Updated safety/feasibility study of concurrent tumor treating fields (TTFields) and radiation therapy for newly diagnosed glioblastoma.

e14535 Background: Tumor Treating Fields (TTFields), a non-invasive, loco-regional, anti-mitotic treatment comprises low-intensity alternating electric fields. In the phase III EF-14 study in newly diagnosed glioblastoma (ndGBM), TTFields in combination with temozolomide (TMZ) significantly improved survival compared to TMZ alone. In preclinical studies TTFields had a radiosensitizing effect and increased the efficacy of radiation therapy (RT). This pilot study [NCT03780569] evaluated the feasibility and safety of TTFields administered concurrently with RT and TMZ in ndGBM patients. Methods: Patients with histologically confirmed ndGBM were treated with TTFields/RT/TMZ followed by adjuvant TMZ/TTFields. TTFields (200 kHz) were delivered for ≥18 hours/day with transducer arrays removed during RT delivery. RT was administered to the tumor bed in 30 fractions (total dose 60 Gy) in combination with daily TMZ (75 mg/m2). In the adjuvant phase, patients received monthly TMZ (150–200 mg/m2 for 5 days) plus TTFields. The primary outcome was safety of the combined therapies; secondary outcomes included progression-free survival (PFS) and overall survival (OS). Adverse events (AEs) were graded per CTCAE v4.0. Results: Ten patients were enrolled at a single center between April and December 2017. Median age was 60.2 years, median Karnofsky Performance Score was 90.0, and eight (80%) patients were male. Five (50%) patients had undergone tumor resection while the remainder had biopsy only. Eight patients experienced ≥1 RT treatment delay; delays were unrelated to TTFields treatment. All patients experienced ≥1 AE. Three patients suffered from serious AEs (urinary tract infection, confusional state, and decubitus ulcer) that were considered unrelated to TTFields. The most common AE was skin toxicity, reported in eight (80%) patients; all were of low severity (CTCAE grade 1–2) and were reported as related to TTFields treatment. Median PFS from enrollment was 8.9 months; median OS was not reached at the time of study closure. Conclusions: Eighty percent of patients experienced grade 1–2 TTFields-related skin toxicity. No other TTFields-related toxicities were observed and there was no increase in RT- or TMZ-related toxicities as a result of combining TTFields with these therapies. Based on the safety and preliminary efficacy results of this pilot study, a phase 2 randomized trial (N = 60; NCT03869242) and the Phase 3 TRIDENT trial have been initiated to further investigate the efficacy of concomitant RT/TMZ/TTFields in ndGBM. Clinical trial information: NCT03780569.

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P14.71 Tumor Treating Fields combined with radiotherapy and temozolomide for newly diagnosed glioblastoma: final safety and efficacy results from a pilot study

Neuro-Oncology ◽

10.1093/neuonc/noz126.306 ◽

2019 ◽

Vol 21 (Supplement_3) ◽

pp. iii84-iii84

Author(s):

R Grossman ◽

F Bokstein ◽

D Blumenthal ◽

C Ben Harush ◽

D Limon ◽

...

Keyword(s):

Pilot Study ◽

Electric Fields ◽

Randomized Study ◽

Progression Free Survival ◽

Skin Toxicity ◽

Phase Iii ◽

Newly Diagnosed ◽

Tumor Treating Fields ◽

Newly Diagnosed Glioblastoma ◽

Sensitizing Effect

Abstract BACKGROUND Tumor Treating Fields (TTFields) are a non-invasive, loco-regional, anti-mitotic treatment consisting of low intensity alternating electric fields. The combination of TTFields with maintenance temozolomide significantly improved survival versus temozolomide alone in the phase 3 EF-14 study in newly diagnosed glioblastoma (ndGBM). In preclinical studies, TTFields increased the number of glioma cells undergoing cellular death following radiotherapy (RT) by inhibiting DNA damage repair, suggesting a radio-sensitizing effect of TTFields. This pilot study is the first to evaluate the safety and feasibility of administering TTFields concomitant to RT and TMZ in ndGBM patients. MATERIAL AND METHODS Patients diagnosed with ndGBM were treated with TTFields/RT/TMZ followed by maintenance TMZ and TTFields for up to 24 months. TTFields (200kHz) were delivered for >18 hours/day while the transducer arrays were removed during delivery of RT. TMZ was administered at a dose of 75 mg/m2/daily for 6 weeks and RT at a total dose of 60 Gy. The primary endpoint was safety of the combined TTFields/RT/TMZ; secondary endpoints included progression-free survival (PFS), overall survival (OS) and toxicity. Adverse events (AEs) were graded according to CTCAE V4.0. RESULTS 10 ndGBM patients that recovered from maximal debulking surgery or biopsy were enrolled at a single center in Israel between April and December 2017. Five patients (50%) had undergone gross total resection while the rest had biopsy only. Eight of the patients were male, median age was 59, median KPS was 80 and median dose of RT was 60 Gy. Six patients (60%) reported at least one AE. The most common AE was TTFields-related skin toxicity, reported in four patients (40%), all of which were grade 1–2 in severity. Two patients reported serious AEs (seizures and general deterioration) that were considered unrelated to TTFields. Median PFS with RT/TMZ/TTFields was 10.5 months. Median OS has not yet been reached. CONCLUSION The proportion of patients with TTFields-related skin toxicity was similar to that reported in ndGBM patients in the randomized Phase III study (52%), where patients started TTFields at least 4 weeks after RT. No other TTFields-related toxicities were reported and there were no increase in RT- or TMZ-related toxicities as a result of combining TTFields with RT in addition to TMZ. Based on the safety and preliminary efficacy results of this pilot study, a phase II randomized study has been initiated to investigate the efficacy of concomitant RT/TMZ/TTFields in 60 ndGBM patients.

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Safety of Tumor Treating Fields and Concomitant Radiation Therapy for Newly Diagnosed Glioblastoma in a Pilot Study

International Journal of Radiation Oncology*Biology*Physics ◽

10.1016/j.ijrobp.2018.07.766 ◽

2018 ◽

Vol 102 (3) ◽

pp. e223

Author(s):

R. Grossman ◽

F. Bukstein ◽

D. Blumenthal ◽

C. Ben Harosh ◽

D. Limon ◽

...

Keyword(s):

Radiation Therapy ◽

Pilot Study ◽

Newly Diagnosed ◽

Tumor Treating Fields ◽

Newly Diagnosed Glioblastoma

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P14.79 Randomized phase II trial of Tumor Treating Fields plus radiation therapy plus temozolomide compared to radiation therapy plus temozolomide in patients with newly diagnosed glioblastoma

Neuro-Oncology ◽

10.1093/neuonc/noz126.314 ◽

2019 ◽

Vol 21 (Supplement_3) ◽

pp. iii86-iii86

Author(s):

D Limon ◽

F Bokstein ◽

D Blumenthal ◽

C Ben Harush ◽

Z Ram ◽

...

Keyword(s):

Radiation Therapy ◽

Pilot Study ◽

Surgical Resection ◽

Phase Ii ◽

Progression Free Survival ◽

Phase Iii ◽

Newly Diagnosed ◽

Free Survival ◽

Tumor Treating Fields ◽

Randomized Phase Ii

Abstract BACKGROUND In last decade, there were numerous attempts to improve the outcome of patients with glioblastoma (GBM), but even after maximal surgical resection, radiation therapy (RT) and temozolomide (TMZ), followed by maintenance TMZ for 6 months the median OS is 14.6 months. In the EF-14 Phase III trial, the addition of Tumor Treating Fields (TTFields) at 200 kHz to maintenance TMZ increased the median OS to 20.9 months, compared with 16.0 months with maintenance TMZ alone (HR, 0.63; 95% CI, 0.53–0.76; p<0.001). Based on these results, the currently accepted standard of care for newly diagnosed GBM (ndGBM) is surgical resection if safely feasible, followed by RT with concomitant TMZ, and then followed by maintenance TMZ in combination with TTFields. Preclinical investigations have shown a radio-sensitizing effect of TTFields on glioma cells, suggesting synergistic effects between TTFields and radiotherapy. In a pilot study of 10 patients with ndGBM, we demonstrated that there was no increased treatment-related toxicity when TTFields were given in combination with RT/TMZ. The only TTFields-related adverse event was skin toxicity below the arrays. Preliminary progression free survival (PFS) data was encouraging. Based on the results of the pilot study, we designed this prospective, randomized Phase II study to further investigate if the addition of TTFields TMZ/RT treatment in ndGBM patients improves treatment efficacy and delays disease progression. MATERIAL AND METHODS Following debulking surgery or biopsy, 60 adult patients (≥18 years) with histologically confirmed GBM, KPS≥70 and life expectancy of at least 3 months will be randomized 1:1 to either a) RT with concomitant TMZ and TTFields (200 kHz) for 6 weeks followed by up to 6 months of maintenance TMZ in combination with TTFields (experimental arm) up to 24 months; or b) RT with concomitant TMZ alone followed by maintenance TMZ in combination with TTFields (control arm). Exclusion criteria: patients with early progressive disease, significant comorbidities precluding maintenance RT or TMZ or patients with an implanted electronic device. The primary endpoint is progression free survival at 12 months (PFS12). Treatment with TTFields will be continued until second progression or 24 months (the earlier of the two). All patients will be followed for survival. Grading and severity of all adverse events will be recorded using CTCAE V5.0. The sample size of 60 patients provides 80% power with a two-sided alpha level of 0.05 to detect a PFS12 of 46.5% with RT/TMZ/TTFields compared to 29.4% with RT/TMZ followed, respectively, by maintenance TMZ/TTFields (calculated from the RT/TMZ followed by maintenance TMZ/TTFields arm of the EF-14 trial). It is forecasted to take 24 months to fully recruit. Follow-up will continue for >12 months from recruitment of the last patient.

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ACTR-46. TUMOR TREATING FIELDS COMBINED WITH RADIOTHERAPY AND TEMOZOLOMIDE FOR THE TREATMENT OF NEWLY DIAGNOSED GLIOBLASTOMA: FINAL RESULTS FROM A PILOT STUDY

Neuro-Oncology ◽

10.1093/neuonc/noz175.088 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi23-vi24 ◽

Cited By ~ 1

Author(s):

Rachel Grossman ◽

Dror Limon ◽

Felix Bokstein ◽

Deborah Blumenthal ◽

Camit Ben Harush ◽

...

Keyword(s):

Pilot Study ◽

Electric Fields ◽

Randomized Study ◽

Progression Free Survival ◽

Skin Toxicity ◽

Tumor Treating Fields ◽

Alternating Electric Fields ◽

Newly Diagnosed Glioblastoma ◽

Secondary Endpoints ◽

Sensitizing Effect

Abstract BACKGROUND Tumor Treating Fields (TTFields) are a non-invasive, loco-regional, anti-mitotic treatment comprising low intensity alternating electric fields approved for GBM. Preclinical data show that TTFields have a radio-sensitizing effect. This pilot study evaluated the safety and feasibility of TTFields/RT/TMZ in ndGBM patients. METHODS Patients with histologically confirmed ndGBM were treated with TTFields/RT/TMZ followed by maintenance TTFields and TMZ for up to 24 months. TTFields (200kHz) were delivered for >18 hours/day with removal of the transducer arrays during RT delivery. TMZ was administered at 75 mg/m2/daily for 6 weeks and RT at a total dose of 60 Gy. The primary endpoint was safety of the combined TTFields/RT/TMZ; secondary endpoints included progression-free survival (PFS), overall survival (OS) and toxicity. Adverse events (AEs) were graded per CTCAE V4.0. RESULTS Ten patients were enrolled at a single center in Israel between April and December 2017. All patients had recovered from maximal debulking surgery or biopsy. Five patients (50%) had undergone gross total resection; rest had biopsy only. Median age was 59 and median KPS was 80. Median dose of RT was 60 Gy. Six patients (60%) reported at least one AE. The most common AE was TTFields-related skin toxicity reported in 4 patients (40%), of Grade 1–2 in severity. Two patients reported serious AEs (seizures and general deterioration) considered unrelated to TTFields. Median PFS with RT/TMZ/TTFields was 10.5 months. Median OS has not been reached. CONCLUSIONS The proportion of patients with TTFields-related skin toxicity was similar to that reported in EF-14 phase 3 study (52%). No other TTFields-related toxicities were reported. There was no increase in RT- or TMZ-related toxicities with TTFields/RT/TMZ combination. A phase 2 randomized study has been initiated to investigate the efficacy of concomitant RT/TMZ/TTFields in 60 ndGBM patients.

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CTNI-74. PHASE 3 TRIDENT TRIAL: CONCOMITANT RADIATION THERAPY (RT) AND TEMOZOLOMIDE +/- TUMOR TREATING FIELDS (TTFIELDS) IN NEWLY DIAGNOSED GLIOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/noaa215.240 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii59-ii60

Author(s):

Wenyin Shi ◽

Lawrence Kleinberg ◽

Suriya A Jeyapalan ◽

Samuel Goldlust ◽

Seema Nagpal ◽

...

Keyword(s):

Radiation Therapy ◽

Progression Free Survival ◽

Phase Iii ◽

Type I ◽

Newly Diagnosed ◽

Phase 3 ◽

Free Survival ◽

Tumor Treating Fields ◽

Newly Diagnosed Glioblastoma

Abstract BACKGROUND Tumor treating fields (TTFields) is a non-invasive, regional antimitotic treatment approved as a standard-of-care for newly diagnosed glioblastoma (ndGBM). In the EF-14 Phase 3 trial, TTFields (200 kHz) plus temozolomide (TMZ) significantly increased survival of ndGBM patients without increasing systemic toxicity. TTFields-related AEs were mainly skin AEs. In preclinical models, TTFields increase the therapeutic effects of radiation therapy (RT). A pilot study showed that TTFields concomitant with RT and TMZ is well tolerated. The benefit of concomitant TTFields with RT and TMZ will be tested in the TRIDENT trial. METHODS TRIDENT is an international phase III randomized trial comparing standard RT with TMZ vs the triple combination of RT/TMZ with concomitant TTFields. RT is delivered through the TTFields arrays. Patients in both arms will receive maintenance TTFields/TMZ. TTFields (200 KHz) will be delivered >18 hours/day using Optune. Patients will continue TTFields treatment until second recurrence. Patients with pathologically confirmed ndGBM, ≥ 18 years, KPS ≥ 70, either sex, post-surgery or biopsy, and amenable for RT/TMZ therapy will be stratified by extent of resection and MGMT promoter methylation status. The primary endpoint is overall survival (OS). Secondary end points: progression free survival (PFS; RANO), 1- and 2-year survival rates, overall radiological response (ORR; RANO), progression-free survival (PFS6M, PF12M, PFS2Y); severity and frequency of AEs (CTCAE V5.0); pathological changes in resected GBM tumors post treatment; quality of life (EORTC QLQ-C30); and correlation of OS to TTFields compliance. The hypothesis is that concomitant TTFields/RT/TMZ will significantly improve OS versus RT/TMZ. Sample size (N=950; 475/arm) will detect a HR< 0.8 with 5% type I error. Survival will be measured from the time of randomization until date of death. At the time of analysis, patients lost to follow-up or still on protocol follow-up will be censored at the last date known to be alive.

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