bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract

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 &lt; 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

Abstract
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

Abstract
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

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] &gt; 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

Abstract
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 &lt; 0.001). Risk of progression was lower in the ChemoID group (HR = 0.25; 95% CI, 0.14-0.44; P &lt; 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

Abstract

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

Abstract
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

Abstract

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

Abstract

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 &gt; 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.