EF-36/Keynote B36: A Pilot, Randomized, Open-label Study of Tumor Treating Fields (TTFields, 150 kHz) Concomitant With Pembrolizumab for First Line Treatment of Advanced or Metastatic Non-small Cell Lung Cancer

Non-small Cell Lung Cancer Clinical Trial

— KEYNOTE B36  

Official title:

EF-36/Keynote B36: A Pilot, Randomized, Open-label Study of Tumor Treating Fields (TTFields, 150 kHz) Concomitant With Pembrolizumab for First Line Treatment of Advanced or Metastatic Non-small Cell Lung Cancer

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04892472
• Other study ID #: EF- 36
• Secondary ID: KEYNOTE-B36
• Status: Recruiting
• Phase: Phase 2
• Start date: July 12, 2021
• Est. completion date: December 2026

Study information

• Verified date: October 2023
• Source: NovoCure Ltd.
• Contact: Kassie Balestrieri, PhD
• Phone: +1 603-436-2809
• Email: clinicaltrials[@]novocure.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a multicenter, randomized, open-label study of Tumor Treating Fields (TTFields) at 150 kHz to the thorax using the NovoTTF-200T System with IV pembrolizumab in subjects previously untreated for advanced or metastatic, PD-L1 positive non-small cell lung cancer (NSCLC). The primary objective is to evaluate the progression-free survival (PFS) by RECIST 1.1 in subjects with TPS ≥1 percent, 1L metastatic/current advanced NSCLC treated with TTFields concomitant with pembrolizumab compared to those treated with pembrolizumab alone. The device is an experimental, portable, battery operated device for chronic administration of alternating electric fields (termed TTFields) to the region of the malignant tumor, by means of surface, insulated electrode arrays.

Description:

TTFields have demonstrated significant activity in vitro and in NSCLC pre-clinical models, both as a single modality treatment and concomitant with chemotherapies and PD-1 inhibitors. TTFields have demonstrated synergistic activity when administered alongside taxanes; while TTFields used concomitantly with PD-1 inhibition have shown additive effects. In a pilot study, 42 advanced stage NSCLC patients, who had tumor progression after at least one line of prior chemotherapy, received pemetrexed together with TTFields (150 kHz) applied to the chest and upper abdomen until disease progression. The combination was well tolerated and the only device-related adverse event was mild to moderate contact dermatitis. Efficacy endpoints were remarkably high compared to historical data for pemetrexed alone. Preclinical models have been used to assess the potency of TTFields concomitant with checkpoint inhibition. In an in vivo experiment, C57Bl/6 mice had LLC-1 cells injected directly into the lungs. TTFields were applied to the mouse lungs for 7 days in parallel to I.P. injections of anti-PD-1. Concomitant TTFields and anti-PD-1 treatments led to a significant decrease in tumor volume compared to control mice and to mice treated with anti-PD-1 alone. The concomitant treatments also resulted in an increase in the percentage of tumor-infiltrating leukocytes (CD45+). Specifically, there was a significantly higher frequency of macrophages (CD45+/CD11b+/F4/80+) and dendritic cells (CD45+/CD11c+) in tumors from mice that were concomitantly treated with TTFields and anti-PD-1. Concomitant therapy upregulated PD-1 expression on macrophages and dendritic cells in mice, suggesting an adaptive immune response to control the inflammation caused by the treatment. Additionally, cytotoxic T-cells isolated from tumors treated with TTFields and anti-PD-1 demonstrated increased production of IFN-γ. Overall, these findings imply that concomitant TTFields and anti-PD-1 therapy enhanced the immune response, which led to better management of the tumor. The study will enroll 100 patients, whose tumors are classified as TPS>1% and in whom EGFR or ALK-directed therapy is not indicated, for examination of the effectiveness and safety of TTFields concomitant with pembrolizumab. In addition, all patients must meet all eligibility criteria. After a Screening Phase of up to 28 days, subjects will be enrolled to receive TTFields (150 kHz) to the thorax using the NovoTTF-200T device for an average of 18 hours a day concomitant with pembrolizumab 200 mg IV every 3 weeks, or pembrolizumab alone. Each subject will participate in the study for approximately 2 years from the time the subject signs the Informed Consent Form (ICF) through the final contact. Treatment with TTFields and pembrolizumab will continue for 24 months (TTFields) and until either: (1) 35 study treatments have been administered (pembrolizumab), (2) there is documented disease progression (per iRECIST criteria), (3) unacceptable adverse event(s), (4) intercurrent illness that prevents further administration of treatment, (5) investigator's decision to withdraw the subject, (6) subject withdraws consent, (7) pregnancy of the subject, (8) non-compliance with study treatment or procedure requirements, or (9) administrative/Sponsor decisions. In case of discontinuation of either of the study treatments due to reasons other than disease progression, the remaining treatment should continue until disease progression or 24 months (TTFields) / 35 cycles (pembrolizumab). If an alternative anticancer therapy is initiated, the patient will be removed from the study. Subjects who discontinue all study treatments prior to disease progression will be monitored for disease status in the Observation Phase until: (1) disease progression is confirmed by the site, (2) a non-study cancer treatment is initiated, (3) consent is withdrawn, or (4) the subject is lost to follow-up. Subjects will have post-treatment monthly follow-up by telephone for disease status until death, withdrawing consent, becoming lost to follow-up, or end of the study.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 100
• Est. completion date: December 2026
• Est. primary completion date: July 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 22 Years and older

Eligibility

Inclusion Criteria:

• Histologically or cytologically confirmed diagnosis of stage III or metastatic NSCLC without EGFR sensitizing mutation or ALK translocation
• Age = 22 years
• Have a PD-L1 positive (TPS=1%) tumor by local laboratory assessment
• Have evaluable (measureable or non-measureable) disease in thorax per RECIST 1.1
• ECOG performance status of 0 to 1
• Have not received prior treatments for metastatic or current advanced NSCLC. Palliative treatment is allowed and subjects who received adjuvant, neoadjuvant chemotherapy or chemoradiotherapy with curative intent for non-metastatic disease are eligible if therapy completed at least 12 months prior to the development of metastatic or current advanced disease.
• Life expectancy of at least 3 months
• Able to operate the NovoTTF-200T device

Exclusion Criteria:

• Has known active or untreated CNS metastases and/or carcinomatous meningitis
• Has an EGFR sensitizing mutation and/ or ALK translocation
• Can be treated with curative intent with either surgical resection and/or chemoradiation
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or an agent directed to another stimulatory or co-inhibitory T cell receptor within the past 12 months
• Has received prior systemic anti-cancer therapy for metastatic or current advanced NSCLC (palliative radiotherapy is allowed)
• Being unable to operate the NovoTTF-200T device independently or with the help of a caregiver
• Pregnancy or breastfeeding
• Received live vaccine in the past 30 days or had major surgery in the last 3 weeks
• Is expected to require any other form of systemic or localized antineoplastic therapy while on study

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Lung Neoplasms
• Non-small Cell Lung Cancer

Intervention

Device:
• NovoTTF-200T
All patients enrolled in this group will receive TTFields treatment, delivered for at an average of least 18 hours a day using NovoTTF-200T concomitant with pembrolizumab, a standard immunotherapy agent, which is delivered intravenously.

Drug:
• Pembrolizumab (MK-3475) 200 mg
Pembrolizumab (MK-3475) 200 mg every 3 weeks (Q3W)

Locations

Country	Name	City	State
United States	Central Alabama Research	Birmingham	Alabama
United States	Aultman Hospital	Canton	Ohio
United States	Gabrail Cancer Research Center	Canton	Ohio
United States	Oncology Specialists of Charlotte	Charlotte	North Carolina
United States	University of Illinois Hospital and Health Sciences System	Chicago	Illinois
United States	UCHealth Memorial Hospital	Colorado Springs	Colorado
United States	Texas Oncology - Sammons Cancer Center	Dallas	Texas
United States	Saint Elizabeth Healthcare	Edgewood	Kentucky
United States	Arnot Ogen Medical Center - Falck Cancer Center	Elmira	New York
United States	Michigan Center of Medical Research	Farmington Hills	Michigan
United States	Parkview Research Center	Fort Wayne	Indiana
United States	Palo Verde Cancer Specialists	Glendale	Arizona
United States	: The University of Texas MD Anderson Cancer Center	Houston	Texas
United States	Franciscan St. Francis Health Indianapolis	Indianapolis	Indiana
United States	Tennessee Cancer Specialists	Knoxville	Tennessee
United States	Cancer Care of North Florida	Lake City	Florida
United States	OptumCare Cancer Care	Las Vegas	Nevada
United States	Baptist Health Oncology Research	Lexington	Kentucky
United States	Cancer Partners of Nebraska	Lincoln	Nebraska
United States	Long Beach Memorial Medical Center	Long Beach	California
United States	Miami Cancer Insititute - Baptist Health South Florida	Miami	Florida
United States	Mayo Clinic	Phoenix	Arizona
United States	Cancer and Leukemia Center	Sterling Heights	Michigan
United States	Lankenau Medical Center	Wynnewood	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
NovoCure GmbH	Merck Sharp & Dohme LLC

Country where clinical trial is conducted

United States, 

References & Publications (23)

Bomzon Z, Urman N, Wenger C, et al. Transducer array layout optimization for treating lung-based tumors with TTFields. J Clin Oncol. 2015;33(suppl; abstr e18503). http://meetinglibrary.asco.org/content/147908-156.

Bomzon Z, Urman N, Wenger C, Giladi M, Weinberg U, Wasserman Y, Kirson ED, Miranda PC, Palti Y. Modelling Tumor Treating Fields for the treatment of lung-based tumors. Annu Int Conf IEEE Eng Med Biol Soc. 2015;2015:6888-91. doi: 10.1109/EMBC.2015.7319976. — View Citation

Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018 Nov;68(6):394-424. doi: 10.3322/caac.21492. Epu — View Citation

Ceresoli GL, Aerts JG, Dziadziuszko R, Ramlau R, Cedres S, van Meerbeeck JP, Mencoboni M, Planchard D, Chella A, Crino L, Krzakowski M, Russel J, Maconi A, Gianoncelli L, Grosso F. Tumour Treating Fields in combination with pemetrexed and cisplatin or car — View Citation

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 Chrom — View Citation

Giladi M, Weinberg U, Schneiderman RS, Porat Y, Munster M, Voloshin T, Blatt R, Cahal S, Itzhaki A, Onn A, Kirson ED, Palti Y. Alternating electric fields (tumor-treating fields therapy) can improve chemotherapy treatment efficacy in non-small cell lung c — View Citation

Kanner AA, Wong ET, Villano JL, Ram Z; EF-11 Investigators. Post Hoc analyses of intention-to-treat population in phase III comparison of NovoTTF-100A system versus best physician's choice chemotherapy. Semin Oncol. 2014 Oct;41 Suppl 6:S25-34. doi: 10.105 — 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 ani — 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. — 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

Kirson ED, Schneiderman RS, Dbaly V, Tovarys F, Vymazal J, Itzhaki A, Mordechovich D, Gurvich Z, Shmueli E, Goldsher D, Wasserman Y, Palti Y. Chemotherapeutic treatment efficacy and sensitivity are increased by adjuvant alternating electric fields (TTFiel — View Citation

Lee SX, Wong ET, Swanson KD. Mitosis Interference of Cancer Cells by NovoTTF-100A Causes Decreased Cellular Viability. Cancer Res. 2013;73; 709. http://cancerres.aacrjournals.org/content/73/8%7B_%7DSupplement/709.abstract.

Mrugala MM, Engelhard HH, Dinh Tran D, Kew Y, Cavaliere R, Villano JL, Annenelie Bota D, Rudnick J, Love Sumrall A, Zhu JJ, Butowski N. Clinical practice experience with NovoTTF-100A system for glioblastoma: The Patient Registry Dataset (PRiDe). Semin Onc — View Citation

Mun EJ, Babiker HM, Weinberg U, Kirson ED, Von Hoff DD. Tumor-Treating Fields: A Fourth Modality in Cancer Treatment. Clin Cancer Res. 2018 Jan 15;24(2):266-275. doi: 10.1158/1078-0432.CCR-17-1117. Epub 2017 Aug 1. — View Citation

Pless M, Droege C, von Moos R, Salzberg M, Betticher D. A phase I/II trial of Tumor Treating Fields (TTFields) therapy in combination with pemetrexed for advanced non-small cell lung cancer. Lung Cancer. 2013 Sep;81(3):445-450. doi: 10.1016/j.lungcan.2013.06.025. Epub 2013 Jul 23. — View Citation

Pless M, Weinberg U. Tumor treating fields: concept, evidence and future. Expert Opin Investig Drugs. 2011 Aug;20(8):1099-106. doi: 10.1517/13543784.2011.583236. Epub 2011 May 9. — View Citation

Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S, Lin NU, Litiere S, Dancey J, Chen A, Hodi FS, Therasse P, Hoekstra OS, Shankar LK, Wolchok JD, Ballinger M, Caramella C, de Vries EGE; RECIST working group. iRECIST: guidelines for respon — 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 — 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, We — 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 Tr — View Citation

Toms SA, Kim CY, Nicholas G, Ram Z. Increased compliance with tumor treating fields therapy is prognostic for improved survival in the treatment of glioblastoma: a subgroup analysis of the EF-14 phase III trial. J Neurooncol. 2019 Jan;141(2):467-473. doi: — View Citation

Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, Gatzemeier U, Boyer M, Emri S, Manegold C, Niyikiza C, Paoletti P. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleura — View Citation

Voloshin T, Kaynan N, Davidi S, Porat Y, Shteingauz A, Schneiderman RS, Zeevi E, Munster M, Blat R, Tempel Brami C, Cahal S, Itzhaki A, Giladi M, Kirson ED, Weinberg U, Kinzel A, Palti Y. Tumor-treating fields (TTFields) induce immunogenic cell death resu — View Citation

* Note: There are 23 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression Free Survival	PFS will be measured from the date of enrollment to date of progression (in months) based on RECIST 1.1 criteria. The analysis will include stratification by PD-L1 expression, TPS=1-49% and TPS=50%, as a secondary outcome.	24 months
Secondary	Overall survival (OS)	Survival will be measured from date of enrollment until date of death. The analysis will include patients with PD-L1 expression TPS=1-49 percent and TPS=50 percent	24 months
Secondary	Objective Response Rate (ORR)	Percentage of patients who have a partial or complete response to therapy based on RECIST 1.1 criteria	24 months
Secondary	Duration of response (DOR)	The analysis will be defined as the time from response to progression/death (P/D) based on RECIST 1.1 criteria	24 months
Secondary	Disease control rate (DCR)	Will be defined as the percentage of patients with advanced or metastatic cancer who have achieved complete response (CR), partial response (PR), and stable disease (SD) by RECIST 1.1 at 18 weeks	18 weeks
Secondary	Safety and Tolerability: adverse events (AEs)	Will be defined as the incidence, frequency and severity of adverse events (AEs) noted in patients treated.	24 months

External Links

•   Novocure Clinical Trial Website