bluuebunny/crossref_metadata_2025 huggingface dataset:
Lessons learned engaging Hispanic communities in cancer research
Authors: Mika V. , Hurd T. C. , Sunil T. , Morning Star L. , Moore F. , Garcia O. , Lopez L. , Martinez M. , Rios R. , Welsh R.
Published: August 2020

1551

Background: Community involvement is critical to advance cancer education and prevention in minority communities. Researchers must be knowledgeable of the target community's basic cultural beliefs and linguistic needs. This study sought to identify the best approach for conducting community based cancer research in South Texas Hispanic communities. We report our experiences and lessons learned with participants and site recruitment and retention. Methods: We introduced a community based, culturally relevant breast and cervical cancer screening and early detection program, Esperanza y Vida, to address barriers and disparities in four border communities (urban, rural, colonia, and small border town). These areas represent the diverse South Texas Mexican American population in terms of language use, immigration status, and length of time in the US. Within these communities we recruited a grassroots community organization, faith-based health center, rural hospital district, and federally qualified health center. Results: Focus groups were conducted with women and men to assess knowledge, attitudes, and beliefs about women's cancers. To successfully recruit participants, we implemented various techniques to engage the community and establish sustainable relationships. These included community health worker recruitment of community members, traditional recruitment (flyers, posters, word of mouth), key community and cultural leader support, and discussions with local groups and health organizations. We and our community partners identified and overcame investigator/community barriers (lack of community knowledge, community integration into the research process, community understanding of research methods, reluctance to develop innovative approaches). Consequently, participants are eager to remain with the program and are individually and collectively mobilizing others to create a sustainable and durable program. Conclusions: 1. Cultural leader engagement worked best for participant recruitment in the small border town and colonia settings, while key community leader engagement was most effective in the small city urban and rural settings. 2. Research/community partners must identify and discuss project barriers regardless of the fear of creating discordance to reach solutions.

No significant financial relationships to disclose.
Current survival statistics for patients with newly diagnosed glioblastoma treated with radiation and temozolomide on research studies in the United States
Authors: Grossman S. A. , Ye X. , Piantadosi S. , Desideri S. , Nabors L. B. , Rosenfeld M. , Fisher J.
Published: August 2020

2003

Background: Many novel agents are being studied in combination with radiation and temozolomide (RT+TMZ) in newly diagnosed glioblastoma using survival as the primary endpoint. These single arm phase II studies generally plan to compare their results with those reported from the phase III EORTC RT+TMZ study (Stupp, NEJM, 2005). Methods: The NABTT CNS Consortium has completed accrual to three RT+TMZ+ novel agent studies using the same eligibility criteria. A total of 281 patients with newly diagnosed glioblastoma were enrolled. The novel agents included talampanel (72 pts), poly ICLC (97 pts), and cilengitide (112 pts). The survival data emerging from these three single arm phase II studies was compared with the published EORTC data. Results: The median age, KPS, and percent undergoing debulking surgery for EORTC patients was 56, 86% (WHO 0–1), and 84% and for NABTT patients receiving talampanel 60, 90, and 77%, poly ICLC 56, 90, 86%, and cilengitide 55, 90, and 76%. A total of 247 patients (88%) were ages 18–70 making them comparable to the EORTC patient population. Currently available survival data for these NABTT and EORTC studies are provided below. MGMT methylation status and survival based on dose levels are not currently available. Conclusions: Survival of newly diagnosed glioblastoma patients treated with RT+TMZ + novel agents at 9 NABTT institutions accruing from 2005 to 2008 appears increased compared to RT+TMZ at 85 EORTC institutions accruing from 2000 to 2002. These results do not appear related to a specific effective agent. As a result, caution should be exercised when comparing outcomes from recently conducted Phase II studies in this patient population to published EORTC data.

[Table: see text]

No significant financial relationships to disclose.
Phase I/II study of erlotinib and temsirolimus for patients with recurrent malignant gliomas (MG) (NABTC 04–02)
Authors: Chang S. M. , Kuhn J. , Lamborn K. , Cloughesy T. , Robins I. , Lieberman F. , Yung A. , Dancey J. , Prados M. , Wen P.
Published: August 2020

2004

Background: Glioblastomas (GBM) frequently have EGFR amplification/mutations and inactivation of PTEN. Although single agent EGFR and mTOR inhibitors have limited activity, combinations of these agents may be more effective. Methods: The North American Brain Tumor Consortium conducted a phase I/II study of the EGFR inhibitor erlotinib in combination with the mTOR inhibitor temsirolimus in recurrent MG. Eligibility criteria were histologically proven GBM and anaplastic gliomas (AG), radiologic progression, >18 years old, KPS >60, adequate bone marrow and organ function. There was no limit on the number of prior relapses for phase I and no more than two prior relapses for phase II. Patients must not be receiving enzyme-inducing antiepileptic drugs. The dose of erlotinib was 150 mg/d in phase I and titrated up to maximum of 200mg/d in phase II depending on tolerability. Patients initially received temsirolimus 50 mg i.v. once weekly and the dose adjusted based on toxicities. Escalation was performed in groups of three. MTD was defined as the dose with 1/6 or fewer patients with dose-limiting toxicities (DLTs). Primary endpoint for the phase II component was PFS6. Results: In phase I, 22 patients were enrolled (15 GBM; 7 AG). Median age was 54 years (26–74); median KPS 90 (70–100); median prior relapses 1 (0–3). The MTD was determined to be 150 mg of erlotinib daily combined with 15 mg of temsirolimus weekly. DLTs were rash, mucositis, and liver function abnormalities. Pharmacokinetic data were similar to that for single agent erlotinib and temsirolimus; there was no interaction between the two drugs. AUC accumulation ratios between cycle 1 and 2 for erlotinib and OSI-420 were 3.6 and 4.6, respectively. In phase II, there were 56 patients (including 12 phase I patients treated at the MTD): 40 GBM; 16 AG, median age 47 years (20–72); median KPS 90 (range 60–100), median prior relapses 1 (range 1–3). Six patients discontinued therapy as a result of toxicities. For GBM patients, there was no PR, 30% SD, and PFS6 was 12.5%. For AG patients there was 12.5% PR, 12.5% SD, and PFS6 was 6.25%. Conclusions: The combination of erlotinib and temsirolimus was associated with a higher than expected incidence of toxicities and had minimal activity in recurrent MG.

[Table: see text]
Phase I/II study of sorefenib and erlotinib for patients with recurrent glioblastoma (GBM) (NABTC 05–02)
Authors: Prados M. , Gilbert M. , Kuhn J. , Lamborn K. , Cloughesy T. , Lieberman F. , Puduvalli V. , Robins H. I. , Lassman A. , Wen P. Y.
Published: August 2020

2005

Background: Single agent targeted therapy has been disappointing in GBM. Combination therapy simultaneously targeting both EGFR and the MAP kinase pathway may be more effective. Methods: The NABTC conducted a phase I/II study of sorafenib (VEGFR/PDGFR/Raf inhibitor) in combination with erlotinib (EGFR inhibitor) in recurrent GBM. Eligibility criteria included histologically proven GBM, radiologic progression, > 18 yrs old, KPS > 60, adequate bone marrow reserve, and organ function. There was no limit on the number of prior therapies for phase I and no more than two prior relapses for phase II. No enzyme-inducing antiepileptic drugs were allowed. Dose-finding used a standard 3 + 3 design and the MTD was defined as the dose with DLTs in 1/6 or fewer patients. The primary endpoint for the phase II component was PFS6 (p0 = 15%; p1 = 35%). A 2-stage design was used. If > 4 of the initial 19 patients achieved PFS6, an additional 14 patients would be accrued for a total of 33 patients. Results: In phase I, 17 patients were enrolled. Median age 50 years (35–69); median prior chemotherapy 1 (1–3). The initial doses were sorafenib 200 mg bid and erlotinib 100mg qd. MTD was 400 mg bid of sorafenib daily combined with 100 mg of erlotinib daily. At this dose 1/6 evaluable patients had a DLT (grade 4 lipase). Other grade 3 or 4 toxicities included transaminitis, hypertension, hypophosphatemia, and increased lipase. Pharmacokinetic studies showed no alterations in sorafenib PK, but no accumulation of erlotinib, suggesting a drug-drug interaction with sorafenib altering erlotinib metabolism or clearance. In phase II, 19 patients were accrued to stage I. Median age 51 years (30–75); median prior chemotherapy 2 (range 1–3). Phase II toxicity and outcome data are not yet mature but will be available at the time of presentation. Conclusions: This combination was moderately well-tolerated. MTD was below other combination phase I studies. Sorafenib affected the PK of erlotinib preventing drug accumulation. Phase II toxicity and outcome data will be reported.

[Table: see text]
RTOG 0625: A phase II study of bevacizumab with irinotecan in recurrent glioblastoma (GBM)
Authors: Gilbert M. R. , Wang M. , Aldape K. , Lassman A. , Sorensen A. G. , Mikkelson T. , Groves M. , Werner-Wasik M. , Regine W. , Mehta M.
Published: August 2020

2011

Background: Angiogenesis is a hallmark of GBM, making the tumor vasculature an attractive therapeutic target. In gliomas, vascular endothelial growth factor (VEGF) promotes both angiogenesis and invasion of tumor cells. Bevacizumab is a humanized monoclonal antibody against VEGF-A that rapidly reduces the concentration of VEGF in the circulation. Irinotecan may enhance efficacy by synergistic tumor endothelial cell death or improved tumor delivery of the chemotherapy via “normalized” tumor vasculature. Prior studies of this combination demonstrated high radiographic response and 6-month progression free (6-mPFS) rates. This study was designed to determine the efficacy and safety of this regimen in the cooperative group setting. Methods: Eligibility included age ≥ 18, centrally confirmed GBM or gliosarcoma, progressive or recurrent disease. Enzyme-inducing anticonvulsants were not allowed. Treatment was intravenous bevacizumab 10 mg/kg and irinotecan 200 mg/m2 every 2 weeks. Accrual goal was 57 eligible patients. Primary endpoint was 6-mPFS rate where an estimate of ≥ 35% would define efficacy (15% improvement over historical data). Results: Full enrollment (57) was achieved, median age was 57, median KPS was 80; all had prior radiation and temozolomide treatment. The 6m-PFS rate was 37% (95% CI: 24–50%), with 21 of 57 patients progression-free at 6 months. Moderate toxicity was noted with 21(37%) grade 3, seven (12%) grade 4, and one (<2%) treatment-related death (intracranial hemorrhage). There were six episodes of venous thrombosis, 14 episodes of grade 3 or 4 hematologic toxicity, predominantly lymphopenia (7), and neutropenia (4), no opportunistic infections or febrile neutropenia were noted. Other toxicities included fatigue (9), diarrhea (2), and hypertension (2). Conclusions: These results, in the cooperative group context, corroborate the efficacy of the bevacizumab and irinotecan combination for recurrent GBM with the 6m-PFS surpassing the predetermined efficacy threshold. Previously described toxicities were confirmed with a moderately high rate of venous thrombosis, one intracranial hemorrhage, and moderate hypertension. Studies to determine the contribution of the cytotoxic agent to efficacy and the role of bevacizumab in newly diagnosed GBM are planned.

[Table: see text]
The paradoxical effect of targeted antivascular agents in the therapy of CNS malignancies
Authors: Neuwelt E. A. , Frenkel E.
Published: August 2020

2013

Background: The rationale of vascular targeted agents (i.e., inhibitors of vascular endothelial growth factors [VEGF] or endothelial intergrins) in the therapy of central nervous system (CNS) malignancies is based upon the concept that normalization of tumor vasculature, with a decrease in tumor interstitial pressure, will improve access of cytoreductive drugs. However, previous studies in our laboratory have raised the serious concern that these agents rapidly normalize the blood-brain barrier (BBB) and therefore may result in restoration of the low permeability characteristics of the BBB. Methods: To evaluate this, we studied the effects of bevacizumab, an anti-VEGF agent on tumor vasculature by MRI, using gadolinium-enhanced T1 weighted sequences to assess permeability and the blood pool agent ferumoxytol to assess blood volume. Patient imaging studies were done on IRB approved protocols. Results: Utilizing two rat brain tumor models, we documented that bevacizumab rapidly decreases tumor enhancement, a pattern equivalent to administration of high dose steroid therapy. Correlative studies in rats and humans exploiting T2 weighted imaging, demonstrated resolution of tumor enhancement with occasional concomitant increase in tumor volume. In a parallel evaluation, pseudo-progression was seen in 9 of 14 glioblastoma patients treated with combined chemo-radiation. These inflammatory responses to treatment, when examined by dynamic MRI, were associated with a transient increase in tumor permeability and decreased cerebral blood volume. This increase could be blocked or reduced by decreasing vascular permeability with bevacizumab. Conclusions: These animal and human studies provide evidence that anti-vascular agents have a steroid-like effect; and in the CNS, may result in reduced delivery of cytoreductive agents to the tumor, thereby compromising standard chemo-radiotherapy.

[Table: see text]
Safety and efficacy of the addition of bevacizumab (BV) to temozolomide (TMZ) and radiation therapy (RT) followed by BV, TMZ, and irinotecan (CPT-11) for newly diagnosed glioblastoma multiforme (GBM)
Authors: Vredenburgh J. J. , Desjardins A. , Reardon D. A. , Peters K. , Herndon J. E. , Kirkpatrick J. , Gururangan S. , Bailey L. , Friedman A. H. , Friedman H. S.
Published: August 2020

2015

Background: Standard GBM treatment includes TMZ and RT, and results in a median progression-free survival and median survival of 6.9 and 15.8 months, respectively. GBM have high concentrations of vascular endothelial growth factor (VEGF), higher levels are associated with poorer prognosis. BV is a humanized antibody to VEGF with activity in recurrent GBMs. This study aims to improve the survival of newly diagnosed GBM patients by incorporating an anti-angiogenic agent with RT and TMZ, and adding a topoisomerase I inhibitor, and an anti-angiogenic agent to TMZ post-RT therapy. Methods: Patients received standard RT and TMZ at 75 mg/m2/day, with BV at 10 mg/kg every 14 days beginning a minimum of 28 days post-operatively. Following the completion of RT, patients received 6 cycles of BV, TMZ and CPT-11. Each cycle was 28 days. BV was given at a dose of 10 mg/kg on days 1 and 15, TMZ at 200 mg/m2 on days 1–5 and CPT-11 on days 1 and 15 at 125 mg/m2 for patients not on an enzyme inducing anti-epileptic drug (EIAED) and 340 mg/m2 for patients on an EIAED. The study was designed to differentiate between a 16-month survival rate of 45% and 60% with type I and II error rates of 0.05. Results: 75 patients were enrolled between 8/07 and 9/08. All the patients have completed RT; 40 patients continue to receive BV, TMZ, and CPT-11. Twenty-two patients have completed 6 cycles of BV, TMZ, and CPT-11; 17 of them had a cold PET One patient developed a CNS hemorrhage (grade 2) necessitating stopping BV. Five patients developed thrombocytopenia for which TMZ was held (grade 3, n = 1; grade 4, n = 4). There were no other ≥ grade 3 toxicities, including no wound dehiscence during RT. Twelve patients had tumor progression, and 14 stopped because of toxicity, including: 6 with fatigue; 3 with PEs; 2 with grade 4 thrombocytopenia; the patient with CNS hemorrhage, and one each with a rectal abscess and sepsis. There have been 7 deaths: 5 from tumor progression; one each from sepsis and PEs. At a median follow-up of 9 months, 81% remain alive and progression-free. Conclusions: Adding BV to TMZ and RT followed by BV, TMZ with CPT-11 is tolerable and efficacious.

No significant financial relationships to disclose.
Role of IκBα as a negative regulator of EGFR and a molecular determinant of prognosis in glioblastoma multiforme
Authors: Bredel M. , Renfrow J. , Yadav A. , Alvarez A. , Lin D. , Scholtens D. , He X. , Chandler J. , Scheck A. , Harsh G.
Published: August 2020

2028

Background: Glioblastoma multiforme is a complex disease that involves the deregulation of overlapping signaling pathways. Constitutive activation of the transcription factor nuclear factor-κB (NF-κB) has been broadly associated with various human cancers, including glioblastomas, and their therapy resistance and may be due to cross-coupling with other oncogenic pathways, such as epidermal growth factor signaling. Methods: Multidimensional analysis involving gene and transcript data for the endogenous NF-κB modulator IκBα/NFKBIA and clinical patient profiles of 482 glioblastomas/high-grade gliomas from multiple institutions in the United States and The Cancer Genome Atlas Pilot Project. Functional analyses using LN229, U87, and U118 glioblastoma cells, and human embryonic kidney 293T cells with transgene phenotypes for IκBα. IκBα promoter and coding sequence and promoter methylation analyses in a resistance model of 15 glioblastomas cell lines with in vitro and/or in vivo resistance to O6-alkylating agents. Results: We have identified a regulatory circuit between NF-κB and EGFR signaling in glioblastomas, where IκBα binds to EGFR and attenuates EGFR signaling by immobilizing its kinase domain into an inactive conformation. We found the NFKBIA gene at 14q13.2 deleted in 25% of glioblastomas and its occurrence mutually exclusive with EGFR amplification. Loss of NFKBIA associates independently with patient survival. Functional analyses uncover a bona fide tumor suppressor role for IκBα in glioblastoma cells, where it functions to constrain tumorigenic and migratory potential, and induce spontaneous cellular senescence, and apoptosis in response to treatment. IκBα expression is an independent predictor of patient prognosis in multiple glioblastoma populations. Glioblastomas with initially high IκBα expression significantly repress IκBα upon tumor recurrence, suggesting an acquired mechanism to evade its tumor-suppressive and/or chemo-sensitizing effects during tumor progression. Conclusions: IκBα is a molecular determinant of biological tumor behavior and patient survival in glioblastoma multiforme. Deletion of NFKBIA could present an alternate mechanism to activate EGFR signaling in EGFR non-amplified glioblastomas.

No significant financial relationships to disclose.
Use of CDK6 oncogene amplification and 17q gain to predict poor clinical risk groups in adult medulloblastoma
Authors: Pfister S. M. , Remke M. , Benner A. , Werft W. , Mendrzyk F. , Scheurlen W. , Kulozik A. , Lichter P. , Korshunov A.
Published: August 2020

2030

Background: While in children medulloblastoma comprises the most common malignant brain tumor, it accounts for only 1% of intracranial malignancies in adults. The infrequent appearance of MB in adults poses the question, whether these tumors are the same in adults and children in terms of biological and clinical peculiarities. Methods: Array-CGH was performed for a total 34 adult medulloblastoma samples (>18 years) and results were compared with data from 101 pediatric patients. Selected genomic regions were further investigated by FISH analysis in an independent cohort of 415 samples (112 adult and 303 pediatric). All 146 adult patients received a standard treatment regimen consisting of tumor resection, irradiation of the neuroaxis with 36 Gy, a boost of 20–23 Gy to the posterior fossa, and eight cycles of vincristin, lomustine, and cisplatin. To identify novel prognostic markers, DNA copy-number information was correlated with survival data using log rank and chi-square tests. Results: Copy-number gains of chromosome 17q as well as high-level amplifications of CDK6 were identified as significant adverse prognostic markers in adult medulloblastoma. Apart from one exception, CDK6 amplifications were only observed in adult patients (9% in adults versus 0.2 % in children), whereas amplifications of MYC or MYCN were significantly overrepresented in the pediatric cohort, but when present were also associated with dismal prognosis in adults. Monosomy of chromosome 6, in contrast to the pediatric cohort, was not significantly associated with good prognosis, although nuclear ß-catenin accumulation was detected in most cases (r = 0.68). Based on these results, we propose a molecular staging system for adult medulloblastoma: i) cases with oncogene amplification (10% of cases, 5-year OS = 0%); ii) cases with chromosome 17q gain without oncogene amplification (25% of cases, 5-year-OS = 35%); and iii) cases without oncogene amplification or 17q gain (65% of cases, 5-year OS = 92%). Conclusions: We report on the largest cohort of adult medulloblastoma investigated for genomic imbalances to date. We propose a model for the molecular risk stratification of adult medulloblastoma comprising three distinct genomic risk groups with significantly different survival and tumor biology.

No significant financial relationships to disclose.
A phase I trial of tumor-associated antigen-pulsed dendritic cell immunotherapy for patients with brain stem glioma and glioblastoma
Authors: Phuphanich S. , Rudnick J. , Chu R. , Mazer M. , Wang H. , Serrano N. , Francisco M. , Wheeler C. , Singh M. , Yu J. S.
Published: August 2020

2032

Background: Previous immunotherapy trials for malignant glioma (Yu, J.,et al, Cancer Res. 2001;61:842–7 and 2004;64;4973–9) have demonstrated efficacy in generating a tumor specific immune response. Here we set out to determine feasibility and immunogenecity of dendritic vaccination with specific glioma-associated antigens. Methods: The goal of this study is to use tumor associated antigens (TAA) known to be expressed on gliomas and pulse dendritic cells with these antigens in an MHC compatible fashion using epitopes of HER-2, TRP-2, gp100, MAGE-1, IL13R alpha, and AIM-3. In this phase I trial, HLA-A1 and/or HLA-A2-positive patients with newly diagnosed or recurrent glioblastoma were eligible. Leukapheresis was used to isolate mononuclear cells which were differentiated into dendritic cells in culture, pulsed with tumor peptide, and then administered intradermally three times at 2-week intervals. Results: Twenty patients, 15 males and five females, were enrolled between November 2006 and December 2008 with one screen failure. The median patient age was 47 years (range: 26–65) and patients had a median Karnofsky performance status of 90% (range: 90–100). There were 16 newly diagnosed and three recurrent glioblastoma multiforme (GBM) patients, who underwent surgery prior to vaccination. Our data on 19 patients and 54 courses of dendritic cell vaccines demonstrate zero grade 3 /4 toxicities that were attributable to the vaccination. Thirteen patients continue to have stable disease (ranging from 15 to 115 weeks), six patients have demonstrated tumor progression. Median survival from surgery was 60 weeks (ranging from 26 to 115 weeks). Of 15 patients tested to date, six patients demonstrated an antigen-specific cytotoxic T-cell response to at least one antigen after vaccination. Only 17% of CTL responders (1/6) demonstrated tumor progression compared to 56% (5/9) of nonresponders to date. Conclusions: This phase I study demonstrated the feasibility, safety, and bioactivity of a TAA-pulsed dendritic cell vaccine for patients with glioblastoma progression free survival correlated with CTL response.

[Table: see text]
Phase II trial of sunitinib malate in patients with temozolomide refractory recurrent high-grade glioma
Authors: Neyns B. , Chaskis C. , Dujardin M. , Everaert H. , Sadones J. , Nupponen N. N. , Michotte A.
Published: August 2020

2038

Background: High-grade gliomas (HGG) are characterized by neo-angiogenesis. Sunitinib is a small molecule tyrosine kinase inhibitor that inhibits multiple receptors (including VEGFR, PDGFR, and c-Kit). We investigated sunitinib for the treatment of patients (pts) with temozolomide (TMZ) refractory recurrent HGG. Methods: Pts were recruited according to a 2-stage phase II design and received a daily dose of 37.5 mg sunitinib. T1 ± Gd and T2 weighted MRI images were obtained after 4 and 8 weeks of sunitinib and q8 weeks thereafter. We assessed the antiangiogenic effect by calculating the cerebral blood volume (CBV) and cerebral blood flow (CBF) from dynamic susceptibility (DSC) based perfusion MRI and determined the lesion-to-normal-white matter CBV (CBVLTN) and CBF (CBFLTN) ratios. Uptake of fluorinated fenyl-methyl-alanine within the CNS was assessed by PET at baseline and reassessed in responding pts. Results: 21 pts were enrolled (median age 43 [range 34–71]; M/F 15/6; KPS 90–80: 11 pts, KPS 70–60: 10 pts). All pts had PD following surgery, RT and TMZ. A total of 142 treatment weeks (range 2–84) were evaluated; 81% of the administrations were at the 37,5 mg-, 19% at the 25 mg dose level. Most frequent AEs were: skin toxicity (gr2, n = 1; gr 3, n = 1), fatigue (gr 2, n = 4), hypertension (gr 2, n = 3), diarrhea (gr 2, n = 2), mucositis (gr 3; n = 1), afebrile- (gr 2, n = 3) and febrile neutropenia (gr 3, n = 1; gr 4, n = 1), thrombocytopenia (gr 2, n = 4; gr 3, n = 1; gr 4, n = 1), and lymphocytopenia (gr 2, n = 2; gr 3, n = 4). Decrease in CBVLTN and CBFLTN was observed in 6/14 evaluable pts after 4 weeks of sunitinib, 5/19 evaluable pts had SD on T1±Gd after 8 weeks; one pt experienced a marked clinical improvement with a reduction in the tumor metabolism on PET. After a median follow-up of 11 months, median TTP and -OS are1,6 and 3,8 months respectively. Three pts with a secondary glioblastoma (age <40 year) had an objective PR when administered CCNU at PD under sunitinib (with a TTP of 2, 8 and +9 mths respectively). Characterization of the VEGFR, PDGFR, and Kit gene copy numbers and protein expression in the tumors is ongoing. Conclusions: Sunitinib at a continuous daily dose of 37.5 mg has a transient antiangiogenic effect in pts with recurrent HGG but is of insufficient clinical benefit to warrant further investigation as a single agent.

[Table: see text]
Pazopanib and lapatinib in patients with relapsed malignant glioma: Results of a phase I/II study
Authors: Frentzas S. N. , Groves M. D. , Barriuso J. , Harris D. , Reardon D. , Curtis M. C. , Suttle A. B. , Ma B. , Lager J. J. , de Bono J. S.
Published: August 2020

2040

Background: Pazopanib (paz) is an oral angiogenesis inhibitor targeting VEGFR, PDGFR, and c-kit; and lapatinib (lap) is an oral tyrosine kinase inhibitor of EGFR (ErbB1) and HER-2 (ErbB2). Combination of VEGFR, PDGFR, and ErbB1 inhibitors may provide synergistic antitumor activity in malignant glioma. Phase I determined the optimally tolerated regimen (OTR) of paz and lap when given with enzyme-inducing anticonvulsants (EIACs). Phase II, which evaluated the efficacy of daily paz/lap (400 mg/1000mg) in relapsed grade 4 glioma without EIACs, was previously reported. Methods: Patients (pts) with grade 3 or 4 glioma, on EIACs, and with adequate organ function were eligible. Doses of paz and lap were escalated in a 3 + 3 design. OTR was defined as the highest dose of paz/lap at which no more than 1 of 6 pts had dose limiting toxicity (DLT) and target concentrations were achieved. Results: 32 pts have been enrolled at doses of paz/lap (mg, daily unless specified) of 200/1500 (N = 4), 800/1500 (N = 6), 800/500 bid (N = 5), 800/750 bid (N = 7), 800/1000 bid (N = 6), and 600 bid/1000 bid (N = 4). Data on 28 pts: the most common adverse events (AEs) were: fatigue (25%); diarrhea (25%); headache (21%); ALT increase (18%); nausea (18%); and insomnia (14%). Hepatobiliary lab abnormalities were reversible, uncomplicated, and included: AST elevation (11%), hyperbilirubinemia (7%), ALT elevation (36%; 7% Gr 3), and Alk phos elevation (14%). DLTs were elevated liver enzymes (800/1500; 1 pt), elevated lipase (800/750 bid; 1 pt) and thrombocytopenia, fatigue, diarrhea, confusion (800/1000 bid; 1 pt). 2 pts dose reduced and 3 pts had a dose interruption. At 600 bid/1000 bid, the target paz Cmin of 17.5 μg/mL was achieved; median lap Cmin of 0.447 μg/mL approached the target of 0.5 μg/mL. Phase I best response (MacDonald criteria) was PR in 3 pts (11%) and SD ≥ 8 weeks in 5 pts (18%). Two pts remain on the phase II, at 21 months (PR) and 23 months (CR) of therapy. Conclusions: The paz/lap combination has a manageable safety profile with a preliminary OTR with EIACs of paz 600 mg bid/ lap 1000 mg bid. EIACs decreased plasma paz and lap concentrations. Responses and lengthy periods without disease progression were seen in some pts in phase I and II.

[Table: see text]
A phase II trial of single-agent bevacizumab given every 3 weeks for recurrent malignant gliomas
Authors: Raizer J. J. , Grimm S. , Rice L. , Muro K. , Chandler J. , Tellez C. , Mellot A. L. , Newman S. , Nicholas M. K. , Chamberlain M.
Published: August 2020

2044

Background: Increasingly target specific agents are used in the treatment of malignant gliomas (MG). Among targeted agents, bevacizumab appears most promising and when combined with CPT-11. As CPT-11 has limited activity in recurrent MG, a single agent phase II trial of bevacizumab given every 3 weeks in with recurrent MG was performed. Methods: All patients (pts) had to sign an IRB informed consent except six pts who were treated at a different site in a similar fashion. All pts had to have at least one relapse with the first sixteen required to have two relapses before protocol amendment. Inclusion criteria required > 18 year of age, KPS > 60, on a non-enzyme inducing anticonvulsant, adequate bone marrow, liver and renal function, and normal urine protein and creatinine. MRI with perfusion was done at baseline (if patient consented) and then every 6 weeks. Patients were assessed using Macdonald criteria and continued on trial until tumor progression or toxicity. Treatment was bevacizumab 15 mg/kg every 3 weeks. Results: 61 patients (35 male; 26 female; 50 GBM, 5 AA, 6 AO/AOA) with a median age of 51 were treated. Median number of doses given was 4 (range 1–18). PFS-6 was 32% (median PFS was 3.9 m; median OS was 6.6 m). Best radiographic response included 0% CR, 25% PR and 50% SD. Grade 3+ toxicities were non-fatal intracranial hemorrhage (1), fatal GI perforation (1), DVT (1), fatigue (4), rectal bleeding (1), weakness (1), and lack of drive (1). Conclusions: Bevacizumab as a single agent given every 3 weeks at 15 mg/kg is effective and safe for recurrent MG. The observed PFS-6 and OS is lower than reported bevacizumab regimens administered every 2 weeks; this difference may be related to patient selection.

[Table: see text]
Phase II study of bevacizumab plus erlotinib for recurrent malignant gliomas
Authors: Sathornsumetee S. , Desjardins A. , Vredenburgh J. J. , Rich J. N. , Gururangan S. , Friedman A. H. , Friedman H. S. , Reardon D. A.
Published: August 2020

2045

Background: Bevacizumab (B), a neutralizing VEGF monoclonal antibody, has anti-glioma activity as single agent and in combination with cytotoxic therapy. Erlotinib (E), an EGFR tyrosine kinase inhibitor, may exhibit anti-tumor activity in some malignant glioma (MG) patients. B plus E was associated with clinical benefit in several solid tumors. We performed a single-arm, phase II study to evaluate the efficacy of B and E in patients with recurrent MG. Methods: The primary endpoint was 6-month progression-free survival (PFS-6). Radiographic response, pharmacokinetics and correlative biomarkers were secondary endpoints. E was orally administered daily at 200 mg/day for patients not on enzyme-inducing anticonvulsants (EIAC) and 500 mg/day for patients on EIAC. All patients received 10 mg/kg of B intravenously every two weeks. Key eligibility criteria included: age ≥ 18 years; KPS ≥ 60; > 4 weeks from prior surgery, XRT or chemotherapy. Patients with either > 3 prior progressions, requirement for therapeutic anti-coagulation or acute hemorrhage on pre-treatment imaging were excluded. Results: Fifty-six patients with recurrent MG (n = 24 for glioblastoma multiforme [GBM] and n = 32 for anaplastic gliomas [AGs]) were assessable for outcome. The PFS-6 rates were 25% for GBM and 50% for AGs. There was no survival difference between EIAC and non-EIAC groups. Rash (54% grade 1–2 and 38% grade 3) was the most common side effect. Nausea, diarrhea, and fatigue were common but mostly grade 1–2. Serious side effects were rare and included two patients with pulmonary embolism, single patients with either intestinal perforation, ischemic stroke, gastric bleeding, or nasal septal perforation. Pharmacokinetic and tissue biomarker profiles are in preparation. Conclusions: Among heavily pretreated recurrent MG patients, bevacizumab plus erlotinib is tolerated and associated with encouraging anti-tumor benefit.

No significant financial relationships to disclose.
A phase II study of XL184 in patients (pts) with progressive glioblastoma multiforme (GBM) in first or second relapse
Authors: De Groot J. F. , Prados M. , Urquhart T. , Robertson S. , Yaron Y. , Sorensen A. G. , Norton A. , Batchelor T. , Drappatz J. , Wen P.
Published: August 2020

2047

Background: XL184 is a potent orally bioavailable inhibitor of MET, RET, KIT, and VEGFR2. Elevated levels of VEGFR2 and its ligand VEGF are found in GBM, and elevated levels of MET and KIT are correlated with poor prognosis in GBM pts. Treatment with XL184 results in potent inhibition of GBM in preclinical models. Methods: This is a phase II study of 46 pts with recurrent GBM who received XL184 175mg PO qd. Co-primary objectives are 6-month progression-free survival (PFS6) and safety. Secondary objectives include response rate (per MacDonald Criteria), duration of response, overall survival, pharmacodynamic and pharmacokinetic parameters, vascular imaging, and changes in steroid usage. Results: As of January 6, 2009, all 46 pts have been enrolled. At least 1 post-baseline tumor assessment at 4 weeks was available for 26 pts. Of these, 17 pts had not received prior therapy with an anti-angiogenic agent, whereas 9 pts had received prior therapy with bevacizumab (n = 6), vandetanib (n = 2), or VEGF-TRAP (n = 1). Safety: 6 pts have experienced a total of 9 possibly related grade 3/4 SAEs including increased troponin I and myocarditis (n = 1); dehydration, nausea, and fatigue (n = 1); elevated ALT (n = 1); pulmonary embolism (n = 2); and CNS hemorrhage (n = 1). 24/46 (52%) pts have required a dose interruption or reduction due to AEs or SAEs. Based on investigator assessment of bidimensional contrast-enhancing tumor measurements, 10 pts (38%) had a best radiologic response of >= 50% reduction from baseline (including 1 pt with a 100% reduction), 9 pts (35%) had tumor measurement changes ranging from +24% and -49%, and 7 pts (27%) had a >= 25% increase in tumor burden. Of the 17 anti-angiogenic-naïve pts, 9 (53%) had a best radiologic response of >= 50% reduction in tumor burden. 1 pt with prior vandetanib therapy has experienced a best radiologic response of >= 50%. Of the 4 pts with > 6 months follow-up, 3 remain on study with a sustained radiologic response. Conclusions: XL184 at a dose of 175 mg PO qd, has demonstrated substantial activity in pts with progressive or recurrent GBM. Updated safety and efficacy results including centrally reviewed PFS6 and response rate will be reported.

[Table: see text]
Hematologic adverse events associated with temozolomide (TMZ)
Authors: Villano J. L. , Letarte N. , Yu J. M. , Shakir A. R. , Bressler L.
Published: August 2020

2053

Background: Secondary acute myeloid leukemia (AML) is reported to occur in 3%-10% of patients treated with alkylating agents for Hodgkin's lymphoma, non-Hodgkin's lymphoma, ovarian cancer, breast cancer, and multiple myeloma. The incidence of secondary AML is greatest at 5–10 years after treatment, and AML often follows myelodysplastic syndrome (MDS). TMZ is a pro-drug of methyl-triazeno-imidazole-carboxamide (MTIC), an alkylating metabolite of dacarbazine. Chemotherapy induced aplastic anemia is usually dose-related versus an idiosyncratic mechanism. A small number of fatal cases of TMZ-induced aplastic anemia have been reported. The FDA, in a Drug Safety Newsletter, described 18 cases of aplastic anemia reported between 1999 and 2006. TMZ use in brain tumors and in melanoma is increasing, with little known on the incidence of severe hematologic adverse events. Methods: We searched the FDA MedWatch database for TMZ and obtained all entries submitted to the FDA from November 1, 1997 to September 3, 2008. We also obtained the number of aplastic anemia cases reported from Schering Plough's Global Pharmacovigilance department, as of December 13, 2007. Results: During this time period, 5,127 reports (on any side effect) on 3,490 patients were submitted to MedWatch. Among these patients, we identified 140 cases that we labeled as major hematologic adverse events: agranulocytosis (8 cases), aplasia (42), aplastic anemia (52), leukemia (26), MDS (6), and lymphoma (6). Gender was reported in 133 cases. Of these, 56 were male and 77 were female. The overall mean age in cases of major hematologic adverse events was 54 years. Schering Plough reports 25 cases of aplastic anemia and estimates the frequency to be 10.22 per 100,000 patients exposed to TMZ. Conclusions: TMZ's major hematologic adverse event profile seems to differ compared with other alkylating chemotherapy. Aplastic anemia is a significant concern with TMZ use and should be disclosed to patients. Risk of leukemia/MDS from our review may also be significant, but length of follow-up is insufficient and the real risk is likely still unknown.

No significant financial relationships to disclose.
The infiltrative, diffuse pattern of recurrence in patients with malignant gliomas treated with bevacizumab
Authors: Potthast L. , Chowdhary S. , Pan E. , Yu D. , Zhu W. , Brem S.
Published: August 2020

2057

Background: There is no standard of care for recurrent gliomas; however, bevacizumab is often used as a salvage chemotherapy regimen. A diffuse, infiltrative pattern of recurrence, as evidenced by MR imaging, was seen manifesting as multifocal disease or presumed CSF dissemination with subependymal spread. Methods: We conducted a retrospective analysis of 40 recurrent glioma patients followed at Moffitt Cancer Center from September 2006 through December 2008 treated with bevacizumab alone or in combination with irinotecan. Histologies included glioblastoma (GB), anaplastic astrocytomas (AA), anaplastic oligodendrogliomas (AO), anaplastic oligoastrocytomas (AOA), and low-grade astrocytomas. Rate of diffuse, infiltrative recurrence, progression free survival (PFS) and overall survival (OS) were analyzed and correlated with respect to specific prognostic variables. Results: 38% (15) of the patients were female and 63% (25) were male. The median (range) age was 51 (20–72) years. The median (range) KPS was 80 (50–100). Twenty-six (65%) patients had GB, 8 (20%) AA, 2 (5%) AO, and 3 (8%) AOA and 1 (3%) had LGA. Five (13%) patients had a gross total resection (GTR), 23 (58%) a subtotal resection (STR) and 12 (30%) had biopsy only. The median (range) number of prior therapies was 2 (1–7). At time of analysis 28 (70%) patients had died. Incidence of diffuse, infiltrative recurrence was seen in 8 (20%) of patients (95% CI: [9%, 36%]). This recurrence seems to be negatively associated with age: rate for age<=50: 6/18 (33%); (95% CI: [13%, 59%]) while rate for age>50: 2/22 (9%); (95% CI: [1%, 29%]), with an odds ratio (OR) of 5.0. Conclusions: There appears to be an increase in a diffuse, infiltrative pattern of recurrence among recurrent glioma patients treated with bevacizumab as a salvage regimen. In our experience, this appears most prevalent in patients less than 50 years of age. It is unclear why the disparity among this subset of patients occurs, however, we hypothesize that this may once again highlight the distinct tumor biology among young glioma patients. The impact of this observation on clinical decision making on whether to utilize bevacizumab in young recurrent glioma patients warrants further investigation.

[Table: see text]
Prognostic significance of early changes in the apparent diffusion coefficient that occurs after treatment of patients with glioblastoma multiforme with bevacizumab
Authors: Paldino M. , Desjardins A. , Friedman H. S. , Vredenburgh J. J. , Barboriak D. P.
Published: August 2020

2058

Background: To determine the prognostic significance of changes in parameters derived from diffusion tensor imaging (DTI) that occur in response to combination chemotherapy with the antiangiogenesis agent bevacizumab (BEV) in patients with recurrent glioblastoma multiforme (GBM). Methods: 16 patients (10 men, 6 women; age range 38–62 years) with recurrent GBM underwent serial 1.5T MR imaging. Axial single-shot echo planar DTI (TR/TE 6000/100; flip angle 90 degrees; voxel: 1.72 x 1.72 x 5mm; b value of 1000 sec/mm2; 12 directions) was obtained on scans performed 3 days and 1 day prior to and 1 day after initiation of therapy with BEV and irinotecan (CPT-11). Clinical follow-up and survival status was documented up to 20 months after the date of initial MR imaging. Apparent diffusion coefficient (ADC) and fractional anisotropy (FA) maps were aligned to whole brain contrast-enhanced 3D FLASH and 3D FLAIR image volumes (1 mm isotropic voxels) using a rigid body normalized mutual information algorithm. Based on two pre-treatment scans, the 95% confidence limits for change (95%CL) in ADC and FA were calculated in volumes of tumor-related contrast-enhancement (TRE) and FLAIR signal abnormality (FSA). A patient was considered to have a change in FA or ADC after therapy if the difference between the pre- and post-treatment values was greater than the 95% CL for that parameter. Progression was defined on contrast-enhanced MRI using MacDonald criteria by neuro-oncologists blinded to the DTI findings. Survival was compared using the log rank test. Results: DTI detected a change in ADC within FSA after therapy in three patients (2 increased, 1 decreased). Patients with a change in ADC within FSA had significantly shorter overall (p < 0.0012) and progression free (p < 0.015) survival than those with no change. Median survival in the patient group with a change in ADC was 24.7 (95% CI [17.3, 39.4]) weeks and 56.4 (95% CI [41.7, 96]) weeks in those patients with no change. Conclusions: In patients with GBM treated with BEV and CPT-11, a change in ADC after therapy in areas of FSA is associated with decreased survival. Parameters derived from DTI may, therefore, potentially serve as early markers of treatment failure in patients with GBM.

[Table: see text]
Bevacizumab for recurrent ependymoma
Authors: Green R. M. , Cloughesy T. , Stupp R. , DeAngelis L. M. , Woyshner E. A. , Ney D. E. , Lassman A. B.
Published: August 2020

2060

Background: Ependymoma is a rare type of glioma, representing less than 5% of brain tumors in adults. Radiotherapy (RT) is commonly administered, but there is no standard chemotherapy. At recurrence ependymoma is notoriously refractory to therapy and the prognosis is poor. In recurrent glioblastoma, encouraging responses with bevacizumab have been observed. Therefore, we treated patients with recurrent ependymoma and anaplastic ependymoma with bevacizumab containing chemotherapy regimens. Methods: We retrospectively identified adults treated for recurrent ependymoma and anaplastic ependymoma with bevacizumab containing chemotherapy regimens. We determined radiographic response (Macdonald criteria) and estimated median time to progression (TTP) and overall survival (OS) by the Kaplan-Meier method. Results: There were six patients, four women and two men, with a median age of 29 years (range, 20–65). Prior treatment included RT in all and temozolomide in four. Bevacizumab (5–10 mg/kg) every other week was combined with cytotoxic agents: irinotecan (3), carboplatin (2), or temozolomide (1). Five patients achieved a partial response (83%); in one patient the disease was stable. Median TTP and OS were 6.5 (95% CI: 2.7–10.2) and 9.4 (95% CI: 6.3–12.6) months, respectively, with a median follow up of 18.7 months for the two surviving patients. One additional patient is initiating bevacizumab monotherapy (not included in this analysis). Conclusions: Bevacizuamb has efficacy in the treatment of recurrent ependymoma. Prospective study is warranted.

[Table: see text]
Extraneural metastasis of medulloblastoma
Authors: Mazloom A. , Zangeneh A. H. , Teh B. S. , Paulino A. C.
Published: August 2020

2065

Background: Medulloblastoma is the most common childhood intracranial tumor to spread extraneurally. Information regarding prognostic factors and best therapeutic approach of extraneural metastasis (ENM) of medulloblastoma is mostly limited to case reports. The purpose of this study was to perform a comprehensive literature review and analysis of reported cases dealing with ENM to identify the characteristics, prognostic factors, optimal treatment modalities, and survival of these patients. Methods: A PubMed search of English language articles from 1963–2007 was performed, yielding 47 articles with 119 patients. Factors analyzed included age, time interval to ENM, CNS involvement at the time of ENM, location of ENM, treatment, and outcome. Results: Location of ENM included bone in 84%, bone marrow in 27%, lung in 6%, liver in 6%, and lymph nodes in 15%. Of patients with available data regarding location of RT after ENM, 87% of patients received this treatment to the site of ENM. The 1-year disease free survival (DFS) and overall survival (OS) after the diagnosis of ENM was 35% and 42%, respectively. The 1-year OS for patients with and without radiotherapy (RT) after ENM was 58% and 35%, respectively (p = 0.019). For patients without CNS involvement at the time of ENM the 1-year OS for those treated with and without RT was 82% and 51%, respectively (p = 0.030), however RT did not significantly improve OS for those with CNS involvement. ENM in the lung or liver was found to be a negative prognostic factor (p = 0.002). 1-year OS of patients with time interval to ENM of <18 months was 25% while those with time interval greater than or equal to 18 months it was 61% (p = 0.001). Conclusions: Negative prognostic factors for patients with ENM include CNS involvement at the time of ENM, lung or liver involvement, and duration to ENM <18 months. Patients without CNS involvement who received RT after ENM had an OS and DFS benefit compared to those not receiving RT.

No significant financial relationships to disclose.