bluuebunny/crossref_metadata_2025_split huggingface dataset:
CTIM-33. EFFICACY AND SAFETY STUDY OF NEOADJUVANT EFINEPTAKIN ALFA (NT-I7) AND PEMBROLIZUMAB IN RECURRENT GLIOBLASTOMA
Authors: Webb Mason , Sener Ugur , Burns Terry , Twohy Erin , Kizilbash Sani H , Ruff Michael , Uhm Joon , Galanis Evanthia , D'Andre Stacy , Riviere-Cazaux Cecile , Lee Byung Ha , Flickinger Lynn , Parney Ian , Campian Jian 
Published: November 2023

Abstract
Glioblastoma (GBM) is the most common and aggressive form of brain tumor in adults. Despite maximal surgical resection, irradiation, and chemotherapy, median overall survival (OS) for recurrent GBM (rGBM) remains at only 30 weeks. GBM tumors have an immune-suppressive microenvironment with low numbers of tumor-infiltrating lymphocytes (TILs). Interleukin 7 (IL-7) plays a key role in T cell homeostasis and survival, with IL-7 inducing T cell expansion in lymphopenic conditions. Efineptakin alfa (NT-I7), a long-acting IL-7, has been shown to increase effector CD8 T cells and reduce suppressor T-regulatory cells in murine GBM models, with subsequently improved OS. We recently completed a Phase I study in newly diagnosed GBM patients which showed that NT-I7 is safe, well-tolerated, and increased absolute lymphocyte counts (ALCs), and determined maximum tolerated dose for Phase II. We hypothesized that NT-I7 may not only mitigate GBM treatment-associated immune suppression, but also potentiate the effect of immune checkpoint blockade, leading to an increase in TILs and improved survival. The purpose of this study is to evaluate the safety and efficacy of combining NT-I7 and pembrolizumab in rGBM patients. This is an open-label, single arm one-stage Phase II study of NT-I7 and pembrolizumab as neoadjuvant and adjuvant therapy with surgery for adult patients with rGBM. We plan to enroll 30 evaluable patients, including a 6-patient safety run-in. The primary endpoint is the 9-month OS rate. Secondary endpoints include progression-free survival, objective response rate, changes in ALC, and adverse events profile. The correlative endpoints include studies to assess the anti-glioma immune response, changes in T cell subsets and functionality, peripheral cytokine quantification, and immunohistochemical analysis of GBM tissue. Longitudinal cerebrospinal fluid proteomics is optional. This study opened in Jan 2023. Six (6) of the planned thirty (30) patients had been enrolled by time of submission.
CTIM-36. IMMUNOHISTOCHEMISTRY EVALUATION ON PRE-TREATMENT TUMOR TISSUE PREDICTS TREATMENT RESPONSE TO MN-166 (IBUDILAST) AND TEMOZOLOMIDE COMBINATION THERAPY IN GLIOBLASTOMA PATIENTS
Authors: Lathia Justin , Lauko Adam , Matsuda Kazuko , Makhay Malath , Nayak Lakshmi , Chukwueke Ugonma , Lee Eudocia , Reardon David , Beroukhim Rameen , Batchelor Tracy , Aquilanti Elisa , Wen Patrick 
Published: November 2023

Abstract

STUDY DESIGN
MN-166-GBM-1201 is a Phase I/II open-label clinical trial to evaluate MN166 (ibudilast) and temozolomide (TMZ) combination treatment in newly diagnosed and recurrent glioblastoma (GBM) patients. 62 GBM patients (34 newly diagnosed and 28 recurrent) were enrolled in the study. All patients received MN-166 and TMZ combination treatment until disease progression or withdrawal from the study for other reasons.

METHODS
Pre-treatment tumor tissue at initial surgery from 24 study participants was evaluated to determine potential predictors of response to MN-166, which has been shown to inhibit the interaction between macrophage migration inhibitory factor (MIF) and CD74 with ERK phosphorylation downstream of CD74. We looked at CD11b and CD3 expression to characterize the immune profile within the tumors and Ki67 to determine percentage of proliferating tumor cells, all of which were calculated by a masked researcher. Then, patients were stratified based on progression within the first five months after receiving MN-166 and TMZ.

RESULTS
Patients who did not progress within 5 months had a significantly lower percentage of CD3+ T cell infiltration than nonresponding patients (p = 0.045), and CD74 expression was lower in patients with no progression (p = 0.16). The other markers demonstrated no differences. MN-166 and TMZ combination therapy was generally safe and well tolerated.

CONCLUSION
CD3 expression was a good predictor for tumor progression for five months in recurrent GBM patients treated with MN-166 and TMZ. T cell infiltration within GBM tumors has been an active area of research with the success of immune checkpoint blockade (ICB) therapies in other cancers. Moreover, MN-166 has been shown to impact immune suppressive myeloid cells, which are linked to the immune suppressive tumor microenvironment and a resistance mechanism to ICB. Collectively, we postulate that the efficacy of MN-166 for treatment of GBM could be further enhanced by co-treatment with ICBs.
CTIM-38. NEUROTOXICITY AND MANAGEMENT OF PRIMARY AND SECONDARY CNS LYMPHOMA AFTER ADOPTIVE IMMUNOTHERAPY WITH CD19-DIRECTED CAR T-CELLS
Authors: Karschnia Philipp , Arrillaga-Romany Isabel , Eichler April , Forst Deborah , Gerstner Elizabeth , Jordan Justin T , Ly Ina , Plotkin Scott R , Wang Nancy , Martinez-Lage Maria , Winter Sebastian F , Tonn Joerg-Christian , Rejeski Kai , von Baumgarten Louisa , Cahill Daniel , Nahed Brian V , Shankar Ganesh M , Abramson Jeremy S , Barnes Jeffrey A , El-Jawahri Areej , Hochberg Ephraim P , Johnson P Connor , Soumerai Jacob D , Takvorian Ronald W , Chen Yi-Bin , Frigault Matthew J , Dietrich Jorg 
Published: November 2023

Abstract

BACKGROUND
Chimeric antigen receptor (CAR) T-cells targeting CD19 have been established as a leading engineered T-cell therapy for systemic B-cell lymphomas; however, efficacy data for patients with CNS involvement are limited. Also, there are concerns about increased neurotoxicities (denoted by the term 'ICANS') when the target antigen is present within the CNS.

METHODS
We retrospectively report on CNS-specific toxicities, management, and CNS response of 45 consecutive CAR T-cell transfusions for patients with active CNS lymphoma at the Massachusetts General Hospital over a five-year period.

RESULTS
Our cohort includes 17 patients with primary CNS lymphoma (PCNSL; one patient with two CAR T-cell transfusions) and 27 patients with secondary CNS lymphoma (SCNSL). Mild ICANS (grade 1-2) was observed after 19/45 transfusions (42.2%) and severe ICANS (grade 3-4) after 7/45 transfusions (15.6%). No fatalities were directly attributed to ICANS. A larger increase in C-reactive protein (CRP) levels and higher rates of ICANS were detected in SCNSL. Early fever and baseline C-reactive protein levels were associated with ICANS occurrence. CNS response was seen in 31 cases (68.9%), including a complete response of CNS disease in 18 cases (40.0%) which lasted for a median of 11.4 ± 4.5 months. Similar response rates were seen in both patients with parenchymal and leptomeningeal involvement. Dexamethasone dose at time of lymphodepletion (but not at or after CAR T-cell transfusion) was associated with an increased risk for CNS progression (HR per mg/d: 1.16, p = 0.031). If bridging therapy was warranted, the use of ibrutinib translated into favourable CNS-progression free survival (5 versus 1 month, HR 0.28, CI 0.1-0.7; p = 0.010).

CONCLUSION
CAR T-cells exhibit promising anti-tumor effects and a favourable safety profile in CNS lymphoma. Further evaluation of the role of bridging regimens and corticosteroids is warranted to boost the success of such therapy.
CTIM-39. A PHASE 1B STUDY OF PEMBROLIZUMAB, IBRUTINIB AND RITUXIMAB IN RECURRENT/REFRACTORY (RR) PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA (PCNSL)
Authors: Chukwueke Ugonma , Wright Isobel , Muzikansky Alona , Russ Alyssa , Fontana Brittney , Kats Vanessa , O'Donnell Colin , Scalfani Renee , Acevedo-Naranjo Brenda , Lee Eudocia , Castro Luis Nicolas Gonzalez , McFaline-Figueroa Jose Ricardo , Aquilanti Elisa , Youssef Gilbert , Beroukhim Rameen , Forst Deborah , Reardon David , Wen Patrick , Batchelor Tracy , Torres Alexandra , Stefanik Jennifer , Fisher Jennifer , Meredith David , Murakami Mark , Garcia Yuri , Shipp Margaret , Nayak Lakshmi 
Published: November 2023

Abstract

BACKGROUND
PCNSL exhibit B-cell receptor (BCR) pathway activation due to CD79B and MYD88 mutations, concurrently with 9p24.1/PD-L1/PD-L2 copy number alterations. These genetic features suggest complementary approaches of targeting PD1, BCR/BTK (Bruton’s tyrosine kinase) and CD20. Pembrolizumab, ibrutinib and rituximab have each been used as monotherapy in RR PCNSL. We investigate these agents in combination to determine tolerability and synergistic efficacy.

METHODS
This is a phase 1b/2 study of pembrolizumab, ibrutinib and rituximab in RR PCNSL patients. In phase 1b, patients were accrued using a 3 + 3 design to determine the maximum tolerated dose/recommended phase 2 dose (MTD/RP2D). Patients were treated with pembrolizumab 200mg IV every 3 weeks, ibrutinib oral daily and rituximab 375mg/m2 IV weekly (for 4 doses). Two dose levels (DL) of ibrutinib (DL1: 560 mg, DL2: 840 mg) were evaluated. Primary endpoint is progression-free survival at six months (PFS6); secondary endpoints include safety, tolerability, objective response rate (ORR), duration of response (DOR), progression-free and overall survival.

RESULTS
We completed accrual on the phase 1b part and report results of 10 evaluable patients (50% women). The median age was 74 years (38-82) and median ECOG 1 (0-1). There was 1 DLT at DL1 (grade 4 transaminases) and 2 DLTs at DL2 (hypertension, flu-like symptoms); the MTD/R2PD of ibrutinib with pembrolizumab and rituximab is 560mg. The most common grade 3/4 adverse events were elevated transaminases and decrease in lymphocyte counts. There were 13 dermatologic events, all &lt; grade 3. Reasons for discontinuing treatment include progression (6), consent withdrawal (1), toxicity (2). The ORR is 80% (6 complete responses, 2 partial responses). As of June 2023, the median DOR is 177 days (49-619); PFS6 is 50%.

CONCLUSIONS
The combination of pembrolizumab, ibrutinib and rituximab is well-tolerated with manageable side effects and encouraging efficacy. The phase 2 portion of the study is open.
CTIM-40. EARLY RADIOGRAPHIC RESPONSE AND ENGRAFTMENT OF PHASE I FIRST-IN-HUMAN BICISTRONIC CAR T CELLS CORRELATE WITH REAL-TIME AUTOLOGOUS GBM ORGANOID CYTOLYSIS
Authors: Logun Meghan , Bagley Stephen J , Wang Xin , Zhang Daniel , Sun Yusha , Ming Guo-li , Nabavizadeh Ali , Marshall Amy , Maloney Eileen , Hwang Wei-Ting , Fraietta Joseph , Gonzalez Vanessa , Desai Arati , Bagley Linda , Hexner Elizabeth , Nasrallah MacLean P , Song Hongjun , Binder Zev , O'Rourke Donald M 
Published: November 2023

Abstract
Glioblastoma (GBM) is a highly treatment-resistant cancer, in part due to prominent inter- and intratumoral heterogeneity. To date, monovalent CAR T-cell therapies have failed to overcome this heterogeneity. Bivalent CAR-T cells may overcome this challenge by expanding the population of target-positive tumor cells. NCT05168423 is first-in-human, phase 1 dose escalation study to assess safety and feasibility of intrathecal delivery of autologous bicistronic CAR-T cells, targeting both EGFR and IL13Rα2, in patients with EGFR-amplified recurrent GBM. For each patient enrolled in this study, high-fidelity glioblastoma organoids (GBOs) are derived from tumor tissue and utilized to test the autologous CAR-T product in real-time. GBOs are co-cultured with autologous CAR-T cells and individually monitored using modified impedance spectroscopy assays over six days for quantification of real-time tumor cytolysis. CAR-T efficacy in GBOs was correlated to matched clinical trial patient outcomes, including CAR-T engraftment. To date, three patients have been treated at the initial dose level (10,000,000 CART-EGFR-IL13Rα2 cells). All three patients demonstrated tumor shrinkage on MRI obtained within 24-48hrs post-infusion. MRI changes were accompanied by significant tumor-inflammation associated neurotoxicity that resolved with steroids and IL1R blockade. Serial CSF collection for qPCR following CAR-T infusion revealed average peaks of &gt;100,000 copies of CAR-T cells/μg of gDNA, comparable to CART19-treated patients. Cytotoxicity values in GBOs strongly correlated with peak CSF engraftment levels of CAR-T cells in all three patients (r = 0.998, p = 0.037). In summary, we present striking radiographic and biological responses from the first cohort of recurrent GBM patients treated with a bivalent, intrathecally delivered CAR T cell product simultaneously targeting EGFR and IL13Rα2. Potent anti-tumor activity of CART-EGFR-IL13Rα2 cells was also observed by treating patient-derived GBOs with the patients’ corresponding autologous CAR T-cell products, providing a parallel, ex vivo system for real-time prediction of CAR T-cell engraftment.
CTNI-05. INTRATHECAL PEMETREXED FOR LEPTOMENINGEAL METASTASES FROM SOLID TUMOR: A MULTICENTER, PHASE I/II, OPEN-LABEL STUDY (PMLM, NCT 05289908)
Authors: Pan Zhenyu , Yang Guozi , Wang Zhuo , Shen Longhai , Yuan Tingting , Pang Xiaochuan , Li Sijia , Dong Lihua 
Published: November 2023

Abstract

OBJECTIVES
This phase I/II study was to evaluate maximum tolerated dose (MTD) of intrathecal pemetrexed (IP) with vitamin supplementation and antitumor activity for leptomeningeal metastases (LM) from solid tumors.

METHODS
Phase I study followed the classic 3 + 3 design, with dose escalated from 15 mg. Phase II followed Simon 2-stage design with recommended dose determined in phase I. IP was administered twice per week for 2 weeks (induction therapy), followed by once per week for 4 weeks (consolidation therapy). Vitamin B12 (1000 μg) and folic acid (400 μg, q.d.) were given at the beginning of treatment. Primary end points were MTD in phase I and clinical response rate (CRR) in phase I/II.

RESULTS
Between Feb 2022 and Jan 2023, 34 patients were enrolled, including non-small cell lung cancer (20), small-cell lung cancer (3), breast cancer (8), others (3). Ten patients were enrolled in phase I. Three of 4 patients receiving IP at 15 mg completed induction and consolidation treatment without dose limiting toxicity (DLT). Two DLT (1 grade 4 hematologic toxicity and 1 grade 5 arachnoiditis) occurred in 6 patients at 20 mg. MTD was determined to be 15 mg. Then 24 patients were enrolled in phase II and given 15 mg of IP. 82.4% (28/34) and 58.8% (20/34) patients completed induction and consolidation therapy, respectively. Adverse events (AEs) rate was 73.5% (25/34). 50% (17/34) patients showed grade ≥ 3 AEs. Overall CRR was 41.2% (14/34), including 10 (29.4%) with improved neurological dysfunction, 11 (32.4%) with CSF cytological response and 4 (11.8%) with neuroimaging improvement. Median survival was 7.6 (range 0.3–13.7) months in phase I, while has not yet been achieved in phase II.

CONCLUSION
MTD of IP was 15 mg with folic acid and vitamin B12 supplementation. IP is an optimal therapeutic option for LM from solid tumors.
CTNI-13. CONCURRENT INTRATHECAL CHEMOTHERAPY AND INVOLVED-FIELD RADIOTHERAPY FOR LEPTOMENINGEAL METASTASIS FROM SOLID TUMORS: A PHASE II STUDY (NCT03082144)
Authors: Yang Guozi , Pan Zhenyu , Chen Kunzhi , Jiang Tongchao , Song Yuanyuan , Dong Lihua , He Hua , Ye Xiaojun , Wang Min , Zhou Tao 
Published: November 2023

Abstract

BACKGROUND
The role of involved-field radiation therapy (IFRT) and intrathecal chemotherapy (IC) in leptomeningeal metastasis (LM) from solid tumors was gradually underestimated in the era of targeted therapy. This study was aimed to investigate the safety and effectiveness of concurrent IFRT and intrathecal methotrexate (MTX)/cytarabine (Ara-C) for LM, particularly for those who developed LM while receiving targeted therapy.

METHODS
Enrolled patients were randomly assigned to two subgroups (IFRT&IC-MTX and IFRT&IC-Ara-C), and first treated with induction IC (MTX or Ara-C) twice per week, up to 4 times. Then patients were given concurrent treatment, which consisted of IFRT (40 Gy total; 2 Gy/f) and IC (MTX 15 mg or Ara-C 50 mg, once per week). The involved field consisted of symptomatic or painful sites and disease observed on magnetic resonance imaging (MRI), including the whole brain and basis crania and/or segment of spinal canal. Primary endpoint was clinical response rate (RR). Secondary endpoints were safety and overall survival (OS).

RESULTS
Fifty-three patients received induction intrathecal MTX (n = 27) or Ara-C (n = 26). Forty-two patients completed concurrent therapy. Total RR was 34% (18/53). The improvement rate of neurological symptoms and KPS scores were 72% (38/53) and 66% (35/53) respectively. Adverse events (AEs) rate was 28% (15/53). Eight patients (15%, 8/53) showed grade 3-4 AEs, including myelosuppression (n = 4) and radiculitis (n = 5). Median OS was 6.5 months (95% CI, 5.3-7.7 months). Median survival for 18 patients who had clinical response was 7.9 months (95% CI, 4.4-11.4 months), and 0.8 months (95% CI, 0.08-1.5 months) for 6 patients who had LM progression. The median survival in 22 patients who received prior targeted therapy was 6.3 months (95% CI, 4.5-8.1 months).

CONCLUSION
Concurrent IFRT and intrathecal MTX or Ara-C was proved to be a feasible treatment option with an acceptable safety profile for LM from a common tumor entity.
CTNI-14. NEOADJUVANT STEREOTACTIC RADIOSURGERY (NASRS) FOR LARGE BRAIN METASTASES (BRM): RESULTS OF AN INTERNATIONAL MULTICENTER PHASE II TRIAL
Authors: Shultz David , Li Dianna , Rodriguez Ruth Lau , Higazy Randa , Laperriere Normand , Millar Barbara-Ann , Conrad Tatiana , Zadeh Gelareh , Kalyvas Aristotelis , Senger Carolin , Acker Gueliz , Spears Julian , Kongkham Paul 
Published: November 2023

Abstract

BACKGROUND
We conducted an international multi-center phase II trial evaluating NASRS for BrM. We hypothesized that radiation necrosis (RN) would be lower than post-operative cavity radiotherapy since the tissues receiving the highest radiation dose are resected in NASRS.

METHODS
BrM patients with 1 index lesion ( &gt;2 and &lt;5 cm in greatest diameter) suitable for resection, and 9 or less additional BrM (&lt; 3 cm in greatest diameter, not requiring resection) were recruited across 3 centres. SRS was administered a median 3 (range: 2-21) days prior to surgical resection. A single fraction of 15-21 Gy was delivered, targeting the index tumor with a 2mm margin. From a sample of 30 patients, the primary endpoint was the 1-year rate of grade 2+ (G2+) RN from the index lesion. Secondary endpoints included local failure (LF), leptomeningeal disease (LMD) and overall survival (OS).

RESULTS
We enrolled 35 patients [Mean age (SD): 58.9 (12.9) years, 46% female] between 2018 and 2022. The most common primary histologies were lung (40%), and gastrointestinal (20%) cancers. The median BrM volume prior to surgery was 16.6 cc (range 3.2 -38.0); median index lesion size was 3.2 (range: 1.9-4.5) cm. All participants received planned protocol treatment; n = 30 are currently available for 1 year outcomes. No patients developed G2+ RN; 5 had a LF (1-year rate 38%) at 5-12-months following surgery, all of whom had an en-bloc resection. One patient each developed classic LMD and pachymeningeal failure 3 and 11 months after surgery, respectively. Median OS was 11.5 months.

CONCLUSION
No patients in our study experienced G2+ RN. The 1-year rate of LF was higher than anticipated, indicating the potential benefit of considering a higher radiation dose or larger margins for improved outcomes.
CTNI-15. PILOT STUDY OF HIGH-DOSE PEMETREXED FOR PROGRESSIVE CHORDOMA
Authors: Kesari Santosh , Wagle Naveed , Carrillo Jose , Sharma Akanksha , Nguyen Minhdan , Truong Judy , Gill Jaya , Nersesian Raffi , Nomura Natsuko , Rahbarlayegh Elnaz , Barkhoudarian Garni , Sivakumar Walavan , Kelly Daniel , Krauss Howard , Bustos Matias , Hoon Dave , Anker Lars , Singh Arun , Sankhala Kamalesh , Juarez Tiffany 
Published: November 2023

Abstract

INTRODUCTION
Chordomas are ultra-rare tumors of the spine, and no systemic therapy is approved for refractory disease. Pemetrexed is a multitargeted antifolate that inhibits thymidylate synthase (TS) and other enzymes involved in nucleotide biosynthesis. Considering the majority of chordomas do not express TS, we sought to evaluate the therapeutic activity and safety of high-dose pemetrexed.

METHODS
Adults with previously-treated chordoma were enrolled on an open-label, single-institution, single-arm, pilot clinical trial. Pemetrexed 900 mg/m2 was administered intravenously every 3 weeks, with supportive medications of folic acid, vitamin B12, and dexamethasone. The primary endpoint was objective response rate according to RECIST v1.1. Secondary and exploratory endpoints included adverse events, progression-free survival (PFS), tumor molecular profiles, and alterations in potential tissue and blood-based biomarkers before and after treatment.

RESULTS
Fifteen patients with chordoma received a median of 15 (range 4-31) doses of pemetrexed. Median PFS was 10.5 months (95% CI 9 months-undetermined) and 6-month PFS was 67%. Out of 14 response-evaluable patients, two (14%) achieved a partial response and ten (71%) demonstrated stable disease. Adverse events were generally mild at grades 1-2, the most common being fatigue, rash, nausea, constipation, diarrhea, mucositis, vomiting, alopecia, pruritus, lower extremity edema, and alanine transaminase increased. One Grade 3 creatinine increase, one Grade 3 lymphopenia, and one Grade 4 lymphopenia occurred and there were no Grade 5 adverse events, unexpected toxicities, or dose-limiting toxicities. Clinical improvement in disease-related symptoms occurred in several patients. Tumor molecular profiling revealed low mutational burden and though not statistically significant, positive TS expression trended negatively with disease progression. Cell-free microRNAs (cfmiRs) were concordantly detected in plasma and tissues and a blood cfmiR signature was identified that distinguished chordoma from health donors.

CONCLUSION
High-dose pemetrexed is safe and well-tolerated in chordoma patients. A phase II study is in development. (NCT03955042)