bluuebunny/crossref_metadata_2025 huggingface dataset:
CTIM-28. MULTILAMELLAR MRNA LIPID PARTICLES INDUCE IMMUNOLOGIC REPROGRAMMING IN CANINE AND HUMAN GLIOBLASTOMA PATIENTS
Authors: Mendez-Gomez Hector , DeVries Anna , Stover Brian , Zhang Dingpeng , Grippin Adam , Von Roemeling Christina , Weidert Frances , Karachi Aida , Qdaisat Sadeem , Thomas Nagheme , McGuiness James , Castillo Paul , Huang Jianping , Ligon John , Silver Natalie , Kellish Patrick , Doty Andria , Carrera-Justiz Sheila , Prados Michael , Mueller Sabine , Rahman Maryam , Ghiaseddin Ashley , Mitchell Duane , Sayour Elias
Published: November 2022

BACKGROUND

Although mRNA vaccines have been deployed with great success against COVID-19, unlocking this technology against glioblastoma will necessitate new lipid-nanoparticle formulations that overcome cancer tolerance and immunosuppression.

OBJECTIVE/METHODS

We sought to develop a novel mRNA vaccine system to make tolerogenic tumor antigens appear more dangerous through use of unmodified nucleosides (pathogen associated molecular patterns, PAMPs) and highly cationic lipid shells that elicit a systemic damage response against cancer antigens.

RESULTS

We developed a novel vaccine formulation that increases payload packaging of tumor amplified mRNA into multilamellar (onion-shaped) particles for systemic (intravenous) administration. We demonstrate significant immunogenicity and efficacy of multilamellar RNA-NPs in syngeneic murine models for high-grade glioma (KR158b-pp65), and diffuse midline glioma (H3K27M DMG). Remarkably, RNA-NPs significantly improve median survival outcomes of DMG bearing mice beginning therapy at endpoint (Day 35 after midline intracranial implantation). Unlike prototypical mRNA vaccines that activate endosomal toll-like receptors (i.e. TLR7), multilamellar RNA-NPs elicit immunologic response predominantly through intracellular pathogen recognition receptors (RIG-I); long-term survival benefits from RNA-NPs were completely abrogated in RIG-I knockout mice. In canines (pet dogs) with spontaneous gliomas, RNA-NPs elicit massive recruitment/activation of peripheral blood mononuclear cells (PBMCs) which correlate with their trafficking into lymphoreticular organs (in follow-up murine studies). In canines receiving neoadjuvant RNA-NPs, prior to glioma biopsy, we see significant reprogramming of the glioma microenvironment with increased gene signatures for antigen processing/presentation, interferon signaling and cytotoxicity. Upon translation into human clinical trials for glioblastoma patients (NCT04573140), RNA-NPs elicit rapid (within hours) release of cytokines (e.g. IL-1, IL-6, IL-12 TNF-α, interferons) and chemokines (e.g. MIP1α, MCP-1, IP-10), which correlate with mobilization of PBMCs and activation of dendritic cells/CD8 lymphocytes.

CONCLUSION

First-in-human application of systemic multilamellar RNA-NP vaccines results in significant biologic effects and rapid immunologic reprogramming.
CTNI-01. EFFECT OF PRE-OPERATIVE STEREOTACTIC RADIOSURGERY ON BRAIN METASTASIS: ANALYSIS OF DNA AND RNA GENOMIC PROFILES FROM PHASE-II CLINICAL TRIAL NCT03398694
Authors: Shireman Jack , Huff Wei , Monaco Gina , Agrawal Namita , Watson Gordon , Dey Mahua
Published: November 2022

BACKGROUND

With improved systemic therapy that has limited impact on the intracranial compartment, the incidence of brain metastasis (BM) from solid cancers is rising. Treatment varies based on presentation, however, for patients with < 4 symptomatic BMs current clinical practice involves surgical resection followed by stereotactic radiosurgery (SRS) to the resection cavity. Post-operative SRS is associated with increased risk of leptomeningeal disease (LMD) and local recurrence. We hypothesize that pre-operative SRS will decrease the incidence of LMD as well as local recurrence, and increase patient’s OS by delivering a lethal dose of radiation to tumor cells before they are disturbed by surgical resection. In a Phase II clinical trial (NCT03398694) we are treating patients with 1-4 symptomatic BMs with pre-operative SRS while collecting DNA and RNA sequencing data from core and peripheral edges of the resected tumor to examine the genomic effects of SRS on tumor.

METHODS

Post-SRS resected tumor specimens were divided into two groups: ‘center’ and ‘periphery’ with respect to the center of SRS treatment with periphery within 50% isodose line. Previously resected untreated BMs were used as control.

RESULTS/CONCLUSIONS

Our initial data analyses show that pre-treatment with SRS results in significant genomic changes at DNA and RNA levels throughout the tumor when compared to non-radiated tumors. In matched center and peripheral samples DNA damage levels, measured by high impact mutation load, were similar indicating no evidence of radiation dose fall off effect on DNA damage. However, differing DNA damage locations and RNA expression profiles between center and matched samples are present, which may indicate unequal DNA repair processes between the center and periphery of tumors. Furthermore, global DNA mutation and RNA expression profiles differed significantly between the metastasis of different primary cancers signaling the importance of the primary cancer location in determining viable therapeutic targets.
CTNI-04. TRAM-01: A PHASE 2 STUDY OF TRAMETINIB FOR PEDIATRIC PATIENTS WITH NEUROFIBROMATOSIS TYPE 1 AND PLEXIFORM NEUROFIBROMAS
Authors: Kiaei Dorsa Sadat , Larouche Valerie , Décarie Jean-Claude , Tabori Uri , Hawkins Cynthia , Lippe Sarah , Ellezam Benjamin , Ospina Luis H , Theoret Yves , Desjardins Leandra , Metras Marie-Elaine , Sultan Serge , Cantin Edith , Routhier Marie-Eve , Mailloux Chantal , Bertrand Marie-claude , Caru Maxime , McKeown Tara , Vairy Stephanie , Legault Geneviève , Bouffet Eric , Ramaswamy Vijay , Coltin Hallie , Lafay-Cousin Lucie , Hukin Juliette , Erker Craig , Jabado Nada , Dehaes Mathieu , Perreault Sébastien
Published: November 2022

BACKGROUND

Plexiform neurofibromas (PN) are observed in up to 50% of patients with neurofibromatosis type 1 (NF1). Trametinib has been used widely to treat PN but limited data has been reported on its efficacy within a clinical trial.

METHODS

This ongoing multicenter phase II trial includes patients with pediatric low-grade glioma and PN. Patients received daily oral trametinib (MEK inhibitor) for eighteen 28-day cycles. The volumes of PN were centrally quantified using a new semi-automatic 3D segmentation method.

RESULTS

As of May 15, 2022, 46 patients with PN were enrolled in the study and the recruitment was completed for this study arm. Thirty-four completed treatment and were available for analysis. For these patients, the median age was 10.5 years (range 0.7-19.8). The median volume of PN at baseline was 51cm3 (range 2.6 to 487.6). Among the 34 patients, 28 (82.4%) completed 18 cycles as planned. Two patients discontinued due to adverse reaction, three patients refused to continue treatment and one patient discontinued treatment based on physician decision. Median duration of treatment was 16.8 months (range 2.8 to 16.8). Median duration of follow-up was 30.4 months (range 8.2 to 42). A total of 38 PN were available for volumetric analysis. Using RECIST evaluation, the overall response rate was 13.1%. Volumetric assessment demonstrated an overall response rate of 64.7% (22/34 patients), and 65.8% (25/38 PN) of PN showed a decrease of more than 20% in volume. Median volume change was -30% (range -93.5 to 14.3). Thirty-one patients (91.1%) had durable response without progression (lasting ≥ 1 year). After discontinuation of treatment, one patient underwent surgery and three patients resumed MEK inhibitor.

CONCLUSION

We report outcome and volumetric quantification of PN treated with trametinib within a large clinical trial. Based on the current results, trametinib is effective and offers durable response.
CTNI-06. IMPROVING INSOMNIA IN PATIENTS WITH PRIMARY BRAIN TUMORS USING COGNITIVE BEHAVIORAL THERAPY: RESULTS FROM AN NRG NCORP PILOT TRIAL
Authors: Loughan Ashlee , Lanoye Autumn , Willis Kelcie , Fox Amber , Zukas Alicia , Ravyts Scott
Published: November 2022

BACKGROUND

Sleep disturbance is among the most common symptoms endorsed by patients with primary brain tumor (PwPBT), with many reporting clinically-elevated insomnia and poor management of sleep-related symptoms by their medical team. Though Cognitive Behavioral Therapy for Insomnia (CBT-I) remains the front-line treatment for sleep disturbance, CBT-I has yet to be evaluated in PwPBT.

METHODS

PwPBT were recruited locally by direct referral and fliers, and nationally by social media support group postings. Forty PwPBT and insomnia enrolled in a six-week group-based telehealth CBT-I phase IIa single-arm proof-of-concept trial: 50.0% female, 68.2% non-Hispanic white, 55.0% high-grade, 42.5% oligodendroglioma, Mage = 52.4 (SD = 12.0, range 31-77). Participants completed data collection at baseline and post-intervention. Self-report measures assessed insomnia (ISI), fatigue (BFI), mood (PHQ-9, GAD-7) and quality-of-life (QLQ-30). Cognitive assessment included measures of attention (WAIS-IV Digits, TMT), verbal fluency (COWAT) and memory (HVLT). Intervention effects for self-report outcomes were analyzed using paired t-tests; effects for cognitive outcomes were analyzed using repeated-measures ANCOVA controlling for age.

RESULTS

Among those with complete data (n=34), significant improvements were identified for insomnia (t(33) = 8.6, p < .001, Cohen’s d = 1.5) and fatigue (t(30) = 4.7, p < .001, Cohen’s d = 0.8) symptoms. Depression (t(33) = 5.2, p < .001, Cohen’s d = 0.9) and anxiety symptoms (t(33) = 4.2, p < .001, Cohen’s d = 0.7) also improved. Quality-of-life improved with respect to role (t(33) = 2.8, p = .01, Cohen’s d = 0.5), emotional (t(33) = 2.8, p = .01, Cohen’s d = 0.5), cognitive (t(33) = 3.9, p < .001, Cohen’s d = 0.7), and social functioning (t(33) = 3.5, p = .001, Cohen’s d = 0.6)—but not physical functioning (t(33) = 0.5, p = .60, Cohen’s d = 0.1). No clinically or statistically significant cognitive changes were found.

CONCLUSION

This trial is the first to preliminarily assess efficacy of CBT-I, a non-pharmacological treatment for insomnia, in PwPBT. Results suggest promising benefit of CBT-I in insomnia severity, fatigue, mood, and most quality-of-life indices for individuals challenged by PBT and insomnia. These findings support further study in a scientifically rigorous phase IIb randomized feasibility trial.
CTNI-07. LOMUSTINE/TEMOZOLOMIDE CHEMOTHERAPY FOR NEWLY DIAGNOSED MGMT-METHYLATED IDHWT GLIOBLASTOMA ACCORDING TO CETEG/NOA-09: REAL-WORLD EXPERIENCE IN A MULTICENTER COHORT
Authors: Weller Johannes , Zeyen Thomas , Schlegel Uwe , Lazaridis Lazaros , Werner Jan-Michael , Onken Julia , Zeiner Pia , Drexler Richard , Hau Peter , Seidel Clemens , Grosse Lucia , Clusmann Hans , Sabel Michael , Ringel Florian , Pichler Josef , Grauer Oliver , Hundsberger Thomas , Schnell Oliver , Mair Maximilian J , Uhl Martin , Schmidt-Graf Friederike , Glas Martin , Galldiks Norbert , Unteroberdörster Meike , Steinbach Joachim , Ricklefs Franz , Renovanz Mirjam , Delev Daniel Ivanov , Turgut Merih O , Flesch Oliver R , Cipriani Debora , Preusser Matthias , Kebir Sied , Misch Martin , Goldbrunner Roland , Westphal Manfred , Tabatabai Ghazaleh , Schäfer Niklas , Schneider Matthias , Vatter Hartmut , Giordano Frank , Schaub Christina , Herrlinger Ulrich
Published: November 2022

INTRODUCTION

The CeTeG/NOA-09 trial demonstrated superior median overall survival (mOS, 48.1 months) in MGMT-methylated glioblastoma treated with lomustine/temozolomide compared to temozolomide. We retrospectively analyzed an off-study cohort of patients treated with lomustine/temozolomide to gather real-world data on this new regimen.

METHODS

Adult patients from 20 centers in Germany, Austria and Switzerland were included. Inclusion criteria were MGMT-methylated IDHwt glioblastoma newly diagnosed prior to end of 2020, and lomustine/temozolomide treatment as part of first-line therapy.

RESULTS

321 patients with a median age of 57 years (range, 21-78) and a median follow-up of 19.9 months were included. In the whole cohort, mOS was 41.0 months (95%CI, 33.0 – not reached). In patients starting lomustine/temozolomide immediately upon initiation of radiotherapy strictly following the CeTeG protocol (88%), mOS was 52.8 months (35.8 – not reached) as compared to 24.6 months (17.6 – not reached) in patients starting lomustine/temozolomide after completion of radiotherapy/concomitant temozolomide (12%, logrank test: p = 0.06). Patients with a KPS < 80 had a shorter mOS of 19.7 months (95%CI, 16.6 – not reached) compared to 41.0 months (33.0 – not reached, p = 0.009) in KPS 80-100. Gross total resection (GTR, 53.9%) was associated with longer mOS (52.8 months, 95%CI 24.1 – not reached) compared to partial resection/biopsy (30.5 months, 95%CI 36.8 – not reached, p=0.004). Multivariable Cox regression analysis confirmed GTR (HR 0.66, p = 0.033) and younger age ( ≤ 50 years: HR 0.42, p = 0.001), but not KPS (80-100 vs. lower: HR 0.66, p = 0.12) as independent prognostic factors.

DISCUSSION

In this real-world multicenter cohort, survival was similar to the promising results of CeTeG/NOA-09. Further analyses should investigate a potentially reduced benefit from lomustine/temozolomide in patients with low KPS/no GTR and a possible detrimental effect from deferred lomustine/temozolomide initiation. The median follow-up is admittedly short, updated data will be presented.
CTNI-09. DIFFUSE MIDLINE GLIOMA-ADAPTIVE COMBINATORY TRIAL (DMG-ACT): A COMBINATION PLATFORM TRIAL IN PEDIATRIC AND YOUNG ADULT PATIENTS WITH DIFFUSE MIDLINE GLIOMA
Authors: Franson Andrea , Kline Cassie , Molinaro Annette , Zhang Yalan , Hitchner Kelly , Gupta Nalin , Koschmann Carl , Prados Michael , Nazarian Javad , Mueller Sabine
Published: November 2022

Despite advances in understanding the biology of diffuse midline gliomas (DMGs), clinical outcomes have not significantly improved. Therapy development is limited by: lack of preclinical data across multiple models and laboratories, limited knowledge about blood-brain barrier penetrance, and lack of multi-agent therapeutic approaches. We aimed to address these limitations by designing and implementing an innovative platform clinical trial (DMG-ACT). DMG-ACT is an open-label, multi-institutional, international trial of combination therapy for patients with DMG between 2 and 39 years of age. This study utilizes a novel Bayesian drug combination platform design with adaptive shrinkage (ComPAS). ComPAS allows for ongoing assessment of therapy efficacy with data borrowing across arms and the ability to eliminate ineffective drug combinations and add new promising combinations throughout the trial. The current treatment arms include ONC201 in combination with paxalisib. Patients enter one of three cohorts: newly-diagnosed (Cohort 1), post-radiation (Cohort 2), and relapsed/progressive (Cohort 3). Each cohort offers a target validation phase for patients who have not yet undergone biopsy to assess intratumoral pharmacokinetics/pharmacodynamics of pre-biopsy, single-agent dosing. Cohorts 1 and 3 offer radiation (Cohort 1) or re-irradiation (Cohort 3) with concomitant single-agent therapy followed by maintenance with combination therapy. The primary efficacy endpoints are median progression-free survival at 6 months (Cohorts 1 and 2) and overall survival at 7 months (Cohort 3). Exploratory endpoints include intratumoral drug concentrations; toxicity profile of combination therapy during radiation; toxicity profile and efficacy of combination therapy; CSF, ctDNA, stool, and flow cytometry biomarker analyses; and health related quality of life, cognitive, and patient/proxy-reported outcome measures. Additional therapy combinations that have shown additive or synergistic benefit in preclinical testing will be incorporated in future trial iterations and several are currently in development. The trial was launched in October 2021, with a total of 21 patients enrolled as of May 2022.
CTNI-12. PHASE II MULTICENTRIC ITALIAN TRIAL ON REPOSITIONING OF THE ANTIPSYCHOTIC DRUG CHLORPROMAZINE AND ITS COMBINATION WITH TEMOZOLOMIDE IN MGMT UNMETHYLATED GLIOBLASTOMA PATIENTS: THE RACTAC TRIAL
Authors: Pace Andrea , Lombardi Giuseppe , Matteoni Silvia , Villani Veronica , Benincasa Dario , Abruzzese Claudia , Cerretti Giulia , Caccese Mario , Silvani Antonio , Paggi Marco Giorgio
Published: November 2022

The poor prognosis of patients affected by glioblastoma (GBM) prompts the search for new and more effective therapies, particularly for GBMs with unmethylated MGMT. In this regard, drug repurposing, can represent a safe and inexpensive way to bring novel pharmacological approaches from bench to bedside. Chlorpromazine, a medication in use since six decades for the therapy of psychiatric disorders, shows in vitro features that make it eligible for repositioning in GBM therapy. In our experimentation on six GBM cell lines, chlorpromazine inhibited cell viability in an apoptosis-independent way, induced polyploidy, reduced cloning efficiency as well as neurosphere formation and downregulated the expression of stemness genes. Notably, we found that chlorpromazine synergized with temozolomide, in reducing cell viability and strongly cooperated in reducing cloning efficiency and inducing cell death in vitro for all the GBM cell lines assayed. With these assumptions, we started a multicentric Phase II clinical trial on newly diagnosed GBM patients with unmethylated MGMT by adding chlorpromazine to temozolomide in the adjuvant phase of the standard first-line therapeutic protocol. The experimental procedure involves the combination of CPZ with standard treatment with TMZ in the adjuvant phase of the Stupp protocol. CPZ is administered orally at a dose of 50 mg/day – GG 1-28 – of every cycle of the adjuvant treatment with TMZ. At present, 53 patients out of 60 patients planned have been enrolled, without relevant toxicity.
CTNI-14. A PHASE 0 ‘TRIGGER’ TRIAL OF NIRAPARIB IN NEWLY-DIAGNOSED GLIOBLASTOMA PATIENTS
Authors: Sanai Nader , Margaryan Tigran , Molloy Jennifer , Knight William , Harmon Jocelyn , Hong Amy , Wanebo John , Kennedy William , Garcia Michael , Barani Igor , Yoo Wonsuk , Tien An-Chi , Tovmasyan Artak , Mehta Shwetal
Published: November 2022

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.
CTNI-17. A MULTI-INSTITUTIONAL RANDOMIZED CLINICAL TRIAL COMPARING ASSAY - GUIDED CHEMOTHERAPY WITH PHYSICIAN-CHOICE TREATMENT FOR RECURRENT HIGH-GRADE GLIOMA (NCT03632135)
Authors: Ranjan Tulika , Sengupta Soma , Glantz Michael , Green Richard , Yu Alexander , Aregawi Dawit , Chaudary Rekha , Chen Ricky , Zuccarello Mario , Lu-Emerson Christine , Moulding Hugh , Belman Neil , Glass Jon , Mammoser Aaron , Anderson Mark , Marko Nicholas , Schroeder Jason , Jubelirer Steven , Chow Frances , Alberico Anthony , Howard Candace , Lirette Seth , Denning Krista , Valluri Jagan , Claudio Pier Paolo
Published: November 2022

The presence of therapy-resistant cancer stem cells (CSCs) in recurrent high-grade glioma (HGG) patients contributes to poor clinical outcomes. The ChemoID functional anti-cancer assay targets cancer stem cells along with the bulk of the tumor cells. This trial aims to determine if ChemoID assay-guided treatment improves survival rates for recurrent HGG patients compared to the empirically physician-selected treatment. Patients with grade-III/IV recurrent glioma who failed standard of care (SOC) therapy were randomized (1:1) between two intervention groups. They received one of fourteen mono or combination chemotherapies based on the ChemoID assay or physician choice. The study met the primary outcome in the first interim analysis of 50 patients as per protocol. The ChemoID group had an improved survival rate (vs physician-choice). Median OS (mOS) was 12.5 months in the ChemoID group (95% CI, 10.2-14.7) vs 9 months in the physician-choice (95% CI, 4.2-13.8; log-rank P = .010). Mortality risk was lower in the ChemoID group (HR = 0.44; 95% CI, 0.24-0.81; P = .008). Median progression-free survival was 10.1 months in the ChemoID group vs 3.5 months in the physician choice (95% CI, 4.8-15.4 vs 1.9-5.1; log-rank < 0.001). Risk of progression was lower in the ChemoID group (HR = 0.25; 95% CI, 0.14-0.44; P < 0.001). The intention to treat (ITT) analysis of 78 patients showed substantially improved OS. The ChemoID group had a statistically significant longer median survival of 4.5 months. mOS was 12.0 months in the ChemoID group (95% CI, 10.8-13.2) vs 7.5 in the physician-choice group (95% CI, 3.5-11.5; log-rank P = .009). The ChemoID group had a decreased mortality risk (HR = 0.52; 95% CI, 0.24-0.81; P = .008). Compared with the physician-choice, the ChemoID group had a significantly longer OS in the ITT population. Our findings support that screening standard cytotoxic chemotherapies with a patient-specific anti-cancer assay improves survival outcomes in recurrent HGG patients.
CTNI-18. FIRST MULTICENTRIC REAL-LIFE EXPERIENCE WITH THE COMBINATION OF CCNU AND TEMOZOLOMIDE IN NEWLY DIAGNOSED MGMT PROMOTER METHYLATED IDH WILDTYPE GLIOBLASTOMA
Authors: Lazaridis Lazaros , Bumes Elisabeth , Spille Dorothee Cäcilia , Schulz Tim , Heider Sina , Agkatsev Sarina , Schmidt Teresa , Blau Tobias , Oster Christoph , Feldheim Jonas , Stummer Walter , Kessler Almuth Friederike , Seidel Clemens , Grauer Oliver , Hau Peter , Sure Ulrich , Keyvani Kathy , Herrlinger Ulrich , Kleinschnitz Christoph , Stuschke Martin , Herrmann Ken , Deuschl Cornelius , Breuer Stella , Hattingen Elke , Scheffler Björn , Kebir Sied , Glas Martin
Published: November 2022

BACKGROUND

The randomized phase 3 CeTeG/NOA-09 trial assessed whether CCNU plus temozolomide was superior to temozolomide alone in newly diagnosed MGMT promoter methylated glioblastoma patients. Survival was significantly improved from 31.4 months (temozolomide) to 48.1 months (CCNU plus temozolomide). In view of this encouraging data, we assessed safety and efficacy of this regimen under real-life conditions.

METHODS

We retrospectively collected clinical and radiographic data from adult newly diagnosed MGMT promoter methylated IDH wildtype glioblastoma patients from five neuro-oncology centers in Germany. For inclusion in our analysis, treatment with CCNU and temozolomide had to be performed for at least six weeks (one course).

RESULTS

Seventy patients were included. Median progression-free survival was 14.4 months and median overall survival 33.8 months. Patients with TTFields treatment for at least eight weeks and CCNU plus temozolomide (n = 22, 31%) had a prolonged progression-free survival compared to those with TTFields treatment for less than eight weeks (n = 48, 69%) (21.5 versus 11.2 months; p = 0.0105). In a multivariable Cox regression analysis, TTFields treatment for eight weeks or longer together with CCNU plus temozolomide and a Karnofsky performance score ≥ 90% were independent prognostic factors for progression-free and overall survival. Pseudoprogression occurred in n = 16 (33%) of investigated n = 49 (70%) patients. In n = 31 (44%) patients high-grade hematotoxicity was observed.

CONCLUSIONS

The results from this multicentric trial indicate - under real-life conditions - toxicity and survival estimates comparable to the CeTeG/NOA-09 trial. TTFields therapy for at least eight weeks in combination with this regimen was independently associated with prolonged survival.
CTNI-21. TROTABRESIB (CC-90010) IN COMBINATION WITH CONCOMITANT TEMOZOLOMIDE PLUS RADIOTHERAPY AND ADJUVANT TEMOZOLOMIDE IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA: UPDATED RESULTS FROM A PHASE 1B/2 STUDY
Authors: Vieito Maria , Sepulveda Juan Manuel , Moreno Victor , de Vos Filip , Geurts Marjolein , Lorenzi Elena , Macchini Marina , van den Bent Martin , Del Conte Gianluca , Martín-Soberón Maria Cruz , Brandal Petter , Garcia Maria Martinez , Amoroso Barbara , Sanchez-Perez Tania , Zuraek Marlene , Hanna Bishoy , Filvaroff Ellen , Chang Henry , Parro Marina Arias , Wei Xin , Liu Yu , Nikolova Zariana , Simonelli Matteo
Published: November 2022

Trotabresib, a novel bromodomain and extraterminal protein inhibitor, has demonstrated antitumor activity and blood–brain barrier penetration in patients with high-grade gliomas, and enhanced the antiproliferative effects of temozolomide in preclinical models. CC-90010-GBM-002 (NCT04324840) is a phase 1b/2 study investigating the addition of trotabresib to standard-of-care (SOC) concomitant temozolomide plus radiotherapy and adjuvant temozolomide, followed by maintenance trotabresib, in patients with newly diagnosed glioblastoma. The design of the dose escalation (part A) has been described previously (Vieito M, et al. SNO 2021. Abstract CTNI-51). Primary objectives of part A were to establish the safety, tolerability, and maximum tolerated dose/recommended phase 2 dose (RP2D) of trotabresib. In part A, addition of trotabresib to SOC was safe and well tolerated in the concomitant (N = 14) and adjuvant (N = 18) cohorts; the most frequent grade 3/4 treatment-related adverse event was thrombocytopenia (7/14 and 9/18 patients, respectively). The RP2D for trotabresib was 30 mg/day 4 days on/24 days off in both settings. At data cutoff (February 20, 2022), median duration of treatment was 34 weeks (concomitant cohort) and 33 weeks (adjuvant cohort); progression-free survival data are not yet mature. Trotabresib plasma pharmacokinetics and pharmacodynamics were consistent with monotherapy. At last follow-up, 6 and 5 patients remained on treatment in the concomitant and adjuvant dose-escalation cohorts, respectively, including 1 patient in cycle 20 with ongoing complete response. The ongoing randomized phase 2 dose expansion (part B; planned N = 162) is comparing concomitant trotabresib at the RP2D + SOC followed by adjuvant trotabresib at the RP2D + SOC, followed by maintenance trotabresib 45 mg/day 4 days on/24 days off, versus SOC alone in patients with newly diagnosed IDH–wild-type glioblastoma. Key objectives are to compare progression-free and overall survival, safety, and tolerability. Longer follow-up from part A and the first disclosure of data from part B will be presented.
CTNI-24. SINGLE CENTER EXPERIENCE OF DOPAMINE ANTAGONIST ONC-201 FOR RECURRENT H3K27M-MUTANT GLIOBLASTOMA IN ADULTS
Authors: Ekhator Chukwuyem , Rak Ramin , Tadipatri Ramya , Fonkem Ekokobe , Grewal Jai
Published: November 2022

OBJECTIVE

To report single center experience of three adult subjects receiving ONC-201 as part of the ONC018 expanded access clinical trial [NCT03134131].

BACKGROUND

ONC-201 is an oral investigational antagonist against the D2 dopamine receptor that has shown encouraging results for malignant gliomas harboring the H3K27M mutation in the H3 histone complex. Responses have been reported in pediatric subjects with such tumors. An expanded access clinical trial (ONC018) was available to eligible patients allowing them access to this agent pending FDA review. Design/

METHODS

Our site enrolled three subjects on the ONC018 trial. We present the demographic, clinical, and molecular characteristics for our enrolled subjects. We report the tolerability, adverse events, and outcome measures including survival, Karnofsky Performance Status [KPS] and quality-of-life measured by the MD Anderson symptom inventory instrument [MDASI].

RESULTS

Three subjects were registered at our site onto ONC018 with age range 18–44yrs, 2/3 female, residing in Norway, India, and United states. Tumor locations: brainstem, corpus callosum and thalamus. Pathology: Glioblastoma (3/3), MGMT methylated (2/3), IDH1 mutant (0/3), EGFR amplification (0/3) and ATRX (3/3). Median change from baseline KPS: ≤20 % decrease; MDASI:2/3 experienced decrease from baseline [median 6%], consistent with improved quality of life. No clinically significant laboratory abnormalities. All adverse events were grade I–II.

CONCLUSIONS

We found that the study drug was quite tolerable. No serious adverse events nor radiographic responses were seen. Analyses of the larger study cohort and additional randomized controlled trials are necessary to provide insight into the safety and efficacy.
CTNI-29. INVESTIGATING SAFETY AND EFFICACY OF TTFIELDS PRIOR AND CONCOMITANT TO RADIOTHERAPY IN NEWLY DIAGNOSED GLIOBLASTOMA - FIRST RESULTS OF THE PRICOTTF PHASE I/II TRIAL
Authors: Kebir Sied , Lazaridis Lazaros , Schmidt Teresa , Oster Christoph , Feldheim Jonas , Pierscianek Daniela , Proescholdt Martin , Hau Peter , Grosu Anca-Ligia , Krex Dietmar , Sure Ulrich , Scheffler Björn , Kleinschnitz Christoph , Pöttgen Christoph , Stuschke Martin , Glas Martin
Published: November 2022

Background

A synergistic inhibiting effect on glioblastoma cell proliferation was reported for the combination of TTFields and radiotherapy. Based on these preclinical findings, we performed the phase I/II PriCoTTF trial in adult nGBM patients to investigate the safety and efficacy of TTFields therapy initiated prior and concomitant to radiochemotherapy.

MATERIAL AND METHODS

In this phase I/II trial, TTFields therapy was initiated following surgery and continued throughout radiochemotherapy and adjuvant chemotherapy for a total of approximately 9 months. TTFields rechallenge was allowed at recurrence. Radiotherapy was conducted with arrays applied on the patients’ scalp. Safety and tolerance are the study’s primary endpoint, determined by a selection of pre-specified treatment-limiting toxicities (TLTs).

RESULTS

A total of 33 patients have been enrolled. Patients' characteristics were mostly typical for glioblastoma, except for a rather low fraction of patients with gross total resection (GTR, 22.5%). The distribution of adverse events of ≥ common toxicity criteria (CTC) grade 3 was comparable to that of established glioblastoma trials. Notably, skin toxicity of ≥ CTC grade 3 was uncommon (n = 2, 6%). No patient developed TLTs. Median TTFields treatment duration was 8.4 months. Overall survival data was not mature enough (event rate 48%) to allow for a definite conclusion

Notably, on multivariable Cox regression, the number of days with TTFields adherence > 23 hours was independently associated with overall survival (HR 0.96, 95% confidence interval 0.93 - 0.99, p = 0.008).

CONCLUSION

The PriCoTTF trial met its primary endpoint indicating that combined TTFields and radiotherapy is safe and well tolerated. High-grade skin toxicity was quite uncommon and the patients with high TTFields adherence seem to perform particularly well. An extended follow-up is required to provide first estimates regarding putative efficacy. At that point in time, the reduced overall TTFields duration and fraction of patients with GTR need to be factored in.
CTNI-33. CSNO2012001 STUDY: A PHASE III TRIAL ON ADJUVANT TEMOZOLOMIDE CHEMOTHERAPY WITH OR WITHOUT INTERFERON-ALPHA IN NEWLY DIAGNOSED HIGH-GRADE GLIOMAS
Authors: Chen ZhongPing , Guo Chengcheng , Chen JianGen
Published: November 2022

Purpose The therapeutic efficacy and toxicity of the combination of temozolomide (TMZ) with interferon-alpha (IFN-α) and TMZ alone were compared in newly diagnosed high-grade glioma (HGG) patients.Patients and Methods Following surgery, patients with newly diagnosed HGG (World Health Organization [WHO] grade 3 or 4)were eligible and randomized into two groups. All the patients were received standard radiotherapy concurrent with TMZ. After a 4-week break,patients in group A received standard TMZ (200mg/m2 for 5 days) combined with interferon-α (3mIU, subcutaneous, d1, d3, and d5) every 28 days. Patients in group B were received standard TMZ.Results A total of 199 HGG patients were enrolled, with a median follow-up time of 77.9 months. The median overall survival (OS) of patients in the TMZ+IFN group was significantly longer than that in the standard group, although the progression-free survival (PFS) of both groups was similar . In grade 3 gliomas, the median OS was 39.57 months in the TMZ+IFN group versus 29.40 months in TMZ alone. The median PFS was also longer in the TMZ+IFN group (24.33 months) than that in the TMZ group (14.13 months) . In grade 4 gliomas, the difference in PFS survival between TMZ+IFN and TMZ group showed no significant difference . However, the TMZ+IFN group had a longer OS than that of the TMZ alone group. TMZ+IFN also significantly improved the OS in O6-methylguanine-DNA methyltransferase (MGMT) unmethylation patients. The incidence of toxic effects such as neutropenia, thrombocytopenia, anemia, increased transaminase, skin reactions, fatigue, nausea, or vomiting, and skin reactions were similar in both groups. However, seizure and influenza-like symptoms were more common in the combination group but can be easily controllable.Conclusions Compared with the standard regimen, TMZ+IFN combination treatment could prolong the survival time of HGG patients, especially MGMT promoter unmethylated patients, and the toxicity remained tolerable.
CTNI-34. PRECISION NEURO-ONCOLOGY - A PILOT ANALYSIS OF PERSONALIZED TREATMENT IN RECURRENT GLIOMA
Authors: Lazaridis Lazaros , Schmidt Teresa , Oster Christoph , Blau Tobias , Pierscianek Daniela , Siveke Jens , Bauer Sebastian , Schildhaus Hans-Ulrich , Sure Ulrich , Keyvani Kathy , Kleinschnitz Christoph , Stuschke Martin , Herrmann Ken , Deuschl Cornelius , Scheffler Björn , Kebir Sied , Glas Martin
Published: November 2022

PURPOSE

When brain cancer relapses, treatment options are scarce. The use of molecularly matched targeted therapies may provide a feasible and efficacious way to treat individual patients based on the molecular tumor profile. Since little information is available on this strategy in neuro-oncology, we retrospectively analyzed the clinical course of 41 patients who underwent advanced molecular testing at disease relapse.

METHODS

We performed Sanger sequencing, targeted next generation sequencing, and immunohistochemistry for analysis of potential targets, including programmed death ligand 1, cyclin D1, phosphorylated mechanistic Target of Rapamycin, telomerase reverse transcriptase promoter mutation, cyclin-dependent kinase inhibitor 2A/B deletion, or BRAF-V600E mutation. In selected patients, whole exome sequencing was conducted.

RESULTS

The investigation included 41 patients of which 32 had isocitrate dehydrogenase (IDH) wildtype glioblastoma. Molecular analysis revealed actionable targets in 31 of 41 tested patients and 18 patients were treated accordingly (matched therapy group). Twenty-three patients received molecularly unmatched empiric treatment (unmatched therapy group). In both groups, 16 patients were diagnosed with recurrent IDH wildtype glioblastoma. The number of severe adverse events was comparable between the therapy groups. Regarding the IDH wildtype glioblastoma patients, median progression-free survival (mPFS) and median overall survival (mOS) were longer in the matched therapy group (mPFS: 3.8 versus 2.0 months, p = 0.0057; mOS: 13.0 versus 4.3 months, p = 0.0357).

CONCLUSIONS

These encouraging data provide a rationale for molecularly matched targeted therapy in glioma patients. For further validation, future study designs need to additionally consider prevalence and persistence of actionable molecular alterations in patient tissue.
CTNI-38. UPDATE ON GBM AGILE: A GLOBAL, PHASE 2/3 ADAPTIVE PLATFORM TRIAL TO EVALUATE MULTIPLE REGIMENS IN NEWLY DIAGNOSED AND RECURRENT GLIOBLASTOMA
Authors: Buxton Meredith , Alexander Brian , Berry Donald , Cavenee Webster , Colman Howard , de Groot John , Ellingson Benjamin , Gordon Gary , Khasraw Mustafa , Lassman Andrew , Lee Eudocia , Li Wenbin , Lim Michael , Mellinghoff Ingo , Mikkelsen Tom , Nelli Apoorva , Perry James , Sulman Erik , Tanner Kirk , Weller Michael , Wen Patrick Y , Alfred Yung W K , Cloughesy Timothy
Published: November 2022

BACKGROUND

GBM AGILE (Glioblastoma Adaptive, Global, Innovative Learning Environment) is a biomarker based, multi-arm, international, seamless Phase 2/3 response adaptive randomization platform trial designed to rapidly identify experimental therapies that improve overall survival and confirm efficacious experimental therapies and associated biomarker signatures to support new drug approvals and registration. GBM AGILE is a collaboration between academic investigators, patient organizations and industry to support new drug applications for newly diagnosed and recurrent GBM.

METHODS

The primary objective of GBM AGILE is to identify therapies that effectively improve the overall survival in patients with ND or recurrent GBM. Bayesian response adaptive randomization is used within subtypes of the disease to assign participants to investigational arms based on their performance. Operating under a Master Protocol, GBM AGILE allows multiple drugs from different pharmaceutical/biotech companies to be evaluated simultaneously and/or over time against a common control. New experimental therapies are added as information about promising new drugs is identified while therapies are removed as they complete their evaluation. The master protocol/ trial infrastructure includes efficiencies through an adaptive trial design, shared control arm and operational processes to serve the goal of helping patients receive optimal care in a fast and efficient manner. GBM AGILE has screened over 1200 patients and enrollment rates are 3 to 4 times greater than traditional GBM trials, with active sites averaging 0.75 to 1 patients/sites/month. There are 41 active sites in the US, 4 active sites in Canada and 3 active sites in Europe with more sites anticipated to open across 5 countries in Europe. Expansion to China and Australia are under progress. Through the use of improved and flexible processes, GBM AGILE serves as a global trial that supports the efficient and rapid incorporation and evaluation of new experimental therapies for patients with GBM.Clinical trial information: NCT03970447.
CTNI-41. TRANSITION OF LONG-TERM TREATMENT RESULTS OF 493 CASES OF NEWLY DIAGNOSED GLIOBLASTOMA AND SURVIVAL BENEFIT BY COMBINATION WITH PDT AND AFTV - AIMING TO ESTABLISH NEW STANDARD TREATMENT
Authors: Nitta Masayuki , Muragaki Yoshihiro , Saito Taiichi , Tsuzuki Shunsuke , Koriyama Shunichi , Kuwano Atsushi , Ikuta Soko , Kawamata Takakazu
Published: November 2022

INTRODUCTION

Glioblastoma has the worst prognosis of brain tumors. Evidence for improving prognosis by maximal tumor removal is being established, and in recent years, new treatments such as photodynamic therapy (PDT, 2014 in Japan), and TTF therapy (2018) have been approved, the treatment results are improving. In principle, our facility performs maximum tumor removal using intraoperative MRI (iMRI) follow by the standard chemoradiation. Intraoperative PDT and autologous tumor vaccine (AFTV) will be given to desired patients. We retrospectively analyzed the long-term clinical results of the patients with newly diagnosed glioblastoma who underwent surgical treatment at our facility, and the treatment results by era and treatment method.

METHODS

The clinical features, extent of removal (EOR), OS and PFS of the adult patients with newly diagnosed glioblastoma treated from 2001 to 2021 were analyzed retrospectively. Clinical results of those patients who received PDT and AFTV treatment was also investigated.

RESULTS

The number of cases was 493, median age 58 years (18-85 years), 293 males, 200 females. The median and average EOR of contrast-enhanced lesions were 98% and 96.6%, respectively. The median PFS and OS of all cases (including biopsy) were 9.4 months and 22.7 months, respectively. When the cases were analyzed separately for 2001-2006 (before TMZ), 2007-2010, 2011-2015, and 2016-2021, the median OS for each age group was 12.9 months, 22.9 months, 23 months, and 31.1 months. The treatment results improved with age ( p < 0.0001). In particular, the median OS of 23 cases treated with PDT and AFTV was 63.1 months. The efficacy of AFTV for newly diagnosed glioblastoma is currently being verified in a multicenter Investigator-led clinical trial.

CONCLUSION

The treatment results for glioblastoma have improved over the years. The combination of maximal tumor removal using iMRI, PDT and AFTV may aim for a 5-year survival rate of 50%.
CTNI-42. GENOME-WIDE DNA METHYLATION PATTERNS IN VERTU: A RANDOMIZED PHASE II TRIAL OF VELIPARIB, RADIOTHERAPY AND TEMOZOLOMIDE IN PATIENTS WITH MGMT-UNMETHYLATED GLIOBLASTOMA
Authors: Sim Hao-Wen , Lwin Zarnie , Barnes Elizabeth , McDonald Kerrie , Koh Eng-Siew , Rosenthal Mark , Foote Matthew , Back Michael , Wheeler Helen , Buckland Michael , Walsh Kyle , Fisher Lauren , Leonard Robyn , Hall Merryn , Ashley David , Yip Sonia , Simes John , Sulman Erik , Khasraw Mustafa
Published: November 2022

BACKGROUND

VERTU was a randomized phase II trial evaluating veliparib, a brain-penetrant PARP inhibitor, combined with radiotherapy and temozolomide, for patients with newly diagnosed MGMT-unmethylated glioblastoma. As part of planned correlative work after study completion, we assessed genome-wide DNA methylation patterns to predict methylation class, glioblastoma subtype and MGMT status.

METHODS

Patients were randomized 2:1 to experimental (60Gy/30 fractions with veliparib 200mg bid, then temozolomide 150-200mg/m2 D1-5 + veliparib 40mg bid D1-7 Q28D for 6 cycles) versus standard arm (60Gy/30 fractions with temozolomide 75mg/m2 daily, then temozolomide 150-200mg/m2 D1-5 Q28D for 6 cycles). The primary objective to improve 6-month progression-free survival (PFS-6m) was not met (doi: 10.1093/neuonc/noab111). Methylation data were generated using the Illumina Infinium Methylation EPIC bead chip array. Tumor tissues were categorized using the Heidelberg methylation-based classifier.

RESULTS

Methylation data were successfully generated for 98/125 patients (poor quality DNA [n = 12], no consent [n = 11], insufficient tissue [n = 4]). Those with classifier scores below 0.5 (n = 25), tumor microenvironment only (n = 6) and rediagnosis as pleomorphic xanthoastrocytoma (n = 1) were excluded, leaving n = 66. Methylation classes were GBM RTK II (n = 23, PFS-6m 43% [95%CI 23-62]), RTK I (n = 20, PFS-6m 50% [95%CI 27-69]), MES (n = 20, PFS-6m 40% [95%CI 19-60]), MID (n = 2) and G34 (n = 1). Glioblastoma subtypes were mesenchymal (n = 28, PFS-6m 50% [95%CI 30-66]), proneural (n = 24, PFS-6m 50% [95%CI 29-68]) and classical (n = 14, PFS-6m 36% [95%CI 13-59]). MGMT status were unmethylated (n = 58, PFS-6m 48% [95%CI 35-60]) and methylated (n = 8, PFS-6m 38% [95%CI 9-67]). There was no evidence of interaction between treatment arm and methylation class (excluding GBM MID and G34, P = 0.45), glioblastoma subtype (P = 0.68) or MGMT status (P = 0.52).

CONCLUSIONS

Genome-wide DNA methylation patterns in VERTU identified a spectrum of methylation-defined subgroups, reflecting tumoral heterogeneity. This may have utility for future clinical trials and practice. The effect of veliparib in VERTU appeared to be consistent across subgroups. ACTRN12615000407594.
CTNI-59. MATRIX REGIMEN FOR NEWLY DIAGNOSED PRIMARY CNS DIFFUSE B-CELL LYMPHOMA
Authors: Green Richard , Thornton Colleen , Guzman Ruben
Published: November 2022

We report our experience treating 22 patients with newly diagnosed primary CNS diffuse B-cell lymphoma with the MATRix regimen as reported by Ferreri, et al in 2016. The median age was 64 y (range 45-85); 10 patients were men and 12 were women. Twenty had cerebral mass lesions, 1 had a paraspinal mass, and 1 leptomeningeal disease. Treatment consisted of 4 cycles of rituximab 375 mg/sq m (Days 1, 6); methotrexate 3.5 g/sq m (Day 2); cytarabine 2 g/sq m every 12 h (Days 3, 4); and thiotepa 30 mg/sq m (Day 5). Patients without disease progression received carmustine 400 mg/sq m and thiotepa 5 mg/kg followed by autologous bone marrow transplantation. Four patients were switched to MATRix after 6 cycles of methotrexate and rituximab and received only 2 initial cycles including cytarabine and thiotepa. Overall, 16 patients completed initial chemotherapy. Fourteen of these 16 went on to transplantation; one patient had had early disease progression, and in one no stem cells could be collected. Five patients (median 73 y; range 64-85 y) died early after 1-2 cycles. The causes of early death were neutropenic fever, septic thrombophlebitis, and cardiac arrest. One patient who completed the entire regimen including transplantation died of fungal pneumonia and the other 13 experienced no serious acute toxicity. One patient had late disease progression and one developed symptomatic leukoencephalopathy. Fourteen of the 22 patients remain alive. Median OS for the cohort is 663 days. These preliminary data suggest that the MATRix regimen in safe and highly effective in the newly diagnosed setting. However, the high incidence of early death in patients over 65 y suggests that the regimen may be too toxic for older individuals.