CTNI-48. A PHASE 0 ‘TRIGGER’ TRIAL OF CDK4/6 PLUS ERK1/2 INHIBITORS IN RECURRENT GLIOBLASTOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi70-vi71
Author(s):  
Nader Sanai ◽  
Yu-Wei Chang ◽  
Tigran Margaryan ◽  
Anita DeSantis ◽  
Mackenna Elliott ◽  
...  
Keyword(s):  
Tumor Tissue ◽  
Drug Dose ◽  
Recurrent Glioblastoma ◽  
Optimal Time ◽  
Time Interval ◽  
Tumor Proliferation ◽  
Drug Concentrations ◽  
Phase 0 ◽  
Recurrent Gbm ◽  
Dual Drug

Abstract BACKGROUND This dual-drug Phase 0 study (NCT04391595) evaluates the tumor pharmacokinetics (PK) and tumor pharmacodynamics (PD) of abemaciclib, a selective CDK4/6-inhibitor, plus LY3214996, a selective ERK1/2 inhibitor, in recurrent GBM patients. METHODS Adult recurrent GBM patients (n=10) with intact RB expression, > 30% pERK expression, and CDKN2A/B deletion or CDK4/6 amplification received six days of abemaciclib (150mg BID) plus LY3214996 (200mg QD) prior to a planned resection at 3-5 or 7-9 hour time interval after the final drug dose in a Time-Escalation Arm. Tumor tissue (gadolinium [Gd]-enhancing and nonenhancing regions), cerebrospinal fluid (CSF), and plasma were collected. Total and unbound drug concentrations were measured using validated LC-MS/MS methods. Tumor PD effects, including RB and RSK phosphorylation, were compared to matched archival or pre-treatment biopsied tissue. A PK ‘trigger’ (i.e., unbound concentration > 5x biochemical IC50) was set for each drug. Gd-nonenhancing tumor tissue exhibiting abemaciclib and LY3214996 concentrations in excess of their trigger threshold qualified patients for postoperative dual-drug therapy. RESULTS No dose-limiting toxicities were observed. In Gd-nonenhancing tumor regions, median unbound concentrations of abemaciclib were 31.2 nM (3-5 hour cohort) and 25.1 nM (7-9 hour cohort) while median unbound concentrations of LY3214996 were 52.0 nM (3-5 hour cohort) and 10.2 nM (7-9 hour cohort). Tumor RB and RSK phosphorylation decreased in 6/10 and 2/10 patients, respectively. Tumor proliferation (MIB-1) was decreased in 8/10 patients. 5/10 patients exceeded PK thresholds for both abemaciclib (12 nM) and LY3214996 (25 nM), thereby entering the study’s therapeutic expansion phase. CONCLUSION Abemaciclib and LY3214996 achieve pharmacologically-relevant concentrations in Gd-non-enhancing GBM tissue and are associated with suppression of RB pathway and tumor proliferation. The Optimal Time Interval (OTI) for tissue sampling was 3-5 hours after the final drug dose. Based on this interim analysis, the trial will accrue an additional 25 patients at this OTI.

A Phase 0 ‘trigger’ trial of CDK4/6 plus ERK1/2 inhibitors in recurrent glioblastoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2005-2005
Author(s):  
Nader Sanai ◽  
Yu-Wei Chang ◽  
Tigran Margaryan ◽  
Anita DeSantis ◽  
Mackenna Elliott ◽  
...  
Keyword(s):  
Interim Analysis ◽  
Tumor Tissue ◽  
Mapk Signaling ◽  
Drug Dose ◽  
Time Interval ◽  
Tumor Proliferation ◽  
Drug Concentrations ◽  
Phase 0 ◽  
Recurrent Gbm ◽  
Dual Drug

2005 Background: The RB-CDK4/6 and MAPK signaling pathways are dysregulated in glioblastoma (GBM). Our recent phase 0 study of ribociclib in recurrent GBM patients suggested that CDK4/6 inhibitor monotherapy is not durable. In this ongoing, dual-drug phase 0 study (NCT04391595), we evaluate the tumor pharmacokinetics (PK) and tumor pharmacodynamics (PD) of abemaciclib, a selective CDK4/6-inhibitor, plus LY3214996, a selective ERK1/2 inhibitor, in recurrent GBM patients. Methods: Adult patients eligible for this open-label, multi-center phase 0 protocol had recurrent GBM with (1) intact RB expression, (2) >30% pERK expression, and (3) CDKN2A/B deletion or CDK4/6 amplification. Prior to a planned resection, patients received six days of abemaciclib (150mg BID) plus LY3214996 (200mg QD). In a Time-Escalation Arm, ten patients were assigned to 3-5 hour or 7-9 hour intervals from final drug dose to tumor removal. Tumor tissue (gadolinium [Gd]-enhancing and nonenhancing regions), cerebrospinal fluid (CSF), and plasma were collected. Total and unbound drug concentrations were measured using validated LC-MS/MS methods. Tumor PD effects, including RB and RSK phosphorylation, were compared to matched archival or pre-treatment biopsied tissue. A PK ‘trigger’ ( i.e., unbound concentration > 5x biochemical IC50) was set for each drug. Gd-nonenhancing tumor tissue exhibiting abemaciclib and LY3214996 concentrations in excess of their trigger threshold qualified patients for postoperative dual-drug therapy. Results: In this interim analysis, no dose-limiting toxicities were observed. In Gd-nonenhancing tumor regions, median unbound concentrations of abemaciclib (including its equipotent M2 and M20 metabolites) were 31.2 nM (3-5 hour cohort) and 25.1 nM (7-9 hour cohort). In the same tissue, median unbound concentrations of LY3214996 were 52.0 nM (3-5 hour cohort) and 10.2 nM (7-9 hour cohort). Tumor RB and RSK phosphorylation decreased in 6/10 and 2/10 patients, respectively. Gd-enhancing tumor proliferation (MIB-1) was decreased in 8/10 patients. 5/10 patients exceeded PK thresholds for both abemaciclib (12 nM) and LY3214996 (25 nM), thereby entering the study’s therapeutic expansion phase. Conclusion: Abemaciclib and LY3214996 achieve pharmacologically-relevant concentrations in Gd-non-enhancing GBM tissue and are associated with suppression of the RB pathway and tumor proliferation. Following 6 days of presurgical drug exposure, the Optimal Time Interval (OTI) for tissue sampling was 3-5 hours after the final drug dose. Based on this interim analysis, the trial will accrue an additional 25 patients at this OTI. Clinical trial information: NCT04391595.

scholarly journals DDRE-10. METABOLIC TARGETING OF HUMAN GLIOBLASTOMA USING 5-AMINOLEVULINIC ACID (ALA)-MEDIATED SONODYNAMIC THERAPY: A FIRST-IN-HUMAN STUDY

2020 ◽  
Vol 3 (Supplement_1) ◽  
pp. i8-i8
Author(s):  
Stuart Marcus ◽  
Nader Sanai
Keyword(s):  
Brain Tumor ◽  
Internal Control ◽  
Tumor Tissue ◽  
Aminolevulinic Acid ◽  
Clinical Care ◽  
Human Study ◽  
Time Interval ◽  
Sonodynamic Therapy ◽  
Phase 0 ◽  
Recurrent Gbm

Abstract Heme biosynthesis is altered in glioblastoma (GBM). Systemic dosing with ALA, the first committed molecule in the heme pathway, results in accumulation of the fluorescent intermediate, protoporphyrin IX (PpIX) only within tumor tissue (Gleolan label, 2019). PpIX is a photosensitizer that is effective in photodynamic therapy (PDT); in recurrent GBM patients, the safety and feasibility of ALA PDT has been demonstrated (Johansson A, et al. Lasers Surg Med 2013;45:225), although the practicality of this strategy in clinical care remains uncertain. Importantly, preclinical models of GBM show that PpIX is also a sonosensitizer and, in combination with transcranial MRI-guided focused ultrasound (MRgFUS), leads to non-ablative cytotoxic effects in vivo (Jeong EJ et al, Ultrasound in Medicine and Biology 2013:38;2143, Suehiro S et al, J Neurosurg 2018: 1377, Wu et al Nature Sci Reports 2019: 9;10465). The Ivy Brain Tumor Center is conducting a first-in-human study of 5-ALA sonodynamic therapy (SDT) for recurrent GBM (NCT 04559685). In this Phase 0/1 clinical trial, nontherapeutic, single-treatment SDT is administered prior to planned tumor resection. A Dose-Escalation Arm varies the power/energy of the MRgFUS while using a fixed time-interval from exposure to surgery. A subsequent Time-Escalation Arm varies the interval between MRgFUS and surgical resection, but fixes the power/energy of the delivered ultrasound. In both Arms, patient tumor tissue is assessed for sonodynamic and pharmacodynamic effects. In each patient, half of the tumor volume is not targeted with SDT and serves as an internal control. This first-in-human study will demonstrate the safety and feasibility of ALA sonodynamic therapy in GBM and may provide the first-ever biological evidence of sonosensitization in a brain tumor patient. If successful, this Phase 0 trial will introduce a new, metabolically-driven, GBM treatment modality that may be applicable to any brain tumor that selectively accumulates PpIX after ALA administration.

Phase II trial of the phosphatidyinositol-3 kinase (PI3K) inhibitor BKM120 in recurrent glioblastoma (GBM).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2015-2015 ◽  
Author(s):  
Patrick Y. Wen ◽  
W. K. Alfred Yung ◽  
Ingo K. Mellinghoff ◽  
Kathleen Lamborn ◽  
Shakti Ramkissoon ◽  
...  
Keyword(s):  
Phase Ii ◽  
Pi3k Pathway ◽  
Homozygous Deletion ◽  
Recurrent Glioblastoma ◽  
Pi3k Inhibitor ◽  
Eligibility Criteria ◽  
Drug Concentrations ◽  
Recurrent Gbm

2015 Background: The PI3K pathway is activated in most GBMs and represents a potential therapeutic target. BKM120 is an oral, pan-Class I PI3K inhibitor that enters the brain at therapeutic concentrations demonstrated to inhibit PI3K pathway, and potently inhibits the growth of U87 GBM tumors and human glioma tumor spheres in vitro and in vivo. Methods: The Ivy Foundation Early Phase Clinical Trials Consortium is conducting a phase II study of BKM120 in recurrent GBM patients with activation of the PI3K pathway (mutation, homozygous deletion or loss of IHC of PTEN, PIK3CA or PIK3RI mutations, or detectable pAKT). Additional eligibility criteria included radiologic progression, 1st or 2nd relapse, > 18 yrs, KPS > 60, adequate bone marrow and organ function, controlled blood glucose, and no enzyme-inducing antiepileptic drugs. Patients received BKM120 100mg daily. The study consisted of 2 parts conducted concurrently. Part 1 involved up to 15 patients who received BKM120 daily for 8-12 days prior to surgery for recurrent disease. Patients underwent FDG PET, pharmacokinetic (PK) studies, and tumor was obtained for drug concentrations and pharmacodynamic effects. Part 2 consisted of up to 50 patients with unresectable GBM treated with BKM120. The primary endpoint for Part 2 was 6-month progression-free survival (p0 =15%; p1= 32%). Results: To date 7 patients have been enrolled into Part 1, 33 into part 2. There were 5 women and 35 men. Median age was 54 yrs (29-68). Treatment was fairly well-tolerated. Major grades 3/4 toxicities were asymptomatic lipase elevation (5), fatigue (3), hyperglycemia (3), rash (3) elevated AST (1), and depression (1). Analysis of tumor from Part 1 showed reduction of pAkt by IHC. Genotyping of tumor specimens is ongoing. To date 33 patients had positive pAkt, 21 had PTEN loss by IHC. Of the first 19 patients who underwent whole exome sequencing, 3 had PIK3Ca mutations and 6 had PTEN mutations. Conclusions: BKM120 is generally well tolerated in patients with recurrent GBM and achieves adequate tumor concentration to inhibit pAkt. Updated PK and efficacy data and correlation of the latter with tumor genotype will be presented. Clinical trial information: NCT01339052.

scholarly journals ACTR-10. PHASE 0 TRIAL OF CERITINIB IN BRAIN METASTASES AND RECURRENT GLIOBLASTOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi14-vi14
Author(s):  
Roberto Fiorelli ◽  
Jing Li ◽  
Xun Bao ◽  
Alanna DeRogatis ◽  
Chelsea Pennington-Krygier ◽  
...  
Keyword(s):  
Brain Metastasis ◽  
Brain Metastases ◽  
Tumor Tissue ◽  
Tumor Resection ◽  
Immunohistochemical Analysis ◽  
Recurrent Glioblastoma ◽  
Drug Binding ◽  
Drug Concentrations ◽  
Orally Bioavailable ◽  
Cns Penetration

Abstract BACKGROUND Ceritinib is an orally bioavailable, small molecule inhibitor for ALK/IGFR1/FAK, which are highly expressed in glioblastoma and brain metastases. Preclinical and clinical reports suggest ceritinib activity in central nervous system (CNS) malignancies, yet there is no direct evidence in patients. This study assessed the pharmacokinetics (PK) and pharmacodynamics (PD) of ceritinib in brain metastases and recurrent glioblastoma patients. METHODS Ten patients with brain metastases (n=3) or glioblastoma (n=7) exhibiting high expression of pSTAT5b/pFAK/pIGFR1 were treated with 10 days of oral ceritinib (750 mg daily) prior to tumor resection. Plasma, tumor, and cerebrospinal fluid (CSF) samples were collected at ~ 4 and 24 h following the last dose. Total and unbound drug concentrations were determined using LC-MS/MS. PD response was assessed by immunohistochemical analysis of pALK, pFAK, pIGFR1, and pIRS1 staining in treated tumor and matched archival tissues. RESULTS Ceritinib was highly bound to human plasma protein (median fraction unbound (Fu), 1.4%) and to brain tumor tissue (median Fu, 0.073% and 0.14% in enhancing and non-enhancing regions respectively). There was a large interindividual variability in drug CNS penetration, with the median unbound concentrations in enhancing, non-enhancing, and CSF of 0.040, 0.006, and 0.012 µM, respectively. The median unbound tumor-to-plasma ratio was 2.44 and 0.33 in enhancing and non-enhancing areas, respectively. In one brain metastasis patient, drug binding to enhancing tumor was significantly lower (Fu, 1.62%), resulting in a higher unbound drug tumor and CSF concentration as compared to all other patients. In all patients, no pharmacodynamic response was detected in sampled tumor tissue. CONCLUSION Ceritinib is highly bound to plasma proteins and tumor tissues. Unbound drug concentrations in brain metastasis and glioblastoma appear insufficient for target modulation. Despite recent reports of clinical response, our findings suggest no role for ceritinib in treating glioblastoma and an unfavorable profile for brain metastases.

CTNI-20. FEASIBILITY OF SINGLE-PASS STEREOTACTIC NEEDLE BIOPSY IN RECURRENT GLIOBLASTOMA PATIENTS TO SUPPORT CLIA-CERTIFIED TUMOR PHARMACODYNAMICS FOR A PHASE 0/2 CLINICAL TRIAL

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi63-vi63
Author(s):  
Yu-Wei Chang ◽  
Anita DeSantis ◽  
Chelsea Pennington-Krygier ◽  
Jennifer Molloy ◽  
Shwetal Mehta ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Needle Biopsy ◽  
Stereotactic Biopsy ◽  
Recurrent Glioblastoma ◽  
Experimental Therapy ◽  
Time Interval ◽  
Single Pass ◽  
Phase 0 ◽  
Before And After ◽  
Pre Treatment

Abstract BACKGROUND In neuro-oncology clinical trials, pharmacodynamic (PD) analysis of tumor tissue before and after experimental therapy is challenging. Today, Phase 0 studies in brain tumor patients typically employ archival tissue from a prior resection as the baseline PD comparator. However, the time-interval between tissue acquisitions can be months to years and often includes confounding exposure to other therapies. Here, we demonstrate the feasibility of a pre-treatment, single-pass stereotactic needle biopsy to support CLIA-certified genetic screening and tumor PD analysis in a Phase 0/2 clinical trial. METHODS In support of an ongoing Phase 0/2 ‘trigger’ trial testing CDK4/6 plus ERK1/2 inhibition in recurrent glioblastoma (GBM), a single-pass stereotactic biopsy was completed in select patients prior to enrollment. Each biopsy yields six tissue cores for immunohistochemistry (IHC) and genetic characterization. Using CLIA-certified protocols, genomic DNA (gDNA) was extracted from two cores, followed by library preparation and next-generation sequencing of a customized panel of 37 genes (IvySeq). In the four remaining cores, IHC staining was performed for RB, pRB, pERK, pS6, CDKN2A, MIB-1, ClCas-3 and pH2AX. RESULTS Single-pass stereotactic needle biopsies were collected from five recurrent GBM patients. No intraoperative, perioperative, or radiographic evidence of morbidity was observed. 800-2400ng of gDNA was isolated from each stereotactic biopsy. IvySeq analysis detected CDKN2A deletion, ATRX loss, and mutations in IDH, PTEN and TP53 genes. Based on IHC and genetic analyses of the biopsied samples, three patients were enrolled into the Phase 0/2 clinical trial and baseline value were used for PD analysis. CONCLUSION Single-pass stereotactic needle biopsy is a feasible and safe strategy to collect pre-treatment tissue in support of a Phase 0 clinical trial, enabling CLIA-certified genetic analysis for trial screening and tumor PD analysis.

Vorinostat, temozolomide, and bevacizumab for patients with recurrent glioblastoma: A phase I/II trial.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2027-2027 ◽  
Author(s):  
Katherine B. Peters ◽  
James J. Vredenburgh ◽  
Annick Desjardins ◽  
Henry S. Friedman ◽  
James Emmett Herndon ◽  
...  
Keyword(s):  
Pulmonary Embolism ◽  
Phase I ◽  
Bowel Perforation ◽  
Previous Treatment ◽  
Progression Free Survival ◽  
Recurrent Glioblastoma ◽  
Time Interval ◽  
Open Label ◽  
Eligibility Criteria ◽  
Recurrent Gbm

2027 Background: Prognosis for recurrent glioblastoma (GBM) remains poor with median survival between 3 to 6 months. Use of anti-vascular endothelial growth factor inhibitor, bevacizumab (BEV), has advanced this area of research, but continued studies have focused on whether the addition of other chemotherapies can improve efficacy in recurrent GBM. Vorinostat, a small molecule inhibitor of histone deactylase (HDAC), has anti-tumor activity directly through HDAC inhibition and indirectly by promoting anti-angiogenesis. Its good oral bioavailability and favorable toxicity profile make it a promising additive agent to standard therapy. Thus, we evaluated the efficacy of vorinostat in combination with BEV and daily temozolomide (TMZ) in recurrent GBM. Methods: This was a phase I/II open-label, single arm study in recurrent GBM patients. Primary endpoint was 6-month progression free survival (PFS). Secondary endpoints were safety/tolerability, radiographic response, PFS, and overall survival of recurrent GBM patients treated with BEV plus daily TMZ and vorinostat. Chief eligibility criteria included age ≥ 18 years, KPS ≥ 70, time interval ≥ four weeks from previous treatment, and maximum of 2 prior progressions. Dosing regimen was as follows: BEV 10 mg/kg IV every two weeks, TMZ 50 mg/m2 po daily, and vorinostat 400 mg po for 7 days on then 7 days off in a 28 day cycle. Results: 46 recurrent GBM patients were enrolled with 42 of those patients receiving a vorinostat dose of 400 mg. Most common grade 2 and above toxicities were leukopenia (36%), neutropenia (29%), fatigue (24%), and thrombocytopenia (19%). Serious toxicities included 4 grade 4 toxicities (grade 4 hyperglycemia, pulmonary embolism, bowel perforation and intracranial hematoma) and 1 patient expired on day of informed consent due to pulmonary embolism (grade 5). With a median follow-up of 11.3 months (95% CI: 10.1, 13.1 months), the 6-month PFS was 52.4% (95% CI: 36.4%, 66.1%). Best radiographic responses were 2 complete responses, 17 partial responses, 20 stable responses, and 1 radiographic progression. Conclusions: In summary, combination of BEV, daily TMZ, and vorinostat has promising efficacy on recurrent GBM with reasonable toxicity/safety.

Feasibility and phase I trial of tandutinib in patients with recurrent glioblastoma

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2039-2039 ◽  
Author(s):  
J. G. Supko ◽  
S. A. Grossman ◽  
D. M. Peereboom ◽  
S. Chowdhary ◽  
G. J. Lesser ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Phase I Study ◽  
Tumor Tissue ◽  
Recurrent Glioblastoma ◽  
The Mean ◽  
Grade 3 ◽  
Recurrent Gbm

2039 Background: Platelet-derived growth factor signaling is important in gliomagenesis and PDGFR-β is expressed on >90% of endothelial cells in glioblastoma specimens. Methods: We report the results of a feasibility and phase I study of tandutinib (MLN518), an orally bioavailable, quinazoline-based inhibitor of type III receptor tyrosine kinases including PDGFR-β, FLT-3, and c-Kit, in patients with recurrent glioblastoma (GBM) conducted in the New Approaches to Brain Tumor Therapy (NABTT) consortium. Results: A feasibility study was conducted in 6 recurrent GBM patients in whom resection was clinically indicated. These patients received tandutinib 500-mg BID for 7 days prior to resection. In these patients, the drug was measured in tumor tissue and plasma samples obtained shortly before and after the resection by LC/MS. The mean ± SD concentration of tandutinib in tumor tissue was 7.2 ± 3.2 μg/mL and the mean ratio of its concentration in brain tumor-to-plasma was 9.6 ± 7.7. A phase I study was conducted in 19 patients to determine the MTD in this recurrent GBM population with sequential assessment of the following dose levels: 500-, 600-, and 700-mg BID. Four patients were replaced due to early withdrawal unrelated to toxicity. Dose limiting toxicities were observed in 1/6 patients at 500-mg BID (grade 3 phosphorous, grade 3 fatigue, grade 3 somnolence in 1 patient); 1/6 patients at 600-mg BID (grade 3 phosphorous); 2/3 patients at 700-mg BID (grade 3 fatigue, grade 3 weakness). 600-mg BID was declared the MTD and a phase II study has been initiated at this dose level. Conclusions: The mean brain tumor tissue-to-plasma ratio of tandutinib in GBM patients receiving 500-mg BID exceeded the estimated threshold ratio of 0.33 that was considered as being necessary to achieve local cytotoxic concentrations in brain tumors. The MTD of tandutinib in the recurrent GBM population is 600-mg BID. A phase II trial has been initiated at this dose level. [Table: see text]

scholarly journals Machine-Learning-Based Radiomics MRI Model for Survival Prediction of Recurrent Glioblastomas Treated with Bevacizumab

Diagnostics ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 1263
Author(s):  
Samy Ammari ◽  
Raoul Sallé de Chou ◽  
Tarek Assi ◽  
Mehdi Touat ◽  
Emilie Chouzenoux ◽  
...  
Keyword(s):  
Machine Learning ◽  
Therapeutic Option ◽  
Binary Classification ◽  
Progression Free Survival ◽  
Recurrent Glioblastoma ◽  
Machine Learning Algorithms ◽  
Survival Prediction ◽  
Classification Models ◽  
Angiogenic Therapy ◽  
Recurrent Gbm

Anti-angiogenic therapy with bevacizumab is a widely used therapeutic option for recurrent glioblastoma (GBM). Nevertheless, the therapeutic response remains highly heterogeneous among GBM patients with discordant outcomes. Recent data have shown that radiomics, an advanced recent imaging analysis method, can help to predict both prognosis and therapy in a multitude of solid tumours. The objective of this study was to identify novel biomarkers, extracted from MRI and clinical data, which could predict overall survival (OS) and progression-free survival (PFS) in GBM patients treated with bevacizumab using machine-learning algorithms. In a cohort of 194 recurrent GBM patients (age range 18–80), radiomics data from pre-treatment T2 FLAIR and gadolinium-injected MRI images along with clinical features were analysed. Binary classification models for OS at 9, 12, and 15 months were evaluated. Our classification models successfully stratified the OS. The AUCs were equal to 0.78, 0.85, and 0.76 on the test sets (0.79, 0.82, and 0.87 on the training sets) for the 9-, 12-, and 15-month endpoints, respectively. Regressions yielded a C-index of 0.64 (0.74) for OS and 0.57 (0.69) for PFS. These results suggest that radiomics could assist in the elaboration of a predictive model for treatment selection in recurrent GBM patients.

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 CTNI-14. A 3-ARM, PHASE IIA TRIAL OF SAFETY & EFFICACY OF OLINVACIMAB, A MONOCLONAL ANTIBODY TO VEGFR2 IN PATIENTS WITH RECURRENT GLIOBLASTOMA MULTIFORME WITH IMAGING AND PK/PD ASSESSMENTS: FINAL REPORT

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii44-ii45
Author(s):  
Lawrence Cher ◽  
Anna Nowak ◽  
George Iatropoulos ◽  
Samantha Bowyer ◽  
Hui Gan ◽  
...  
Keyword(s):  
Recurrent Glioblastoma ◽  
Final Report ◽  
Recurrent Glioblastoma Multiforme ◽  
Open Label ◽  
Impaired Wound Healing ◽  
Significant Difference ◽  
Angiogenic Effect ◽  
Vegf Pathway ◽  
Recurrent Gbm

Abstract The VEGF pathway remains an important target in GBM given its vascularity and autocrine VEGF signalling. Olinvacimab (TTAC-0001) is a fully humanised VEGFR2 Mab that binds and inhibits the receptor. This report assesses the safety, dosing schedules and efficacy of Olinvacimab in recurrent GBM. We conducted a two-site, 3 arm, open-label study of Olinvacimab in recurrent GBM. Eligible patients were ≥18 years with RANO-measurable lesion, KPS ≥ 80, and had completed chemoradiotherapy without prior bevacizumab therapy. We assessed three arms, 8 mg/kg and 12mg/kg weekly for 3 of every 4 weeks, and 12 mg/kg weekly. Three patients were treated in arms 1 and 2 and 6 in arm 3. Safety assessments were performed prior to dose escalation. The main toxicity was development of grade 1 (67%) and 2 (8%%) cutaneous haemangiomas. Common toxicities seen with other VEGF directed therapies, including hypertension, impaired wound healing, and proteinuria were not seen in this cohort. Efficacy was assessed by MRI using RANO criteria. 6 month PFS was 17%, with disease control in 25%, with steroid dose reduction. The longest response was 15 months. On DCE MRI, there was no significant difference in perfusion parameters between baseline and 1st follow-up MRI comparing those with SD and PD. However, 6 of 12 patients showed decreased Ktrans > 20 % of baseline, consistent with an anti-angiogenic effect of Olinvacimab. Pharmacokinetics showed a decreased clearance rate and increased half-life of Olinvacimab compared to the prior Phase I study. Pharmacodynamic studies showed significantly higher levels of angiogenic markers, particularly VEGF-A in those treated at 12mg/kg vs arm 1. VEGF-A, C and D levels were elevated in patients with SD compared to those with PD. Conclusion: Olinvacimab was well tolerated with a different toxicity profile to other VEGFR directed therapies. There were promising responses in 25% of patients.

Sign in / Sign up

Export Citation Format

Share Document