bluuebunny/crossref_metadata_2025_split huggingface dataset:
CTIM-29. CLINICAL EVALUATION OF CHLOROTOXIN-DIRECTED CAR T CELLS FOR PATIENTS WITH RECURRENT GLIOBLASTOMA
Authors: Brown Christine , Blanchard M Suzette , Aftabizadeh Maryam , Hibbard Jonathan , Dodia Ramsinh , Lingaraju Chetan Raj , Starr Renate , D'Apuzzo Massimo , Forman Stephen J , Portnow Jana , Ressler Julie A , Stiller Tracey , Barva Baishakhi , Kilpatrick Julie , McNamara Paige , Wagner Jamie R , Wang Dongrui , Barish Michael , Badie Behnam 
Published: November 2021

Abstract
Chlorotoxin (CLTX), a peptide component of scorpion venom, exhibits selective and broad binding to glioblastoma (GBM) and other tumors with minimal activity against non-malignant cells. We have developed a novel CAR that utilizes CLTX as the tumor targeting domain. Preclinical studies established that CLTX-CAR T cells target GBM through recognition of a receptor complex incorporating membrane-bound matrix metalloprotease-2 (MMP-2). Here, we report initial clinical findings for our phase I trial evaluating safety and bioactivity of CLTX-CAR T cells in patients with MMP2+ recurrent GBM (NCT04214392). Weekly infusions of CLTX-CAR T cells are delivered locoregionally, either directly into the tumor cavity (ICT; Arm 1), or in combination with intracerebroventricular (ICV) delivery (dual ICT/ICV; Arm 2). At this interim analysis, four participants have received at least three cycles of CLTX-CAR T cells ICT (Arm 1; 3-8 cycles) at dose level 1 (DL1; 4M, 20M, 20M CAR T cells per cycle). None of the participants experienced dose limiting toxicity (DLT) during the DLT evaluation period of 28-days, although one participant experienced a serious adverse event of grade 3 cerebral edema, possibly attributed to CAR T cells. Overall, Arm 1-DL1 was well-tolerated, and the next patient cohort will be treated on Arm 2-DL1 (dual ICT/ICV; 8M, 40M, 40M CAR T cells per cycle), as per protocol design. Disease response was assessed by RANO, overall survival, and time to progression; three of four participants achieved a best response of stable disease. Liquid biopsy detected persistent CAR T cells in the tumor cavity throughout treatment, suggesting that the therapeutic cells are not immunogenic. Ongoing studies are evaluating biomarkers of response and resistance, including CAR T cell activation and inflammatory cytokines. This clinical study provides first-in-human evidence for the safety and feasibility of CLTX-CAR T cells as a new class of toxin-based CARs for treatment of GBM.
CTIM-32. IMMUNE CHECKPOINT INHIBITOR NIVOLUMAB IN PEOPLE WITH RECURRENT SELECT RARE CNS CANCERS: RESULTS OF INTERIM ANALYSIS IN A HEAVILY PRETREATED COHORT
Authors: Penas-Prado Marta , Yuan Ying , Wall Kathleen , Vera Elizabeth , Ikiddeh-Barnes Ukeme , Blackburn Katie , Chambers Claudia , Ratnam Nivi , Frederico Stephen , Acquaye Alvina , Aldape Kenneth , Briceno Nicole , Choi Anna , Christ Alexa , Jammula Varna , Leeper Heather , Levine Jason , Lindsley Matthew , Reyes Jennifer , Roche Kayla , Rogers James , Timmer Michael , Boris Lisa , Burton Eric , Lollo Nicole , Panzer Marissa , Polskin Lily , Pillai Valentina , Quezado Martha , Theeler Brett , Wu Jing , Armstrong Terri , Gilbert Mark 
Published: November 2021

Abstract

INTRODUCTION
Standard and experimental therapies for patients with rare CNS tumors are scarce. Nivolumab (PD-1 inhibitor) is approved for several non-CNS cancers. This ongoing Phase II trial (NCT03173950) will determine the efficacy of nivolumab in adults with recurrence/progression of one of 11 selected rare primary CNS tumors. Efficacy is measured by Disease Control Rate (DCR; confirmed CR/PR or durable SD for ≥ 6 months) in 2 cohorts: heavily and non-heavily pretreated patients (heavily pretreated: ≥ 3 prior therapies; non-heavily pretreated: ≤ 2). We report efficacy and safety results of a preplanned interim analysis in the heavily pretreated cohort.

METHODS
Eligibility includes recurrence/progression of an eligible tumor; age ≥ 18 years; tumor tissue available for histopathology, molecular and immune profiling; KPS ≥ 70; and no steroids at study entry. A total of 150 evaluable patients will be enrolled (75 to each cohort). Prior therapies include radiation and/or standard or investigational drugs. Nivolumab treatment is 240 mg IV every 2 weeks (4 doses); then 480 mg every 4 weeks (14 additional doses). Interim analysis was planned when sample size reached 32 in each cohort.

RESULTS
As of March 10, 2021, DCR exceeded the minimum required for interim analysis in the heavily pretreated cohort. Among 30 patients, 4 achieved SD &gt; 6 months (medulloblastoma, anaplastic ependymoma, myxopapillary ependymoma, metastatic atypical meningioma). Safety profile (related AEs): grade 3 = 7; grade 4 = 1. Most frequent grade 3-5 AEs regardless of attribution: tumor progression (6); anemia, hydrocephalus, lymphopenia (3 each); cerebral edema, headache (2 each).

CONCLUSION
DCR exceeded the “go” boundary (i.e., &gt; 2) in the heavily pretreated cohort. Nivolumab showed safety profile consistent with other studies. This cohort will continue to stage 2 and complete total accrual of 75 patients. The trial is currently being expanded to 10 additional sites across the BTTC/NCI-CONNECT consortium.
CTNI-02. NERATINIB FOR TREATMENT OF LEPTOMENINGEAL METASTASES FROM HER2-POSITIVE BREAST CANCER IN EXTENDED ACCESS PROGRAM: PRELIMINARY RESULTS
Authors: Pellerino Alessia , Palmiero Rosa , Bruno Francesco , Muscolino Erminia , Franchino Federica , Rudà Roberta , Soffietti Riccardo 
Published: November 2021

Abstract

INTRODUCTION
The aim of the study was to evaluate the activity of neratinib in LM from HER2-positive BC after the failure of multiple lines of treatment.

PATIENTS AND METHODS
Inclusion criteria were as follows: age ≥ 18 years; histological diagnosis of primary HER2-positive BC; newly-diagnosed LM (LANO criteria); KPS ≥ 60; coexistence of BM that have or not received radiotherapy; life expectancy ≥ 3 months; previous drugs, including capecitabine, trastuzumab, T-DM1, pertuzumab, and hormone therapy, were allowed, with the exclusion of lapatinib or other investigational agents. Neratinib was administered 240 mg daily continuously. Primary endpoint was the OS. Secondary endpoints were progression-free survival (PFS), neurological benefit, radiological response rate, and tolerability.

RESULTS
Nine patients with LM have been enrolled with a median age of 44 years, and a median KPS of 80. Median time since LM onset from the diagnosis of primary BC was 42 months, and patients underwent a median number of adjuvant treatments before LM of 3. Three patients developed LM alone, and other 6 had LM associated with multiple BM. Six-months and 1-year OS were 66.7% and 22.3%, respectively, with a median OS of 8 months (95%CI 3-13*). Median PFS was 3.5 months (95%CI 2-6) after the start of treatment. A neurological improvement was reported in 2/9 patients (22.2%), while in other 4/9 patients (44.5%) was achieved a neurological stabilization lasting for a median time of 5 months (95%CI 2-19). The best radiological response was a stable disease in 5/9 patients (55.6%), while no complete or partial were achieved according to LANO criteria. A CSF clearance was observed in 1 patient only (11.1%). Grade III-IV adverse events were not reported, and 2 patients only (22.2%) had mild diarrhea correlated with neratinib.

CONCLUSIONS
Neratinib might be a safe and effective treatment in LM from heavily pretreated HER2-positive BC.
CTNI-03. EXTENDED BENEFITS IN PATIENTS WITH RECURRENT HIGH GRADE GLIOMA THAT CONTINUOUSLY RECEIVE TOCA FC AFTER TOCA 511 TREATMEN
Authors: Walbert Tobias , Damek Denise , Nina L Martinez , Piccioni David , Singer Samuel , Cloughesy Timothy 
Published: November 2021

Abstract
Toca 511 (vocimagene amiretrorepvec) is an investigational nonlytic, retroviral replicating vector (RRV) constructed with a codon-optimized yeast cytosine deaminase (CD) gene. Toca 511 infects cancer cells, and stably delivers CD gene whose protein product converts courses of the prodrug TocaFC (5-fluorocytosine) into 5-fluorouracil (5-FU). Several phase 1 studies and a phase 2/ 3 clinical study tested Toca511 in combination with TocaFC in patients undergoing planned resection for recurrent glioblastoma (rGBM) or anaplastic astrocytoma (rAA). The last trial was completed in 2019, and although the Phase 2/3 study did not meet the primary objective, patients who appeared to benefit from the treatment elected to continue TocaFC through an expanded access or compassionate use pathway. Seven patients continued on treatment: 3 men and 4 women; 5 with rGBM, 2 with rAA. Duration of treatment with TocaFC ranges from 29 months to 7 years and 5 months (average 49.2 months). Six patients who are still on active treatment with TocaFC have either stable disease or complete response. TocaFC is well tolerated in these patients, typical side effects include diarrhea. Some patients with rGBM or rAA appear to benefit from extended TocaFC treatment after Toca511. Individual cases will be discussed.
CTNI-06. TRAM-01: A PHASE 2 STUDY OF TRAMETINIB FOR PATIENTS WITH PEDIATRIC GLIOMA WITH ACTIVATION OF THE MAPK/ERK PATHWAY
Authors: Perreault Sébastien , Larouche Valérie , tabori uri , Hawkins Cynthia , Lippe sarah , Ellezam Benjamin , decarie Jean-Claude , Ospina Luis H , theoret yves , Desjardins Leandra , Metras Marie-Elaine , Sultan serge , Cantin Edith , Routhier Marie-Eve , Caru Maxime , Vairy Stephanie , Legault Geneviève , Bouffet Eric , Lafay-Cousin Lucie , Hukin Juliette , Erker Craig , Jabado Nada 
Published: November 2021

Abstract

BACKGROUND
Pediatric low-grade gliomas (PLGG) are the most frequent brain tumors in children. It is known that the majority of PLGG have activation of the MAPK/ERK pathway.

METHODS
This ongoing multicenter phase II trial includes three progressing/refractory PLGG groups: NF1 patients, KIAA1549-BRAF fusion patients and patients with other activation of the MAPK/ERK pathway (excluding V600E). The primary objective was to evaluate the overall response rate based on RANO criteria after daily oral trametinib administration for 18 cycles, lasting 28 days each. Secondary objectives include the assessment of progression-free survival, tolerability of trametinib, serum levels of trametinib and quality of life evaluation during treatment.

RESULTS
As of February 12 2021, 50 patients have been enrolled (NF1: n=10; KIAA1549-BRAF fusion: n=31; other: n=9 including 5 patients with FGFR1 alterations). Median age is 8.8 years (range 2.4-25.5). Median follow-up is 17.5 months (range 4.7-28.5). Forty-three patients are evaluable. The overall response includes: 4 partial response (PR) (9%), 18 minor response (MR) (42%), 17 stable disease (40%), 4 progressive disease (9%). Median time to response is 5.5 months (range 2.4-13.8). Median duration of response is 6.1 months (range 0.6-26.5). Progression free survival at 12 months is 79.9% (95% CI 68.5-93.6%) and median progression free survival has not yet been reached. Treatment was discontinued for 30 patients: 16 after completing 18 cycles as planned, 5 for progressive disease, 5 for adverse events, 4 for other reasons. A total of 8 patients progressed after discontinuation of treatment including 6 patients (37.5%) that completed 18 cycles. Five of these patients had achieved minor response prior to discontinuation.

CONCLUSION
Trametinib is a potentially effective targeted therapy for patients with recurrent/refractory PLGG. Treatment was overall well tolerated. This ongoing trial will continue to gather data on response rate, duration of response and safety of trametinib for PLGG.
CTNI-12. PHASE II MULTICENTRIC ITALIAN TRIAL ON REPOSITIONING OF THE ANTIPSYCHOTIC DRUG CHLORPROMAZINE AND ITS SYNERGISM WITH TEMOZOLOMIDE IN MGMT UNMETHYLATED GLIOBLASTOMA PATIENTS: THE RACTAC TRIAL
Authors: Pace Andrea , Lombardi Giuseppe , Matteoni Silvia , Villani Veronica , Abruzzese Caludia , Cerretti Giulia , Padovan Marta , Caccese Mario , Benincasa Dario , Silvani Antonio , Paggi Marco 
Published: November 2021

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, 28 patients out of 41 patients planned have been enrolled, without relevant toxicity.
CTNI-15. PHASE 0/I TRIAL OF MYCOPHENOLATE MOFETIL COMBINED WITH RADIATION TO OVERCOME GLIOBLASTOMA TREATMENT RESISTANCE BY TARGETING DE-NOVO PURINE METABOLISM: INTERIM REPORT
Authors: Umemura Yoshie , Sun Yilun , Junck Larry , Leung Denise , Kim Michelle , Al-Holou Wajd , Sagher Oren , Heth Jason , Schipper Matthew , Lyssiotis Costas , Marini Bernard , Lawrence Theodore , Wahl Daniel 
Published: November 2021

Abstract

BACKGROUND
De novo purine synthesis promotes glioblastoma growth and stemness, invasiveness, and resistance to chemoradiation. Mycophenolate mofetil (MMF) is an FDA-approved inhibitor of de novo purine synthesis that sensitizes glioblastoma to radiation and chemotherapy in mice. This Phase 0/I trial of MMF with Radiotherapy in Recurrent Glioblastoma (NCT04477200) aims to determine the maximum-tolerated dose of MMF that can be combined with radiation,and the extent to which the active metabolite of MMF accumulates in brain tumors and inhibits de novo purine synthesis.

METHODS
Key eligibility criteria are age ≥18, KPS score ≥60%, and recurrent glioblastoma or gliosarcoma with clinical indication for re-irradiation (phase I) or re-resection/biopsy (phase 0). Patients with tumors involving ≥3 lobes or leptomeningeal space or bevacizumab use within 8 weeks are excluded. MMF 500-2000mg PO BID is given one week pre-operatively in Phase 0 (N=8), and up to 2000mg PO BID (starting 1000mg) on TITE-CRM dose escalation on Phase 1 cohort (N=30).

RESULTS
Since 7/2020, three Phase 0 and six Phase I subjects have been enrolled. On the phase I cohort, 1500mg BID dose has been reached. Studyrelated toxicities have been limited to mainly grade 1-2 nausea and fatigue. No notable study related hematotoxicity have been noted. Additionally, mass spectrometry-based correlative measurements of the activity of de novo GTP synthesis are ongoing.

CONCLUSION
MMF has been well tolerated up to 1500mg BID combined with radiotherapy in recurrent glioblastoma patients in this interim analysis. An additional upfront glioblastoma cohort with MMF with standard of care will activate in 2021. These studies will determine the maximum tolerated dose of MMF in combination with radiation and chemotherapy and provide a preliminary efficacy estimate at that dose. Encouraging results would support a randomized clinical trial to determine efficacy of MMF combined with chemoradiation in glioblastoma, and to define potential biomarkers for effectiveness.
CTNI-19. CONCURRENT CHEMORADIATION AND TUMOR TREATING FIELDS (TTFields, 200 kHz) FOR PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA MAY INCREASE THE RATE OF DISTANT RECURRENCE
Authors: Ali Ayesha S , Niazi Muneeb , Bar-Ad Voichita , Werner-Wasik Maria , Andrews David , Farrell Christopher , Evans James , Judy Kevin , Glass Jon , Nina L Martinez , Alnahhas Iyad , Chervoneva Inna , Shi Wenyin 
Published: November 2021

Abstract
INTRODUCTION: Current standard of care for glioblastoma (GBM) includes concurrent chemoradiation and maintenance temozolomide (TMZ) along with Tumor Treating Fields (TTFields). Preclinical studies suggest TTFields and radiation treatment have synergistic effects. Secondary analysis of EF14 trial demonstrated TTFields treatment may increase the rate of distant recurrence. We report our experience evaluating areas of progression in our pilot clinical trial of concurrent chemoradiation with TTFields. METHODS: This is a single arm pilot study (clinicaltrials.gov Identifier: NCT03477110). Adult patients (age ≥ 18 years) with KPS ≥ 60 with newly diagnosed GBM were eligible. All patients received concurrent scalp-sparing radiation (60 Gy in 30 fractions), standard concurrent TMZ (75 mg/m2 daily), and TTFields. Maintenance therapy included standard TMZ and continuation of TTFields. Radiation treatment was delivered through TTFields arrays. Incidence and location of progression was documented. Distant recurrence was defined as recurrence more than 2 cm from primary enhancing lesion. RESULTS: A total of 30 patients were enrolled on the trial. Twenty were male, and ten were female, with median age 58 years (19-77 years). Median KPS was 90 (70-100). Median follow-up was 11.6 months (1.7-22.1 months). Twenty (66.7%) patients had an unmethylated MGMT promotor status and ten (33.3%) patients had a methylated promoter status. Twenty patients (66.7%) had progression, with median PFS of 9.1 months (range 1.6 to 12.9 months). Five patients (26%) of patient presented with distant recurrence, with median distance from primary lesion of 5.1 cm (2.26-9.12 cm). One infratentorial progression was noted. Another patient transferred care and location of progression is unknown. CONCLUSIONS: Concurrent chemoradiation with TTFields for patients with newly diagnosed glioblastoma may have increased incidence of distant recurrence. This finding is suggestive of improved local control of primary site. Further data are needed to validate this finding.
CTNI-20. FEASIBILITY OF SINGLE-PASS STEREOTACTIC NEEDLE BIOPSY IN RECURRENT GLIOBLASTOMA PATIENTS TO SUPPORT CLIA-CERTIFIED TUMOR PHARMACODYNAMICS FOR A PHASE 0/2 CLINICAL TRIAL
Authors: Chang Yu-Wei , DeSantis Anita , Pennington-Krygier Chelsea , Molloy Jennifer , Mehta Shwetal , Sanai Nader , Tien An-Chi 
Published: November 2021

Abstract

BACKGROUND
In neuro-oncology clinical trials, pharmacodynamic (PD) analysis of tumor tissue before and after experimental therapy is challenging. Today, Phase 0 studies in brain tumor patients typically employ archival tissue from a prior resection as the baseline PD comparator. However, the time-interval between tissue acquisitions can be months to years and often includes confounding exposure to other therapies. Here, we demonstrate the feasibility of a pre-treatment, single-pass stereotactic needle biopsy to support CLIA-certified genetic screening and tumor PD analysis in a Phase 0/2 clinical trial.

METHODS
In support of an ongoing Phase 0/2 ‘trigger’ trial testing CDK4/6 plus ERK1/2 inhibition in recurrent glioblastoma (GBM), a single-pass stereotactic biopsy was completed in select patients prior to enrollment. Each biopsy yields six tissue cores for immunohistochemistry (IHC) and genetic characterization. Using CLIA-certified protocols, genomic DNA (gDNA) was extracted from two cores, followed by library preparation and next-generation sequencing of a customized panel of 37 genes (IvySeq). In the four remaining cores, IHC staining was performed for RB, pRB, pERK, pS6, CDKN2A, MIB-1, ClCas-3 and pH2AX.

RESULTS
Single-pass stereotactic needle biopsies were collected from five recurrent GBM patients. No intraoperative, perioperative, or radiographic evidence of morbidity was observed. 800-2400ng of gDNA was isolated from each stereotactic biopsy. IvySeq analysis detected CDKN2A deletion, ATRX loss, and mutations in IDH, PTEN and TP53 genes. Based on IHC and genetic analyses of the biopsied samples, three patients were enrolled into the Phase 0/2 clinical trial and baseline value were used for PD analysis.

CONCLUSION
Single-pass stereotactic needle biopsy is a feasible and safe strategy to collect pre-treatment tissue in support of a Phase 0 clinical trial, enabling CLIA-certified genetic analysis for trial screening and tumor PD analysis.
CTNI-32. CASE SERIES OF BRAF INHIBITORS FOR THE TREATMENT OF BRAFV600E GLIOBLASTOMA
Authors: Wagle Naveed , Carrillo Jose , Sharma Akanksha , Nguyen Minhdan , Truong Judy , Chow Jared , Landa Evie , Heng Annie , Gill Jaya , Barkhoudarian Garni , Kelly Daniel , Kesari Santosh 
Published: November 2021

Abstract
Glioblastoma is the most common and aggressive primary brain tumor. Beyond upfront therapy with radiation and temozolomide chemotherapy there is no standard therapy that has been effective. Inhibitors of BRAF and MEK, a downstream protein immediately following BRAF, have been shown to have survival benefit for patients with other BRAF V600E mutant neoplasm including advanced melanoma. We describe our experience using this combined target therapy for two patients with BRAF V600E mutant glioblastoma. Two adult patients with pathologically diagnosed glioblastoma presented with radiographic evidence of tumor progression after prior treatment with chemotherapy or immunotherapy. Neither had received radiation therapy within 3 months of starting treatment. Molecular characterization was performed though Caris which showed evidence of BRAF V600E mutation. BRAF inhibitors were initiated in combination with standard therapy options. MRI imaging was obtained to monitor for disease progression. BRAF inhibitors were tolerated well without any side effects not previously reported. Partial objective response was seen in both patients on subsequent MRI imaging within 8 weeks of starting treatment. Progression free survival and overall survival have not been reached in either case. BRAF inhibition may have therapeutic benefit in BRAF mutated glioblastoma. Partial response was seen in this case series. The molecular profile of glioblastoma may suggest treatment options beyond standard chemotherapy options. This series supports the use of BRAF inhibitors for the treatment of BRAFV600E glioblastoma A controlled trial should be supported.