Newly-diagnosed Glioblastoma Patients Research Articles

RTID-04. A MULTICENTER, RANDOMIZED, CONTROLLED PHASE 2B TRIAL OF SURVIVIN VACCINE SURVAXM PLUS ADJUVANT TEMOZOLOMIDE FOR NEWLY-DIAGNOSED GLIOBLASTOMA (SURVIVE)

Abstract BACKGROUND Glioblastoma cells express high levels of survivin protein, whose presentation by MHC class I gets recognized by antibodies and cytotoxic T-lymphocytes (CTLs). A phase 2a trial (NCT02455557) demonstrated a median overall survival (OS) of 25.9 months in newly-diagnosed glioblastoma (nGBM) patients with 15-amino-acid-peptide-conjugate survivin vaccine (SurVaxM), which also stimulated production of survivin-directed antibodies and anti-tumor CTL. This phase 2b trial aims to further investigate efficacy and safety of SurVaxM plus adjuvant temozolomide (TMZ) for nGBM. METHODS SURVIVE is an ongoing, multicenter, randomized, placebo-controlled, investigator- and patient-blinded, phase 2b trial that randomizes nGBM patients receiving standard-of-care therapies to either SurVaxM (SurVaxM arm) or saline (control arm) in 3:2 ratio at 15 sites. Included patients have age ≥18 years, normal organ function, KPS≥70, and receive surgical resection with ≤1cm3 residual MRI contrast enhancement within 72 hours post-resection plus TMZ. Patients with recurrent, multicentric, brainstem- or cerebellar-origin GBM are excluded as well as patients on TTFields or other immunotherapies. All patients undergo 3 phases: (1) vaccine priming (VP) phase, starting ≤4 weeks after completing chemoradiation – 4 doses of SurVaxM or placebo administered q2weeks; (2) TMZ phase, started after ≥1 VP dose; and (3) vaccine maintenance phase, started 8 weeks after VP, with SurVaxM or placebo given q8weeks. TMZ phase overlaps with VP and VM phases. Primary endpoint is median OS. Assuming 1-year-OS of 75% in SurVaxM arm, based on prior trials, and 60% for control, the required sample size is N=228; 137 in SurVaxM and 91 in control arm. Accounting for dropouts, we aimed to enroll 239 patients. A log-rank test stratified by KPS (70-80 vs 90-100), MGMT methylation status, and IDH mutation status will be used for analysis. Secondary endpoints are OS and PFS at 15, 18, and 24 months, median PFS, and toxicity. A single sequential OS-driven interim analysis is planned when 50% of deaths occur. Trial is fully enrolled (NCT05163080).

CTNI-50. CLINICAL EFFICACY AND PK/PD RESPONSE IN A PHASE 0/2 STUDY OF NIRAPARIB PLUS RADIOTHERAPY FOR NEWLY-DIAGNOSED, MGMT-UNMETHYLATED GLIOBLASTOMA

Abstract BACKGROUND Poly (ADP-ribose) polymerase (PARP) mediates DNA damage response; niraparib is a PARP1/2-selective inhibitor. This Phase 0/2 study evaluates tumor pharmacokinetics (PK), pharmacodynamics (PD), and clinical efficacy of niraparib plus fractionated radiotherapy in newly diagnosed, O6-methylguanine methyltransferase (MGMT)-unmethylated glioblastoma (GBM). METHODS Newly-diagnosed GBM patients received 4 days of niraparib (300/200 mg QD) prior to planned resection 3-5 (cohort 1) or 8-10 hours (cohort 2) following the last dose. Tumor tissue (gadolinium-enhancing and non-enhancing regions), cerebrospinal fluid (CSF), and plasma were collected. Total and unbound drug concentrations were measured using validated LC-MS/MS methods. PARP inhibition was assessed by quantification of PAR induction after ex vivo irradiation vs non-irradiated control. A PK response was defined as unbound [niraparib] > 5-fold biochemical IC50 (19 nM) in non-enhancing tumor. Patients with MGMT-unmethylated tumors and a PK response were eligible for Phase 2 dosing of niraparib plus radiotherapy followed by niraparib monotherapy. RESULTS All Phase 0 patients (n=46) met the PK threshold. The mean unbound concentrations of niraparib in non-enhancing tumor regions were 335.1 nM (cohort 1; n=43) and 331.9 nM (cohort 2; n=3). Ex vivo PAR suppression was observed in 73% of the patients (24/33). 71.4% patients with unmethylated tumors were enrolled into Phase 2. Five patients in Phase 2 experienced Grade 4 thrombocytopenia related to niraparib and all adverse events resolved without sequelae. At a mean clinical follow-up of 13.4 months, median overall survival was 20.3 months. CONCLUSIONS Niraparib achieves pharmacologically relevant concentrations in non-enhancing, newly-diagnosed GBM tissue. Accompanying PD effects were observed in tumor tissue, no new safety signals were observed, and clinical outcomes were promising. A global Phase 3, open-label, randomized 2-arm study comparing niraparib versus temozolomide in adult patients with newly diagnosed, MGMT-unmethylated glioblastoma is underway.

Niraparib efficacy in patients with newly-diagnosed glioblastoma: Clinical readout of a phase 0/2 "trigger" trial.

2002 Background: Poly (ADP-ribose) polymerase (PARP) mediates DNA damage response; niraparib is an investigational PARP1/2-selective inhibitor. This Phase 0 study evaluates newly-diagnosed glioblastoma (GBM) tumor pharmacokinetics (PK) and pharmacodynamics (PD), graduating patients with O6-methylguanine methyltransferase (MGMT) unmethylated tumors into a therapeutic regimen of niraparib plus fractionated radiotherapy when PK threshold is met. Methods: Presumed newly-diagnosed GBM patients received 4 days of niraparib (300/200 mg QD) prior to planned resection 3-5 (cohort 1) or 8-10 hours (cohort2) following the last dose. Tumor tissue (Gadolinium enhancing and non-enhancing regions), cerebrospinal fluid (CSF), and plasma were collected. Total and unbound niraparib concentrations were measured using validated LC-MS/MS methods. PARP inhibition was assessed by quantification of PAR induction after ex vivo irradiation of surgical vs non-irradiated tissue. A PK ‘trigger’ determined eligibility for the Phase 2 component of the study and was defined as unbound [niraparib] > 5-fold biochemical IC50 (i.e., 19 nM) in non-enhancing tumor. Patients with MGMT unmethylated tumors in excess of the PK threshold were eligible for Phase 2 dosing of niraparib plus radiotherapy followed by a maintenance phase of niraparib monotherapy. Results: All Phase 0 patients (n=46) met the PK threshold. In non-enhancing tumor regions, the mean unbound concentration of niraparib was 335.1 nM (n=43) for cohort 1 and 331.9 nM (n=3) for cohort 2. PAR suppression after ex vivo radiation was observed in 73% of the patients (24/33). Nineteen of 27 (70.3%) patients with unmethylated tumors were enrolled into Phase 2. Five patients in Phase 2 experienced Grade 4 thrombocytopenia related to niraparib. All adverse events resolved without sequelae. At time of data cutoff, median progression-free survival was 11.7 months. Mature overall survival (OS) data will be reported for the first time. Conclusions: Niraparib achieves pharmacologically relevant concentrations in non-enhancing, newly-diagnosed GBM tissue in excess of any other studied PARP inhibitor. Accompanying PD effects were observed in patient tumor tissue. For the first time, we report on the clinical efficacy of the study. A global Phase 3, open-label, randomized 2-arm study comparing niraparib versus temozolomide in adult patients with newly diagnosed, MGMT unmethylated glioblastoma is being planned. Clinical trial information: NCT05076513 .

Abstract CT125: A phase 0/2 ‘trigger’ trial of pamiparib or olaparib plus radiotherapy in patients with newly-diagnosed or recurrent glioblastoma

Abstract Background: This Phase 0/2 clinical trial evaluates the pharmacokinetic (PK), pharmacodynamic (PD), and clinical response of newly-diagnosed and recurrent glioblastoma (GBM) patients to the PARP1/2 selective inhibitors, pamiparib and olaparib, in combination with radiotherapy. Materials/Methods: In this study, newly-diagnosed (Arm A) and recurrent GBM (Arm B) patients received 4 days of pamiparib (60 mg BID) prior to planned resection at 2-4 or 8-12 hours following the final dose. Arm C included recurrent GBM patients who received 4 days of olaparib (200 mg BID) prior to resection. In the Phase 0 component of the study total and unbound drug concentrations were measured using validated LC-MS/MS methods. A PK ‘trigger’, defined as unbound drug > 5-fold biochemical IC50 in Gd-nonenhancing tumor, determined eligibility for Phase 2. PARP inhibition was assessed via ex vivo tumor tissue radiation and quantification of PAR levels compared to non-irradiated control. When demonstrating a PK response, newly-diagnosed, MGMT-unmethylated GBM or recurrent GBM patients were eligible for Phase 2 dosing of pamiparib (Arms A and B) or olaparib (Arm C) with concurrent RT followed by maintenance pamiparib or olaparib. Results: A total of 41 patients (Arm A, n=16; Arm B, n=19; Arm C, n=6) were enrolled in the Phase 0 component of the study. In Arms A and B, mean unbound concentrations of pamiparib in Gd-nonenhancing tumor were 167.3 nM and 104.3 nM respectively, and in Arm C the mean unbound concentration of olaparib was 5.2 nM. All patients in the pamiparib arms (n=35) but only 1 of 6 patients in the olaparib Arm C exceeded the PK threshold. Radiation-induced PAR expression was 2.44-fold in untreated control vs 1.16 in Arm A (p<0.05), 0.82 in Arm B (p<0.01) and 1.11 in Arm C patients. In Arm A, 7 of 11 MGMT-unmethylated GBM patients advanced to Phase 2. Two patients were ineligible due to clinical status, 1 patient was ineligible per physician decision, and 1 patient declined to participate. In Arm B, 11 of 19 patients advanced to Phase 2. Eight patients were ineligible due to clinical status. At a mean follow-up of 5.8 months, median progression-free survival (PFS) was 5.8, 6.0, and 3.8 months for Arms A (n=7), B (n=11), and C (n=1), respectively. Grade 3+ toxicities related to pamiparib occurred in 4 patients, with 2 adverse events resulted in treatment discontinuation. No grade 3+ toxicities were documented in the olaparib arm. Conclusions: Pamiparib achieved pharmacologically-relevant concentrations in Gd-nonenhancing GBM tissue and suppressed induction of PAR levels ex vivo post-radiation. The majority of newly-diagnosed patients with MGMT-unmethylated GBM and recurrent GBM patients advanced to therapeutic dosing in this trial, and pamiparib was generally well-tolerated in these patients. Citation Format: Nader Sanai, Yu-Wei Chang, Jun Jiang, Jennifer Molloy, Chelsea Pennington-Krygier, Jocelyn Harmon, Amy Hong, John Wanebo, William Kennedy, Michael Garcia, Igor Barani, Wonsuk Yoo, Artak Tovmasyan, An-Chi Tien, Jing Li, Shwetal Mehta. A phase 0/2 ‘trigger’ trial of pamiparib or olaparib plus radiotherapy in patients with newly-diagnosed or recurrent glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT125.

BIOM-06. LONGITUDINAL CEREBROSPINAL FLUID LIQUID BIOPSY IN PHASE 0/2 TRIAL OF NIRAPARIB FOR NEWLY-DIAGNOSED GLIOBLASTOMA

Abstract INTRODUCTION Effective drug development in glioblastoma (GBM) requires visualization of tumor evolution in response to experimental therapy. Today, genetic and epigenetic mechanisms of tumor resistance are undetected in clinical trials. Here, we establish the feasibility of a liquid biopsy paradigm in tracking tumor evolution in response to a novel therapeutic using an intra-cavitary reservoir for serial cerebrospinal fluid (CSF) collection. METHODS We conducted a Phase 0/2 clinical trial of niraparib, a potent PARP1/2 inhibitor, in newly-diagnosed GBM patients (NCT05076513). Intra-cavitary reservoirs were placed in select patients following tumor resection. Monthly outpatient CSF samples were collected to longitudinally examine cell-free tumor DNA (cfDNA) using a 293-gene amplicon-based next-generation sequencing (NGS) panel and circulating tumor cells using single cell RNA-sequencing (scRNA-seq). Concordance analysis was performed using paired tumor tissue samples against multiple liquid biopsies. RESULTS Tumor-derived cfDNA and circulating tumor cells were successfully isolated from intra-cavitary reservoirs at regular intervals for the duration of the clinical trial. Twelve patients so far have been implanted with the reservoirs for CSF collection. Among 55 CSF samples, 53 (94%) has detectable cfDNA. Radiographic tumor burden is associated with concentration of cfDNA (ng/ml, p< 0.01). No adverse events were observed during liquid biopsy acquisition. CSF sequencing data was highly concordant with NGS analyses of tumor tissue. cfDNA and single-cell analyses from serial CSF samples reflected the disparate evolution of GBM patient tumors in the face of PARP1/2 inhibition. CONCLUSION This is the first reported experience of serial CSF liquid biopsy to monitor DNA- and RNA-based tumor evolution in the context of an experimental therapy. Our data demonstrate the feasibility of cfDNA NGS and scRNA-seq using longitudinal CSF sampling of clinical trial patients. This new strategy for serial tumor profiling will be an important component of future drug development efforts targeting the moving biology of glioblastoma.

IMMU-14. SINGLE CELL RNASEQ OF PBMCS FROM NEWLY-DIAGNOSED GLIOBLASTOMA PATIENTS

Abstract INTRODUCTION A multitude of recently published papers have found immunosuppression caused by glioblastoma (GBM) is not limited to the tumor microenvironment and impacts the peripheral immune system. Our group has recently reported an expansion of granulocyte macrophage precursors, a subset of hematopoietic stem and progenitor populations (HSPCs), in glioma-bearing mice relative to healthy, age-matched controls. Thus we sought to determine if GBM causes cell fate dysfunction in CD34+ HSPCs in patients. METHODS CD34+ cells were magnetically isolated from peripheral blood of newly-diagnosed GBM patients and healthy age-matched donors and processed for single-cell RNA sequencing. CD34+ cells were magnetically isolated from peripheral blood of newly-diagnosed GBM patients and healthy age-matched donors and processed for single-cell RNA sequencing using the 10X Genomics platform. CellRanger was used for primary analysis with default parameters. After quality control removal of doublets, dead, and low quality cells automated cell type annotation was performed using the Azimuth Hubmap Consortium human bone marrow reference. The annotated single cell object was then read into R and Seurat was used for differential expression analysis and visualization. RESULTS AND CONCLUSIONS There we no significant expansions of stem and progenitor populations. GBM patient CD34+ samples had upregulation of VWF, a marker of myeloid-bias cell subset. Within the mature immune cell compartments, we observed a significant expansion of NK cells in GBM patients including 1,997 genes differentially expressed in the NK cell cluster between cohorts. This includes downregulation of SLAMF6, which triggers cytolytic activity in NK cells, in GBM patients. Upregulation of early NK cell activation markers CD69 and JUN were seen in GBM patient samples. These results strongly suggest NK are likely activated in the context of GBM, but may not be functional.

CTNI-22. A PHASE 0/2 ‘TRIGGER’ TRIAL OF NIRAPARIB IN PATIENTS WITH NEWLY-DIAGNOSED GLIOBLASTOMA

Abstract BACKGROUND Poly (ADP-ribose) polymerase (PARP) mediates DNA damage response; niraparib is an investigational PARP1/2-selective inhibitor. This Phase 0 study evaluates newly-diagnosed glioblastoma (GBM) tumor pharmacokinetics (PK) and pharmacodynamics (PD), graduating patients with O6-methylguanine methyltransferase (MGMT) unmethylated tumors into a therapeutic regimen of niraparib plus fractionated radiotherapy when PK threshold is met. METHODS Presumed newly-diagnosed GBM patients received 4 days of niraparib (300/200 mg QD) prior to planned resection 3-5 or 8-12 hours following the last dose. Tumor tissue (enhancing and non-enhancing regions), cerebrospinal fluid (CSF), and plasma were collected. Total and unbound niraparib concentrations were measured using validated LC-MS/MS methods. PARP inhibition was assessed by quantification of PAR induction after ex vivo irradiation of surgical vs non-irradiated tissue. A PK ‘trigger’ determined eligibility for the therapeutic expansion phase and was defined as unbound [niraparib] > 5-fold biochemical IC50 (i.e., 19 nM) in non-enhancing tumor. Patients with MGMT unmethylated tumors and positive PK were eligible for phase 2 dosing of niraparib plus radiotherapy followed by a maintenance phase of niraparib. RESULTS All phase 0 patients (n = 44) met the PK threshold. In non-enhancing tumor regions, the mean unbound concentration of niraparib was 226.7 nM (n = 38). PAR suppression after ex vivo radiation was observed in 71% of the patients (20/28). Eighteen out of 26 patients with unmethylated tumors enrolled in phase 2. Five of the 18 initial patients in phase 2 experienced grade 4 thrombocytopenia related to niraparib. All adverse events were resolved without sequelae. For patients who completed at least 6 months of follow-up, PFS6 was 64% (n = 11) with 9.2-month median follow-up. Median follow-up for all patients (n = 18) was 4.2 months with 8 patients remaining on treatment and 2 patients ongoing PFS6 follow-up. CONCLUSIONS Niraparib achieves pharmacologically-relevant concentrations in non-enhancing, newly-diagnosed GBM tissue in excess of any other studied PARP inhibitor.

CTNI-61. MYCOPHENOLATE MOFETIL INHIBITS GLIOBLASTOMA PURINE METABOLISM IN HUMANS: AN INTERIM RESULT OF PHASE 0/1 CLINICAL TRIAL TO OVERCOME TREATMENT RESISTANCE IN NEWLY DIAGNOSED AND RECURRENT GLIOBLASTOMA

Abstract BACKGROUND Mycophenolate mofetil (MMF), a purine synthesis inhibitor, improves radiation and temozolomide efficacy in preclinical glioblastoma models. This phase 0/1 trial (NCT04477200) is the first-in-human study to assess the tolerability of MMF with chemoradiation in glioblastoma, MPA accumulation, and purine synthesis inhibition in tumor. METHODS Adult patients meeting eligibility are given MMF 500-2000 PO BID using TITE-CRM dose assignment. Thirty recurrent glioblastoma patients receive MMF one-week prior to and concurrently with re-irradiation (40.5 Gy), with 28 days of dose-limiting toxicity (DLT) period. Thirty newly-diagnosed glioblastoma patients receive MMF one-week prior to and concurrently with chemoradiation and followed for 28 days for DLT1-period. During the adjuvant temozolomide (days 1-5/28-day cycle) period, MMF is given days 0-5 on a separate dose-escalation (DLT2 period = cycles 1-2). Tissues from phase-0 recurrent glioblastoma patients (N = 8) receiving MMF 500-2000mg BID one-week pre-operatively are analyzed using mass spectrometry. RESULTS Enhancing and non-enhancing tumor from phase 0 subjects yielded above 1 µM active drug metabolite, and the GTP/IMP ratio was decreased by 75% in enhancing tumor in MMF-treated patients compared to untreated controls (p = 0.009), indicating effective target engagement and inhibition of purine synthesis. No DLT has been observed with adjuvant cyclic temozolomide in phase 1 newly-diagnosed group (N = 26), nor in the recurrent-disease group (N = 18) with re-irradiation. In newly diagnosed arm, 3 subjects experienced DLT1 at 2000mg BID; grade-3 hemiparesis and cognitive disturbance, and grade-4 thrombocytopenia. Other main toxicities are mild nausea and fatigue. Interim median overall survival in recurrent phase 1 is 15.6 months, and not reached yet in newly diagnosed phase 1. CONCLUSION MMF combined with chemoradiation has been reasonably well tolerated in glioblastoma patients with preliminary promising evidence of intracranial target engagement of its active metabolite. This study will yield a recommended phase 2 dose and preliminary efficacy estimate for future randomized phase 2/3 trial.

A Combined Phase 0/2 "Trigger" Trial Evaluating Pamiparib or Olaparib with Concurrent Radiotherapy in Patients with Newly-Diagnosed or Recurrent Glioblastoma

This study evaluates the pharmacokinetic (PK) and pharmacodynamic (PD) profiles and clinical efficacy of PARP1/2 selective inhibitors, pamiparib and olaparib, in newly-diagnosed or recurrent glioblastoma (GBM) patients in combination with radiotherapy (RT). In this combined phase 0/2 trial presumed newly-diagnosed (Arm A) or recurrent (Arm B) GBM patients received 4 days of pamiparib (60 mg BID) prior to resection either 2-4 or 8-12 hours following the final dose. Arm C enrolled patients with recurrent GBM to 4 days of olaparib (200 mg BID) prior to resection. Enhancing and nonenhancing tumor tissue, cerebrospinal fluid (CSF) and plasma were collected. Total and unbound drug concentrations were measured using validated LC-MS/MS methods. A PK 'trigger', defined as unbound drug and gt; 5-fold biochemical IC 50 in nonenhancing tumor, determined eligibility for the therapeutic expansion phase 2. PARP inhibition was assessed via ex vivo radiation and quantification of PAR levels compared to non-radiated control. Newly-diagnosed MGMT unmethylated GBMs and recurrent GBMs exceeding the PK threshold were eligible for an expansion phase of pamiparib (Arms A and B) or olaparib (Arm C) with concurrent RT followed by maintenance pamiparib or olaparib. RT was 60 Gy in 30 fractions in newly-diagnosed patients and 40 Gy in 15 fractions in recurrent patients, delivered using volumetric-modulated arc therapy (VMAT). A total of 38 patients (Arm A, n = 16; Arm B, n = 16; Arm C, n = 6) were enrolled in the initial phase 0 study. The mean unbound concentrations of pamiparib in nonenhancing tumor region for Arm A and Arm B were 167.3 nM and 109.4 nM respectively, and in Arm C the mean unbound concentration of olaparib was 5.2 nM. All patients in the pamiparib arms (n = 32/32) but only 1 of 6 patients in the olaparib Arm C exceeded the PK threshold. Radiation-induced PAR expression was 2.44-fold in untreated control vs 1.16 in Arm A (p<0.05), 0.85 in Arm B (p<0.01) and 1.11 in Arm C patients, respectively. In Arm A, 11 patients had unmethylated tumors, and of those, 7 patients enrolled in phase 2. In Arm B, 9 of the 16 clinically eligible patients with positive PK results were enrolled in phase 2. At a median follow-up of 8.4 months [range: 1.3-15.7 months], the median progression-free survival (PFS) was 5.4, 6.0, and 3.8 months for Arms A (n = 7), B (n = 9), and C (n = 1), respectively. Grade 3+ toxicities related to pamiparib occurred in 4 patients, with 2 adverse events resulting in treatment discontinuation. No grade 3+ toxicities were documented in the olaparib arm. Pamiparib achieved pharmacologically-relevant concentrations in nonenhancing GBM tissue and suppressed induction of PAR levels ex vivo post-radiation. The majority of patients with MGMT-unmethylated GBM advanced to the phase 2 portion of the trial, and pamiparib was generally well-tolerated in these patients.

Dosimetric patterns of failure in the era of novel chemoradiotherapy in newly-diagnosed glioblastoma patients

BackgroundPatterns of failure (POF) may provide an alternative quantitative endpoint to overall survival for evaluation of novel chemoradiotherapy regimens with glioblastoma. Materials and MethodsPOF of 109 newly-diagnosed glioblastoma patients per 2016 WHO classification who received conformal radiotherapy with concomitant and adjuvant temozolomide were reviewed. Seventy-five of those patients also received an investigational chemotherapy agent (everolimus, erlotinib, or vorinostat). Recurrence volumes were defined with MRI contrast enhancement. POF at protocol (POFp), initial (POFi), and RANO (POFRANO) progression timepoints were characterized by the percentage of recurrence volume within the 95% dose region. POFp, POFi, and POFRANO of each patient were categorized (central, non-central, or both). ResultsPOF of the temozolomide-only control cohort were unchanged (79% central, 12% non-central, and 9% both) across protocol, initial, and RANO progression timepoints. Unlike the temozolomide-only cohort, POF of the collective novel chemotherapy cohort appeared increasingly non-central when comparing POFi with POFp, with a non-central component increasing from 16% to 29% (p = 0.078). POF did not correlate with overall survival or time to progression. ConclusionPOF of patients receiving a novel chemotherapy appeared to be influenced by the timepoint of analysis and were increasingly non-central at protocol progression as compared with initial recurrence, suggesting that recurrence originates from the central region. Addition of everolimus and vorinostat appeared to influence POF, despite similar survival outcomes with the temozolomide-only control group. In studies dealing with novel therapeutic agents, robust and properly-timed dosimetric POF analysis may be helpful to evaluate biologic aspects of novel agents.

EE90 Cost-Effectiveness Analysis of Tumor Treating Fields in the Treatment of Newly Diagnosed Glioblastoma Based on Real-World Data

Glioblastoma (GBM) is the most aggressive and common primary brain malignancy. TTFields, a novel therapy that can be added to chemotherapy for the treatment of GBM, has proven efficacy in GBM treatment. At present, the evidence on health economics evaluation of TTFields therapy is limited. The objective of the study is to evaluate the cost-effectiveness of TTFields+TMZ compared with TMZ in newly-diagnosed GBM patients and provide economic evidence as a framework for policy and decision making in GBM treatment from Chinese context.

INNV-33. FUNCTIONAL EX VIVO TESTING PROSPECTIVELY IDENTIFIES NEWLY DIAGNOSED GLIOBLASTOMA PATIENTS SENSITIVE TO TEMOZOLOMIDE TREATMENT IRRESPECTIVE OF MGMT METHYLATION STATUS

Abstract Standard of care (SOC) therapy for newly diagnosed (ND) glioblastoma (GBM) patients consist of temozolomide (TMZ) concurrent with radiation therapy. It is well known that patients with an unmethylated MGMT promoter are less likely to respond to TMZ, however, this trend is not universal. We have previously shown that 3D Predict™ glioma can identify patient response to TMZ, often differentially than the methylation status would predict. Here we present expanded clinical data relating to functional ex vivo testing capable of identifying patients responsive to alkylating therapies such as TMZ, regardless of methylation status. METHODS Fresh tissue specimens taken from ND GBM patients enrolled into the 3D PREDICT clinical study were examined by 3D Predict glioma to evaluate ex vivo therapeutic response to TMZ. Overall Survival (OS) and Progression Free Survival (PFS) in patients having ≥ 6 months follow-up post-surgery or < 6 months follow up but experiencing progression/death as of September 1, 2022 will be presented. Prospective correlation of clinical response and test-predicted response will be demonstrated in this expanded cohort of ND GBM patients. IMPACT This data has the potential to change treatment for ND GBM patients by stratifying according to functional therapeutic response rather than epigenetic factors that are not completely predictive of clinical response. It is feasible that 3D Predict glioma could dramatically impact patient care by determining which unmethylated patients should be treated with TMZ, and methylated patients who would potentially derive greater benefit from clinical trials or other treatment regimens.

CTNI-44. A PHASE 0 ‘TRIGGER’ TRIAL OF PAMIPARIB IN NEWLY DIAGNOSED AND RECURRENT GLIOBLASTOMA PATIENTS

Abstract This study evaluates glioblastoma (GBM) pharmacokinetics (PK) and pharmacodynamics (PD) of pamiparib, a PARP1/2-selective inhibitor, graduating patients to a therapeutic expansion phase of drug plus radiotherapy. Newly-diagnosed (Arm A) and recurrent GBM (Arm B) patients received 4 days of pamiparib (60 mg BID) prior to planned resection at 2-4 or 8-12 hours following the final dose. Arm C included recurrent GBM patients who received 4 days of olaparib (200 mg BID). Tumor tissue cerebrospinal fluid (CSF), and plasma were collected. Total and unbound drug concentrations were measured using validated LC-MS/MS methods. A PK ‘trigger’, defined as unbound drug > 5-fold biochemical IC50 in nonenhancing tumor determined eligibility for the therapeutic expansion phase. PARP inhibition was assessed via ex vivo radiation and quantification of PAR levels compared to non-radiated control. All patients exceeding the PK threshold were eligible for an expansion phase of study drug plus radiotherapy followed by maintenance regimen. In Arms A (n = 20) and B (n = 15), the mean unbound concentrations of pamiparib in Gd-nonenhancing tumor region were 171.5 nM and 102.9 nM, respectively and in Arm C (n = 4) the mean unbound concentration of olaparib was 11.0 nM. All patients in Arms A and B, but only one in Arm C, exceeded the PK threshold to qualify for the expansion phase of the study. 12/20 (60%), 7/14 (50%), and 1/4 (25%) patients in Arms A, B, and C, respectively progressed to expansion phase. Radiation-induced PAR expression was 2.44 fold in untreated control vs 1.16 in Arm A, 0.82 in Arm B and 1.11 in Arm C patients, respectively. The median progression-free survival was 5.4 (Arm A) (n = 7), 5.0 months (Arm B) (n = 6), and 2.7 months (Arm C) (n = 1), respectively. Pamiparib was generally well-tolerated, achieved pharmacologically-relevant concentrations in nonenhancing GBM tissue and suppressed induction of PAR levels ex vivo post-radiation.

CTNI-14. A PHASE 0 ‘TRIGGER’ TRIAL OF NIRAPARIB IN NEWLY-DIAGNOSED GLIOBLASTOMA PATIENTS

Abstract BACKGROUND Poly (ADP-ribose) polymerase (PARP) mediates DNA damage response; niraparib is an investigational PARP1/2-selective inhibitor. This Phase 0 study evaluates newly-diagnosed glioblastoma (GBM) tumor pharmacokinetics (PK) and pharmacodynamics (PD), graduating patients to a therapeutic regimen of niraparib plus fractionated radiotherapy when high unbound drug concentrations are present in gadolinium-nonenhancing tumor. METHODS Presumed newly-diagnosed GBM patients received 4 days of niraparib (300 mg QD) prior to planned resection at 3-5 or 8-12 hours following the last dose. Tumor tissue (enhancing and nonenhancing regions), cerebrospinal fluid (CSF), and plasma were collected. Total and unbound niraparib concentrations were measured using validated LC-MS/MS methods. A PK ‘trigger’ determined eligibility for the therapeutic expansion phase and was defined as unbound [niraparib] > 5-fold biochemical IC50 (i.e., 19 nM) in non-enhancing tumor. PARP inhibition was assessed by quantification of PAR induction after 10 Gy ex vivo irradiation in surgical tissue compared to non-irradiated control tissue. Patients with unmethylated MGMT tumors exceeding the PK threshold were eligible for expansion phase dosing of niraparib plus radiotherapy followed by a maintenance phase of niraparib. RESULTS Nineteen patients were enrolled into the Phase 0 study; all tumors met the study’s PK threshold and five unmethylated patients continued onto the expansion phase. One expansion phase patient experienced treatment-related Grade 3 serious adverse event (ALT and AST elevation) and four remain on treatment (median 4.2 months). In nonenhancing regions, the mean unbound concentrations of niraparib were 353.4 nM and 331.9 nM in the 3-5 hr cohort (n= 17) and the 8-12 hr (n = 3) cohort, respectively. The suppression of PAR levels after ex vivo radiation was observed in 69% of the patients (11/16). CONCLUSIONS Niraparib achieves pharmacologically-relevant concentrations in non-enhancing, newly-diagnosed GBM tissue in excess of any other studied PARP inhibitor.

Prognostic Significance of Preoperative Albumin to Alkaline Phosphatase Ratio in Patients with Glioblastoma.

Objective: To explore the prognostic value of preoperative albumin to alkaline phosphatase ratio (AAPR) in patients with newly-diagnosed glioblastoma (GBM) and its association with clinical characteristics.Patients and methods: A retrospective analysis was carried out on patients with newly diagnosed GBM who had undergone operation at the Department of Neurosurgery at West China Hospital between June 1st 2016 to December 31st 2018. X-tile software was applied to determine the optimal cut-off values for AAPR, neutrophil to lymphocyte ratio (NLR), and albumin. Cox regression analyses were applied to evaluate the prognostic value of AAPR in GBM. PSM analysis was conducted to verify the results.Results: A total of 197 and 154 GBM patients were included in original cohort and PSM cohort respectively. The optimal cut-off value for AAPR, NLR, and albumin were 0.56, 4.55 and 42.2 g/L respectively. High AAPR was only significantly related to longer overall survival (OS) (p=0.010) in original cohort. In PSM cohort, no clinical variable was evidently related to the level of AAPR. AAPR was determined to be an independent prognostic indicator in both original cohort (HR=0.599, 95%CI 0.437-0.822, p=0.001) and PSM cohort (HR=0.649, 95%CI 0.459-0.918, p=0.015). Prognostic models including AAPR had better prognostic accuracy than that including albumin.Conclusion: Preoperative AAPR was determined to be an independent risk factor of prognosis in newly-diagnosed GBM patients, and its prognostic ability was stronger than albumin. And PSM analysis also validated the results.

The 70-year-old newly diagnosed glioblastoma patients are older than the 65-year-old? Outcome evaluation of the two categories in a matched case control study with propensity score balancing

BackgroundThe standard of care for elderly, newly-diagnosed glioblastoma patients consists, if feasible, of surgical resection followed by a short course of radiation therapy (RT) with concomitant and adjuvant temozolomide chemotherapy (TMZCHT). To date, the literature lacks of consistence in the definition of elderly, if older than 65 years, or 70 years. Aim of this study was to explore whether differences exist between these two cohorts, comparing outcomes using a propensity score matched analysis (PSM). Materials and methodsTwo hundred twenty-one elderly newly diagnosed glioblastoma patients were included. All patients received surgery followed by RT with concurrent and adjuvant TMZCHT. The RT dose prescribed was 60 Gy/30 fractions for patients 65–69-year-old or 40.5 Gy/15 fractions for ≥70-year-old. After 1:1 matching there were 86 patients in each group. Distribution of covariates was adequately balanced in the matched data set. ResultsAfter PSM median PFS time, 1,2,3-year PFS rates were 10 months, 33.3%, 13.1%, and 6.6% for the 65–69-year group, 9 months, 34.7%, 11% and 4.8% for the ≥70-year group (p = 0.530). Median OS time, and 1,2,3-year OS rates were 14 months, 54.1%, 23.4%, 13.9% for the 65–69-year old group, and 12 months, 49.3%, 21.5%, 10% for the ≥70-year group (p = 0.357). No differences were recorded in relation to different groups of age. ConclusionsThe PSM analyses showed a similar outcome in 65–69-year old patients compared to older ones notwithstanding a more burdensome RT schedule. Hypofractionated RT treatment has to be considered also in this group of younger elderly, newly-diagnosed GBM patients.

Survival impact of delaying postoperative chemoradiotherapy in newly-diagnosed glioblastoma patients.

BackgroundMaximal safe resection followed by adjuvant chemoradiotherapy (CRT) with temozolomide (TMZ) is the standard treatment for newly diagnosed glioblastoma multiforme (GBM) patients. Time of initiation of postoperative adjuvant therapy has been demonstrated to impact on prognosis. For GBM patients, the optimal interval between definitive surgery and CRT is still uncertain. Current study aims to find whether the delayed initiation of CRT after surgery has a negative impact on patients’ outcome.MethodsSixty-six consecutively patients with newly-diagnosed GBM treated with surgery and adjuvant CRT from April 2014 to September 2019 at Ruijin Hospital School of Medicine Shanghai Jiaotong University were retrospectively reviewed. The impact of postoperative time from surgery to adjuvant treatment on patient’s overall survival (OS) and progression-free survival (PFS) were evaluated by univariate Log-rank test and multivariate Cox regression analysis. Factors including age, Karnofsky performance status (KPS), maximum diameter of primary tumor, extent of resection, isocitrate dehydrogenase (IDH) mutation status and O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation status were also analyzed in Cox regression model.ResultsThe median OS for patients who started CRT less than 6 weeks (n=48) and more than 6 weeks (n=18) were 26.6 months (95% CI: 18.3–34.9) and 15.7 months (95% CI: 9.2–22.3) (P=0.001). The median PFS for the short interval group was 16.3 months (95% CI: 14.7–18.0) and for the long interval group was 9.1 months (95% CI: 4.7–13.4) (P=0.006). On multivariate Cox regression analysis, high KPS and initiation of CRT less than 6 weeks were two independent prognostic factors for better OS and PFS (all P<0.05).ConclusionsInitiation of adjuvant CRT beyond 6 weeks contributed to worse survival in GBM patients, therefore CRT should be initiated within 6 weeks after surgery.

379P Impact of MGMT and ABCB1 single nucleotide polymorphisms on temozolomide-induced thrombocytopenia in newly diagnosed glioblastoma

Chemo-induced thrombocytopenia is a limiting adverse event in glioblastoma patients receiving temozolomide (TMZ). Constitutional single nucleotide polymorphisms (SNP) of genes involved in the pharmacodynamics and pharmacokinetics of TMZ were described to be associated with increased risk of TMZ-induced myelotoxicity in retrospective cohorts. We prospectively investigate the risk of thrombocytopenia (<100G/L) regarding MGMT rs2308327 and ABCB1 rs1045642. A total of 100 newly-diagnosed glioblastoma patients, receiving standard treatment (concomitant TMZ and radiotherapy [RT] followed by TMZ maintenance phase), were included in the study. Loss of function allelic variants rs2308327 of the MGMT gene; and rs1045642 of the ABCB1 gene were characterized using Taqman® PCR. Using univariate and multivariate logistic regression we investigated the association between SNPs and TMZ-induced thrombocytopenia occurrence along first-line treatment schedule and overall survival. This study is ancillary to the ongoing prospective phase 2 GLIOPLAK trial (NCT02617745). Overall, 23/100 patients experienced TMZ-induced thrombocytopenia: 11 patients during the RT-TMZ phase and 12 other patients during the TMZ maintenance phase. Among them, 7 patients experienced severe thrombocytopenia <50 G/l. Observed allele frequencies were in accordance with those reported for Caucasians (11% for MGMT rs2308327 and 47.5% for ABCB1 rs1045642). Harboring rs2308327 or rs1045642 was not associated with TMZ-induced thrombocytopenia: odds ratio (OR) 1.1 [CI 95% 0.3-3.2, p=0.56] and OR 1.01 [0.49-2.09, p=0.55] respectively. Severe thrombocytopenia (<50 G/L, n=7 patients) were not associated with any of the two SNPs. Wild-type versus heterozygous or homozygous SNP did not influence overall survival, log-rank test p=0.19 and p=0.34 respectively. Occurrence of thrombocytopenia <100 G/l induced an underexposure to TMZ in maintenance phase: median 3 cycles vs 5 in the no thrombocytopenia group. rs2308327 and rs1045642 were not associated with TMZ-related thrombocytopenia in a prospective population of glioblastoma.

Socioeconomic disparities in MGMT promoter methylation testing for glioblastoma patients.

7029 Background: MGMT promoter methylation holds important prognostic and predictive implications for glioblastoma (GBM) patients. Herein we evaluate whether any barriers faced MGMT testing. Methods: Adults with newly-diagnosed GBMs were identified from the U.S. National Cancer Database (2010-2016). Patient socioeconomic, tumor, and cancer program features were evaluated for association with MGMT testing by multivariable logistic regression. Results: Of 12,380 GBM patients, only 57% had MGMT testing–a rate that increased to 74% by 2016. Testing was independent of patients' sex or race/ethnicity (all p &gt; 0.05); and was largely independent of GBM histology, size, and location. Older patients were less likely to receive testing (54% of ≥70-years-olds vs 62% of those in their 40s, p = 0.01). Insurance status was an independent predictor of testing: only 43% of uninsured patients had testing, vs 61% of privately-insured or 55% of Medicare patients (p≤0.01). The uninsured rate dropped from 3.6% in 2010 to 2.5% in 2016 and was associated with Medicaid expansion under the Affordable Care Act. Patients from non-expansion states had the lowest rates of testing (55%), vs patients from expansion states (58%, p &lt; 0.001). Additionally, household incomes were independently associated with testing: only 50% of patients living in the poorest quartile of households had testing vs 61% in the richest quartile (p = 0.001). Diagnosing hospital type was also an independent predictor of testing: patients diagnosed at academic/NCI-designated cancer programs were most likely to have testing (65%), vs only 45% of community and 44% of comprehensive community cancer program patients were provided testing (all p &lt; 0.001). By 2016, testing rates had improved in all program types–particularly at comprehensive community (67%) and academic (80%) programs, but lagged at community programs (56%, p &lt; 0.001). Patients without MGMT testing received less chemotherapy (mOR = 0.66, p &lt; 0.001) and were associated with worse overall survival (mHR = 1.08, p = 0.002). Conclusions: Newly-diagnosed GBM patients in the U.S. who were uninsured, from the poorest quartile of households, or diagnosed at community cancer programs faced significant barriers to receiving MGMT testing. Medicaid expansion under the ACA was associated with reduced uninsurance, increased Medicaid insurance, and improved rates of testing. Reduced testing rates were associated with less chemotherapy and worse OS. Together our results indicate that substantial socioeconomic and care setting disparities exist in MGMT testing for GBM patients.

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

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