bluuebunny/crossref_metadata_2025 huggingface dataset:
Temozolomide chemotherapy versus radiotherapy in molecularly characterized (1p loss) low-grade glioma: A randomized phase III intergroup study by the EORTC/NCIC-CTG/TROG/MRC-CTU (EORTC 22033-26033).
Authors: Baumert Brigitta G , Mason Warren P. , Ryan Gail , Bromberg Jacoline E , Van Den Bent Martin J. , Hoang-Xuan Khê , Brandes Alba Ariela , Kantor Guy , Taphoorn Martin JB , Ben Hassel Mohamed , Rees Jeremy , Wick Wolfgang , Von Deimling Andreas , Hartmann Christian , Kros Johan M , Hegi Monika E. , Dif Nicolas , Lacombe Denis A. , Gorlia Thierry , Stupp Roger
Published: March 2020

2007

Background: Outcome of low-grade glioma (LGG) is highly variable. We investigated whether primary chemotherapy in comparison to standard radiotherapy (RT) prolongs progression-free (PFS) and overall survival (OS), and whether prognostic molecular factors could be defined. Methods: Progressive, symptomatic or high-risk patients with a LGG requiring treatment other than surgery were randomized (after stratification for 1p-status) to either conformal RT (50.4 Gy/28 fractions) or dose-dense temozolomide [TMZ] (75 mg/m² daily x 21 days, q28 days, max. 12 cycles). Primary endpoint was PFS, secondary analyses included OS and impact of 1p status. Results: 477 patients were randomized (2005-2012, median FU 45.5 months). Analysis was performed after 246 progression events. Hematological toxicity ≥ grade 3 was observed in 9.4% of TMZ patients. PFS was not significantly different, median OS not reached. 1p deletion was a positive prognostic factor irrespective of treatment (p-value stratified by treatment (PFS: 0.0003;HR=0.59 95% CI(0.45-0.78)/OS: 0.002;HR=0.49 95% CI (0.32-0.77)). Conclusions: First-line treatment with TMZ compared to RT did not improve PFS in high-risk LGG patients. Although interaction test was not significant, there was a trend for inferior PFS in patients treated by TMZ with 1p intact, while OS may be better when 1p-deleted patients receive TMZ upfront. Survival analysis requires further maturation of the data. Clinical trial information: EudraCT number 2004-002714-11. [Table: see text]
A phase II study of a temozolomide-based chemoradiotherapy regimen for high-risk low-grade gliomas: Preliminary results of RTOG 0424.
Authors: Fisher Barbara Jean , Lui Jeff , Macdonald David R. , Lesser Glenn Jay , Coons Stephen , Brachman David , Ryu Samuel , Werner-Wasik Maria , Bahary Jean-Paul , Hu Chen , Mehta Minesh P. ,   Radiation Therapy Oncology Group
Published: March 2020

2008

Background: The primary endpoint of RTOG 0424 was to compare the 3-year survival (OS) of a regimen of concurrent and adjuvant temozolomide (TMZ) and radiotherapy (RT) in a high-risk low-grade glioma (LGG) population to the 3 year (yr) OS rate of the high risk EORTC LGG patients (pts) reported by Pignatti et al (J Clin Oncol 2002;20(8):2076-84). Secondary endpoints were: progression-free survival (PFS), toxicity, neurocognitive and quality of life data and molecular analysis. Methods: Pts with LGG's and >=3 high risk factors (age> = 40, astrocytoma dominant histology, tumor crossing midline, tumor > = 6 cm or preoperative neurological function status >1) were eligible and treated with conformal RT (54 Gy/30 fractions) plus concurrent TMZ 75 mg/m2 /day for 6 weeks and post-RT TMZ 150-200 mg/m2/day days 1-5 q28 days for up to 12 cycles. The study was designed to detect a 43% increase in median survival time (MST) from 40.5 to 57.9 months, and a 20% improvement in 3 yr OS rate from 54% to 65%, at a 10% significance level (1 sided) and 96% power. Results: Between January 2005-August 2009 136 pts were accrued, 129 (75 males, 54 females) were evaluable. Median age was 49 years, 91% had a Zubrod score 0-1 and 69%, 25% and 6% of pts had 3,4 and 5 high risk factors respectively. With a median follow-up time of 4.1 yrs, minimum follow-up of 3 yrs, MST has not yet been reached. Three year OS rate was 73.1% (95%CI:65.3-80.8%), significantly improved from historical control with a p-value <0.0001. No difference in OS rates for pts with 3, 4 or 5 high risk factors was seen. 3 year PFS was 59.2% (95% CI:50.7-67.8%). Grade 3 adverse events (AE) occurred in 43% of pts and grade 4 AE in 10%, primarily hematologic, constitutional or gastrointestinal (nausea, anorexia) toxicity. One patient died of herpes encephalitis. Secondary analyses are ongoing. Radiation Quality Assurance was per protocol/ acceptable in 95% and 74% of pts completed chemotherapy per protocol. Conclusions: The 3 year OS rate of 73.1% for these high risk LGG pts is significantly higher than those reported for historical controls (54%, p < 0.0001, one-sided) and the study-hypothesized 65%. Supported by RTOG U10 CA21661 and CCOP U10 CA37422 grants from NCI and Merck Clinical trial information: NCT00114140.
Temozolomide plus bevacizumab in elderly patients with newly diagnosed glioblastoma and poor performance status: An Anocef phase II trial.
Authors: Reyes-Botero German , Honnorat Jerôme , Chinot Oliver L. , Taillandier Luc , Catry-Thomas Isabelle , Barriere Jerome , Guillamo Jean Sebastien , Fabbro Michel , Frappaz Didier , Benouaich Amiel Alexandra , Le Rhun Emilie , Campello Chantal , Tennevet Isabelle , Ghiringhelli François , Tanguy Marie-Laure , Mokhtari Karima , Delattre Jean-Yves ,   ANOCEF: Association des Neuro-Oncologues d'Expression Française
Published: March 2020

2020

Background: The optimal treatment of glioblastoma multiforme (GBM) in elderly patients (age ≥70 years) with impaired functional status (Karnofsky performance status, KPS<70) remains to be established. A previous study using temozolomide (TMZ) alone suggested an increase in median overall survival (OS) compared to supportive care (25 weeks vs. 12-16 weeks, respectively). Median progression-free survival (PFS) was 16 weeks and 26% of patients became transiently capable of self-care (IK>70) (J Clin Oncol. 2011; 29: 3050-5). The present clinical trial evaluated the efficacy and safety of the combination of TMZ with bevacizumab (BV) as an initial treatment for elderly patients with GBM and KPS<70. Methods: Patients aged ≥ 70 years with KPS < 70 and a newly supratentorial GBM diagnosed by biopsy were eligible for this multicentric, prospective and non-randomised phase II trial. The primary endpoint was the OS and secondary endpoints included median PFS, quality of life, safety and cognition. Treatment consisted of TMZ 130-150 mgs/m2/d for 5 days every 4 weeks plus BV 10mgs/kg every 2 weeks, until 12 cycles or tumoral progression. Neither surgical resection nor radiotherapy was performed. Follow-up included clinical assessment every 2 weeks and brain MRI every 8 weeks. Results: Between October 2010 and March 2012, 66 patients (median age, 77 years; median KPS, 60) were enrolled. Median OS was 24 weeks (95% CI, 19-27.6) and median PFS was 16 weeks (95% CI, 13.1–19.3). Twenty-five patients (38%) became transiently capable of self-care (IK>70). Grade 3 and 4 haematological toxicity occurred in 13(19.6%) cases, whereas non-haematological toxicities were reported in 21(32%), including high blood pressure in 7(10%), thromboembolic events in 3(4.5%), intracerebral haemorrhage in 2(3%) and intestinal perforation in 2(3%) cases. Conclusions: This study confirms that TMZ-based treatment is of help in elderly GBM patients with poor KPS. However, the addition of bevacizumab does not appear to be of benefit in term of PFS and OS.
Long-term survival in primary glioblastoma revisited: The contribution of isocitrate dehydrogenase mutations.
Authors: Weller Michael , Hentschel Bettina , Simon Matthias , Westphal Manfred , Schackert Gabriele , Tonn Joerg Christian , Loeffler Markus , Reifenberger Guido , Pietsch Torsten , von Deimling Andreas , Hartmann Christian ,   German Glioma Network
Published: March 2020

2027

Background: The determinants of long-term survival in glioblastoma have remained largely obscure. Isocitrate dehydrogenase (IDH) 1 or 2 mutations are common in WHO grade 2/3 gliomas, but rare in primary glioblastomas, and associated with longer survival. Methods: We compared clinical and molecular characteristics of 69 patients with centrally confirmed glioblastoma and survival > 36 months (LTS-36), including 33 patients surviving > 60 months (LTS-60), with 259 patients surviving < 36 months. MGMT promoter methylation, 1p/19q codeletions, EGFR amplification, TP53 mutations and IDH1/2mutations were determined by standard techniques. Results: The rate of IDH1/2 mutations in LTS-36 patients was 34% (23/67 patients) as opposed to 4.3% in controls (11/257 patients). Long-term survivors with IDH1/2 -mutant glioblastomas were younger, had almost no EGFR amplifications, but exhibited more often 1p/19q codeletions and TP53 mutations than LTS patients with IDH1/2 wild-type glioblastomas. Among LTS-36 patients, wild-type TP53 status, MGMT promoter methylation, and absence of EGFR amplification, but not IDH1/2 mutation, were associated with prolonged survival. Among 11 patients with IDH1/2-mutant glioblastomas without long-term survival, the only difference to IDH1/2-mutant long-term survivors was less frequent MGMT promoter methylation. Compared with LTS-36 patients, LTS-60 patients had been treated initially with radiotherapy alone and had TP53 mutations less frequently. Conclusions: IDH1/2 mutations define a subgroup of tumors of LTS patients that exhibit molecular characteristics of WHO grade 2/3 gliomas and secondary glioblastomas. Determinants of LTS with IDH1/2 wild-type glioblastomas, which exhibit typical molecular features of primary glioblastomas, beyond MGMT promoter methylation, remain to be identified.
Association of VEGFA SNP rs2010963 with prognosis and prediction of vascular toxicity of bevacizumab in recurrent glioblastomas.
Authors: Di Stefano Anna Luisa , Lombardi Giuseppe , Gallego Perez-Larraya Jaime , Boisselier Blandine , Labussiere Marianne , Ducray Francois , Zagonel Vittorina , Cheneau Caroline , Delattre Jean-Yves , Sanson Marc
Published: March 2020

2028

Background: VEGFA has become an attractive target in high grade gliomas but there is no predictor of response or toxicity to anti-VEGF therapy. We investigated here the association between functional single nucleotide polymorphism (SNP) +405 G>C (rs2010963), located in 5’ untranslated terminal region of VEGFA gene, survival, response to bevacizumab (BVZ), and vascular toxicity. Methods: The rs2010963 was analyzed in blood DNA using a Taqman SNP Genotyping Assay and confronted to Progression Free Survival (PFS), Overall Survival (OS) in the general population of gliomas, and -for the glioblastomas (GBM) treated with BVZ at recurrence- with Response, PFS, and thrombo-hemorragic events. Results: In the general population of 954 gliomas stratified per grade (362 grade 2, 269 grade 3, 323 grade 4) there was no association between rs2010963 and OS or PFS. In the population of 123 recurrent GBM treated with BVZ, we observed a favourable trend in PFS associated with the C allele of rs2010963 (5.4 vs 4.2 months, p = 0.07). Most importantly the CC genotype was associated with the occurrence of thrombo-hemorragic events (6/16 vs 2/107 in CG+GG, p <0.0001). Conclusions: Our data suggest that rs2010963 status has not prognostic significance in gliomas, but is associated with vascular events in recurrent GBM treated with BVZ. The impact of rs2010963 on response to BVZ needs to be further investigated.
High-dose methotrexate with and without rituximab for the treatment of newly diagnosed primary CNS lymphoma: Johns Hopkins Hospital experience.
Authors: Holdhoff Matthias , Sarai Guneet , Abdelaziz Ahmed , Bonekamp David , Grossman Stuart A. , Ye Xiaobu
Published: March 2020

2034

Background: The current institutional standard for treatment of patients with newly-diagnosed primary CNS lymphomas (PCNSL) at Johns Hopkins Hospital (JHH) consists of treatment with high-dose methotrexate plus rituximab (hd-MTX/R) every 2 weeks until complete response (CR), progression or unacceptable toxicities. Once CR is achieved, this is followed by monthly treatments for a total of up to one year for consolidation. Prior to 2008, the institutional standard had been treatment with hd-MTX alone. The benefit of adding rituximab to hd-MTX has not been formally evaluated. Methods: This is a retrospective study of HIV-negative adult patients with newly-diagnosed PCNSL treated at JHH with either hd-MTX or hd-MTX/R as initial therapy. Patients were identified using the cancer center registry (1995-2012) and were included if they had received at least one cycle of therapy (intention-to-treat). Primary objectives were CR rate (patients with sufficient imaging data; centrally reviewed) and overall survival (OS, all patients included). Results: A total of 81 patients were analyzed (median age of 65 yrs; 52% male). 54 patients received hd-MTX alone (median age, 65 yrs) and 27 patients received hd-MTX/R (median age, 66 yrs). 37 and 24 patients in the two groups were evaluable for response, respectively. Among these, the CR rate was 51% in patients treated with hd-MTX alone (overall response rate, ORR, 76%) and 79% in patients treated with hd-MTX/R (ORR 96%). The median number of cycles to CR was 5 and 4.5, respectively. Median OS among all patients (both groups combined) was 26 months (95% CI: 11-44). Conclusions: These data show potential clinical benefit from the addition of rituximab to hd-MTX for newly diagnosed patients with PCNSL based on a higher CR rate. Analysis of OS benefit between patients treated with hd-MTX and hd-MTX/R is pending maturation of further survival data.
A prospective phase II study to determine the efficacy of GDC 0449 (vismodegib) in adults with recurrent medulloblastoma (MB): A Pediatric Brain Tumor Consortium study (PBTC 25B).
Authors: Gajjar Amar J. , Gururangan Sridharan , Qaddoumi Ibrahim A , Packer Roger , Goldman Stewart , Prados Michael , Desjardins Annick , Fouladi Maryam , Takebe Naoko , Li Shaoyi , Ellison David W. , Curran Tom , Gilbertson Richard J. , Boyett James M.
Published: March 2020

2035

Background: Almost 80% of adult medulloblastoma are of the SHH subtype. Second line therapy for adult MB is limited; therefore we tested the efficacy of vismodegib, a small molecule inhibitor of Smoothened (SMO) among patients with this disease. Methods: Adult patients with refractory or recurrent MB and who had measureable disease were enrolled on the study. Immunohistochemistry (IHC) was used to stratify patients to Stratum A (non-SHH group); Stratum B (SHH tumors) and Stratum C (indeterminate). All patients were treated with vismodegib at 150 mg/day PO daily. Tumor response, which had to be maintained for 8 weeks to meet protocol definition of sustained response, was assessed using RECIST criteria and central imaging review. Separate but identical Simon 2-stage MinMax designs (α = 0.10) were used in strata A and B to test for evidence that sustained response rates exceeded 5% with 90% power to detect 25% sustained response rates. Thus, 3/20 sustained responses were needed to declare potential activity of vismodegib. Results: 32 patients with a median age of 30 years (range 22.4-51.9) were enrolled on the study [Stratum A (n = 8); Stratum B (n = 20); Stratum C (n = 4)], including 18 males and 14 females. No responses were observed in Strata A or C and the median duration of treatment was 1.5 months (range 0.66-2.33). Three of 20 patients enrolled on Stratum B had sustained responses. The median duration of therapy for Stratum B patients was 2.76 months (range 0.33- 13.61). Six patients were on treatment for ≥6.44 months and 3 remain on treatment after 5.42, 9.34 and 13.61 months. During course 1, 2 patients experienced grade 3 decrease in lymphocytes; 1 experienced a grade 4 thromboembolic event; and 2 experienced grade 3 toxicities (back pain & syncope). During course 2, 3 patients experienced grade 3 toxicities (decrease in lymphocytes; myalgia & seizure). One other patient experienced grade 3 hypophosphatemia in courses 1 and 2. Conclusions: Vismodegib has activity against recurrent or refractory adult ‘SHH-subtype’ medulloblastoma and should be considered as a therapeutic option for newly diagnosed patients with this disease. Clinical trial information: NCT00939484.
A phase I clinical trial of veliparib and temozolomide in children with recurrent central nervous system tumors: A Pediatric Brain Tumor Consortium report.
Authors: Su Jack M. , Thompson Patrick Andrew , Adesina Adekunle , Li Xiao-Nan , Kilburn Lindsay Baker , Onar-Thomas Arzu , Kocak Mehmet , Chyla Brenda , McKeegan Evelyn Mary , Warren Katherine E. , Goldman Stewart , Pollack Ian , Fouladi Maryam , Chen Alice , Smith Malcolm A. , Giranda Vincent L. , Boyett James M. , Blaney Susan , Kun Larry E. ,   Pediatric Brain Tumor Consortium
Published: March 2020

2036

Background: A phase I trial of veliparib (ABT-888), an oral poly(ADP-ribose) polymerase (PARP) inhibitor, and temozolomide (TMZ) was conducted in children with recurrent brain tumors to: 1) estimate the maximum tolerated doses (MTD) or recommended phase II doses (RP2D) of veliparib and TMZ using the Continual Reassessment Method; 2) describe the toxicities of this regimen; and 3) evaluate plasma pharmacokinetics (PK) and peripheral blood mononuclear cell (PBMC) PARP inhibition after veliparib treatment. Methods: TMZ was given once daily and veliparib twice daily for 5 days, every 28 days. Five veliparib/TMZ dose levels were studied: 20/180; 15/180; 15/150; 20/135; and 25/135 mg/m2/dose, respectively. Baseline and serial veliparib PK samples were obtained on days 1 and 4. PBMC poly(ADP-ribose) (PAR) levels were also measured using an ELISA assay. A total of 12 subjects were enrolled at the RP2D. Results: Thirty-one patients (29 evaluable) with a median age of 7.0 years (range 1.3-19.8) were enrolled. Dose-limiting toxicities (DLT) included grade 4 neutropenia and thrombocytopenia at the 20/180 and 15/180 mg/m2/dose levels. Based on the toxicity profile, PKs and PBMC PAR results, the RP2D were veliparib, 25 mg/m2 BID, and TMZ, 135 mg/m2/day, for 5 days every 28 days. No objective responses were observed, although 4 subjects had SD > 6 months duration, including one patient each with glioblastoma multiforme, anaplastic ependymoma, pilocytic astrocytoma, and optic pathway glioma. At the veliparib RP2D, the PK parameters included: Cmax, 1.2 ± 0.7 µM; AUC0-12 hr, 1.53 ± 0.61 µg•hr/mL; and Cl/F, 173 ± ml/min/m2. PARP inhibition was observed in PBMC but did not correlate with veliparib dose levels. Conclusions: The combination of veliparib and TMZ was well tolerated in children with recurrent CNS tumors. Veliparib PK parameters at RP2D are similar to those in adults. PBMC PARP inhibition did not correlate with veliparib dose levels, perhaps due to the smaller number of patients at each dose level and the technical limitations of specimen collection/processing and the ELISA assay. A phase II trial of veliparib/TMZ in children with recurrent primary brain tumors is planned. Clinical trial information: NCT00946335.
Survival outcome of early versus delayed bevacizumab treatment in patients with recurrent glioblastoma.
Authors: Hamza Mohamed Ali , Mandel Jacob , Conrad Charles A. , Gilbert Mark R. , Yung W. K. Alfred , Puduvalli Vinay K. , De Groot John Frederick
Published: March 2020

2042

Background: Bevacizumab (BEV) is widely used for treatment of patients with recurrent glioblastoma (GB). Differences in outcome between early versus delayed BEV treatment of recurrent GB are not well defined. We examined the relationship between the time of start of BEV treatment and outcomes in patients with recurrent GB. Methods: In this retrospective chart review derived from our longitudinal database, we identified patients with recurrent GB between 2001 and 2011, who were treated with BEV alone or BEV-containing regimens. Data was analyzed to determine overall survival (OS) from time of diagnosis and progression free survival (PFS) from time of BEV start. Early BEV was defined as start of BEV treatment at first recurrence, while delayed BEV was defined as start of treatment at second recurrence or later. Results: A total of 298 patients with recurrent GB who received BEV were identified, of whom 149 patients received early BEV, 134 patients received delayed BEV, and 15 patients who were excluded because they received BEV upfront. There were no significant differences in the age, sex, performance status and extent of resection between patients treated with early BEV and those treated with delayed BEV. The median time from diagnosis to first recurrence was more than 6 months (mos.) for both groups (6.5 mos. for early BEV and 7.6 mos. for delayed BEV, p = 0.01). The median time from diagnosis to start of BEV was 7.9 mos. for patients with early BEV and 15.6 mos. for patients with delayed BEV (p<0.001). There was no significant difference in PFS between patients that received early BEV and those that received delayed BEV (5.73 mos. vs. 4.33 mos., p = 0.07). Patients who were treated with delayed BEV had longer OS when compared to those treated with early BEV (25.9 mos. vs. 19.7 mos., p = 0.0002). Conclusions: In patients with recurrent GB, there was no significant difference in PFS between early and delayed BEV; however, patients treated with delayed BEV have longer OS when compared to those treated with early BEV. These results indicate that delaying treatment with BEV is not detrimental and may be associated with a favorable survival outcome.
Prognostic value of 18FET positron emission tomography (18FET-PET) for the clinical course in newly diagnosed glioblastoma.
Authors: Tonn Joerg Christian , Suchorska Bogdana , Jansen Natalie , Linn Jennifer , Kretzschmar Hans A , Simon Matthias , Hentschel Bettina , Kreth Friedrich Wilhelm , Weller Michael , LaFougere Christian ,   for the German Glioma Network
Published: March 2020

2045

Background: Aim of this prospective longitudinal study was to evaluate whether 18FET-PET allow to monitor and quantify the therapeutic effects of surgery, radiotherapy and chemotherapy in newly diagnosed glioblastoma and whether 18FET-PET can provide additional prognostic information on response to therapy and outcome. Methods: 92 patients with newly diagnosed glioblastoma considered eligible for radiochemotherapy (RcX) were included; diagnosis was obtained by biopsy (n=46) or resection (n=46). Patients were to undergo 18FET-PET and cocomitant MRI scans prior to surgery, following RcX and as well as after three cycles of adjuvant temozolomide (TMZ). At each time point, biological tumor volume (BTV), maximal 18FET uptake as ratio to background (SUVmax/BG), and tumor uptake kinetics (TAC) were obtained. Overall survival (OS) was primary endpoint, progression-free survival (PFS) as defined by MRI using Macdonald criteria was a secondary endpoint. ROC analyses were done to determine optimal cut-off values of 18FET-PET parameters for survival outcome. To identify predictors for OS/PFS, Cox regression analysis was performed. Results: 79 patients were eligible for further evaluation. ROC analysis revealed cut-off values for pre-RCX BTV (9.5 ccm) and SUVmax/BG (2.95) with a sensitivity and specificity of both 70% for BTV and 68/73% for SUVmax/BG. Both pre-therapeutic BTV and SUVmax/BG were associated with PFS and OS (p<0.05). In contrast to MRI-based volume, the prognostic value of BTV remained highly significant in the multivariate Cox analysis independently of MGMT status.. Furthermore, 18FET TAC pattern and its changes were related to OS and PFS. Conclusions: Serial 18FET-PET imaging in glioblastoma before and after concomitant radio-/chemotherapy is a highly powerful tool to provide prognostic information for the outcome in newly diagnosed glioblastoma patients. These findings might help to personalize therapy and response evaluation in forthcoming clinical investigations. Clinical trial information: NCT01089868.
Clinical outcome of 1,968 cases of meningiomas from Kaiser Permanente Northern California.
Authors: Nguyen Nathalie T. , Lyon Liisa L , Moes Gregory S , Sahrakar Kamran , Villano John L.
Published: March 2020

2062

Background: Meningioma is the most common primary brain tumor in the United States, but there is limited data on clinical outcomes. Methods: We performed descriptive and survival analysis of meningioma cases diagnosed 2001-2010 from the Kaiser Permanente Northern California Cancer Registry, which began inclusion of benign brain tumors in 2001. Datasets provided variables on gender, age at diagnosis, race, and vital status. Chart review extracted additional information on mortality, histology, imaging, tumor size, tumor site, and treatment. We used Kaplan Meier method to calculate overall survival (OS) and disease-free survival (DFS) and log-rank test to compare survival rates by variables. Cox proportional hazard models were used to analyze variables relative to endpoints. Results: 1968 cases in 1792 patients with meningioma were analyzed. 55% of cases had histological confirmation. 5- and 10-year OS and DFS for all groups were 76% & 61% and 89% & 82%. Disease progression and recurrence presented in 10% of cases at 10 years, resulting in 4% disease-specific mortality (DSM). Statistically significant prognostic factors of worse DFS were age >= 80, WHO grade 2-3, tumor size >= 18 mm, peritumoral edema on imaging, Simpson grades (SG) 4 or 5, and no surgery. Factors associated with significantly worse OS included age >= 60, male gender, tumor size >= 42 mm, peritumoral edema, SG 4 or 5, no histology and no treatment (NT). SG 1-3 groups provided statistically the highest OS and DFS. There was no significant difference in DFS or OS for definitive RT versus surgery and adjuvant RT groups. Definitive RT showed significantly better OS than NT (HR=0.46, 95% CI: 0.21-0.98). Cases with progression or recurrence had 51% DSM with 65% of deaths associated with lack of salvage therapy. Salvage RT provided better OS benefit compared to other salvage groups (HR=0.35, 95% CI: 0.14-0.91). Conclusions: We demonstrated favorable long-term outcome for meningiomas and confirmed the prognostic benefit of Simpson grading. We have identified additional adverse factors affecting outcome. While surgery remains standard, definitive RT demonstrates comparable outcome to cases not amenable to gross total resection. Salvage RT is effective, providing a survival benefit.
Response assessment of novoTTF-100A versus best physician’s choice chemotherapy in recurrent glioblastoma.
Authors: Wong Eric , Lok Edwin , Swanson Kenneth D. , Gautam Shiva , Engelhard Herbert H. , Lieberman Frank S. , Taillibert Sophie , Ram Zvi , Villano John L. ,   on behalf of the EF-11 Trial Investigators
Published: March 2020

2080

Background: The NovoTTF-100A device emits tumor treating electric fields and was tested against Best Physician’s Choice (BPC) chemotherapy in a randomized phase III trial. We analyzed post hoc the characteristics of responders and non-responders in both cohorts. Methods: Macdonald criteria were used to determine tumor response and progression. Kaplan-Meier and Chi-squared statistics were computed for time to response, response duration, progression-free survival (PFS) with and without Simon-Makuch correction, and overall survival (OS). Prognostic factors were compared using the Wilconox rank sum test. Relative hazard rates for responders and non-responders were plotted. Results: The median response duration was 7.3 versus 5.6 months for NovoTTF-100A and BPC chemotherapy respectively (p=0.0009). Five of 14 NovoTTF-100A responders but none of 7 BPC responders had prior low-grade histology. The mean cumulative dexamethasone dose was 35.9 mg for responders versus 485.6 mg for non-responders in the NovoTTF-100A cohort (p<0.0001) as compared to 525.6 mg for responders and 431.0 mg for non-responders in the BPC cohort (p=0.9520). Hazard rate analysis showed delayed tumor progression in responders compared to non-responders. The Simon-Makuch conditional plot, which adjusted for unequal progression-free states, still showed longer PFS in responders than non-responders treated with NovoTTF-100A (χ2=11.5, P=0.0007) or BPC chemotherapy (χ2=5.2, P=0.0222). The median OS was 24.8 months for responders that is longer than 6.2 months for non-responders treated with NovoTTF-100A (χ2=25.7, P<0.0001). In the BPC chemotherapy cohort, the median OS was 20.0 months for responders and 6.8 months for non-responders (χ2=5.1, P=0.0235). There was strong Pearson correlation between response and OS in NovoTTF-100A (P<0.0002) but not in BPC cohort (P=0.2952). Conclusions: Response duration, adjusted Simon-Makuch PFS and OS favor NovoTTF-100A over BPC chemotherapy. Data on prior low-grade histology and dexamethasone dose suggest potential genetic and epigenetic determinants of NovoTTF-100A response. Clinical trial information: NCT00379470.
Patterns of care study of adult medulloblastoma.
Authors: Cosman Rasha , Brown Chris , DeBraganca Kevin , Khasraw Mustafa ,   Cooperative Trials Group for Neuro-Oncology
Published: March 2020

2086

Background: Medulloblastoma (MB) accounts for less than 1% of adult intracranial tumours. While pediatric MB has been investigated in several randomized studies, the evidence in adults is limited to case reports and retrospective series, with no accepted standard of care. The Australian Cooperative Trials Group for Neuro-Oncology (COGNO) sought to determine the range and consistency of clinicians’ approaches to management as a basis for future trials. Methods: We aimed to identify current treatment strategies for adult MB through an international electronic survey launched at the 2012 meeting of the Society of Neuro-Oncology and by email invitation. Clinicians who had treated at least 1 adult patient with MB, central primitive neuroectodermal tumor (cPNET), or pinealoblastoma in the preceding year were asked about their most recent patient and asked to discuss their approach to management of a typical clinical scenario. Results: Between Nov 2012 and Jan 2013, 45 clinicians (11 medical oncologists, 7 radiation oncologists, 5 pediatric oncologists, and 22 others) from Australia (n = 24), USA (n = 3), Europe (n = 4) and other countries (n = 14) completed the survey. Responding clinicians had treated 54 cases in the past 12 months. The commonest histological type was MB (64%), followed by cPNET (20%). Most patients were male (68%), and most had high-risk disease (65%). 56% had complete surgical resection and 32% had molecular testing. Radiotherapy was predominantly craniospinal (92%) and mostly post-resection (80%). Combination chemotherapy was more common than single agent. Vincristine, cisplatin, cyclophosphamide was the most common protocol (43%). Others included carboplatin, etoposide, ifosfamide (29%), vincristine, lomustine, cisplatin (19%), vincristine, lomustine, prednisone (5%). Further details will be presented at the 2013 ASCO Annual Meeting. Conclusions: Our study has shown substantial international variation in the treatment of adult MB, most pronounced in the choice of chemotherapeutic agents, highlighting the need for further collaborative research to guide evidence-based treatment strategies.
Bevacizumab in combination with TMZ in patients with recurrent GBM: Final OS and PFS analysis.
Authors: Sepulveda Juan Manuel , Belda-Iniesta Cristobal , Gil Miquel , Pérez Segura Pedro , Berrocal Alfonso , Reynes Gaspar , Gallego Oscar , Ordonez Jose Manuel , La Orden Beatriz , Balana Carmen
Published: March 2020

2087

Background: BEV provides a consistent clinical benefit in the treatment of relapsing GBM in terms of a delayed progression and increased median overall survival compared to historical controls. The aim of this study is to evaluate the efficacy and toxicity profile of the combination of BEV with dose dense TMZ, reporting the final results of PFS, OS and the toxicity experienced. Methods: A phase II multicenter, national, open-label study in pts diagnosed of recurrent GBM treated with BEV 10 mg/kg day q2w and TMZ 150 mg/m2 days 1-7 and 15-21 q28d d until disease progression or unacceptable toxicity or medical decision, as first line of treatment all pts received radiotherapy and at least 3 cycles of adjuvant TMZ. This study evaluates efficacy by PFS as primary endpoint and as secondary endpoints: OS, RR based on the adapted MacDonald criteria and toxicity profile (NCI CTC v3.0). Results: From June 10 to July 11, 32 evaluable pts were recruited in 8 sites. The baseline characteristics were as follows: 17 males and 15 females, median age 57.5 y (29-74), ECOG PS 0: 25%, PS 1: 50% and PS 2: 25%, 44% patients had gross total resection, 50% had subtotal resection and 6% biopsy only, MGMT promotor was methylated in 12 pts, unmeth in 6 pts and missing in 14 pts. The median number of TMZ or BEV cycles administered across all patients was 4 (TMZ range 1-9 and BEV range 1-25) The median PFS was 4.4 m [IC 95% (3.7 – 5.6)]. The 6m-PFS probability was 29.25%. The median OS (75% events) was 7.5 m[IC 95% (5.98 – 9.11)]. No significant association with MGMT status was found in terms of OS or PFS. BEV related AEs have been reported in 56.2% of the population being most of them mild or moderate. Grade 3-4 most frequent toxicity: lymphopenia 31% and fatigue 12.5%. Six of 32 pts were long term survivors, in this population the median PFS was 9.8 m [IC 95% (8.2 – 24.4)] and median OS (50% events) was 15.9 m [IC 95 %( 9.2 – NA)], no differences in baseline characteristics were identified in comparison with total population. The median number of TMZ cycles administered was 4 and median BEV cycles were 9. Conclusions: Although the combination don’t met the previous reported activity of BEV, 19% of patients had longer survivals which suggest the need to identify patients that benefit for this treatment. Clinical trial information: NCT01115491.
Characterization of glioblastoma (GBM) vasculature and protein expression of surrounding tumor cells on single FFPE sections with a multicycle multiplexed in situ immunofluorescent staining technology.
Authors: Zhang Jingyu , McCulloch Colin , Sui Yunxia , Dinn Sean , Li Qing , Santamaria-Pang Alberto , Sevinsky Christopher J , Graff Jeremy Richard , Weiss Lawrence , Ong Teng Jin , Ginty Fiona
Published: March 2020

2097

Background: GBM is the most common brain tumor in humans and has a dismal prognosis. Although antiangiogenic therapy (bevacizumab) is an option for GBM, there is still unmet need to understand tumor pathophysiology and predictive biomarkers. We built a tissue based multiplexed immunofluorescent assays and developed algorithms to identify and quantify tumor vasculature, that enabled quantification, visualization, and colocalization of multiple protein in surrounding tumor cells at single cell and subcellular levels. This assay provides unique opportunity to explore tumor heterogeneity of tissue morphology and their relationships to vasculature, and is a novel tool for biomarker and treatment discovery. Methods: Tissue micro arrays (TMAs) were constructed from 141 GBM patients. Fluorescent dye labeled antibodies against 18 biomarkers were sequentially applied on single sections of these TMAs. Metrics were built to identify vessels, quantify distance of tumor cells to vessels, and analyze expression profiles of biomarkers, including signaling molecules in EGFR, PI3K/AKT, TGF-beta pathways, and hypoxia marker Glut1, in proximity to blood vessels. Results: CD31 was successfully used to identify blood vessels in GMB. Vessel segmentation and quantification were performed on all of the images. Biomarker profiling in the context of blood vessels demonstrated different patterns in close proximity to vessels, with some biomarkers showing increased levels (e.g. SMA, EGFR, pS6), some showing decreased levels (e.g. p4EBP), and others remain the same (FOXO3a, S6). Quantification of biomarkers showed heterogeneous expression within the same sample and across the cohort. In addition, co-localization of the above markers was visualized and demonstrated on single cell and subcellular levels. Conclusions: We were able to use a novel fluorescent multiplexing technology (MultiOmyx) to study GBM biology. This technology allowed the simultaneous analyses of multiple biomarkers of GBM, and provides new insights on the relationship of markers to each other, tumor heterogeneity and angiogenesis.
A first-in-human phase I study of the CDK4/6 inhibitor, LY2835219, for patients with advanced cancer.
Authors: Shapiro Geoffrey , Rosen Lee S. , Tolcher Anthony W. , Goldman Jonathan Wade , Gandhi Leena , Papadopoulos Kyriakos P. , Tolaney Sara M. , Beeram Muralidhar , Rasco Drew Warren , Kulanthaivel Palaniappan , Li Qian , Hu Tianle , Cronier Damien , Chan Edward M , Flaherty Keith , Wen Patrick Y. , Patnaik Amita
Published: March 2020

2500

Background: Cyclin dependent kinases 4 and 6 (CDK4/6) act with D-type cyclins to inactivate the retinoblastoma (Rb) tumor suppressor protein and enable cell cycle progression from G1 to S phase. LY2835219 is a selective inhibitor of CDK4/6 that shows antitumor activity in preclinical models of human cancer and also distributes efficiently to the brain. We performed a phase 1 study to evaluate safety, pharmacokinetics, pharmacodynamics, and antitumor activity of LY2835219. Methods: 3+3 dose escalation was followed by expansions in 5 tumor types (brain metastases permitted): non-small cell lung cancer (NSCLC), glioblastoma, breast cancer, melanoma, and colorectal cancer. LY2835219 was taken orally every 12 or 24 hours (in escalation) and every 12 hours (in expansions) on days 1-28 of a 28-day cycle. Results: 55 patients (pts) received LY2835219. In escalation, 33 pts received LY2835219 on 1 of 2 schedules: 50, 100, 150, 225 mg every 24 hours (Q24H) or 75, 100, 150, 200, 275 mg every 12 hours (Q12H). On the Q24H schedule, the maximum tolerated dose (MTD) was not identified. On the Q12H schedule, the MTD was 200mg Q12H with dose limiting toxicity of G3 fatigue at 200 mg (1/6 evaluable pts) and 275 mg (2/3 evaluable pts). At 200mg Q12H, the mean Cmax and AUC0-24hr at steady state were 285 ng/mL and 5502 ng-hr/ml, respectively. In skin, LY2835219 induced pharmacodynamic inhibition of both Rb phosphorylation and topoisomerase IIα expression. In the ongoing expansions, 22 pts have received LY2835219. Across the study, the most common related adverse events were diarrhea (52%, including 5% G3), nausea (30%, 4% G3), fatigue (21%, 7% G3), vomiting (18%, 2% G3), and neutropenia (16%, 7% G3). 15 pts have reached ≥4 cycles for stable disease or better with 3 pts achieving 8, 16, and 26 cycles. One pt with ovarian cancer had a durable CA-125 response with >50% decrease for 16 cycles. One pt with KRAS mutant NSCLC had a 27% decrease by RECIST. One pt with CDKN2A-/- NRAS mutant melanoma had a confirmed partial response. Early clinical activity has been observed in ovarian cancer, NSCLC, breast cancer, and melanoma. Conclusions: LY2835219 shows acceptable safety and early clinical activity as a single agent for patients with advanced cancer. Clinical trial information: NCT01394016.
Phase I study of REGN421 (R)/SAR153192, a fully-human delta-like ligand 4 (Dll4) monoclonal antibody (mAb), in patients with advanced solid tumors.
Authors: Jimeno Antonio , LoRusso Patricia , Strother Robert Matthew , Diamond Jennifer Robinson , Plato Leah , Younger Anne , Messersmith Wells A. , Kittaneh Muaiad , Sawyer Doug , Adriaens Lieve , Liu Liming , Kao Richard J. , DiCioccio A Thomas , Brownstein Carrie M. , Lowy Israel , Trail Pamela , Chiorean E. Gabriela
Published: March 2020

2502

Background: Dll4, a Notch receptor ligand, may have a role in tumor angiogenesis and is an emerging anticancer target. REGN421 (R) is a fully human IgG1mAb that binds human Dll4 and disrupts Notch-mediated signaling. Methods: Primary objectives of the dose escalation (3+3 design) trial were to determine safety and a recommended phase II dose (RP2D) of R in patients (pts) with advanced cancer. R was given IV at doses of 0.25, 0.5, 1, 2 and 4mg/kg every 3 weeks (Q3W) or 0.75, 1, 1.5, and 3mg/kg every 2 weeks (Q2W). Secondary objectives were PK, immunogenicity, and antitumor activity. Results: 53 pts (M/F=22/31, ECOG 0/1=18/35) were enrolled; 31 pts were treated Q3W at doses of 0.25 - 4 mg/kg; 22 pts were treated Q2W at doses of 0.75 - 3 mg/kg. Two DLTs occurred: Grade 3 (Gr3) nausea (0.5mg/kg Q3W) and Gr3 abdominal pain (1 mg/kg Q2W). A maximum tolerated dose was not reached on either schedule. Grade 3/4 AEs occurred in 29 pts; nausea, abdominal pain, dyspnea, hypoxia, and hypertension (HTN) were reported in ≥ 5%. Most frequent treatment related AEs were fatigue (30%), headache (26%), HTN (26%), and nausea (15%). Six treatment related SAEs (all reversed off treatment) were reported in 4 patients: BNP increase (0.25mg/kg, Gr1), troponin I increase (4mg/kg, Gr3), right ventricular dysfunction (1.5mg/kg, Gr3), left ventricular dysfunction (3mg/kg, Gr3) and 2 events of pulmonary HTN (1.5mg/kg, Gr 3, and 3mg/kg Gr3). Laboratory abnormalities (≥ Gr3) were neutropenia (3) and anemia (2), and elevated ALP (7), ALT (3), bilirubin (3), AST (2), and decreased albumin (1). Anti-tumor activity included 2 PRs (NSCLC BAL-type with a beta-catenin mutation and ovarian cancer [OvCa]), and 16 pts with SD (3 pts had SD > 6 months). Two of 8 pts with OvCa had CA125 responses. R had non-linear target-mediated PK without accumulation. The half-life of R at 3mg/kg Q2W was 7 days. No immunogenicity was observed. Conclusions: REGN421 had an acceptable safety profile, and RP2Ds of 4mg/kg Q3W and 3mg/kg Q2W. Responses and prolonged SD were noted in OvCa pts and other solid tumors. Dose escalation has concluded and disease specific expansion cohorts are ongoing. Clinical trial information: NCT00871559.
Phase I study of oral selective c-Met inhibitor EMD 1214063 in pts with advanced solid tumors.
Authors: Falchook Gerald Steven , Hong David S. , Amin Hesham M. , Fu Siqing , Piha-Paul Sarina Anne , Janku Filip , Subbiah Vivek , Naing Aung , Wheler Jennifer J. , Klevesath Manfred B. , Köhler Karola , Johne Andreas , Bladt Friedhelm , Kurzrock Razelle
Published: March 2020

2506^

Background: To perform the first-in-human study of EMD 1214063, a highly selective, reversible, ATP-competitive c-Met inhibitor that causes growth inhibition and regression of hepatocyte growth factor-dependent and -independent tumors in preclinical models. Methods: Primary objective of this dose-escalation study (3+3 design) was to establish the EMD 1214063 MTD (NCT01014936). Secondary endpoints included safety, PK, antitumor effect, and pharmacodynamics (Pd). Eligible pts had advanced solid tumors not amenable to standard therapy. Pts received once daily (QD) oral EMD 1214063 on 1 of 3 regimens (all 21-d cycles): d 1–14 followed by 7-d rest (R1), continuous 3 times weekly (R2), or d 1–21 (R3). An optimized formulation (OF) was introduced in Aug 2011. Results: 100 pts were treated (R1:42; R2:41; R3:17). On the initial formulation, doses were escalated from 30–230 mg/d in R1, and 30–115 mg/d in R2. OF data are available for 30–400 mg/d in R1, 60–175 mg/d in R2, and up to 500 mg/d in R3. Cmax and AUC increased with dose; OF showed higher bioavailability. 4 pts experienced DLTs: G4 lipase and G3 amylase increase (R1; 115 mg/d), G3 lipase increase (R2; 60 and 115 mg/d), and G3 nausea and vomiting (R2; 130 mg/d OF). Other G3 drug-related AEs included G3 peripheral edema (1 pt in R3, 300 mg/d OF). G2 drug-related AEs (R1-3) included fatigue (n=8), lipase increase (n=3), nausea (n=2), decreased appetite (n=2), vomiting (n=2), and neutropenia (n=2). 80% pts had no drug-related AE >G1. Pre- and on-treatment tumor biopsies showed inhibition of phospho-c-Met levels in 13/15 evaluable pts. 2 unconfirmed partial responses were observed (NPC and NSCLC). SD >4 mo was observed in 15 pts. 1 pt with sarcomatoid bladder cancer and multiple MET copies due to Chr 7 polysomy had SD for >32 mo. PK/Pd analysis suggested that 500 mg QD was sufficient for target inhibition, consistent with preclinical models. In the 500 mg QD cohort, which was expanded to 12 pts, no DLTs were observed. 500 mg QD was confirmed as the recommended phase 2 dose (RP2D). A formal MTD was not identified despite dose escalation beyond 500 mg. Dose escalation above 1000 mg is not anticipated. Conclusions: EMD 1214063 was safe and demonstrated antitumor activity. 500 mg QD was determined as the RP2D. Clinical trial information: NCT01014936.
Phase I and pharmacokinetic trial of the antitemolerase agent KML001 (KML) and cisplatin (CDDP) in advanced solid tumors.
Authors: Edelman Martin J. , Feliciano Josephine Louella , Styblo Miroslav , Liu Tao , Lapidus Rena G. , Saunders Jesse , Gobburu Joga
Published: March 2020

2515

Background: Telomerase is overexpressed in most solid tumors and rarely expressed in adult tissues and is therefore a promising target. We have previously demonstrated that KML001 (sodium metaarsenite) displaces hTERT from the nucleus and is cytotoxic (Clin Cancer Res 14:4593-602, 2008). We have also demonstrated that it is synergistic with cisplatin. Methods: Pts with advanced solid tumors, PS 0-1, normal renal and hepatic function were eligible. Treatment was with CDDP 75 mg/m2 day 1 and KML p.o. daily days 1-14 on a 21 day cycle. It was planned that KML doses would be escalated by 2.5 mg beginning at 15 mg/day. A 3+3 design was employed. Blood specimens for arsenic and platinum pk were obtained at hours 0,1,2,3,4,5,6, 24 and day 15 and 22. Tumor blocks were required to assess for telomerase expression. Results: 18 patients (7M,11F) are evaluable for toxicity. Pts were heavily pretreated (median number of prior regimens =3). 16 had prior platinum therapy. The dose limiting toxicity was QTc interval prolongation seen in three patients in cohort 3 (20 mg) (two during cycle 1, one during cycle 2). A PR was seen in a patient with heavily pretreated SCLC in cohort 1. 1 other pt with SCLC and 2 with NSCLC also experienced reduction in disease burden. 10/18 pts received >3 cycles of therapy. Other common toxicities observed were nausea, vomiting and cytopenias. Significant, but not dose limiting, neutropenia or thrombocytopenia (> grade 3) was observed in cohorts 1 and 2. Myelosuppression was primarily seen in pts with prior radiotherapy. Non-compartmental analysis for inorganic arsenic (iAs) and the mono (MAs) and dimethylarsenic (DMAs) metabolites was performed (Table). Conclusions: 1. The combination of KML-001 and CDDP is feasible and active. 2. We are currently evaluating CDDP 75 mg/m2 and KML 17.5 mg in an expansion cohorts of advanced SCLC and NSCLC. 3. Studies of telomerase expression are in progress. (R21CA130349-01) Clinical trial information: NCT01110226. [Table: see text]