A Bayesian adaptive randomized phase II multicenter trial of bevacizumab with or without vorinostat in adults with recurrent glioblastoma

Abstract Background Bevacizumab has promising activity against recurrent glioblastoma (GBM). However, acquired resistance to this agent results in tumor recurrence. We hypothesized that vorinostat, a histone deacetylase (HDAC) inhibitor with anti-angiogenic effects, would prevent acquired resistance to bevacizumab. Methods This multicenter phase II trial used a Bayesian adaptive design to randomize patients with recurrent GBM to bevacizumab alone or bevacizumab plus vorinostat with the primary endpoint of progression-free survival (PFS) and secondary endpoints of overall survival (OS) and clinical outcomes assessment (MD Anderson Symptom Inventory Brain Tumor module [MDASI-BT]). Eligible patients were adults (≥18 y) with histologically confirmed GBM recurrent after prior radiation therapy, with adequate organ function, KPS ≥60, and no prior bevacizumab or HDAC inhibitors. Results Ninety patients (bevacizumab + vorinostat: 49, bevacizumab: 41) were enrolled, of whom 74 were evaluable for PFS (bevacizumab + vorinostat: 44, bevacizumab: 30). Median PFS (3.7 vs 3.9 mo, P = 0.94, hazard ratio [HR] 0.63 [95% CI: 0.38, 1.06, P = 0.08]), median OS (7.8 vs 9.3 mo, P = 0.64, HR 0.93 [95% CI: 0.5, 1.6, P = 0.79]) and clinical benefit were similar between the 2 arms. Toxicity (grade ≥3) in 85 evaluable patients included hypertension (n = 37), neurological changes (n = 2), anorexia (n = 2), infections (n = 9), wound dehiscence (n = 2), deep vein thrombosis/pulmonary embolism (n = 2), and colonic perforation (n = 1). Conclusions Bevacizumab combined with vorinostat did not yield improvement in PFS or OS or clinical benefit compared with bevacizumab alone or a clinical benefit in adults with recurrent GBM. This trial is the first to test a Bayesian adaptive design with adaptive randomization and Bayesian continuous monitoring in patients with primary brain tumor and demonstrates the feasibility of using complex Bayesian adaptive design in a multicenter setting.

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Results of a phase II clinical trial of 6-mercaptopurine (6MP) and methotrexate in patients with BRCA-defective tumours

British Journal of Cancer ◽

10.1038/s41416-019-0674-4 ◽

2019 ◽

Vol 122 (4) ◽

pp. 483-490 ◽

Cited By ~ 1

Author(s):

Corran Roberts ◽

Victoria Y. Strauss ◽

Sylwia Kopijasz ◽

Charlie Gourley ◽

Marcia Hall ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Patients ◽

Phase Ii ◽

Clinical Benefit ◽

Parp Inhibitor ◽

Objective Response ◽

Acquired Resistance ◽

Xenograft Model ◽

Progression Free Survival ◽

Breast Cancer Patients

Abstract Background Tumour cells with BRCA1/2 gene mutations demonstrate increased sensitivity to platinum and poly (ADP-ribose) polymerase (PARP) inhibitors. 6-mercaptopurine (6MP) was found to selectively kill BRCA-defective cells in a xenograft model as effectively as the PARP inhibitor AG014699, even after these cells acquired resistance to a PARP inhibitor or cisplatin. Methods This phase II single-arm trial investigated the activity of 6MP 55–75 mg/m2 per day, and methotrexate 15–20 mg/m2 per week in advanced breast or platinum-resistant ovarian cancer patients with a BRCA1/2 germline mutation, who had progressed after ≥1 previous line of chemotherapy. The primary outcome was objective response including stable disease (SD) as an assessment of clinical benefit rate (CBR), at 8 weeks, by RECIST v1.1. Secondary outcomes included overall survival (OS) and progression-free survival (PFS). Results In total, 67 evaluable patients were recruited; 55 ovarian and 11 breast cancer patients. In total, 21 patients had SD (31%), one had a partial response (1.5%); CBR was 33% at 8 weeks. In total, 12/67 patients (18%) had SD at 16 weeks. In total, five ovarian cancer patients had SD for over 200 days. Median OS was 10.3 months (95% CI 6.9–14.5), median PFS 1.9 months (1.7–2.8). Conclusions The overall activity of 6MP and methotrexate in these patients was low; however, there was a small group of patients who appeared to derive longer-term clinical benefit. Trial registration NCT01432145 http://www.ClinicalTrials.gov.

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

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.2013 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 2013-2013 ◽

Cited By ~ 3

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.

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

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.2039 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 2039-2039 ◽

Cited By ~ 1

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]

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

Diagnostics ◽

10.3390/diagnostics11071263 ◽

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.

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

Neuro-Oncology ◽

10.1093/neuonc/noaa215.860 ◽

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.

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Regomune: A phase II study of regorafenib + avelumab in solid tumors—Results of the biliary tract cancer (BTC) cohort.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.4096 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 4096-4096

Author(s):

Sophie Cousin ◽

Carine A. Bellera ◽

Jean Philippe Guégan ◽

Thibault Mazard ◽

Carlos A. Gomez-Roca ◽

...

Keyword(s):

Phase Ii ◽

Adaptive Design ◽

Objective Response ◽

Locally Advanced ◽

Survival Rates ◽

Previous Treatment ◽

Progression Free Survival ◽

Treatment Interruption ◽

Clinical Activity ◽

Open Label

4096 Background: Regorafenib (R) has shown promising efficacy in patients (pts) with BTC refractory to standard chemotherapy. Anti-PD1/PD-L1 antibodies have only limited clinical activity. Synergy between R and anti–PD-1/PD-L1 antibodies has been shown in pre-clinical solid tumor models. Methods: This is a single-arm open-label multicentric phase II trial (Bayesian adaptive design) assessing the efficacy and safety of R (160 mg QD 3weeks/4) + avelumab (A) (10 mg/kg every 2 weeks) combination in BTC pts. The primary endpoint was the objective response rate under treatment, based on central review according to RECIST 1.1. Secondary endpoints included: 1-year progression free survival (PFS), 1-year overall survival (OS), and Safety using NCI-CTCAE v5.0. Correlative studies were planned from pts tumor samples obtained at baseline. Results: Between Nov. 2018 and Nov. 2019, 34 BTC pts were enrolled in 4 centers. Median age was 63 (range 36 – 80). Median follow-up was 9.8 months. Median number of previous treatment lines for metastatic or locally advanced disease was: 2 (range 1 – 4). Twenty-nine (85.3%) pts experienced at least 1 dose modification or treatment interruption of R or A due to an adverse event (AE) related to the treatment. The most common grade 3/4 AEs were : Hypertension (17.6%), Fatigue (14.7%), and maculo-papular rash (11.8%). No death was related to the treatment. Among the 29 pts with at least one imaging tumor assessment, 4 (13.8%) achieved a partial response, and 11 (37.9%) demonstrated stable disease including 10 (34.5%) pts with tumor shrinkage. Fourteen pts (48.3%) had progressive disease. The median PFS and OS were 2.5 months (95%CI 1.9 – 5.5) and 11.9 months (95%CI 6.2 – NA) respectively. Baseline tumor samples were available for 27 pts. High IDO and PD-L1 expression at baseline was associated with better outcome. Conclusions: The R+A combination is associated with significant anti-tumor activity with promising survival rates in this heavily pre-treated population. Full Biomarkers analyses will be presented at the meeting. Clinical trial information: NCT03475953.

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PULSE: A randomized phase II open label study of panitumumab rechallenge versus standard therapy after progression on anti-EGFR therapy in patients with RAS wild-type metastatic colorectal cancer (mCRC).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.3_suppl.tps143 ◽

2021 ◽

Vol 39 (3_suppl) ◽

pp. TPS143-TPS143

Author(s):

John H. Strickler ◽

Fang-Shu Ou ◽

Tanios S. Bekaii-Saab ◽

Christine Megerdichian Parseghian ◽

Andrea Cercek ◽

...

Keyword(s):

Phase Ii ◽

Clinical Benefit ◽

Objective Response ◽

Progression Free Survival ◽

Wild Type ◽

Open Label ◽

Genomic Alterations ◽

Open Label Study ◽

Label Study ◽

Randomized Phase Ii

TPS143 Background: Patients with KRAS and NRAS ( RAS) wild-type mCRC benefit from the epidermal growth factor receptor (EGFR) monoclonal antibodies (Abs) panitumumab and cetuximab, but nearly all patients experience resistance. Blood-based profiling of cell free DNA (cfDNA) can identify genomic alterations that drive acquired EGFR Ab resistance. After discontinuation of anti-EGFR Abs, acquired genomic alterations decay over time to undetectable levels. Some studies have suggested clinical benefit from EGFR Ab rechallenge, but there is limited evidence that EGFR Ab rechallenge improves survival compared to standard of care (SOC) therapies. We hypothesize that cfDNA profiling will identify patients appropriate for panitumumab rechallenge, and that these molecularly selected patients will have improved survival compared to current SOC therapies. Methods: This is a randomized phase II, open label study designed to compare the overall survival (OS) of panitumumab rechallenge versus SOC (investigator choice TAS-102 or regorafenib). Secondary objectives include comparisons of progression free survival, objective response rate, clinical benefit rate, and quality of life as measured by the linear analogue self-assessment (LASA) questionnaire. Eligible patients have radiographically measurable KRAS, NRAS, and BRAF codon 600 wild-type mCRC based on tumor tissue testing, and must have experienced progression or intolerance to treatment with a fluoropyrimidine, oxaliplatin, irinotecan, an anti-VEGF Ab, and an anti-PD-1 Ab if the tumor has mismatch repair deficiency or is MSI-H. Progression after at least 4 months treatment with an anti-EGFR Ab is required. All patients must be enrolled in the COLOMATE cfDNA screening protocol (NCT03765736) and meet molecular eligibility based on Guardant360 cfDNA profiling (absence of amplification of ERBB2, KRAS, NRAS, and MET; absence of mutations of BRAF, EGFR, ERBB2, KRAS, NRAS, and MET [mutant allele frequency > 0.5%]). Greater than 90 days must have elapsed between the most recent treatment with an anti-EGFR Ab and cfDNA profiling. Dosing for all study drugs is according to clinical SOC. 120 patients will be randomized 1:1 to panitumumab rechallenge or SOC. With 83 OS events, this study will have 80% power to detect an improvement in median OS from 6.5 to 10 months (HR=0.65; 1-sided α= 0.15). This study began enrollment in 6/2020. Recruitment is ongoing at 16 sites in the Academic and Community Cancer Research United (ACCRU) network (ACCRU-GI-1623). Clinical trial information: NCT03992456.

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Validation of diffusion MRI phenotypes for predicting response to bevacizumab in recurrent glioblastoma: post-hoc analysis of the EORTC-26101 trial

Neuro-Oncology ◽

10.1093/neuonc/noaa120 ◽

2020 ◽

Vol 22 (11) ◽

pp. 1667-1676

Author(s):

Marianne Schell ◽

Irada Pflüger ◽

Gianluca Brugnara ◽

Fabian Isensee ◽

Ulf Neuberger ◽

...

Keyword(s):

Phase Ii ◽

Diffusion Mri ◽

Cox Regression ◽

Threshold Model ◽

Prognostic Significance ◽

Predictive Ability ◽

Progression Free Survival ◽

Recurrent Glioblastoma ◽

Imaging Biomarker ◽

Molecular Characteristics

Abstract Background This study validated a previously described diffusion MRI phenotype as a potential predictive imaging biomarker in patients with recurrent glioblastoma receiving bevacizumab (BEV). Methods A total of 396/596 patients (66%) from the prospective randomized phase II/III EORTC-26101 trial (with n = 242 in the BEV and n = 154 in the non-BEV arm) met the inclusion criteria with availability of anatomical and diffusion MRI sequences at baseline prior treatment. Apparent diffusion coefficient (ADC) histograms from the contrast-enhancing tumor volume were fitted to a double Gaussian distribution and the mean of the lower curve (ADClow) was used for further analysis. The predictive ability of ADClow was assessed with biomarker threshold models and multivariable Cox regression for overall survival (OS) and progression-free survival (PFS). Results ADClow was associated with PFS (hazard ratio [HR] = 0.625, P = 0.007) and OS (HR = 0.656, P = 0.031). However, no (predictive) interaction between ADClow and the treatment arm was present (P = 0.865 for PFS, P = 0.722 for OS). Independent (prognostic) significance of ADClow was retained after adjusting for epidemiological, clinical, and molecular characteristics (P ≤ 0.02 for OS, P ≤ 0.01 PFS). The biomarker threshold model revealed an optimal ADClow cutoff of 1241*10–6 mm2/s for OS. Thereby, median OS for BEV-patients with ADClow ≥ 1241 was 10.39 months versus 8.09 months for those with ADClow < 1241 (P = 0.004). Similarly, median OS for non-BEV patients with ADClow ≥ 1241 was 9.80 months versus 7.79 months for those with ADClow < 1241 (P = 0.054). Conclusions ADClow is an independent prognostic parameter for stratifying OS and PFS in patients with recurrent glioblastoma. Consequently, the previously suggested role of ADClow as predictive imaging biomarker could not be confirmed within this phase II/III trial.

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Days gained response discriminates treatment response in patients with recurrent glioblastoma receiving bevacizumab-based therapies

Neuro-Oncology Advances ◽

10.1093/noajnl/vdaa085 ◽

2020 ◽

Vol 2 (1) ◽

Author(s):

Kyle W Singleton ◽

Alyx B Porter ◽

Leland S Hu ◽

Sandra K Johnston ◽

Kamila M Bond ◽

...

Keyword(s):

Treatment Response ◽

Proportional Hazards ◽

Cox Regression ◽

Progression Free Survival ◽

Cox Proportional Hazards ◽

Recurrent Glioblastoma ◽

Response To Therapy ◽

Cytotoxic Therapy ◽

Kaplan Meier ◽

Recurrent Gbm

Abstract Background Accurate assessments of patient response to therapy are a critical component of personalized medicine. In glioblastoma (GBM), the most aggressive form of brain cancer, tumor growth dynamics are heterogenous across patients, complicating assessment of treatment response. This study aimed to analyze days gained (DG), a burgeoning model-based dynamic metric, for response assessment in patients with recurrent GBM who received bevacizumab-based therapies. Methods DG response scores were calculated using volumetric tumor segmentations for patients receiving bevacizumab with and without concurrent cytotoxic therapy (N = 62). Kaplan–Meier and Cox proportional hazards analyses were implemented to examine DG prognostic relationship to overall (OS) and progression-free survival (PFS) from the onset of treatment for recurrent GBM. Results In patients receiving concurrent bevacizumab and cytotoxic therapy, Kaplan–Meier analysis showed significant differences in OS and PFS at DG cutoffs consistent with previously identified values from newly diagnosed GBM using T1-weighted gadolinium-enhanced magnetic resonance imaging (T1Gd). DG scores for bevacizumab monotherapy patients only approached significance for PFS. Cox regression showed that increases of 25 DG on T1Gd imaging were significantly associated with a 12.5% reduction in OS hazard for concurrent therapy patients and a 4.4% reduction in PFS hazard for bevacizumab monotherapy patients. Conclusion DG has significant meaning in recurrent therapy as a metric of treatment response, even in the context of anti-angiogenic therapies. This provides further evidence supporting the use of DG as an adjunct response metric that quantitatively connects treatment response and clinical outcomes.

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ACTR-56. PHASE II TRIAL OF NILOTINIB IN PDGFR-ALPHA ENRICHED RECURRENT GLIOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/noz175.098 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi26-vi26

Author(s):

David Picconi ◽

Tiffany Juarez ◽

Santosh Kesari

Keyword(s):

Phase Ii ◽

Phase Ii Study ◽

Objective Response ◽

Philadelphia Chromosome ◽

Recurrent Glioblastoma ◽

Myelogenous Leukemia ◽

Wild Type ◽

Durable Response ◽

Recurrent Gbm ◽

Pdgfr Alpha

Abstract BACKGROUND This phase II study was designed to determine the efficacy of nilotinib in a biomarker-selected population of recurrent glioblastoma (GBM), enriched for platelet-derived growth factor receptor-alpha (PDGFR-alpha) activation. Nilotinib is a multi-kinase inhibitor approved as treatment for Philadelphia-chromosome/Bcr-Abl chronic myelogenous leukemia. In addition to targeting Bcr-Abl tyrosine kinase, it also inhibits PDGFR-alpha signaling. METHODS Patients with recurrent GBM, with either PDGFR-alpha amplification or PDGFR-alpha overexpression by immunohistochemistry (IHC) were enrolled in a single-arm, single institution phase II study. Nilotinib was administered at 400 mg twice a day. The primary end point was progression-free survival at 6 months (PFS6). Secondary end points were safety, overall survival (OS) and Objective Response Rate (ORR). RESULTS 34 patients were treated (22 IDH-wild type GBM, 2 IDH-mutant GBM, 10 GBM NOS). 26 were male and 8 were female. Median age was 55.5 (range 22–78 years). Four patients had PDGFR-alpha amplification, and 30 had overexpression by IHC. Median lines of prior therapy were 1 (range 1–7). 6/34 patients (18%) experienced related adverse events grade ≥ 3. There were no grade 5 events. The PFS6 was 9% (3/34), and PFS12 was 6% (2/34). Median PFS was 1.3 months and the median OS was 6.6 months. Best response was stable disease (SD) for 8 patients and complete response (CR) for one patient. ORR was 1/34 patients (3%). The patient with a CR was IDH-wild type, unmethylated, had PDGFR-alpha overexpression by IHC, and had a durable response > 5 years. CONCLUSION Nilotinib had limited activity in recurrent GBM enriched for PDGFR-alpha, although there were a small number of durable responders. Further molecular characterization is warranted to determine additional biomarkers of response that could be used to select patients that may benefit from nilotinib.

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