow Grove	Pennsylvania
United States	Wake Forest Baptist Medical Center	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
NovoCure Ltd.

Countries where clinical trial is conducted

United States,  Austria,  Belgium,  Canada,  Czechia,  Germany,  Hungary,  Israel,  Italy,  Netherlands,  Poland,  Spain,  Switzerland, 

References & Publications (9)

Giladi M, Schneiderman RS, Voloshin T, Porat Y, Munster M, Blat R, Sherbo S, Bomzon Z, Urman N, Itzhaki A, Cahal S, Shteingauz A, Chaudhry A, Kirson ED, Weinberg U, Palti Y. Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells. Sci Rep. 2015 Dec 11;5:18046. doi: 10.1038/srep18046. — View Citation

Kirson ED, Dbaly V, Tovarys F, Vymazal J, Soustiel JF, Itzhaki A, Mordechovich D, Steinberg-Shapira S, Gurvich Z, Schneiderman R, Wasserman Y, Salzberg M, Ryffel B, Goldsher D, Dekel E, Palti Y. Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors. Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10152-7. doi: 10.1073/pnas.0702916104. Epub 2007 Jun 5. — View Citation

Kirson ED, Giladi M, Gurvich Z, Itzhaki A, Mordechovich D, Schneiderman RS, Wasserman Y, Ryffel B, Goldsher D, Palti Y. Alternating electric fields (TTFields) inhibit metastatic spread of solid tumors to the lungs. Clin Exp Metastasis. 2009;26(7):633-40. doi: 10.1007/s10585-009-9262-y. Epub 2009 Apr 23. — View Citation

Kirson ED, Gurvich Z, Schneiderman R, Dekel E, Itzhaki A, Wasserman Y, Schatzberger R, Palti Y. Disruption of cancer cell replication by alternating electric fields. Cancer Res. 2004 May 1;64(9):3288-95. doi: 10.1158/0008-5472.can-04-0083. — View Citation

Stupp R, Taillibert S, Kanner A, Read W, Steinberg D, Lhermitte B, Toms S, Idbaih A, Ahluwalia MS, Fink K, Di Meco F, Lieberman F, Zhu JJ, Stragliotto G, Tran D, Brem S, Hottinger A, Kirson ED, Lavy-Shahaf G, Weinberg U, Kim CY, Paek SH, Nicholas G, Bruna J, Hirte H, Weller M, Palti Y, Hegi ME, Ram Z. Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs Maintenance Temozolomide Alone on Survival in Patients With Glioblastoma: A Randomized Clinical Trial. JAMA. 2017 Dec 19;318(23):2306-2316. doi: 10.1001/jama.2017.18718. Erratum In: JAMA. 2018 May 1;319(17):1824. — View Citation

Stupp R, Taillibert S, Kanner AA, Kesari S, Steinberg DM, Toms SA, Taylor LP, Lieberman F, Silvani A, Fink KL, Barnett GH, Zhu JJ, Henson JW, Engelhard HH, Chen TC, Tran DD, Sroubek J, Tran ND, Hottinger AF, Landolfi J, Desai R, Caroli M, Kew Y, Honnorat J, Idbaih A, Kirson ED, Weinberg U, Palti Y, Hegi ME, Ram Z. Maintenance Therapy With Tumor-Treating Fields Plus Temozolomide vs Temozolomide Alone for Glioblastoma: A Randomized Clinical Trial. JAMA. 2015 Dec 15;314(23):2535-43. doi: 10.1001/jama.2015.16669. — View Citation

Stupp R, Wong ET, Kanner AA, Steinberg D, Engelhard H, Heidecke V, Kirson ED, Taillibert S, Liebermann F, Dbaly V, Ram Z, Villano JL, Rainov N, Weinberg U, Schiff D, Kunschner L, Raizer J, Honnorat J, Sloan A, Malkin M, Landolfi JC, Payer F, Mehdorn M, Weil RJ, Pannullo SC, Westphal M, Smrcka M, Chin L, Kostron H, Hofer S, Bruce J, Cosgrove R, Paleologous N, Palti Y, Gutin PH. NovoTTF-100A versus physician's choice chemotherapy in recurrent glioblastoma: a randomised phase III trial of a novel treatment modality. Eur J Cancer. 2012 Sep;48(14):2192-202. doi: 10.1016/j.ejca.2012.04.011. Epub 2012 May 18. — View Citation

Taphoorn MJB, Dirven L, Kanner AA, Lavy-Shahaf G, Weinberg U, Taillibert S, Toms SA, Honnorat J, Chen TC, Sroubek J, David C, Idbaih A, Easaw JC, Kim CY, Bruna J, Hottinger AF, Kew Y, Roth P, Desai R, Villano JL, Kirson ED, Ram Z, Stupp R. Influence of Treatment With Tumor-Treating Fields on Health-Related Quality of Life of Patients With Newly Diagnosed Glioblastoma: A Secondary Analysis of a Randomized Clinical Trial. JAMA Oncol. 2018 Apr 1;4(4):495-504. doi: 10.1001/jamaoncol.2017.5082. — View Citation

Vergote I, von Moos R, Manso L, Van Nieuwenhuysen E, Concin N, Sessa C. Tumor Treating Fields in combination with paclitaxel in recurrent ovarian carcinoma: Results of the INNOVATE pilot study. Gynecol Oncol. 2018 Sep;150(3):471-477. doi: 10.1016/j.ygyno.2018.07.018. Epub 2018 Jul 27. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall survival		4 years
Secondary	Progression-free survival		4 years
Secondary	Objective response rate		4 years
Secondary	Next progression-free survival	Measured from the time of randomization to tumor progression on next-line treatment	4 years
Secondary	Time to undisputable deterioration in health-related quality of life (HRQoL)	Measured as the time interval between randomization until the first decrease in HRQoL score = 10-point with no further improvement in HRQoL score = 10 points on any further HRQoL data, based on the EORTC QLQ-C30 questionnaire	4 years
Secondary	Time to first and second subsequent treatment	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 date	4 years
Secondary	Quality of life using the EORTC QLQ C30 questionnaire with the ovarian cancer symptom OV28 module.		4 years
Secondary	Severity and frequency of adverse events		4 years