scholarly journals ACTR-19. REPORT ON THE COMBINATION OF AXITINIB AND TUMOR TREATING FIELDS (TTFIELDS) IN THREE PATIENTS WITH RECURRENT GLIOBLASTOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi16-vi16
Author(s):  
Ellina Schulz ◽  
Almuth F Kessler ◽  
Judith Weiland ◽  
Thomas Linsenmann ◽  
Ralf-Ingo Ernestus ◽  
...  
Keyword(s):  
Treatment Regimen ◽  
Male Patient ◽  
Kinase Inhibitor ◽  
Combined Therapy ◽  
Pilot Trial ◽  
Neurological Status ◽  
Recurrent Glioblastoma ◽  
Tumor Treating Fields ◽  
Initial Surgery ◽  
Newly Diagnosed Glioblastoma

Abstract OBJECTIVE Tumor Treating Fields (TTFields) significantly improved survival of newly diagnosed glioblastoma (ndGBM) patients in the EF-14 trial. Axitinib is an orally available tyrosine kinase inhibitor which is approved for the treatment of metastatic renal cell carcinoma. It has a high affinity and specificity for vascular endothelial growth factor receptors. In phase 2 trials, Axitinib improved response rate and PFS in recurrent GBM (rGBM) patients with a manageable toxicity profile. Here, three rGBM patients treated with TTFields and Axitinib (AxiTTFields) are presented. PATIENT SECTION A 53-year-old male patient (#1) presented with a progressing GBM after initial surgery, radiochemotherapy followed by 4 cycles of temozolomide (TMZ) and TTFields. In a 46-year-old male patient (#2), early progress occurred after surgery, radiochemotherapy and 3 cycles of TMZ combined with TTFields. In both patients Axitinib was added to the treatment regimen to meet the urgent need of an alternative treatment. In a 61-year-old male patient (#3) with rGBM after surgery, radiochemotherapy and 6 cycles of TMZ, TTFields therapy was initiated at recurrence and the treatment regimen was adapted to AxiTTFields. RESULTS No additional adverse events due to the combined therapy of AxiTTFields were observed. Patients #1 and #2 were on AxiTTFields therapy for more than 8 months, presenting an improved neurological status with a partial response in the MRI 3 months after initiating AxiTTFields. #3 declined in his neurological status without any change in the MRI monitoring and died 2.4 months after initiating AxiTTFields. With an average of 77%, the TTFields usage rate was above the independent prognostic threshold of 75%, underlining the feasibility of this approach. CONCLUSION AxiTTFields was feasible and safe in three rGBM patients. The addition of Axitinib to TTFields therapy is a promising approach and safety/feasibility will be further investigated in a pilot trial.

scholarly journals P14.28 First report on the combination of axitinib and Tumor Treating Fields (TTFields) in three patients with recurrent glioblastoma

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii73-iii73
Author(s):  
A F Keßler ◽  
J Weiland ◽  
T Linsenmann ◽  
R Ernestus ◽  
C Hagemann ◽  
...  
Keyword(s):  
Treatment Regimen ◽  
Male Patient ◽  
Kinase Inhibitor ◽  
Combined Therapy ◽  
Combined Treatment ◽  
Pilot Trial ◽  
Case Series ◽  
Neurological Status ◽  
Tumor Treating Fields ◽  
Initial Surgery

Abstract BACKGROUND Adding Tumor Treating Fields (TTFields) to first-line therapy in glioblastoma (GBM) demonstrated significantly improved survival in the EF-14 trial. Furthermore, in a post-hoc analysis of the EF-14 trial, median overall survival increased significantly upon recurrence (rGBM) for patients treated with bevacizumab (Bev) and TTFields compared to Bev monotherapy. Axitinib (Axi) is an orally available tyrosine kinase inhibitor which is approved for the treatment of metastatic renal cell carcinoma. It has a high affinity and specificity for vascular endothelial growth factor receptors, thereby acting similar to Bev. In phase 2 trials, Axi improved response rate and progression free survival in rGBM patients compared to historical controls with a manageable toxicity profile. We report on three rGBM patients treated with TTFields and Axi (AxiTTFields). METHODS A 53-year-old male patient (#1) presented with a multifocal and consistently progressing GBM after initial surgery, radiochemotherapy (RCT) and after 4 cycles of temozolomide (TMZ), combined with TTFields. To meet the urgent need of an alternative treatment, Axi (5mg twice a day) was added to the treatment regimen. In a 46-year-old male patient (#2), an early progress occurred after surgery, RCT and 3 cycles of TMZ combined with TTFields. Similarly to #1, Axi was added to the treatment regimen. In a 61-year-old male patient (#3) with a rGBM after surgery and RCT at the time of the 6th cycle of TMZ, TTFields therapy was initiated at recurrence and treatment regimen was adapted to AxiTTFields. RESULTS In these three patients, AxiTTFields was safe and feasible. #1 and #2 were on AxiTTFields therapy for more than 8 months, presenting an improved neurological status with a partial response in the MRI 3 months initiating the combined treatment of AxiTTFields. #3 declined in his neurological status without any change in the MRI monitoring and died 2.4 months after initiating AxiTTFields. Although, Axi as well as TTFields may cause skin irritations, none were observed in this case series. With an average of 77 % in these three patients, the TTFields usage rate was above the independent prognostic threshold of 75 %, underlining the feasibility of this approach. There were no additional adverse events due to the combined therapy of AxiTTFields. CONCLUSION In summary, AxiTTFields was feasible and safe in three rGBM patients. As the addition of Axi to TTFields therapy is a promising approach, we plan to investigate the safety and feasibility of this combination in a pilot trial. Further studies might explore effects on outcome and survival of AxiTTFields in rGBM.

Phase I trial of vatalanib (PTK787) in combination with standard radiation and temozolomide in patients with newly diagnosed glioblastoma

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2035-2035
Author(s):  
T. Batchelor ◽  
A. F. Eichler ◽  
S. R. Plotkin ◽  
J. Drappatz ◽  
P. Wen ◽  
...  
Keyword(s):  
Phase I ◽  
Kinase Inhibitor ◽  
Wound Dehiscence ◽  
Recurrent Glioblastoma ◽  
Newly Diagnosed ◽  
Study Results ◽  
Diagnostic Biopsy ◽  
Newly Diagnosed Glioblastoma ◽  
Grade 3 ◽  
Endothelial Growth Factor

2035 Background: Anti-vascular endothelial growth factor (VEGF) agents are hypothesized to work synergistically with chemotherapy and radiation (RT). Vatalanib (MW 347, T1/2 4.6 h) is an oral, pan-VEGFR tyrosine kinase inhibitor that has shown activity in patients with recurrent glioblastoma. Methods: This phase I study was designed to determine the maximal tolerated dose of vatalanib in combination with RT and TMZ for patients with newly diagnosed GBM who were taking enzyme-inducing anti-epileptic drugs. RT and TMZ were administered at standard doses. Vatalanib was initiated 5 days prior to the start of RT and continued daily until tumor progression, unacceptable toxicity or a maximum of up to 12 cycles of post-RT TMZ. Cohorts of 3 patients were treated during RT and TMZ at doses of 250mg daily, 250mg BID, or 500mg BID of vatalanib. Following the completion of RT, patients were treated with vatalanib 750mg BID for the remainder of the study. Results: Nineteen patients were enrolled of which 17 took 5 or more days of vatalanib (1 patient withdrew consent prior to start of vatalanib and 1 withdrew consent after only 1 dose). The median age was 58 and the median KPS was 90. Eight patients had a diagnostic biopsy only. The MTD has not been reached. Potentially related grade 3–4 toxicities included elevated transaminases (2 patients), thrombocytopenia (1 patient), leukopenia (1 patient), neutropenia (1 patient), depressed level of consciousness (1 patient), and fatigue (1 patient). Only 1 patient suffered an asymptomatic intracerebral hemorrhage and no patient experienced wound dehiscence or infection. Five patients remain on vatalanib and the median follow-up for all patients is 6.5 months. Seven patients have died. The best responses for the 13 patients who completed combination RT/TMZ/vatalanib was 2 PR, 7 SD, and 2 PD. Two patients were clinically stable with biopsy proven pseudoprogression. Median PFS is 18.4+ months and OS has not been reached. Conclusions: Vatalanib is safe and well tolerated when added to standard RT and TMZ. The MTD has not been reached and dose escalation continues in this population of patients on enzyme inducing anti-epileptic drugs. [Table: see text]

scholarly journals P14.61 Tumor Treating Fields (TTFields) combined with lomustine (CCNU) and temozolomide (TMZ) in newly diagnosed glioblastoma (GBM) patients - a bi-centric analysis

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii81-iii81
Author(s):  
L Lazaridis ◽  
N Schäfer ◽  
T Schmidt ◽  
A Stoppek ◽  
J Weller ◽  
...  
Keyword(s):  
Combined Therapy ◽  
Performance Status ◽  
Methylation Status ◽  
Case Series ◽  
Low Grade ◽  
Newly Diagnosed ◽  
Skin Reactions ◽  
Term Survival ◽  
Tumor Treating Fields ◽  
Newly Diagnosed Glioblastoma

Abstract BACKGROUND TTFields combined with TMZ demonstrated significantly improved PFS, OS and long-term survival in newly diagnosed glioblastoma (ndGBM) patients, compared to TMZ monotherapy in the EF-14 trial; independent of MGMT-promotor methylation-status, age, grade of resection and performance status. Recently, improved efficacy of lomustine (CCNU)/TMZ compared to TMZ monotherapy in ndGBM patients with MGMT-promotor methylation was reported in the CeTeG trial (NOA-09). Taken into account that TTFields showed a strong safety profile as well as a high potential being combined with other modalities and the very encouraging results for methylated MGMT-promotor GBM patients in the CeTeG trial, there is a strong rationale in combining these treatment regimens. Here, we present a case series of patients receiving a combination of both modalities, TTFields and CCNU/TMZ. METHODS Patients with ndGBM and MGMT-promotor methylation underwent a combined therapy of TTFields plus CCNU/TMZ after surgery and radiochemotherapy. Safety, feasibility as well as first efficacy results of this combined therapy are reported at data cut-off (31.12.2018). Most recent data, including compliance to TTFields therapy, will be presented at the EANO annual meeting. RESULTS Twelve patients with MGMT-promotor methylated ndGBM (median, range: age 49.5, 26–69; KPS 90, 60–100) have been treated with a combination of TTFields plus CCNU/TMZ. The analysis included patients with complete resection (n=6), partial resection (n=5) as well as biopsy (n=1). CTCAE grade 3 hematotoxicities were observed in six patients, but were not considered to be related to the addition of TTFields to lomustine/TMZ. Medical device site reactions (low-grade skin reactions) were detected in five patients. At data cut-off, the analyzed patient population demonstrated a median PFS of 18.7 months, whereas the median OS was not yet reached. CONCLUSION The results of this analysis provide first indication that the combination of TTFields/lomustine/TMZ is safe and feasible. Moreover, the observed survival outcomes point to preliminary beneficial effects of the triple combination. Additional follow-up and a higher sample size is required and planned for further toxicity analysis and efficacy assessment of this combination.

scholarly journals EXTH-34. IN VITRO TUMOR TREATING FIELDS (TTFIELDS) APPLIED PRIOR TO RADIATION ENHANCES THE RESPONSE TO RADIATION IN PATIENT-DERIVED GLIOBLASTOMA CELL LINES

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi89-vi89
Author(s):  
Sharon Michelhaugh ◽  
Sandeep Mittal
Keyword(s):  
Cell Lines ◽  
Crystal Violet ◽  
Clonogenic Assay ◽  
Recurrent Glioblastoma ◽  
Control Group ◽  
Newly Diagnosed ◽  
Tumor Treating Fields ◽  
Cell Counts ◽  
Newly Diagnosed Glioblastoma

Abstract Tumor treating fields are FDA-approved for treatment of newly-diagnosed and recurrent glioblastoma. Adding TTFields therapy to standard-of-care extended progression-free survival and overall survival in newly-diagnosed glioblastoma patients. In this study, cell lines generated from newly-diagnosed glioblastoma patients were treated in vitro with TTFields prior to irradiation to determine if the response to radiation would be altered. This study was approved by the WSU Institutional Review Board and written consent obtained from the patients. Single-cell suspensions generated from tumor tissues obtained from newly-diagnosed patients were cultured in DMEM/F12 media with 10% fetal bovine serum and gentamicin. Prior to TTFields initiation, cells were plated on plastic coverslips (5×104cells/coverslip) and incubated overnight. Then, TTFields were applied at 200 kHz with a field intensity of ~1.6 V/cm for 3 days. After TTFields application, cells were irradiated with 2, 4, or 6 Gy, or were untreated. After radiation delivery, cells were harvested and replated in a clonogenic assay. From each group, 3 coverslips were each replated in triplicate. After 3 days (3 doubling times), cells were stained with crystal violet and plates were scanned to determine cell counts. Treatment groups were compared to their control group with t-test. For both patient-derived GBM cell lines tested, TTFields prior to radiation decreased the number of crystal violet-stained cells in the clonogenic assay plates. In cell line 15–037, pretreatment with TTFields decreased cell counts by 16, 29, and 56% after 2, 4, or 6 Gy radiation, respectively, compared to the control cells with no TTFields pretreatment (p< 0.05). The response in 14-015S cells was less radiation dose-dependent, with the decrease in cell counts ranging from 33–47% control across the radiation doses (p< 0.05). These data suggest that the use of TTFields therapy prior to radiotherapy may enhance the response to radiotherapy in GBM patients.

scholarly journals In Vivo Safety of Tumor Treating Fields (TTFields) Applied to the Torso

2021 ◽  
Vol 11 ◽  
Author(s):  
Roni Blatt ◽  
Shiri Davidi ◽  
Mijal Munster ◽  
Anna Shteingauz ◽  
Shay Cahal ◽  
...  
Keyword(s):  
Electric Fields ◽  
Cellular Proliferation ◽  
Complete Blood Count ◽  
Malignant Tumors ◽  
Neurological Status ◽  
Recurrent Glioblastoma ◽  
Activity Level ◽  
Internal Organs ◽  
Tumor Treating Fields

BackgroundTumor Treating Fields (TTFields) therapy is a non-invasive, loco-regional, anti-mitotic treatment modality that targets rapidly dividing cancerous cells, utilizing low intensity, alternating electric fields at cancer-cell-type specific frequencies. TTFields therapy is approved for the treatment of newly diagnosed and recurrent glioblastoma (GBM) in the US, Europe, Israel, Japan, and China. The favorable safety profile of TTFields in patients with GBM is partially attributed to the low rate of mitotic events in normal, quiescent brain cells. However, specific safety evaluations are warranted at locations with known high rates of cellular proliferation, such as the torso, which is a primary site of several of the most aggressive malignant tumors.MethodsThe safety of delivering TTFields to the torso of healthy rats at 150 or 200 kHz, which were previously identified as optimal frequencies for treating multiple torso cancers, was investigated. Throughout 2 weeks of TTFields application, animals underwent daily clinical examinations, and at treatment cessation blood samples and internal organs were examined. Computer simulations were performed to verify that the targeted internal organs of the torso were receiving TTFields at therapeutic intensities (≥ 1 V/cm root mean square, RMS).ResultsNo treatment-related mortality was observed. Furthermore, no significant differences were observed between the TTFields-treated and control animals for all examined safety parameters: activity level, food and water intake, stools, motor neurological status, respiration, weight, complete blood count, blood biochemistry, and pathological findings of internal organs. TTFields intensities of 1 to 2.5 V/cm RMS were confirmed for internal organs within the target region.ConclusionsThis research demonstrates the safety of therapeutic level TTFields at frequencies of 150 and 200 kHz when applied as monotherapy to the torso of healthy rats.

scholarly journals Heterogeneous constitutional mismatch repair deficiency with MSH6 missense mutation clinically benefits from pembrolizumab and regorafenib combination therapy: a case report and literature review

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Tong Xie ◽  
Qin Feng ◽  
Zhongwu Li ◽  
Ming Lu ◽  
Jian Li ◽  
...  
Keyword(s):  
Mismatch Repair ◽  
Kinase Inhibitor ◽  
Checkpoint Inhibitors ◽  
Combined Therapy ◽  
Dual Therapy ◽  
Circulating Tumor Dna ◽  
Targeted Sequencing ◽  
Dna Mismatch ◽  
Repair Deficiency ◽  
Mutation Burden

Abstract Background Germline DNA mismatch repair (MMR) gene aberrations are associated with colorectal cancer (CRC) predisposition and high tumor mutation burden (TMB-H), with increased likelihood of favorable response to immune checkpoint inhibitors (ICIs). Case presentation We present a 32-year old male patient diagnosed with constitutional MMR deficiency (CMMRD) CRC whose MMR immunohistochemistry (IHC) revealed inconsistent results from two tumor blocks. Targeted sequencing of two tumor specimens used in MMR-IHC and plasma-derived circulating tumor DNA consistently revealed the detection of bi-allelic germline MSH6 c.3226C > T (p.R1076C) mutation, TMB-H as well as the genetic heterogeneity of the tumor samples. Unexpectedly, both blocks were microsatellite stable (MSS) after PCR confirmation. Interestingly, the patient failed to show response to ICI monotherapy or dual therapy, but clinically benefitted from combined therapy of ICI pembrolizumab plus multi-kinase inhibitor regorafenib. Conclusion Our case reported a CMMRD patient with heterogeneous MMR results who showed complicated response to ICIs, highlighting the importance of accurate diagnosis using targeted sequencing with multiple specimens to reveal the possible mechanism of response to ICI in patients with CMMRD.

scholarly journals NIMG-37. DELAYED PSEUDOPROGRESSION IN TWO PATIENTS UNDERGOING TTFIELDS TREATMENT FOR NEWLY DIAGNOSED GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii155-ii156
Author(s):  
Allison Lowman ◽  
Sarah Hurrell ◽  
Samuel Bobholz ◽  
Jennifer Connelly ◽  
Elizabeth Cochran ◽  
...  
Keyword(s):  
Dna Methyltransferase ◽  
Radiographic Progression ◽  
Methylation Status ◽  
Underlying Mechanism ◽  
Recurrent Glioblastoma ◽  
Newly Diagnosed ◽  
Methylguanine Dna Methyltransferase ◽  
Specific Effects ◽  
Newly Diagnosed Glioblastoma ◽  
Associated Risk Factors

Abstract PURPOSE Tumor treatment fields (TTFields) are approved by the FDA for newly diagnosed as well as recurrent glioblastoma (GBM). TTFields have been shown to extend survival by 4.9 months in newly diagnosed GBM, and a landmark overall survival rate of 13% at 5 years. However, the specific effects remain widely unknown, which has prevented widespread clinical use of this treatment. METHODS This case study examines two glioblastoma patients, IDH-1 wildtype, MGMT unmethylated, that received TTFields (Optune) in addition to maintenance temozolomide (TMZ) following radiation (RT). Both cases were followed using standard MR imaging. Second resections were performed due to radiographic progression of contrast enhancement. RESULTS Although imaging was concerning for tumor progression, pathology showed only treatment effect, ultimately leading to the diagnosis of pseudoprogression. Both patients fell outside the normal expected timeline for chemo-radiation induced pseudoprogression. Based on the pathology, both patients resumed treatment with TMZ/TTFields. One patient expired at 25 months and one is still alive. CONCLUSIONS Pathologic confirmation was essential for guiding further treatment and allowed patients to continue treatment that was effective despite contrary indications on imaging. These findings suggest that pathological confirmation should be strongly considered in patients receiving TMZ/TTFields who develop radiographic progression, potentially with a less invasive biopsy procedure. Future studies should look to characterize the underlying mechanism of interaction between TTFields/TMZ and quantify the prevalence, associated risk factors and whether there is a genotype more susceptible. Both patients reported here had O(6)-methylguanine-DNA methyltransferase (MGMT) unmethylated GBM, and while about 60% of glioblastomas are diagnosed likewise, it is possible that MGMT methylation status plays a role in TTFields response. Better characterization of this phenomenon will improve treatment guidance, potentially reducing unnecessary surgeries and the discontinuance of successful therapies.

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