scholarly journals Final Report on Clinical Outcomes and Tumor Recurrence Patterns of a Pilot Study Assessing Efficacy of Belinostat (PXD-101) With Chemoradiation for Newly Diagnosed Glioblastoma

2021 ◽  
Author(s):  
Karen Xu ◽  
Karthik Ramesh ◽  
Vicki Huang ◽  
Saumya S Gurbani ◽  
J Scott Cordova ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Final Report ◽  
Control Cohort ◽  
Brain Barrier Permeability ◽  
Target Volumes ◽  
Newly Diagnosed Glioblastoma ◽  
Recurrence Patterns ◽  
Sensitizing Effect

Abstract PurposeGlioblastoma (GBM) is highly aggressive with poor prognosis. Belinostat is a histone deacetylase inhibitor with blood–brain barrier permeability, anti-GBM activity, and potential to enhance chemoradiation. The purpose of this clinical trial was to assess the clinical efficacy of combining belinostat with standard-of-care therapy for GBMs. Methods13 patients were enrolled in each of the control and belinostat cohorts. The belinostat cohort was given a belinostat regimen (500-750 mg/m2 1x/day x 5 days) every 3 weeks (weeks 0, 3, and 6 of RT). All patients received temozolomide and radiation therapy (RT). RT margins of 5-10 mm were added to generate clinical tumor volumes and 3 mm added to create planning target volumes. Patient outcomes included progression-free survival, overall survival (OS), and recurrence pattern analysis of enhancing tumor (rGTV). ResultsMedian OS was 15.8 months for the control cohort and 18.5 months for the belinostat cohort (p=0.53). The rGTVs in the control cohort occurred in areas that received higher radiation doses than that in the belinostat cohort. For those belinostat patients who experienced out-of-the field recurrence, tumors were detectable by spectroscopic MRI before RT. ConclusionThe median OS was slightly longer for the belinostat cohort than the control cohort but not statistically significant. Recurrence analysis suggests better in-field control with belinostat, suggesting a radio-sensitizing effect. This study highlights the potential of belinostat as a synergistic therapeutic agent for GBM treatment. It may be particularly beneficial to combine this radio-sensitizing effect with spectroscopic MRI-guided radiation therapy.

scholarly journals SYST-07. PILOT STUDY UTILIZING THE HDAC INHIBITOR BELINOSTAT WITH CHEMORADIATION FOR NEWLY-DIAGNOSED GLIOBLASTOMA

2021 ◽  
Vol 3 (Supplement_4) ◽  
pp. iv9-iv10
Author(s):  
Hui-Kuo Shu ◽  
Karen Xu ◽  
Karthik Ramesh ◽  
Vicki Huang ◽  
Saumya Gurbani ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Standard Of Care ◽  
Response To Therapy ◽  
Control Cohort ◽  
Free Survival ◽  
Deacetylase Inhibitor ◽  
Brain Barrier Permeability ◽  
Newly Diagnosed Glioblastoma ◽  
Sensitizing Effect ◽  
Tolerable Dose

Abstract PURPOSE Glioblastomas (GBMs) are highly aggressive brain tumors with poor prognosis. Belinostat is a histone deacetylase inhibitor with blood–brain barrier permeability, anti-GBM activity, and potential to enhance chemoradiation. This clinical trial sought to determine a tolerable dose of concurrent belinostat and assess the clinical efficacy of combining this drug with standard-of-care therapy. METHODS 13 patients each were enrolled in control and belinostat cohorts. The belinostat cohort was given a belinostat regimen (500-750mg/m2 1x/day x 5 days) every 3 weeks (weeks 0, 3, and 6 of RT). All patients received standard temozolomide and radiation therapy (RT). Patient outcomes included progression-free survival, overall survival (OS), and analysis of recurrence pattern of the recurrent gross tumor volume (rGTV). RESULTS Belinostat at 750 mg/m2 produce dose-limiting toxicities (DLTs) in 2 of 3 patients while belinostat at 500 mg/m2 did not result in DLTs. Median OS was 18.5 months for the belinostat cohort and 15.8 months for the control cohort (p=0.53). The rGTVs in the control cohort occurred in areas that received higher radiation doses than that in the belinostat cohort. For those belinostat patients that experienced out-of-field recurrences, tumors were detectable by spectroscopic MRI (sMRI) before RT. In particular, one belinostat patient had an IDH-mutant GBM that had an extraordinary response to therapy with significant shrinkage of enhancing tumor much greater than expected. CONCLUSION Belinostat given concurrently at 500 mg/m2 is well-tolerated. While median OS was not significantly increased for the belinostat cohort, recurrence analysis suggests better in-field control with belinostat, suggesting a radio-sensitizing effect. This study suggests that belinostat can act as a synergistic therapeutic agent for GBMs that may be further enhanced by sMRI-guided RT and may be particularly effective against IDH mutant tumors. A trial is currently in development using belinostat with sMRI-guided RT for IDH-mutant high-grade gliomas.

scholarly journals CTNI-13. UPDATES ON CLINICAL OUTCOMES AND TUMOR RECURRENCE PATTERNS OF A HUMAN PILOT STUDY ASSESSING EFFICACY OF BELINOSTAT (PXD-101) COMBINING WITH CHEMORADIATION IN TREATING GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii44-ii44
Author(s):  
Karen Xu ◽  
Vicki Huang ◽  
Karthik Ramesh ◽  
Saumya Gurbani ◽  
Eduard Schreibmann ◽  
...  
Keyword(s):  
Therapeutic Agent ◽  
Standard Of Care ◽  
Adjuvant Temozolomide ◽  
Initial Recurrence ◽  
Deacetylase Inhibitor ◽  
Brain Barrier Permeability ◽  
Target Volumes ◽  
Recurrence Patterns ◽  
The Mean

Abstract INTRODUCTION Glioblastoma (GBM) is highly aggressive with poor prognosis. Belinostat is a histone deacetylase inhibitor with blood–brain barrier permeability that has anti-GBM activity and may enhance effects of chemoradiation. Our institution conducted a clinical trial evaluating clinical efficacy of belinostat with standard-of-care therapy for GBMs. METHODS 13 and 14 patients were enrolled into cohort 1 (c1, control) or cohort 2 (c2, belinostat) with 12 in each group with sufficient follow-up MRIs for recurrence analysis. All patients received concurrent, adjuvant temozolomide and focal radiation therapy (RT). For c2 patients, the belinostat regimen (500-750mg/m2 1x/day x 5 days) was given over three cycles every 3 weeks (weeks -1, 2, and 5 of RT). RT margins of 5–10 mm and 3 mm were added to generate clinical tumor volumes and planning target volumes (PTVs). PTV1 (based on FLAIR MRI) and PTV2 (based on CE-T1w MRI) received 51 and 60 Gy, respectively, over 30 fractions. Volume at initial recurrence (rGTV) was contoured. RESULTS Mean age was 58.3 years for c1 and 51.1 years for c2. Patient/tumor characteristics were similar between cohorts. Median OS were 16.6 and 18.5 months for c1 and c2 (p=0.538), respectively. Average minimum, maximum and mean radiation dose to rGTV was 54.1 Gy, 64.2 Gy and 62 Gy, for c1, and 47.5 Gy, 57.6 Gy and 53.5 Gy, for c2 (p=0.322, 0.088 and 0.071), respectively. The mean overlap between rGTV and PTV1/PTV2 for c1 & c2 were 99.2% & 96.9%/99.8% & 78.7% (p=0.489/0.133), respectively. CONCLUSION Median OS was slightly longer for c2 though not statistically significant. rGTV in c1 received higher radiation doses and had more overlap with PTV2 than in c2. Out-of-field recurrence appears more likely in c2 suggesting better infield control with belinostat. This study highlights the potential of belinostat as a synergistic therapeutic agent for GBM treatment.

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

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.

Treatment of glioblastoma in Venezuela: Limitations using the current standard of care

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e13036-e13036
Author(s):  
E. I. Arbona-Roche ◽  
C. Sucre ◽  
R. Vera-Gimón ◽  
A. Vera-Gimón ◽  
R. Vera-Vera ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Standard Of Care ◽  
High Rate ◽  
Phase Iii ◽  
Stevens Johnson Syndrome ◽  
Hematologic Toxicity ◽  
Current Standard ◽  
Johnson Syndrome ◽  
Newly Diagnosed Glioblastoma ◽  
Grade 3

e13036 Background: The EORTC/NCIC phase III clinical trial using chemoirradiation with temozolomide (TMZ) 75 mg m-2 x 42d, followed by adyuvant TMZ 150–200 mg m-2 daily x 5d q28d x six cycles set a new standard of care for newly diagnosed glioblastoma (GBM). The applicability of this regimen in developing countries can be problematic. Objectives: To review our experience in Venezuela, contrasting overall survival (OS), 6-month progression-free survival (6PFS), and toxicity in our patients with corresponding outcomes from the EORTC/NCIC trial. Methods: We treated 30 patients with this regimen from March 2001 through July 2004. Results: The median age was 51 years; 17 (60%) were men; 27 (90%) had biopsy or partial resection; 27 (90%) took prophylactic anticonvulsants; and 23 (77%) had prophylaxis against P. jiroveci. Most patients (83%) took the full TMZ treatment during radiation, 7% interrupted TMZ during RT, and 10% could not afford the drug. One patient had Stevens-Johnson syndrome and did not complete RT. Twelve (40%) patients had stereotactic radiosurgery for recurrent disease during the adjuvant phase. The 24-month OS was 30%, median OS was 7.5 months, median PFS was 5 months, and 6PFS was 41%. SRS did not have any effect on OS (p = 0.17, logrank). Grade 3–4 hematologic toxicity was seen in two patients (7%). Conclusions: Except for differences in median OS (7.1 mo) and in 6-PFS (12.6 percentage points) all other measures were reasonably close to the EORTC/NCIC trial. Of concern is the high rate of anticonvulsant prophylaxis using enzyme-inducing drugs and the difficult access to TMZ. No significant financial relationships to disclose.

scholarly journals Results of Radiation Therapy as Local Ablative Therapy for Oligometastatic Non-Small Cell Lung Cancer

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5773
Author(s):  
David L. Billing ◽  
Andreas Rimner
Keyword(s):  
Lung Cancer ◽  
Radiation Therapy ◽  
Cancer Patients ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Survival Outcomes ◽  
Ablative Therapy ◽  
Lung Cancer Patients ◽  
Local Ablative Therapy ◽  
The Impact

Oligometastatic cancer is characterized by a limited number of metastatic deposits. Compared with lung cancer patients who have more widespread disease, oligometastatic lung cancer patients have more favorable survival outcomes. Therefore, it has been hypothesized that local ablative therapy (LAT) directed at the metastatic deposits in addition to standard-of-care systemic therapy may further improve survival outcomes in oligometastatic lung cancer patients. One LAT modality that has been utilized in oligometastatic lung cancer is radiation therapy. In particular, ultra-hypofractionated radiotherapy, also known as stereotactic body radiotherapy (SBRT), has been shown to provide excellent local control with a favorable safety profile. Here, we reviewed the retrospective studies and prospective trials that have deployed radiation therapy as LAT in oligometastatic lung cancer, including randomized studies showing benefits for progression-free survival and overall survival with the addition of LAT. We also discuss the impact of targeted therapies and immunotherapy on radiation as LAT.

RTID-05. THE MULTI-ARM GLIOBLASTOMA AUSTRALASIA (MAGMA) TRIAL

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi193-vi194
Author(s):  
Benjamin Kong ◽  
Hao-Wen Sim ◽  
Eng-Siew Koh ◽  
Hui Gan ◽  
Elizabeth H Barnes ◽  
...  
Keyword(s):  
Data Collection ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Phase Iii ◽  
Low Grade ◽  
Newly Diagnosed ◽  
Current Standard ◽  
Future Design ◽  
Multiple Treatment ◽  
Newly Diagnosed Glioblastoma

Abstract BACKGROUND Survival outcomes for patients with newly diagnosed glioblastoma have not changed significantly since the introduction of concurrent temozolomide with post-surgical radiation followed by adjuvant temozolomide. METHODS Multi-Arm Glioblastoma Australasia (MAGMA) is a recently initiated phase III multi-arm, multi-centre randomized trial for patients with newly diagnosed glioblastoma, led by the Australian Cooperative Trials Group for Neuro-Oncology (COGNO), that will concurrently test multiple treatment questions. Initially, a partial factorial design will be implemented to compare the current standard of care with either or both of (1) neoadjuvant temozolomide and (2) aduvant temozolomide continued beyond six months until progression. MAGMA will transition to a multi-arm multi-stage (MAMS) design as additional tratment question are introduced. Treatment allocation to each question will be balanced (1:1) using minimisation over several stratification factors, including study site, age, IDH-mutation status, surgical extent and randomization to the prior treatment question(s). The primary outcome is overall survival. Secondary outcomes include progression-free survival (measured by mRANO), time to first non-temozolomide systemic treatment, clinically significant toxicity as measured by Grade 2/4 adverse events, and health-related quality of life measures. Parsimonious data collection and a streamlined assessment schedule have been incorporated to mitigate the burden of data collection (such as low grade toxicity from temozolomide), and to encourage participation in regional and rural settings. A consortium model has been adopted to foster neuro-oncology expertise and infrastructure and share academic credit and future design opportunities. PROGRESS Recruitment commenced in September 2020. To date, 60 patients have been recruited from an initial sample size target of 250 patients for each of these initial two treatment questions. Of these 60 patients, 45 have been randomized in Question 1 (neoadjuvant chemotherapy) whilst 50 randomized in Question 2 (prolonged adjuvant chemotherapy). To date, 14 of the 27 intended sites are open to recruitment.

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

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi23-vi24 ◽  
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.

scholarly journals Characterizing benefit from temozolomide in MGMT promoter unmethylated and methylated glioblastoma: a systematic review and meta-analysis

2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Iyad Alnahhas ◽  
Mouaz Alsawas ◽  
Appaji Rayi ◽  
Joshua D Palmer ◽  
Raju Raval ◽  
...  
Keyword(s):  
Systematic Review ◽  
Meta Analysis ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Phase Iii ◽  
Current Standard ◽  
Prospective Data ◽  
Free Survival ◽  
Mgmt Promoter ◽  
Newly Diagnosed Glioblastoma

Abstract Background The current standard of care for the management of patients with newly diagnosed glioblastoma (GBM) includes maximal safe resection followed by radiotherapy (RT) with concurrent and adjuvant temozolomide (TMZ). While it is well established that TMZ has better efficacy in patients with MGMT promoter methylation, it remains an area of debate whether TMZ should be omitted when treating GBM patients with unmethylated MGMT. Methods We conducted a systematic review and meta-analysis to provide separate estimates of median overall survival (OS) and progression-free survival (PFS) for patients with methylated and unmethylated GBM treated with RT with or without TMZ. We searched multiple databases from inception to January 13, 2020. Results The median OS for patients with unmethylated GBM treated with RT/TMZ pooled from 5 phase III studies (N = 655) was 14.11 months (95% confidence interval [CI], 13.18–15.04) with a median PFS of 4.99 months (95% CI, 4.25–5.72). In contrast, the median OS for patients with methylated GBM pooled from 6 studies (N = 753) was 24.59 months (95% CI, 22.19–26.99) with a median PFS pooled from 7 studies (N = 805) of 9.51 months (95% CI, 7.41–11.61). There is a paucity of prospective data pertaining to OS/PFS in unmethylated patients treated with RT only and therefore a direct comparison was not possible. Conclusions This meta-analysis provides estimates of survival for patients with MGMT methylated or unmethylated GBM treated with RT/TMZ. Further research is needed to delineate whether TMZ should be withheld for patients with unmethylated GBM outside of the setting of clinical trials.

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