bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bevacizumab in combination with temozolomide in the adjuvant treatment of newly diagnosed glioblastoma multiforme: Preliminary results of a phase II study
Authors: Nicholas M. K. , Lucas R. V. , Arzbaecher J. , Paleologos N. , Krouwer H. , Malkin M. , Omar A. , Vick N. A. 
Published: August 2020

2016 Background: Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. Current standard treatment consists of fractionated radiotherapy (RT) with daily oral temozolomide (TMZ) chemotherapy followed by 6 months of adjuvant TMZ chemotherapy. Median survival is 14.3 months. Because GBM is characterized by vascular proliferation and produces high levels of vascular endothelial growth factor (VEGF), attempts to better control the disease with targeted anti-angiogenesis therapies are underway. Here, we report preliminary safety and tolerability data of bevacizumab (BV) when added to monthly TMZ chemotherapy. Methods: Subjects received standard regional RT to a dose of 60 Gy in 30 fractions with dailyconcurrent TMZ (75 mg/m2) within 3–5 weeks of diagnosis. Four weeks after RT/TMZ, subjects received 5 consecutive daily TMZ doses (150–200 mg/m2) administered every 28 days. BV (10mg/kg) was given every 14 days. Treatment continued until either disease progression or unacceptable toxicity occurred. Results: 42 of 48 planned subjects were enrolled as of 12/30/08. Twenty-three remained on study. Of these, 4 were receiving RT/TMZ, 18 were receiving TMZ/BV and 1 was delayed post-RT/TMZ due to local wound infection. Nineteen were off-study. Eleven of those off-study never received BV due to: study withdrawal (n = 2), toxicity during RT/TMZ (n = 3) and post-RT/TMZ progression (n = 6). Seven subjects progressed while receiving TMZ/BV. Twenty-six of the 42 enrolled received at least one 28-day cycle of TMZ/BV (range 1 - 16 cycles). Duration of treatment, inclusive of RT/TMZ, ranged from 27 to 523 days. Best radiographic responses of evaluable subjects, using MacDonald criteria were: 5 complete, 9 partial, 13 stable and 7 progressive disease. Of those taken off study, 13 were due to disease progression. Of those removed from study due to toxicity, none were unexpected and only 1 (a GI bleed) occurred during the TMZ/BV phase. A statistical analysis of response and survival is pending. Conclusions: The co-administration of TMZ/BV following RT/TMZ for newly diagnosed GBM is safe and well-tolerated. [Table: see text]
Phase I study of vandetanib with radiation therapy and temozolomide for newly diagnosed glioblastoma
Authors: Drappatz J. , Norden A. D. , Wong E. T. , Lassman A. B. , Doherty L. , LaFrankie D. , Gerard M. , Phan P. , Schiff D. , Wen P. Y. 
Published: August 2020

2031 Background: There is increasing evidence that angiogenesis inhibition may potentiate the effects of radiation therapy (RT) and chemotherapy in patients with glioblastoma (GBM). In addition, inhibition of the epidermal growth factor receptor (EGFR) may be of therapeutic benefit, as EGFR is often upregulated in GBM and contributes to radiation resistance. We conducted a phase I study of vandetanib, an inhibitor of VEGFR2 and EGFR, in patients with newly-diagnosed GBM in combination with RT and temozolomide (TMZ). Methods: Using a standard 3 + 3 dose escalation design, 13 newly-diagnosed GBM patients received vandetanib with RT (60 Gy) and concurrent TMZ 75 mg/m2 daily, followed by adjuvant TMZ for up to 12 cycles (150–200 mg/m2 on days 1–5 of each 28 day cycle). The maximum tolerated dose (MTD) was defined as the dose with ≤1/6 dose-limiting toxicities (DLT). Eligible patients were adults with newly-diagnosed GBM or gliosarcoma, Karnofsky performance status of ≥60%, normal organ function, and not taking enzyme-inducing anti-epileptic drugs. MTD was determined by evaluation of DLTs during the first 12 weeks of therapy. Results: Six patients were treated with vandetanib at 200 mg daily. 2/6 patients developed DLTs (grade 5 gastrointestinal hemorrhage and grade 3 thrombocytopenia in one patient and grade 4 neutropenia in one patient). Seven patients were treated at 100 mg daily with no DLTs observed, establishing 100 mg daily as the MTD. Of 10 evaluable patients, one had a minor response (10%), defined as 25% to <50% reduction in enhancing area for 8 weeks; eight had stable disease (80%), defined as <25% increase or decrease; and one had progressive disease (10%). Conclusions: These data suggest that vandetanib may be combined with RT and TMZ in GBM patients. A randomized phase II study in which patients receive RT and TMZ with or without vandetanib 100 mg daily is underway. [Table: see text]
A phase I trial of surgical resection with biodegradable carmustine (BCNU) wafer placement followed by vaccination with dendritic cells pulsed with tumor lysate for patients with malignant glioma
Authors: Rudnick J. D. , Phuphanich S. , Chu R. , Mazer M. , Wang H. , Serrano N. , Francisco M. , Black K. L. , Wheeler C. , Yu J. 
Published: August 2020

2033 Background: Our prior immunotherapy trials demonstrated efficacy in generating a tumor specific immune response in malignant glioma and the potential for high tumor-specific toxicity and sustained tumoricidal activity. Immunotherapy may synergize with chemotherapy and biodegradable carmustine (BCNU) wafers extend overall survival from 11.6 to 13.9 months. Methods: We exploited this synergistic effect to maintain a cytotoxic environment around the tumor milieu. Patients with high-grade glioma were eligible after maximal resection with biodegradable carmustine (BCNU) wafer placement. Screening leukapheresis is used to isolate mononuclear cells which are differentiated into dendritic cells, pulsed with tumor lysate, and then 3 intradermal vaccines are administered at 2-week intervals. Patients continued systemic chemotherapy after vaccine or at progression. Results: Eighteen patients have been enrolled (7 Male, 11 Female) between April 2007 and February 2009 with one screen failure and two patients with clinical progression prior to vaccination. The median patient age was 57 years (26 to 74 ) and median Karnofsky performance status was 90% (80–100). The histology included 3 newly diagnosed glioblastoma multiforme (GBM), 8 recurrent GBM, 2 newly diagnosed anaplastic astrocytoma (AA), and 2 recurrent AA. 15 patients were successfully treated by vaccine injections with 12 patients receiving vaccine every 2 weeks x 3 followed by adjuvant chemotherapy. Our preliminary data on 15 patients and 39 courses of Dendritic Cell vaccines demonstrate one grade 3 toxicity of fever/chest pain. A stable disease interval of 13 to 90 weeks was observed for patients who received vaccine. The 3 newly diagnosed GBM patients have stable disease (18 to 71 weeks). In the recurrent GBM cohort 7/8 patients had progression within 6 months from the post-vaccination MRI. Conclusions: This phase I study demonstrates the safety, feasibility of dendritic cell vaccination with biodegradable carmustine (BCNU) wafers with one grade 3 AE. Immunological data is pending to determine potential synergy of dendritic cell vaccination with intracranial chemotherapy. No significant financial relationships to disclose.
Randomized, active-controlled phase IIb study with trabedersen (AP 12009) in recurrent or refractory high-grade glioma patients: Basis for phase III endpoints
Authors: Bogdahn U. , Schneider T. , Oliushine V. , Parfenov V. , Mahapatra A. K. , Balasubramaniam A. , Venkataramana N. , Stockhammer G. , Heinrichs H. , Schlingensiepen K. 
Published: August 2020

2037 Background: High-grade gliomas (HGG) strongly overexpress TGF-beta 2. Trabedersen (AP 12009), a TGF-beta 2-specific inhibitor, was successfully tested in 3 Phase I/II studies in recurrent or refractory HGG. Methods: The Phase IIb study AP 12009-G004 was an open-label, randomized, active-controlled dose-finding study. Main objectives: to compare response rate, survival, and safety of 2 doses of trabedersen (10 μM or 80 μM) vs. standard chemotherapy (TMZ or PCV). 145 patients with recurrent or refractory HGG (AA WHO grade III or GBM WHO grade IV) were randomized and 134 patients (AA = 39; GBM = 95) received study medication. Trabedersen was given intratumorally by convection-enhanced delivery. Results: AA and GBM patients in both trabedersen groups had long-lasting tumor responses (currently up to 4 years). AA: (10 μM trabedersen vs. control): significantly better overall response rate was noted at 14 months (CR+PR; p=0.034*) and lower tumor progression rates at 6, 12 and 14 months; difference at 14 months was statistically significant (p=0.003*). 2-year survival rate was 2-fold higher (p=0.088**). Tumor progression rate at 14 months and 2-year survival rate correlated with a median overall survival benefit of 17.4 months. GBM: 10 μM trabedersen was as efficacious as standard chemotherapy in all patients. It was clearly superior regarding 2-year survival in the pre-specified subgroup of patients younger than 55 years and the subgroup with a KPS > 80. The superior long-term survival of trabedersen-treated AA and GBM patients was the basis for extending the follow-up period of this Phase IIb study. Conclusions: Based on Phase IIb results, the pivotal Phase III study SAPPHIRE in recurrent or refractory AA patients has started. Primary efficacy endpoint is 2-year survival rate; secondary endpoints are progression rate at 14 months, time to death, quality of life, safety and tolerability. A separate study in GBM is being planned. [Table: see text] [Table: see text]
Feasibility and phase I trial of tandutinib in patients with recurrent glioblastoma
Authors: Supko J. G. , Grossman S. A. , Peereboom D. M. , Chowdhary S. , Lesser G. J. , Nabors L. B. , Mikkelsen T. , Desideri S. , Batchelor T. T. 
Published: August 2020

2039 Background: Platelet-derived growth factor signaling is important in gliomagenesis and PDGFR-β is expressed on >90% of endothelial cells in glioblastoma specimens. Methods: We report the results of a feasibility and phase I study of tandutinib (MLN518), an orally bioavailable, quinazoline-based inhibitor of type III receptor tyrosine kinases including PDGFR-β, FLT-3, and c-Kit, in patients with recurrent glioblastoma (GBM) conducted in the New Approaches to Brain Tumor Therapy (NABTT) consortium. Results: A feasibility study was conducted in 6 recurrent GBM patients in whom resection was clinically indicated. These patients received tandutinib 500-mg BID for 7 days prior to resection. In these patients, the drug was measured in tumor tissue and plasma samples obtained shortly before and after the resection by LC/MS. The mean ± SD concentration of tandutinib in tumor tissue was 7.2 ± 3.2 μg/mL and the mean ratio of its concentration in brain tumor-to-plasma was 9.6 ± 7.7. A phase I study was conducted in 19 patients to determine the MTD in this recurrent GBM population with sequential assessment of the following dose levels: 500-, 600-, and 700-mg BID. Four patients were replaced due to early withdrawal unrelated to toxicity. Dose limiting toxicities were observed in 1/6 patients at 500-mg BID (grade 3 phosphorous, grade 3 fatigue, grade 3 somnolence in 1 patient); 1/6 patients at 600-mg BID (grade 3 phosphorous); 2/3 patients at 700-mg BID (grade 3 fatigue, grade 3 weakness). 600-mg BID was declared the MTD and a phase II study has been initiated at this dose level. Conclusions: The mean brain tumor tissue-to-plasma ratio of tandutinib in GBM patients receiving 500-mg BID exceeded the estimated threshold ratio of 0.33 that was considered as being necessary to achieve local cytotoxic concentrations in brain tumors. The MTD of tandutinib in the recurrent GBM population is 600-mg BID. A phase II trial has been initiated at this dose level. [Table: see text]
Bevacizumab plus etoposide among recurrent malignant glioma patients: Phase II study final results
Authors: Reardon D. , Desjardins A. , Vredenburgh J. J. , Gururangan S. , Peters K. B. , Norfleet J. A. 
Published: August 2020

2046 Background: Significant therapeutic benefit has been observed among recurrent malignant glioma (MG) patients treated with bevacizumab (BV), a neutralizing monoclonal antibody to vascular endothelial growth factor (VEGF) with or without chemotherapy. In this study, we evaluate the efficacy of BV plus etoposide (E), a topoisomerase inhibitor, among recurrent MG patients. Methods: Recurrent patients with no more than three prior episodes of recurrence are eligible, while those with prior BV treatment or prior intracranial hemorrhage are excluded. The primary outcome measure is 6 month progression-free survival (6-PFS). BV is dosed at 10 mg/kg intravenously every other week. Etoposide is orally administered daily (50 mg/m2) for days 1–21 of each 28-day cycle. Results: Fifty-nine patients (GBM, n = 27; grade 3 MG, n = 32) with a median of 2 prior progressions have enrolled. With a median follow-up of 45 weeks, median overall survival (OS) for GBM and grade 3 MG patients were 46 and 47 weeks, while the 6-PFS is 44% and 40.6%, respectively. The most common toxicities were neutropenia (41%), fatigue (22%), and infection (20%) and were grade 2 in most cases. One patient developed grade 1 intracranial hemorrhage and 1 patient had a grade 4 GI perforation. Conclusions: Combination of bevacizumab and etoposide is well tolerated in recurrent MG patients and is associated with encouraging anti-tumor benefit. Accrual is complete and an update of further treatment and follow-up will be presented. No significant financial relationships to disclose.
Influence of expression of EGFR and PTEN on outcome in patients with primary glioblastoma treated with standard radiochemotherapy and cetuximab: Interim analysis from the GERT-Protocol
Authors: Combs S. E. , Hartmann C. , Welzel J. , von Deimling A. , Debus J. , Platten M. , Wick W. , Gaiser T. 
Published: August 2020

2050 Background: The epidermal growth factor receptor (EGFR) is commonly amplified, overexpressed, and mutated in glioblastoma (GBM). Anti-EGFR treatments have shown to be associated with EGFR deletion mutant variant III (EGFRvIII) expression in presence of PTEN expression, suggesting a prognostic role of EGFRvIII expression. We determined molecular biomarkers and correlated these with outcome in the GERT trial. Methods: To date, 39 patients were treated within the GERT protocol (Combs SE et al., 2006) evaluating radiochemotherapy (RCHT) with temozolomide (TMZ) and weekly CTX. Pretreatment paraffin-embedded tumor tissue of 32 patients was available for molecular analysis. Twenty-three patients were male, 9 were female. Median age was 49 years. We analyzed amplification of EGFR, expression of EGFR, EGFRvIII, the tumor-suppressor PTEN and O(6)-methylguanine DNA methyltransferase (MGMT) gene promoter methylation. Results: Median follow-up was 12 months. Overall survival (OS) at 12 and 24 months was 89% and 42%. Progression-free survival (PFS) was 76% and 45% at 6 and 12 months, respectively. MGMT promoter hypermethylation was detected in 16/32 tumours. Methylated MGMT did not impact PFS or OS (p = 0.48 and p = 0.08). Data on EGFR copy number of 31/32 tumors showed EGFR gene amplification in 11 tumors. EGFR protein expression was found in 23/32 patients. EGFR-amplification did not impact PFS or OS (p = 0.56, p = 0.3). Patients with EGFR expression showed longer PFS (p = 0.05), but unaltered OS (p = 0.06). EGFRvIII was seen in 5/32 patients, only in tumors with EGFR amplification. Expression of EGFRvIII did not influence PFS (p = 0.26) or OS (p = 0.09). Reduced PTEN (22/32) did not influence PFS or OS (p = 0.27, p = 0.85). Outcome was not associated with coexpression of EGFRvIII and PTEN (n = 5); coexpression of EGFR and PTEN (n = 13) significantly influenced PFS (p = 0.005), but not OS (p = 0.10). Conclusions: Expression of EGFR, and coexpression of EGFR/PTEN is associated with significant increase in PFS after RCHT with TMZ and CTX. EGFR-amplification, reduction of PTEN expression and expression of EGFRvIII did not impact PFS nor OS. Randomized data in the primary treatment of GBM might help identify patients for anti-EGFR therapies. [Table: see text]
MGMT methylation testing in RTOG 0525: A phase III trial of newly diagnosed glioblastoma
Authors: Aldape K. D. , Jones G. , Wang M. , Hegi M. , Janzer R. C. , Stupp R. , Mehta M. P. , Gilbert M. R. 
Published: August 2020

2051 Background: MGMT promoter methylation has been described as a prognostic marker in glioblastoma (GBM) and may be associated with chemosensitivity to alkylating agents. This study determined the feasibility of real-time determination of MGMT promoter methylation testing in a large international phase III clinical trial. Methods: Paraffin tumor blocks were obtained from patients registered onto RTOG 0525 then distributed to one of two central pathology labs: MD Anderson (Houston TX, K. Aldape) or CHUV (Lausanne, CH, R. Janzer). After histologic confirmation of GBM, unstained slides (40 microns of tumor tissue) were sent to the testing laboratories. Results were used for randomization into a treatment arm. MGMT methylation was assessed using methylation specific real-time PCR (MSP). The assay determined the number of copies of both methylated MGMT and of beta-actin (ACTB) in the sample. The ACTB copy number was used to assess the quality and quantity of the sample DNA. Results: Results were available for 995 samples. Following MSP samples were categorized into one of five possible results: failed (2, 0.2%), methylated (302, 30.2%), non-methylated (602, 60.2%), indeterminate (62, 6.2%), and invalid (27, 2.7%). Among cases that were evaluable as either methylated or unmethylated (n = 904) the MGMT promoter methylation rate in newly diagnosed GBM was approximately 1/3 (33.4%), a rate that is somewhat lower than prior reports. The average time from receipt of sample at the central pathology laboratory to reporting of results was 9.3 days. The time required decreased over the course of the clinical trial. This was due, in part, to training of the sites to deliver samples just before the start of runs. Conclusions: The results demonstrate the feasibility of performing real-time MGMT methylation testing, a tumor based assay, as a stratification factor in a multinational clinical trial. This study confirms that treatment decisions based on the molecular characteristics of the tumor are feasible, thereby providing opportunities to develop more molecularly-based tumor stratification or selection, a major advance in developing personalized treatment regimens. No significant financial relationships to disclose.
Effect of proton pump inhibitor co-medication on imatinib disposition: A healthy volunteer study
Authors: Beumer J. H. , Shah D. D. , Yerk M. , Komazec K. A. , Christner S. , Appleman L. J. , Redner R. R. , Miller B. M. , Egorin M. J. 
Published: August 2020

2503 Background: Imatinib mesylate, a potent inhibitor of Bcr-Abl and c-kit tyrosine kinases, is widely used to treat gastrointestinal stromal tumors and Philadelphia chromosome-positive leukemias. Imatinib often causes gastric upset and is therefore frequently administered with a proton pump inhibitor (PPI). Yet, the resulting elevated gastric pH, delayed gastric emptying, and inhibition of ABC transporters in the gut could change imatinib absorption, thereby affecting the therapeutic effectiveness of imatinib. To test this hypothesis, we sought to define the effect of PPI on the plasma pharmacokinetics of imatinib. Methods: 11 healthy subjects (6 M, 5 F; 21–56 years) were enrolled in a 2-period, open-label, randomized cross-over, fixed- sequence study. In one period, they received a single 400 mg dose of imatinib p.o., in the other, 40 mg omeprazol daily for five days followed by a single 400 mg dose of imatinib p.o.. The periods were separated by a wash-out period of ≥ 14 days. Plasma samples from 0–72 h after dosing were obtained. Plasma concentrations of imatinib and its active metabolite CGP74588 were determined with an LC-MS assay and data were analyzed non-compartmentally. The study was powered to detect a 30% difference in imatinib AUC with 80% power and a 5% type I error. Results: See Table . Conclusions: This study demonstrates that the use of PPI to treat imatinib-induced gastric upset does not significantly affect imatinib plasma AUC. Support: Novartis; NIH/NCRR/CTSA Grant UL1 RR024153 [Table: see text] [Table: see text]
Association of pharmacokinetics and germ-line mutations in EGFR and ABC transporters with erlotinib toxicity in patients with non-small cell lung cancer (NSCLC)
Authors: Hamada A. , Sasaki J. , Saeki S. , Iwamoto N. , Inaba M. , Ushijima S. , Urata M. , Kishi H. , Fujii S. , Semba H. , Saito H. 
Published: August 2020

2506 Background: Erlotinib demonstrates substantial inter-individual differences in response and the development of skin rash (grade≥2) was correlated with efficacy. Erlotinib interacts with its target EGFR and the efflux transporter ABCB1 and ABCG2. EGFR CA repeat is associated with incidence of skin rash. A 421C>A SNP in ABCG2 and 1236C>T, 2677 G>(T/A), and 3435C>T SNPs in ABCB1 are associated with reduced protein expression. The aim of this study was to evaluate the effects of these variants and pharmacokinetics of erlotinib on toxicity grade in Japanese patients treating single agent erlotinib. Methods: Twenty-two patients with NSCLC received erlotinib orally at 150 mg/day and plasma levels of erlotinib were measured on days 1(D1), 8(D8), and stable phase (>day 14) by high-performance liquid chromatography. DNA from plasma was screened for SNPs in the EGFR, ABCB1, and ABCG2 genes using direct nucleotide sequencing or TaqMan assay. Eligibility criteria included: performance status (PS) < 3, age < 75, stage IIIB-IV, and written informed consent. Results: The mean Cmax (±SD) of D1 and D8 were 1.8 ± 1.0 and 3.1 ± 1.4 μg/ml, respectively. Trough concentration (Cmin) at D1 and steady state were 0.9 and 1.7 μg/ml, respectively. Grade 1–2 skin rash or diarrhea occurred in 95% of patients. One patient (Cmax at D1, 3.0 μg/ml) developed interstitial lung disease after continuous treatment with erlotinib for 3 days. The area under curves and Cmax on D1 were correlated with the severity of skin rash (p=0.05 and 0.01), however, Cmin were not correlated. Patients with homozygous variant and heterozygous for ABCB1 1236C>T, 2677 G>(T/A), and 3435C>T genotype as compared to patients carrying the wild-type were associated with higher Cmin at steady state (2.4 vs 1.2 μg/ml, p=0.01). EGFR CA repeat and AGCG2 421C>A genotype were not associated with any pharmacokinetic parameters. All Patients (n=4) with homozygous variant for ABCB1 1236TT- 2677TT/TA/AA-3435TT developed grade≥2 skin rash or diarrhea. Conclusions: The present study suggests that ABCB1 gene polymorphism is associated with the variable toxicity and pharmacokinetics to erlotinib treatment. No significant financial relationships to disclose.