bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of 1–3 cerebral metastases: Results of the EORTC 22952–26001 study
Authors: Mueller R. P. , Soffietti R. , Abaciouglu M. U. , Villa S. , Fauchon F. , Baumert B. G. , Fariselli L. , Tzuk-Shina T. , Collette L. , Kocher M. 
Published: August 2020

2008 Background: The EORTC Radiotherapy and Brain Tumor Groups conducted a phase III trial to define the role of adjuvant whole brain irradiation (WBRT) after local treatment (surgery or radiosurgery) for brain metastases. It was hypothetized that WBRT would increase the duration of functional independence by reducing the number of intracranial relapses. Methods: Pts eligible for radiosurgery (RS) had 1–3 metastases of solid tumors (SCLC excluded) ≤ 3.0 cm in diameter (≤ 2.5 cm for 2–3 lesions). In case of surgery (S), a complete resection was mandatory. Only pts with no or stable systemic disease or with asymptomatic synchronous primary tumors, and with WHO PS 0–2 were allowed. Pts were randomized for adjuvant WBRT or observation (OBS). Primary endpoint was survival with functional independence measured by the time to WHO PS deterioration to > 3. Analysis is by intent-to-treat (Logrank, two-sided α = 0.05). Results: From 1996–2007, 359 pts were recruited. 160 surgical pts had resection of one (96%) or two (4%) metastases, and 185 (of 199 scheduled pts) had RS (marginal dose 20Gy, target dose 25Gy) of one (67%), two (23%), or three (10%) lesions. Adjuvant whole brain irradiation (30Gy/10 fractions) was given to 166/180 pts. (92%) randomized for WBRT and to 4/179 pts (2%) in the OBS arm. Median time to WHO PS > 3 was 9.8 months (95% CI 8.0 - 11.7) in the OBS arm and 9.8 months (95% CI 7.8 - 12.6) in the WBRT arm (p > 0.5). It was only significantly influenced by initial WHO PS and initial systemic disease status (p < 0.01). Overall survival was 10.9 months (95% CI 9.2 - 14.6) in both arms (p > 0.5). Cumulative incidence of intracranial progression at 6 and 24 months was 39.7% (95% CI 32.5 - 46.8) and 54.0% (95% CI 46.7 - 61.3) of the OBS pts, but only 15.2% (95% CI 9.9 - 20.5) and 31.4% (95% CI 24.5 - 38.2) of the WBRT pts (p < 0.0001). Intracranial progression was a cause of the death in 77/179 pts (43%) of the OBS group and in only 45/180 pts (25%) of the WBRT group. Conclusions: After radiosurgery or surgery of 1–3 brain metastases, adjuvant WBRT reduces the frequency of intracranial relapses and neurologic deaths but fails to prolong the time period of functional independence and overall survial time. Updated results will be presented at the Meeting. No significant financial relationships to disclose.
NCCTG phase I trial of temsirolimus (CCI-779) and temozolomide (TMZ) in combination with radiation therapy (RT) in newly diagnosed glioblastoma multiforme (GBM) patients
Authors: Sarkaria J. N. , Galanis E. , Wu W. , Giannini C. , Jaeckle K. A. , Doyle L. , Uhm J. , Brown P. , Dietz A. B. , Buckner J. 
Published: August 2020

2019 Background: The mammalian target of rapamycin (mTOR) functions within the PI3K/Akt signaling pathway as a critical modulator of cell survival. We previously demonstrated significant synergy of the mTOR inhibitor sirolimus with RT in glioma xenografts. Methods: The standard cohorts of 3 design was applied with dose escalation of weekly IV CCI-779 in combination with standard TMZ/RT. CCI-779 was given during both RT (60 Gy)/TMZ (75 mg/m2 daily) and adjuvant TMZ (200 mg/m2 daily x 5 every 28 days). Results: A total of 17 patients were enrolled. CCI-779 therapy during RT/TMZ was well tolerated at dose level 0 (25 mg CCI-779, n = 3) and dose level 1 (50 mg CCI-779, n = 6) with 1 of 9 patients experiencing a DLT (Gr 3 fatigue). Dose level 2 (75 mg CCI-779) exceeded the maximally tolerated dose with two of six patients with DLT (<75% CCI-779 delivered; Gr 4 dyspnea). Despite reasonable tolerance during RT/TMZ, the overall regimen was associated with a high rate of infection associated with lymphopenia. After a patient died from PCP on cycle 2 of adjuvant TMZ/CCI-779, antibiotic prophylaxis was mandated. Two other patients died of gram-negative sepsis despite prophylaxis: one after their first dose of CCI-779 and one during cycle 4 of adjuvant therapy. In contrast to our 18% grade 5 infection rate, only 4% grade 3 (no grade 4/5) infections were observed in 26 other CTEP-sponsored clinical trials involving 1,006 patients treated with CCI-779. Results from translational studies evaluating the effects of treatment on immune function will be presented. Further infections were avoided on this trial after CCI-779 therapy was limited to RT/TMZ. Conclusions: Although CCI-779 in combination with RT/TMZ was well-tolerated, adjuvant therapy with TMZ/CCI-779 was associated with an increased risk of opportunistic infections. [Table: see text]
Phase II and pharmacogenomics study of enzastaurin plus temozolomide and radiation therapy in patients with glioblastoma multiforme or gliosarcoma
Authors: Butowski N. A. , Lamborn K. , Chang S. , Hsieh E. , Fedoroff A. , Parvataneni R. , Nicol S. , Liepa A. , Thornton D. , Prados M. 
Published: August 2020

2020 Background: ENZ, an oral serine/threonine kinase inhibitor, suppresses signaling through PKCβ and the PI3K/AKT pathways to induce apoptosis, reduce proliferation, and suppress angiogenesis. The primary endpoint of this single-arm phase II trial was overall survival (OS). Secondary objectives included progression-free survival (PFS), safety, PK/PD, and patient-reported outcomes (PROs). A concurrent PGx project assessed the value of pretreatment molecular profiles as predictive of outcome. Magnetic resonance spectroscopy (MRS) was also evaluated during treatment for its value in predicting OS. Methods: Patients enrolled with newly diagnosed GBM/GS and KPS ≥60. Treatment started <5 weeks after diagnosis with RT 60 Gy given over 6 weeks and TMZ 75 mg/m2 given daily during RT and then at 200 mg/m2 from days 1–5 of a 28-day cycle. ENZ 250 mg/day was given daily during RT and adjuvantly. Planned treatment duration was 1 year. PGx parameters were: MGMT promoter methylation, mismatch repair status, PKC isoforms, pERK, pCREB, EGFR, PTEN, GSK3B, ser9, VEGF, and pS6. MRS was performed at baseline and at scheduled intervals. Changes in molecular signatures and imaging characteristics relative to survival were estimated using Kaplan-Meier and proportional hazards models. Analyses included phase I patients at ENZ 250 mg/day. Results: From September 2007 to November 2008, 60 phase II patients enrolled; 52 completed RT and eight are receiving RT. Of these, seven patients progressed immediately after RT and 17 progressed after one or more adjuvant cycles; five discontinued due to toxicity; four withdrew from trial. Treatment was well tolerated. The only toxicities seen in more than one-third of pateints were grade 1 fatigue, grade 1 nausea, and grade 1–2 lymphopenia. Grade 1 thrombocytopenia was seen in eight patients and grade 3 lymphopenia in five patients. OS, PFS, PROs, PGx, and imaging findings will be reported. Conclusions: The combination of ENZ plus TMZ during and following RT was well tolerated and may be an active regimen in GBM. This study represents the future of neuro-oncology clinical trial design by employing a novel multi-modal therapy while concurrently studying novel imaging and molecular techniques that may predict efficacy. [Table: see text]
Circulating cytokine and angiogenic factors as predictive biomarkers of glioblastoma response to aflibercept (VEGF Trap)
Authors: Piao Y. , Heymach J. V. , Bekele B. , Camphausen K. , Wen P. Y. , Liu J. , Yung W. K. , De Groot J. 
Published: August 2020

2029 Background: Aflibercept is a recombinant fusion protein that scavenges both vascular endothelial growth factor (VEGF) and placental growth factor (PlGF). In a single-arm phase II study (NABTC06–01; NCT00369590 ), a 22% response rate was seen in recurrent glioblastoma patients receiving aflibercept 4 mg/kg iv every 2 weeks. We performed detailed analyses of circulating and urinary cytokine and angiogenic factors to describe the modulation of markers in response to aflibercept and to identify potential predictive markers. Methods: Plasma samples were collected from 31 of 32 enrolled patients at baseline, 24 hours and every 2–4 weeks until progression. Urine samples were collected at baseline and every 4 weeks. Levels of 41 circulating factors were measured using suspension bead multiplex assays (BioRad) or ELISA. Free VEGF and PlGF levels were determined following sample immunodepletion. Baseline and changes in marker levels over time were correlated with response and progression using logistic regression and Cox proportion hazard models. Results: Treatment with aflibercept resulted in significant increases in total VEGF and PlGF at 24 hours and 28 days (p ≤ 0.001). Free VEGF was rapidly sequestered by 24 hours and remained significantly decreased at 28 days (p = 0.001). However, free PlGF levels rose over time and by 28 days were 45-fold higher than baseline (p < 0.001). Additional modulation of 4 factors at 24 hours included decreases in Groα and MIF (p = 0.001) and increases in urinary VEGF and MIP1β (p ≤ 0.001). At 28 days, levels of IL-18 were significantly decreased (p = 0.02) while SCGFβ and urinary VEGF levels increased (both p < 0.02). Comparing baseline biomarker levels between response groups (PD, SD, and PR), patients with lower levels of GROα, HGF, SCGFβ and higher levels of free VEGF were more likely to have a PR (all p < 0.05). Conclusions: In recurrent glioblastoma, aflibercept resulted in rapid and sustained decreases in free VEGF levels. Although greater than 95% of PlGF remained bound, free PlGF levels significantly increased over time. Treatment significantly modulated multiple cytokine and angiogenic factors with striking increases in MIF and SCGFβ. Potential biomarkers predictive of response to aflibercept include Groα, HGF and SCGFβ. No significant financial relationships to disclose.
Phase I trial of vatalanib (PTK787) in combination with standard radiation and temozolomide in patients with newly diagnosed glioblastoma
Authors: Batchelor T. , Eichler A. F. , Plotkin S. R. , Drappatz J. , Wen P. , Sorensen A. G. , Gerstner E. 
Published: August 2020

2035 Background: Anti-vascular endothelial growth factor (VEGF) agents are hypothesized to work synergistically with chemotherapy and radiation (RT). Vatalanib (MW 347, T1/2 4.6 h) is an oral, pan-VEGFR tyrosine kinase inhibitor that has shown activity in patients with recurrent glioblastoma. Methods: This phase I study was designed to determine the maximal tolerated dose of vatalanib in combination with RT and TMZ for patients with newly diagnosed GBM who were taking enzyme-inducing anti-epileptic drugs. RT and TMZ were administered at standard doses. Vatalanib was initiated 5 days prior to the start of RT and continued daily until tumor progression, unacceptable toxicity or a maximum of up to 12 cycles of post-RT TMZ. Cohorts of 3 patients were treated during RT and TMZ at doses of 250mg daily, 250mg BID, or 500mg BID of vatalanib. Following the completion of RT, patients were treated with vatalanib 750mg BID for the remainder of the study. Results: Nineteen patients were enrolled of which 17 took 5 or more days of vatalanib (1 patient withdrew consent prior to start of vatalanib and 1 withdrew consent after only 1 dose). The median age was 58 and the median KPS was 90. Eight patients had a diagnostic biopsy only. The MTD has not been reached. Potentially related grade 3–4 toxicities included elevated transaminases (2 patients), thrombocytopenia (1 patient), leukopenia (1 patient), neutropenia (1 patient), depressed level of consciousness (1 patient), and fatigue (1 patient). Only 1 patient suffered an asymptomatic intracerebral hemorrhage and no patient experienced wound dehiscence or infection. Five patients remain on vatalanib and the median follow-up for all patients is 6.5 months. Seven patients have died. The best responses for the 13 patients who completed combination RT/TMZ/vatalanib was 2 PR, 7 SD, and 2 PD. Two patients were clinically stable with biopsy proven pseudoprogression. Median PFS is 18.4+ months and OS has not been reached. Conclusions: Vatalanib is safe and well tolerated when added to standard RT and TMZ. The MTD has not been reached and dose escalation continues in this population of patients on enzyme inducing anti-epileptic drugs. [Table: see text]
A phase I study of temozolomide (TMZ) and RAD001 in patients (pts) with glioblastoma multiforme (GBM)
Authors: Mason W. P. , MacNeil M. , Easaw J. , McIntosh L. , Lwin Z. , Chen E. , Eisenhauer E. E. 
Published: August 2020

2036 Background: The mTOR protein kinase is a critical step in the PI3K/Akt/PKB signaling pathway. RAD001 exerts antiproliferative and antiangiogenic effects by mTOR inhibition. This phase I trial was designed to determine the maximum tolerated dose(s) (MTD) and recommended phase II dose(s) of RAD001 in combination with TMZ in patients with GBM. Patients receiving enzyme inducing anti-epileptic drugs (EIAEDs) and those not receiving EIAEDs (NEIAEDs) were studied separately. Methods: Enrollment was restricted to pts with proven GBM, either newly diagnosed following completion of radiotherapy with concurrent TMZ, or at first progression. TMZ was administered at a starting dose of 150 mg/m2/d for 5 days every 28 days, and RAD001 was administered continuously at a starting dose of 2.5 mg orally on a daily schedule starting on day 2 of cycle 1 in 28-day cycles (maximum 10 mg daily unless PK interaction shown). Response was evaluated every 2 cycles. Pharmacokinetics (PK) of TMZ and RAD001 were determined during cycle 1. Results: To date, 16 NEIAEDs and 9 EIAEDs pts have been enrolled and received 79 and 58 cycles respectively. The majority of pts (20/23) were newly diagnosed. In the NEIAEDs group at dose level 2 (RAD001 2.5 mg, TMZ 200 mg/m2) 3 of 4 pts had cycle 2 delays and dose reduction of TMZ because of myelosuppression (neutropenia 2 pts, neutropenia and thrombocytopenia, 1 pt), so further escalation of only RAD001 was undertaken, while fixing TMZ at 150 mg/m2. RAD001 at 10 mg daily with TMZ 150 mg/m2/day has been well tolerated in the NEIAEDs cohort without DLTs; RAD001 PK at this dose level have been comparable to historical single agent RAD001 PK (AUC at steady state is 602 ng*hr/mL in our study vs. 536 ng*hr/mL historical data), so no further escalation is planned. Enrollment in the EIAEDs cohort has been accelerated to 10 mg RAD001 with TMZ 150 mg/m2 because no additional DLTs have been observed in the EIAEDs cohort. Escalation beyond this dose will only take place if supported by evidence of reduced exposure of RAD001 or TMZ when PK results are available. Conclusions: RAD001 at a daily dose of 10mg can safely be combined with TMZ at 150 mg/m2/d and is the recommended dose for GBM pts receiving NEIAEDs. EIAED pts are being enrolled at this dose level; further escalation in this group will depend on PK data. [Table: see text]
Phase II trials of erlotinib or gefitinib in patients with recurrent meningiomas
Authors: Norden A. D. , Raizer J. J. , Lamborn K. R. , Abrey L. E. , Chang S. M. , Gilbert M. R. , Cloughesy T. F. , Prados M. D. , Lieberman F. , Wen P. 
Published: August 2020

2062 Background: No effective treatment is available for recurrent meningiomas when surgical and radiation options are exhausted. The epidermal growth factor receptor (EGFR) is often over-expressed in meningiomas and may promote tumor growth. In open label, single arm phase II studies of the EGFR inhibitors gefitinib (NABTC 00–01) and erlotinib (NABTC 01–03) for recurrent malignant gliomas, we included exploratory subsets of recurrent meningioma patients. We have pooled the data and report the results here. Methods: Patients with recurrent histologically confirmed meningiomas and no more than two previous chemotherapy regimens were treated with gefitinib 500 mg/day or erlotinib 150 mg/day until tumor progression or unacceptable toxicity. Results: Twenty-five eligible patients were enrolled with median age 57 years (range 29–81) and median Karnofsky performance status (KPS) score 90 (range 60–100). Sixteen patients (64%) received gefitinib and nine (36%) erlotinib. Eight patients (32%) had benign tumors, 9 (36%) atypical, and eight (32%) malignant. For benign tumors, the 6-month progression-free survival (PFS6) was 29%, 12-month PFS (PFS12) 0%, 6-month overall survival (OS6) 63%, and 12-month OS (OS12) 50%. For atypical/malignant tumors, PFS6 was 25%, PFS12 19%, OS6 81%, and OS12 68%. There were no significant PFS or OS differences by histology. Of 21 evaluable patients, there were no responses; eight patients (38%) had stable disease, and 13 (62%) had progressive disease. Treatment was well-tolerated. Rash was not a significant predictor of PFS or OS. Conclusions: Neither gefitinib nor erlotinib appear to have significant activity against recurrent meningioma. The role of EGFR inhibitors in meningiomas is unclear but evaluation of EGFR inhibitors in combination with other targeted molecular agents may be warranted. No significant financial relationships to disclose.
Functional pathway mapping of human glioblastoma multiforme and brain metastases for patient tailored therapy
Authors: Khalil M. , Wulfkuhle J. , Fillmore H. , Deng J. , Liotta L. , Petricoin E. , Watson J. , Broaddus W. 
Published: August 2020

2076 Background: Genome scanning analysis of human glioblastoma multiforme (GBM) has suggested that this form of cancer is a protein pathway disease. Since genomic analysis cannot directly predict protein activation, analysis of protein pathway activation is required. With the current focus on targeted translational therapeutic modalities, a functional understanding of the GBM signaling repertoire is critical, and yet largely unknown. Methods: Twelve tumors were included in this study: 10 GBMs (9 primary, 1 recurrent) and two brain metastases (1 breast and 1 lung). Pure tumor cell populations were obtained from fixed frozen tissue sections using Laser Capture Microdissection. Protein pathway mapping was performed using Reverse Phase Protein Microarrays (RPMA) whereby the activation of 85 key signaling proteins was quantitatively measured at once. Unsupervised and supervised analysis was used to explore pathway activation. Results: Unsupervised hierarchical clustering of all tumors in the study set revealed largely patient-specific signaling portraits yet also identified distinct pathway subsets. The two metastatic tumors clustered separately and distinctly from the GBMs. The GBM specimens clustered according to pathway activity. Statistical analysis demonstrated significant correlations between certain phosphorylated endpoints detected and overall survival. Phosphorylation of cofilin (S3) was associated with shorter survival time, while Stat1 (Y701) and Shc (Y317) phosphorylation were both positively correlated with longer overall survival. Conclusions: This study represents the most comprehensive proteomic analysis of human GBM pathway mapping to date. Since certain pathway biomarkers are themselves being targeted by current investigational therapies, the ability to map pathway activation and identify critical pathway biomarkers can lead to targeted therapeutics tailored to each patient's tumor. The ability to segregate short from long-term survivors according to protein pathway activation is promising. [Table: see text]
Effect of the combination of retinoic acid and rapamycin on cerebellar granule cell and medulloblastoma proliferation
Authors: Gershon T. R. , Shirazi A. , Kenney A. M. 
Published: August 2020

2077 Background: Cerebellar granule cell precursors (CGCPs) are neuroblasts that proliferate in early postnatal life and may become transformed, giving rise to medulloblastoma. The proliferation of CGCPs is driven by mitogenic signals including Sonic Hedgehog (SHH), and growth factors that activate the protein mTOR. Dysregulation of these intercellular signals can promote medulloblastoma formation. We propose that microenvironmental signals that down-regulate the response of CGCPs to mitogens may inhibit medulloblastoma growth. Retinoic acid (RA) is an endogenous signaling molecule with potent anti-neoplastic effects. We investigated whether SHH, mTOR, and RA signaling pathways interact to regulate CGCP and medulloblastoma proliferation. Methods: We measured proliferation in cultured CGCP explants and the CGCP-derived murine medulloblastoma cell line PZp53 using quantitative phosphohistone-H3 immunocytochemistry. We examined the effects of adding to culture medium SHH, the mTOR inhibitor rapamycin, and all trans-RA (ATRA) in specific combinations. We compared CGCPs from wild type animals to CGCPs from mice with constitutive mTOR activation due to TSC2 mutation. Results: A minimum concentration of 1uM ATRA inhibited SHH-driven CGCP proliferation measurably but incompletely, while 10uM ATRA caused widespread necrosis. CGCPs from TSC2 mutant animals, in which mTOR was constitutively active, were 50% less effected by 1uM ATRA than wild type CGCPs. PZp53 medulloblastoma cells were relatively resistant to ATRA, tolerating 10uM ATRA with reduced but persistent proliferation. 10nM rapamycin decreased but did not eliminate PZp53 proliferation. The combination of rapamycin and ATRA, however, acted synergistically, suppressing proliferation >90%. This suppression persisted at 10-fold lower drug concentrations. Conclusions: CGCPs and CGCP-derived medulloblastoma cells integrate signals transduced by SHH, mTOR, and RA pathways. These signaling pathways can be manipulated by pharmacologic agents in combinations that confer dramatically enhanced antineoplastic effect. We are investigating the molecular basis of the synergy of rapamycin and ATRA. We plan to test the combination in xenografts and ultimately in patients with medulloblastoma. No significant financial relationships to disclose.