bluuebunny/crossref_metadata_2025_split huggingface dataset:
CTIM-34. JACOB: JOINT ADMINISTRATION OF CDNA FOR TP53, CHECKPOINT INHIBITION, AND BOOST/HYPO FRACTIONATED RADIATION. A PHASE 0/1 STUDY IN CHILDREN WITH RECURRENT, PROGRESSIVE, OR REFRACTORY CNS MALIGNANCIES
Authors: Fonseca Adriana , Kim Sang Soo , Cruz Russell , Ladra Matthew , Pirollo Kathleen , Chang Esther , Packer Roger , Hwang Eugene 
Published: November 2023

Abstract

BACKGROUND
Pediatric patients with recurrent, progressive, or refractory brain tumors have dismal prognoses and few therapeutic options. Due to the complex biological mechanisms of resistance in these tumors, targeted agents and immunotherapeutic approaches in isolation have yielded disappointing results. The combination of SGT-53, anti-PD-1, and hypofractionated radiation has shown encouraging results in preclinical studies. SGT-53 is a novel nanoparticle carrying cDNA encoding human wild-type human TP53; the nanoparticle uses a single-chain antibody fragment recognizing the human transferrin receptor, leading to excellent blood-brain barrier penetrance and anti-tumor targeting. TP53 therapy work synergistically with immune checkpoint inhibitors like anti-PD-1. Hypofractionated radiation provides additional synergy, increasing vascular access, cytokine production and activating tumor-specific T-cells.

METHODS
JACOB is a prospective, phase 0/1 clinical trial to evaluate the safety and efficacy of SGT-53 in combination with hypofractionated radiation and anti-PD-1 in children with recurrent, progressive, or refractory CNS malignancies. Inclusion criteria: patients age ≥ 3 and ≤ 21 years, measurable disease, performance status &gt;50 and adequate organ function. The 3 + 3 de-escalation design will be used to determine the maximum tolerated dose (MTD) of SGT-53 in combination with ICI and radiation. Dose limiting toxicities will be evaluated. SGT-53 will be administered two times per week. Hypofractionated radiation will be given in week 2, and anti-PD-1 (once in 2 weeks) will begin on the second week of treatment. A maintenance phase of SGT-53 and anti-PD-1 will be continued for up to 12 months. Primary endpoints evaluate toxicities related to SGT-53 and plasma pharmacokinetics. Secondary and exploratory endpoints include best radiological response, and immunobiological markers. Twelve patients will be treated in the phase I/dose de-escalation cohort. After the MTD has been identified, a target validation/ phase 0 cohort will include up to 4 patients receiving 2 doses of SGT-53 prior to undergoing surgical resection to determine tissue-specific response.
CTNI-03. EFFICACY OF WSD0922-FU IN OSIMERTINIB-RESISTANT NSCLC WITH CENTRAL NERVOUS SYSTEM (CNS) METASTASES – UPDATES FROM THE DOSE ESCALATION COHORT OF A FIRST-IN-HUMAN PHASE 1 CLINICAL TRIAL (MC1914)
Authors: Kizilbash Sani H , Jaeckle Kurt , Mrugala Maciej , Allred Jacob , Safgren Stephanie , McGovern Renee , Remick Adam , Reid Joel , Lammers Anita , Zhong Wei , Leventakos Konstantinos , Mansfield Aaron , Shanshal Mohamed , Ma Wen , Uhm Joon , Campian Jian , Ruff Michael , Sener Ugur , Galanis Evanthia , Burns Terry , Parney Ian , Raghunathan Aditya , Vaubel Rachael , Jentoft Mark , Roden Anja , Giannini Caterina , Sarkaria Jann , Adjei Alex 
Published: November 2023

Abstract
WSD0922-Fu is an oral, CNS-penetrant, small molecule EGFR inhibitor which potently inhibits EGFR aberrations specific to non-small cell lung cancer (NSCLC) and high-grade astrocytoma (HGA). MC1914 (NCT04197934) is a first-in-human phase 1 trial in patients with EGFR aberrant recurrent HGA and NSCLC. Adult patients with either recurrent EGFR mutant NSCLC with CNS metastases or recurrent EGFR aberrant HGA were enrolled and treated across six cohorts (40 mg once daily to 320 mg twice daily, 28-day cycles) to determine the maximum tolerated dose (MTD). 25 patients (17 HGA, 8 NSCLC) were enrolled (median age = 57 years; 24% female; 36% ECOG 0). All patients with HGA received prior radiation and temozolomide. All patients with NSCLC had previous disease progression on EGFR inhibitor therapy (prior osimertinib 88%). The median duration of WSD0922-Fu exposure among all patients was 55 days (range 3 to &gt;279 days) [NSCLC median = 131 days; HGA median = 51 days]. Common treatment-related adverse events are comparable to other EGFR inhibitors (fatigue, acneiform rash, diarrhea, nausea, pruritis). At Cycle 1 Day 15 for patients treated at MTD (160 mg twice daily), the mean terminal elimination half-life (%CV) in the plasma was 31.6 h (102%) (median 14.5 h). The mean Cmax, Tmax, oral clearance at steady state, and AUC (0-12 h) (%CV) were 4513 ng/mL (50%), 2.0 hr (69%), 6.9 L/hr/m2 (42%), and 28084 h*ng/mL (52%), respectively. Among patients with NSCLC treated at MTD or higher dose levels and with available response data, 100% (5/5) of patients demonstrated clinical benefit (SD + PR) while 60% of patients had partial responses. Intracranial and extracranial efficacy was concordant. Furthermore, prolonged stable disease (9 cycles) was observed in a patient with EGFRvIII mutant GBM. Expansion cohorts are in progress to optimize WSD0922-Fu dose and schedule for future phase 2 development.
CTNI-08. TUCATINIB, TRASTUZUMAB, AND CAPECITABINE WITH STEREOTACTIC RADIOSURGERY IN PATIENTS WITH BRAIN METASTASES FROM HER-2 POSITIVE BREAST CANCER (TUTOR): A MULTICENTER PHASE 1 CLINICAL TRIAL
Authors: Ahluwalia Manmeet , Ozair Ahmad , Khosla Atulya , Bellur Shreyas , Kotecha Rupesh , McDermott Michael , Mehta Minesh , Sandoval-Leon Ana , Mahtani Reshma , Peereboom David 
Published: November 2023

Abstract

BACKGROUND
20-40% of HER-2-positive breast cancer patients develop brain metastases (BMs), which are frequently tackled with stereotactic radiosurgery (SRS). Tucatinib, an oral HER-2 selective tyrosine kinase inhibitor (TKI), has demonstrated efficacy for HER-2-positive breast cancer in combination with capecitabine and trastuzumab. We hypothesize that a combinatorial approach for HER-2 positive breast cancer BMs (BCBM) will lead to better long-term control of BMs and systemic disease.

METHODS
This is an in-progress, prospective, single-arm, multicenter, phase 1 clinical trial that aims to determine the safety of combination of tucatinib, capecitabine, and trastuzumab with SRS in patients with HER-2 positive BCBM. Patients with age 18-80 years, ECOG 0-2, normal organ function, and up to 10 newly-diagnosed BMs are enrolled at six US centers. Any number of prior systemic therapies are allowed, except tucatinib and capecitabine. The primary endpoint of the study is the maximum tolerated dose (MTD) of tucatinib with SRS. This de-escalation study starts tucatinib at a dose level of 300 mg BID. Dose level -1 is 250 mg BID and level -2 is 200 mg BID. Upto 40 patients will be enrolled based on a 3 + 3 design. We plan to expand the cohort at MTD to 40 patients to assess the safety and efficacy of the combination. Secondary endpoints include efficacy as determined by response rate, intracranial PFS, extracranial PFS, and overall survival. Patients are administered oral tucatinib with SRS, followed by oral tucatinib for two weeks which is the dose-limiting toxicity (DLT) period. This is followed by tucatinib, trastuzumab, and capecitabine until progression or intolerable toxicity. DLTs are defined by Grade 3 or 4 thrombocytopenia, grade 4 anemia, grade 4 neutropenia lasting more than seven days, febrile neutropenia, and any non-hematologic toxicity of grade 3 or greater (excluding alopecia). The trial started enrollment in February 2023. Trial Information: NCT05553522.
CTNI-10. SACITUZUMAB GOVITECAN FOR BREAST CANCER BRAIN METASTASIS
Authors: Balinda Henriette , Kelly William , Ghamasaee Pegah , Gilbert Andrea , Michalek Joel , Kaklamani Virginia , Lathrop Kate , Surapaneni Prathibha , Floyd John , Brenner Andrew 
Published: November 2023

Abstract
Breast cancer brain metastasis (BCBM) is a challenge that significantly impacts patient prognosis and quality of life. Sacituzumab govitecan (SG), an antibody-drug conjugate, has demonstrated antitumor activity and is approved for triple negative and HR+/HER2 negative metastatic breast cancer. It consists of a humanized anti-Trop-2 monoclonal antibody linked to a potent topoisomerase I inhibitor, SN-38. SG activity was tested in a breast cancer intracranial mouse model. We conducted a prospective, single center, window of opportunity trial (NCT03995706) to examine the intra-tumoral concentrations of SN-38 in patients undergoing craniotomy for breast cancer brain metastases (n = 13). We enrolled patients aged ≥18 years diagnosed with brain metastatic breast cancer to receive a single intravenous dose of SG at 10 mg/kg one day before surgical resection. Tumor and corresponding serum were collected during surgery to measure their levels of SN-38. Following recovery, patients resumed SG treatment at 10 mg/kg on days 1 and 8 of 21-day cycles and were assessed for responses by MRI every third cycle using response assessment in neuro-oncology (RANO) criteria. Trop-2 and carbonic anhydrase IX (CAIX) expression was investigated by IHC. SG significantly inhibited tumor growth and increased overall survival in mice. An average of 1953.79 ng/ml in serum and 134.3 ng/g in tissue of SN-38 was quantified in patient samples. Trop-2 expression was observed in 100% of patient tumors. 41% of the samples showed high expression of CAIX. A positive correlation between the tissue:serum [SN-38], Trop-2 and gH2AX staining was observed. Median overall survival of 34.5 months (5.7 - 35.6 months) and progression free survival of 7.4 months (2 – 24.4 months) were observed. Our data suggest that SG has therapeutic potential in patients with breast cancer brain metastasis. A prospective multicenter cooperative trial of SG for BCBM, S2007, is ongoing and an update on accrual will be provided.
CTNI-41. PHASE II AND PHASE 0 RESULTS OF ABTC 1801: A MULTI-ARM CLINICAL TRIAL OF THE PARP INHIBITOR PAMIPARIB WITH VERY LOW DOSE METRONOMIC TEMOZOLOMIDE IN RECURRENT IDH MUTANT GLIOMAS
Authors: Schiff David , Bindra Ranjit S , Li Jing , Ye Xiaobu , Ellingson Benjamin , Walbert Tobias , Campian Jian , Nabors Burt , Lieberman Frank , Ozer Byram , Desai Arati , Omuro Antonio , Wen Patrick , Desideri Serena , Danda Neeraja , Grossman Stuart 
Published: November 2023

Abstract

BACKGROUND
Preclinical studies have demonstrated that IDH1-mutant (IDHmt) gliomas harbor a BRCAness phenotype with a defect in homologous recombination that confers PARP inhibitor sensitivity.

METHODS
The phase II component of ABTC 1801 examined the efficacy of the combination of pamiparib (BeiGene BGB-290) with low dose metronomic temozolomide in recurrent IDHmt grade 2 and 3 gliomas. In this two-stage design, Arm A enrolled patients who had failed two lines and Arm B a single line of alkylator therapy. Pamiparib and temozolomide doses based on phase I results was 60 mg BID and 20 mg daily. Primary endpoint was objective response rate (ORR).

RESULTS
39 patients (Arm A 15, Arm B 24) enrolled in the phase II. Median age was 45 (range: 25-69), 56% male, and median KPS 90. 72% of tumors were MGMT methylated. There were no confirmed responses in Arm A and one in Arm B; neither arm met the threshold for additional accrual. One-third of subjects discontinued treatment for reasons other than progressive disease. Estimated median PFS was 5.8 months in Arm A and 11.3 months in Arm B. Seven subjects (Arm A 3, Arm B 4) developed DLT during treatment. Grade 3+ toxicity was principally hematologic; 9 patients had grade 3 anemia, 7 grade 3 and 3 grade 4 neutropenia, and 3 grade 3 thrombocytopenia. In enhancing and non-enhancing tumors from 8 surgical arm patients, median unbound drug tumor/plasma ratios were 0.98 and 0.92, respectively; and median unbound pamiparib tumor concentrations were 209 and 188 nmol/L (or nmol/kg), respectively, which were &gt;20-fold the in vitro IC50 for PARP inhibition.

CONCLUSIONS
While pamiparib appeared to achieve sufficient pharmacologically active concentrations in both enhancing and non-enhancing tumors, combination with temozolomide did not produce a meaningful ORR in IDHmt recurrent gliomas. Cumulative hematologic toxicity was substantial.
CTNI-45. UPFRONT CHEMOTHERAPY AND SUBSEQUENT RESECTION UTILIZING NEOADJUVANT STRATEGY FOR OLIGODENDROGLIOMAS
Authors: Sasaki Hikaru , Kitamura Yohei , Toda Masahiro , Hirose Yuichi 
Published: November 2023

Abstract
Although both of functional preservation and higher extent of resection are required in glioma surgery, maximal resection with the risk of functional sequela is uniformly performed regardless of tumor pathology and treatment sensitivity in the current practice. Oligodendrogliomas are known to be associated with relatively favorable prognosis, however, many patients still eventually succumb to death due to tumors. Improvement in the long-term survival rate and functional preservation would be the next step to be achieved. In our hospital, patients with 1p/19q-codeleted glioma have been treated by upfront chemotherapy, if deemed in need of adjuvant treatment after initial resection, since 2006. If the initial resection was incomplete, the second surgery was intended following tumor volume decrease by chemotherapy (second-look resection, SLR). Intentional staged resection was performed in several cases for whom presence of 1p/19q codeletion was strongly suggested based on preoperative imaging characteristics. Utility of this strategy was evaluated. Forty-one patients with 1p/19q-codeleted glioma have been treated with the strategy. Of these, 30 were grade 2, and 11 were grade 3 tumors. In 9 of the 41 cases, radiotherapy was prescribed immediately after chemotherapy or SLR. Median tumor volume decrease rate by chemotherapy in the cases with initial incomplete resection was -35%. SLR following tumor volume decrease was performed in 22 cases. Median progression-free survival and overall survival after the initiation of chemotherapy were 81 months and 175 months for each in both of the total 41 cases and 32 cases for whom radiotherapy was deferred. Most of the recurrence occurred in the residual FLAIR high intensity. Upfront chemotherapy and subsequent resection strategy utilizing chemotherapeutic response provides more precise resection as well as reduction of resection volume as compared with one-time maximal safe resection. Radiotherapy may be indicated for the cases with residual FLAIR abnormality after chemotherapy or SLR.
CTNI-50. UPDATE REPORT OF THE RESPECT-GBM PHASE I/IIA DOSE ESCALATION TRIAL OF RHENIUM-186 NANOLIPOSOME (186RNL) IN RECURRENT GLIOMA [RGBM] VIA CONVECTION ENHANCED DELIVERY (CED)
Authors: Brenner Andrew , Michalek Joel , Moore Melissa , Hedrick Marc , Bao Ande , Phillips William , Patel Toral , Weinberg Jeffrey , Floyd John , Youssef Michael , Huang Shiliang , LaFrance Norman 
Published: November 2023

Abstract

BACKGROUND
A Phase1/2a dose-escalation trial was initiated to determine the safety and recommended phase2 186RNL-dose(RP2D). Liposomal-rhenium-186(186RNL) is a source of high-energy beta-particles with gamma-photons representing attractive brain CED properties.

METHODS
A 3 + 3 Phase1 design was implemented per protocol [modified-Fibonacci dosing sequence]. We report safety and overall survival (OS) in 27 patients assigned to cohorts1-8. Patients with biopsy proven recurrent glioma had computerized treatment planning and placement of up to 5 intracranial catheter(s) single CED-186RNL administration. Whole body planar and SPECT/CT imaging through ~1 week following treatment was performed. Patients were followed for safety, sufficiency of delivery and OS. The significance of variation in OS was assessed with a 2-sided logrank test with α = 0.05.

RESULTS
Cohorts dosing ranged from 1mCi-in-0.6mL to 41.5mCi-in-16.3ml, MTD not reached, and no CED failures. No dose limiting toxicities were observed. Most common AEs were pre-existing GBM related signs/symptoms [weakness, fatigue, headache, seizure, scalp discomfort after CED] and &gt;80% of AEs unrelated/unlikely relationship. Median absorbed radiation dose to the tumor (MARDT) was 308.4 Gy (8.9 Gy to 739.5 Gy). Patients were stratified by MARDT (&lt; 100 Gy, ≥100 Gy). In all patients (N = 27), the median overall survival (OS) was 8 months (m), 95% CI 5 m to 13 m). In those receiving &lt;100 Gy (N = 10), the median OS was 5 m (95% CI 1 m to 11 m) and in those with ≥ 100 Gy (N = 17) the median was 12 m (95% CI 5 m to 30 m), p &lt; 0.001.

CONCLUSION
A single administration of 186RNL by CED in recurrent glioma patients is feasible, safe, and potentially effective in increasing overall survival when &gt;100Gy radiation is delivered to the tumor. A RP2D of 22.3mCi in 8.8mL was selected for patients with tumor size of ≤20mL in the planned Phase 2B.
CTNI-51. A RANDOMIZED DOUBLE-BLIND PHASE 3 STUDY OF VORASIDENIB VS PLACEBO IN PATIENTS WITH MUTANT IDH1/2 DIFFUSE GLIOMA (INDIGO): EXPLORATORY ANALYSIS OF VARIANT ALLELE FREQUENCY AND PROGRESSION-FREE SURVIVAL
Authors: Cloughesy Timothy , Mellinghoff Ingo , van den Bent Martin , Blumenthal Deborah , Touat Mehdi , Peters Katherine , Clarke Jennifer , Mendez Joe , Yust-Katz Shlomit , Mason Warren , Ducray Francois , Umemura Yoshie , Nabors L Burt , Holdhoff Matthias , Hottinger Andreas , Arakawa Yoshiki , Sepúlveda Juan , Wick Wolfgang , Soffietti Riccardo , Perry James , Giglio Pierre , de la Fuente Macarena , Maher Elizabeth , Choe Sung , Zhao Dan , Pandya Shuchi , Steelman Lori , Hassan Islam , Tron Adriana , Wen Patrick 
Published: November 2023

Abstract

INTRODUCTION
Vorasidenib is an oral, brain-penetrant, inhibitor of mutant isocitrate dehydrogenase (mIDH) 1/2 enzymes. The INDIGO study (NCT04164901) showed significantly improved radiographic progression-free survival (PFS) by blinded independent review committee (BIRC) with vorasidenib, compared with placebo, in patients with mIDH1/2 adulttype diffuse glioma (hazard ratio [HR] 0.39, 95% CI 0.27–0.56; one-sided P = 0.000000067 [Mellinghoff N Engl J Med 2023]). The key secondary endpoint of time-to-next-intervention was also met.

METHODS
In this double-blind Phase 3 study, patients aged ≥ 12 years with residual/recurrent grade 2 mIDH1/2 oligodendroglioma or astrocytoma, measurable non-enhancing disease, and no prior treatment for glioma were randomized 1:1 to receive vorasidenib 40 mg or placebo daily in 28-day cycles. An investigational clinical trial assay centrally confirmed IDH1 R132H/C/G/S/L or IDH2 R172K/M/W/S/G mutation variants. Pretreatment (archival) tumor tissue was analyzed by next-generation sequencing for CDKN2A/B homozygous deletion and other co-mutations (ACE Extended Cancer Panel).

RESULTS
As of Sep 6, 2022 (preplanned second interim analysis), 168 patients were randomized to vorasidenib and 163 to placebo (median age, 40.0 years; Karnofsky performance scale = 100, 53.5%; oligodendroglioma, 172; astrocytoma, 159; mIDH1, 315; mIDH2, 16). Two patient subgroups were defined by baseline IDH1/2 variant allele frequency (VAF): lower/higher than the median value (0.377). The median PFS results favored vorasidenib over placebo in both subgroups (low VAF, one-sided P = 0.0116; high VAF, one-sided P &lt; 0.0001). Vorasidenib and placebo groups had similar and a low number of co-mutations in known/likely oncogenic genes at baseline (median number of co-mutations across both groups was 4). CDKN2A homozygous deletion was detected in only two participants (both in the placebo group). Additional data will be presented.

CONCLUSION
In the first randomized Phase 3 study of a targeted therapy in grade 2 mIDH1/2 glioma, vorasidenib prolonged median PFS by BIRC, relative to placebo, irrespective of IDH1/2 VAF.
CTNI-66. DECODING GLIOBLASTOMA SURVIVAL: UNRAVELING THE PROGNOSTIC POTENTIAL OF OLFACTORY FUNCTION IN A PROSPECTIVE OBSERVATIONAL STUDY
Authors: Oster Christoph , Hummel Thomas , Hattingen Elke , Schmidt Teresa , Lazaridis Lazaros , Jokisch Daniel , Jokisch Martha , Agkatsev Sarina , Ahmadipour Yahya , Sure Ulrich , Stuschke Martin , Kleinschnitz Christoph , Scheffler Björn , Deuschl Cornelius , Kebir Sied , Glas Martin 
Published: November 2023

Abstract

BACKGROUND
Olfactory impairment is a common neurologic deficit among glioblastoma patients. We have previously shown that glioblastoma patients with reduced smell sensitivity had lower overall survival rates compared to those with normal olfactory function. A notable limitation in that study was the unequal distribution of prognostic factors between the two groups, and the absence of continuous olfactory assessments during treatment to investigate if therapy-associated neurotoxicity could be a contributing factor to diminished olfactory acuity. Question: Can Olfactory Function Serve as an Independent Prognostic Indicator in Glioblastoma Patients?

METHODS
This prospective, multicenter study is set to recruit 64 glioblastoma patients alongside 64 healthy controls. Stratification of participants will be based on prognostically relevant variables such as resection status, MGMT promoter methylation status, radiographic involvement of olfactory brain areas, olfactory function, age, and Karnofsky performance status scale. We will utilize Sniffing Sticks to evaluate olfactory function through identification and threshold tests, and this assessment will be carried out longitudinally throughout the therapy starting from tumor diagnosis. Infiltration of the olfactory brain areas will be scrutinized using coronal T2 and T1 MRI sequences. MRI images will be independently reviewed by two board-certified radiologists from distinct institutions, who are blinded to the patients' olfactory function status. Furthermore, quality of life data, neuropsychological testing, and psychosomatic screening will be performed at specific intervals throughout the study. Also, we'll examine next-generation sequencing results to investigate potential genetic associations with hyposmia in glioblastoma patients.

RESULTS
The first participant was enrolled in May 2023. Plans are underway to open a second study site in 2024, with the aim to complete recruitment by December 2025. Follow-up assessments will continue until December 2027. We anticipate that the final results of the study will be available in 2028.