CTIM-26. PHASE I/II STUDY OF THE COMBINATION OF PEMBROLIZUMAB (MK-3475) AND LASER INTERSTITIAL THERMAL THERAPY (LITT) IN RECURRENT GLIOBLASTOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi56-vi56
Author(s):  
Jian Campian ◽  
Omar Butt ◽  
Ashley Ghinaseddin ◽  
Maryam Rahman ◽  
Milan Chheda ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Interim Analysis ◽  
Progression Free Survival ◽  
High Grade Glioma ◽  
Recurrent Glioblastoma ◽  
Thermal Therapy ◽  
Two Phase ◽  
Laser Interstitial Thermal Therapy ◽  
Cns Penetration

Abstract BACKGROUND The blood brain barrier (BBB) remains a potential barrier to central nervous system (CNS) penetration of novel immunotherapies in recurrent glioblastoma (rGBM). Laser interstitial thermal therapy (LITT) was recently demonstrated to induce BBB disruption. When combined with anti-PD1 blockade, LITT may therefore potentiate host T-cell mediated cytotoxicity. This phase I/II study aims to evaluate the safety and efficacy of combining LITT and the PD-1 inhibitor pembrolizumab for rGBM. METHODS Phase I treated eligible bevacizumab-naïve high grade glioma patients with LITT and the anti-PD1 inhibitor pembrolizumab at 3 dose levels (100, 150, and 200 mg IV Q3W; 3 patients at each level), while phase II was restricted to rGBM patients only with the recommended phase II dose (RP2D) of pembrolizumab. Phase II was initially designed to randomize rGBM to either pembrolizumab or pembrolizumab+LITT but was later amended to receive only pembrolizumab+LITT after 16 patients were randomized (10 pembrolizumab+LITT arm, 6 pembrolizumab-alone arm). Progression-free survival (PFS) and overall survival (OS) were evaluated using the Kaplan Meier method, and adverse events (AE) documented. RESULTS Phase I enrolled 9 patients (7 rGBM and 2 anaplastic astrocytomas, 33% IDH-mut, 44% MGMTp-methylated) with no dose limiting toxicities (DLT), prompting selection of 200mg Q3W as the RP2D. Phase II interim analysis included 34 rGBM patients (9% IDH-mut, 50% MGMTp-methylated; 6 receiving pembrolizumab alone and 28 pembrolizumab+LITT) plus two Phase I rGBM patients who received RP2D. On per-protocol analysis, pembrolizumab+LITT cohort had improved PFS (median PFS 10.5 months vs 2.1 months) and OS (median OS 11.4 months vs 5.2 months) than pembrolizumab alone. A single treatment-related grade 3 AE was noted (respiratory infection). CONCLUSION: LITT may be safely combined with pembrolizumab for rGBM with promising clinical outcomes on interim analysis. Enrollment for Phase II, correlative studies, and continued AE documentation are ongoing. Clinical Trial ID NCT02311582.

Interim analysis of a phase I/II study of panobinostat in combination with bevacizumab for recurrent glioblastoma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2013-2013 ◽  
Author(s):  
Eudocia Quant Lee ◽  
David A. Reardon ◽  
David Schiff ◽  
Jan Drappatz ◽  
Alona Muzikansky ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Interim Analysis ◽  
Safety Data ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Recurrent Glioblastoma ◽  
Free Survival ◽  
Deacetylase Inhibitor ◽  
Recurrent Gbm

2013 Background: Bevacizumab is frequently used to treat recurrent GBM, but responses are generally not durable. Panobinostat is a histone deacetylase inhibitor with anti-neoplastic and anti-angiogenic effects in GBM and may work synergistically with bevacizumab. We conducted a multicenter phase I/II trial of panobinostat in combination with bevacizumab in patients with recurrent GBM. Methods: In the phase II trial, patients with recurrent GBM were treated with oral panobinostat 30 mg three times per week, every other week, in combination with bevacizumab 10 mg/kg every other week. The primary endpoint was 6-month progression-free survival (PFS6) and the study was powered to discriminate between a 35% and 55% PFS6 rate (85% power at an alpha level of 0.07). A planned interim analysis specified suspension of accrual and careful data review if 12 or more of the first 21 patients accrued to the study progress within 6 months of initiating treatment. Patients with recurrent GBM enrolled in the phase I study at the maximum tolerated dose (which is the phase II dose) were eligible for inclusion in the interim analysis. Results: Thirteen of the first 21 patients accrued to the GBM arm of the study had progressed within 6 months of initiating study treatment. The study was closed to further accrual and a planned interim analysis was performed. Median age was 53 (range 22-66) and median KPS was 80% (60%-100%). PFS6 rate was 33.9% [95% CI 12.8, 56.5), median was PFS 5 months [95% CI 3 months, NR], and median OS was 342 days [95% CI 203 days, NR]. Five patients (23.8%) achieved partial responses. Conclusions: Although reasonably well-tolerated, this phase I/II study of panobinostat and bevacizumab in recurrent GBM did not meet criteria for continued accrual and the study was closed. Updated outcome and safety data will be presented at the meeting. Study Supported by: Novartis and Genentech Clinical trial information: NCT00859222.

scholarly journals SURG-13. LASER INTERSTITIAL THERMAL THERAPY FOR RECURRENT GLIOBLASTOMA: A REVIEW OF SURVIVAL OUTCOMES COMPARED TO A MATCHED SURGICAL COHORT

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii206-ii206
Author(s):  
Hassan Fadel ◽  
Sameah Haider ◽  
Jacob Pawloski ◽  
Hesham Zakaria ◽  
Farhan Chaudhry ◽  
...  
Keyword(s):  
Surgical Resection ◽  
Subgroup Analysis ◽  
Tumor Volume ◽  
Progression Free Survival ◽  
Recurrent Glioblastoma ◽  
Thermal Therapy ◽  
Survival Outcomes ◽  
Repeat Surgery ◽  
Laser Interstitial Thermal Therapy ◽  
Recurrent Gbm

Abstract INTRODUCTION Glioblastoma (GBM) is uniformly associated with a poor prognosis and inevitable recurrence. Management of recurrent GBM remains unclear, with repeat surgery often employed with varying degrees of success. We evaluated the efficacy of Laser Interstitial Thermal Therapy (LITT) for recurrent GBM when compared to a carefully matched cohort of patients treated with repeat surgical resection. METHODS A retrospective single-institution database was used to identify patients who underwent LITT or surgical resection of recurrent GBM between 2014-2019. LITT patients were matched with surgical resection patients according to baseline demographics, comorbidities, tumor location, and eloquence. Subgroup analysis matching similar patients for tumor volume was also completed. Overall survival (OS) and progression-free survival (PFS) were the primary endpoints. RESULTS A LITT cohort of 20 patients was matched to 50 similar patients who underwent repeat surgical resection. Baseline characteristics were similar between both cohorts apart from tumor volume, which was larger in the surgical cohort (17.5 cc vs. 4.7 cc, p< 0.01). On long-term follow-up, there was no difference in OS (HR, 0.72; 95%CI, 0.36-1.45) or PFS (HR, 0.67; 95%CI, 0.29-1.53) between the LITT and surgical cohorts when controlling for tumor volume. Subgroup analysis of 23 LITT patients matched according to tumor volume with 23 surgical patients with similar clinical characteristics also found no difference in OS (HR, 0.66; 95%CI, 0.33-1.30) or PFS (HR, 0.58; 95%CI, 0.90-1.05) between the cohorts. LITT patients had shorter length of stays (1 vs. 4 days, p< 0.001) and a higher rate of home discharge (84% vs. 67%, p=0.172) compared to the surgical cohort. CONCLUSION After matching for demographic, clinical, and tumor characteristics, there was no difference in outcomes between patients undergoing LITT compared to surgical resection for recurrent GBM. LITT patients had similar survival outcomes yet shorter hospital stays and more favorable dispositions, potentially mitigating post-treatment complications.

scholarly journals Laser interstitial thermal therapy for newly diagnosed and recurrent glioblastoma

2016 ◽  
Vol 41 (4) ◽  
pp. E12 ◽  
Author(s):  
Jonathan G. Thomas ◽  
Ganesh Rao ◽  
Yvonne Kew ◽  
Sujit S. Prabhu
Keyword(s):  
Median Survival ◽  
Progression Free Survival ◽  
Primary Brain Tumor ◽  
Recurrent Glioblastoma ◽  
Thermal Therapy ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Laser Interstitial Thermal Therapy ◽  
Median Progression Free Survival ◽  
Recurrent Gbm

OBJECTIVE Glioblastoma (GBM) is the most common and deadly malignant primary brain tumor. Better surgical therapies are needed for newly diagnosed GBMs that are difficult to resect and for GBMs that recur despite standard therapies. The authors reviewed their institutional experience of using laser interstitial thermal therapy (LITT) for the treatment of newly diagnosed or recurrent GBMs. METHODS This study reports on the pre-LITT characteristics and post-LITT outcomes of 8 patients with newly diagnosed GBMs and 13 patients with recurrent GBM who underwent LITT. RESULTS Compared with the group with recurrent GBMs, the patients with newly diagnosed GBMs who underwent LITT tended to be older (60.8 vs 48.9 years), harbored larger tumors (22.4 vs 14.6 cm3), and a greater proportion had IDH wild-type GBMs. In the newly diagnosed GBM group, the median progression-free survival and the median survival after the procedure were 2 months and 8 months, respectively, and no patient demonstrated radiographic shrinkage of the tumor on follow-up imaging. In the 13 patients with recurrent GBM, 5 demonstrated a response to LITT, with radiographic shrinkage of the tumor following ablation. The median progression-free survival was 5 months, and the median survival was greater than 7 months. CONCLUSIONS In carefully selected patients with recurrent GBM, LITT may be an effective alternative to surgery as a salvage treatment. Its role in the treatment of newly diagnosed unresectable GBMs is not established yet and requires further study.

scholarly journals Results of the NeuroBlate System first-in-humans Phase I clinical trial for recurrent glioblastoma

2013 ◽  
Vol 118 (6) ◽  
pp. 1202-1219 ◽  
Author(s):  
Andrew E. Sloan ◽  
Manmeet S. Ahluwalia ◽  
Jose Valerio-Pascua ◽  
Sunil Manjila ◽  
Mark G. Torchia ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Dose Escalation ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Recurrent Glioblastoma ◽  
Thermal Therapy ◽  
Laser Interstitial Thermal Therapy ◽  
Karnofsky Performance Status Score ◽  
Performance Status Score

Object Laser interstitial thermal therapy has been used as an ablative treatment for glioma; however, its development was limited due to technical issues. The NeuroBlate System incorporates several technological advances to overcome these drawbacks. The authors report a Phase I, thermal dose–escalation trial assessing the safety and efficacy of NeuroBlate in recurrent glioblastoma multiforme (rGBM). Methods Adults with suspected supratentorial rGBM of 15- to 40-mm dimension and a Karnofsky Performance Status score of ≥ 60 were eligible. After confirmatory biopsy, treatment was delivered using a rigid, gas-cooled, side-firing laser probe. Treatment was monitored using real-time MRI thermometry, and proprietary software providing predictive thermal damage feedback was used by the surgeon, along with control of probe rotation and depth, to tailor tissue coagulation. An external data safety monitoring board determined if toxicity at lower levels justified dose escalation. Results Ten patients were treated at the Case Comprehensive Cancer Center (Cleveland Clinic and University Hospitals–Case Medical Center). Their average age was 55 years (range 34–69 years) and the median preoperative Karnofsky Performance Status score was 80 (range 70–90). The mean tumor volume was 6.8 ± 5 cm3 (range 2.6–19 cm3), the percentage of tumor treated was 78% ± 12% (range 57%–90%), and the conformality index was 1.21 ± 0.33 (range 1.00–2.04). Treatment-related necrosis was evident on MRI studies at 24 and 48 hours. The median survival was 316 days (range 62–767 days). Three patients improved neurologically, 6 remained stable, and 1 worsened. Steroid-responsive treatment-related edema occurred in all patients but one. Three had Grade 3 adverse events at the highest dose. Conclusions NeuroBlate represents new technology for delivering laser interstitial thermal therapy, allowing controlled thermal ablation of deep hemispheric rGBM. Clinical trial registration no.: NCT00747253 (ClinicalTrials.gov).

scholarly journals RADT-26. LASER INTERSTITIAL THERMAL THERAPY FOR RECURRENT GLIOBLASTOMA: POOLED ANALYSES OF AVAILABLE LITERATURE

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii187-ii187
Author(s):  
Amanda Munoz Casabella ◽  
Masum Rahman ◽  
Mohammed Alvi ◽  
Desmond Brown
Keyword(s):  
Overall Survival ◽  
Survival Data ◽  
Yttrium Aluminum Garnet ◽  
Meta Analysis ◽  
Progression Free Survival ◽  
Recurrent Glioblastoma ◽  
Thermal Therapy ◽  
Fe Model ◽  
Free Survival ◽  
Laser Interstitial Thermal Therapy

Abstract INTRODUCTION Laser Interstitial Thermal Therapy (LITT) is a novel treatment modality that has been used for an array of intracranial pathology. In the current manuscript, we sought to conduct a systematic review and meta-analysis to summarize all available literature to date, on outcomes of patients with recurrent GBM (r-GBM) undergoing LITT, pooling together quantitatively the overall survival and progression-free survival data. METHODS A comprehensive literature search was performed to retrieve all studies investigating overall survival, post-procedure survival, and progression-free survival outcomes of patients with r-GBM undergoing LITT. All statistics were pooled together by the meta-analysis of the mean using a weighted random-effects (RE) or fixed-effect (FE) model. RESULTS Eleven studies were included in the final cohort, representing a total of 134 patients with rGBM. The pooled mean age of the cohort at the time of recurrence diagnosis was found to be 56.7 ± 4.56 while 41% of the cohort were females. For the delivery of LITT, two studies utilized neodymium-yttrium aluminum-garnet laser (Neodp-YAG Laser), three studies utilized the Visualase system, five studies utilized the Neuroblate system, and one study used both the Neuroblate and the Visualase system. A total of eight studies with 107 patients had available data for overall median survival. The pooled overall survival was found to be 18.6 months (95%CI 16.2-21.1). A total of six studies with 93 patients had available data for post-LITT survival. The pooled post-LITT survival was found to be 10.1 months (95%CI 8.8-11.6). A total of eight studies with 119 patients had available data for progression-free survival. The pooled progression-free survival was found to be 6 months (95%CI 5.3-6.7). CONCLUSION LITT is a novel minimally invasive procedure which, when used with optimal adjuvant therapy, may confer survival benefit for patients with r-GBM.

CTIM-09. PHASE I STUDY OF PD-L1 INHIBITION WITH AVELUMAB AND LASER INTERSTITIAL THERMAL THERAPY IN PATIENTS WITH RECURRENT GLIOBLASTOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi51-vi51
Author(s):  
Adilia Hormigo ◽  
Daniel Chiu ◽  
Mary Hahn ◽  
Jingjing Qi ◽  
Brian Lee ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Primary Objective ◽  
Recurrent Glioblastoma ◽  
Thermal Therapy ◽  
Treatment Modalities ◽  
Dependent Manner ◽  
Serious Adverse Events ◽  
Laser Interstitial Thermal Therapy ◽  
Peripheral Blood Plasma ◽  
Grade 3

Abstract BACKGROUND The treatment of glioblastoma (GBM) poses many challenges. The use of immune checkpoint inhibition (ICI) has been disappointing as GBM is characterized by a low mutational burden and low infiltration by T cells. The combination of ICI with other treatment modalities may improve efficacy. METHODS Patients with recurrent GBM were treated with 800 mg avelumab, a human IgG1 antibody directed against PD-L1, either alone (in part A) or within a week after MRI-guided laser interstitial thermal therapy (LITT, in part B) and by-weekly thereafter (NCT03341806). To spare steroid use, bevacizumab was allowed to be combined with avelumab. The primary objective was to characterize the tolerability and safety of the regimen. The secondary objectives included overall survival, progression-free survival, and signature of plasma analytes. RESULTS A total of 12 patients (median age 64, range 37 - 73) enrolled from June 2018 to November 2019, 5 in part A and 7 in part B. Three serious adverse events (SAE) occurred in the same patient, not leading to death. There were 94 AEs reported, 5 grade 3, 28 grade 2, and 61 grade 1. The median PFS was 16.7 weeks (range 7.4-56.7) for patients in Part A and 30.9 weeks (range 8.5-77.7) for patients in Part B. The median survival for patients in part A was 11 months and 13.5 months for part B. The risk ratio of death by combining bevacizumab was 0.573 (p=0.258) with significantly decreased levels of peripheral blood plasma inflammatory markers such as EGF, CXCL5, VEGFA, LAP.TGβ1, ANGPT2 in women. CONCLUSIONS Avelumab was generally well-tolerated, and the combination with LITT had a manageable safety profile and increased survival in a subset of patients. The addition of bevacizumab may increase survival by lowering cytokine expression in a gender-dependent manner. These results warrant further investigation in the next phase study.

scholarly journals Nurses’ educational needs when dealing with aggression from patients and their families: a mixed-methods study

BMJ Open ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. e041711
Author(s):  
Kana Sato ◽  
Yoshimi Kodama
Keyword(s):  
Mixed Methods ◽  
Nursing Students ◽  
Phase I ◽  
Phase Ii ◽  
Mixed Methods Study ◽  
Self Awareness ◽  
Two Phase ◽  
Sequential Mixed Methods ◽  
Nursing Professionals ◽  
Educational Contents

ObjectivesTo explore the type of education needed for nurses when dealing with aggression from patients and their families.DesignA two-phase sequential mixed-methods study.SettingThis study was conducted in Japan, with phase I from March to November 2016 and phase II in November 2018.Main outcome measuresThe challenges faced by nurses when dealing with incidents of aggression from the neutral perspective of neither nurse nor patient/family and perceptions of the educational contents developed in this study. Descriptive analyses were used to examine the data retrieved from both phases.ParticipantsPhase I entailed semistructured interviews among 11 neutral-party participants who observed aggressive incidents between nurses and patients/families. Phase II consisted of a web survey conducted among 102 nursing students and 308 nursing professionals.ResultsPhase I resulted in the identification of the following five main educational components: understanding the mechanisms of anger and aggression, maintaining self-awareness, observant listening, managing the self-impression, and communicating based on specific disease characteristics. Each component was related to improved communication through self-awareness. The results of phase II indicated that participants positively perceived these educational contents as likely to be effective for dealing with aggression from patients/families.ConclusionsThis study clarified the type of education needed for nurses when dealing with aggression based on multiple viewpoints. Specifically, neutral-party interviews revealed that communication should be improved through self-awareness. A subsequent survey among nurses and nursing students showed that the identified educational contents were positively received.

scholarly journals AT-46 * VORINOSTAT AND BEVACIZUMAB FOR RECURRENT HIGH-GRADE GLIOMA: INTERIM ANALYSIS OF A PHASE II CLINICAL TRIAL

2014 ◽  
Vol 16 (suppl 5) ◽  
pp. v18-v18
Author(s):  
K. Peters ◽  
D. Reardon ◽  
D. Randazzo ◽  
S. Dutton ◽  
A. Edwards ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase Ii ◽  
Interim Analysis ◽  
High Grade Glioma ◽  
Phase Ii Clinical Trial ◽  
High Grade

scholarly journals Marizomib alone or in combination with bevacizumab in patients with recurrent glioblastoma: phase I/II clinical trial data

2021 ◽  
Author(s):  
Daniela A Bota ◽  
Warren Mason ◽  
Santosh Kesari ◽  
Rajiv Magge ◽  
Benjamin Winograd ◽  
...  
Keyword(s):  
Phase I ◽  
Blood Brain Barrier ◽  
Dose Escalation ◽  
Safety Profile ◽  
Clinical Trial Data ◽  
Progression Free Survival ◽  
Recurrent Glioblastoma ◽  
Brain Barrier ◽  
Part C ◽  
Blood Brain

Abstract Background This phase I/II trial in patients with recurrent glioblastoma (GBM) evaluates the safety and preliminary efficacy of marizomib, an irreversible pan-proteasome inhibitor that crosses the blood–brain barrier. Patients and Methods Part A assessed the safety and efficacy of marizomib monotherapy. In Part B, escalating doses of marizomib (0.5–0.8 mg/m2) in combination with bevacizumab were evaluated. Part C explored intra-patient dose escalation of marizomib (0.8–1.0 mg/m2) for the combination. Results In Part A, 30 patients received marizomib monotherapy. The most common AEs were fatigue (66.7%), headache (46.7%), hallucination (43.3%), and insomnia (43.3%). One patient (3.3%) achieved a partial response. In Part B, the recommended phase II dose of marizomib was 0.8 mg/m2 when combined with bevacizumab 10 mg/kg. In Part C, dose escalation to 1.0 mg/m2 was not tolerated. Pooled analysis of 67 patients treated with marizomib ≤0.8 mg/m2 and bevacizumab showed a non-overlapping safety profile consistent with the known safety profile of each agent: the most common grade ≥3 AEs were hypertension (16.4%), confusion (13.4%), headache (10.4%), and fatigue (10.4%). The overall response rate was 34.3%, including 2 patients with complete response. Six-month progression-free survival was 29.8%; median overall survival was 9.1 months. Conclusions The safety profile of marizomib as monotherapy and in combination with bevacizumab was consistent with previous observations that marizomib crosses the blood–brain barrier. Preliminary efficacy did not demonstrate a meaningful benefit of the addition of marizomib to bevacizumab for the treatment of recurrent GBM.

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