bluuebunny/crossref_metadata_2025 huggingface dataset:
Multicenter randomized phase II trial of methotrexate (MTX) and temozolomide (TMZ) versus MTX, procarbazine, vincristine, and cytarabine for primary CNS lymphoma (PCNSL) in the elderly: An Anocef and Goelams Intergroup study.
Authors: Omuro Antonio Marcilio Padula , Chinot Oliver L. , Taillandier Luc , Ghesquieres Herve , Soussain Carole , Delwail Vincent , Lamy Thierry , Gressin Remy , Choquet Sylvain , Soubeyran Pierre-Louis , Maire Jean Philippe , Benouaich Amiel Alexandra , Lebouvier-Sadot Sophie , Gyan Emmanuel , Barrie Maryline , Sierra del Rio Monica , Gonzalez Alberto , Houillier Caroline , Tanguy Marie-Laure , Hoang-Xuan Khê
Published: March 2020

2032

Background: There is no standard chemotherapy defined in PCNSL. Elderly patients (pts) are not candidates for whole brain radiotherapy and therefore establishing an optimal MTX-based regimen is crucial. This prospective multicenter study conducted in 13 French institutions tested two promising MTX-based chemotherapy regimens in elderly pts with newly diagnosed PCNSL. Methods: Pts with histologically confirmed newly diagnosed PCNSL with age ≥60 and KPS ≥40 were stratified by institution and KPS, then randomized to receive three 28-day cycles of MTX (3.5 g/m2 D1 and D15) and TMZ (100-150mg/m2 D1-5 and 15-19) [MT arm] or 3 cycles of MTX (3.5 g/m2 D1 and D15), procarbazine 100mg/m2 (D1-7), vincristine (1.4mg/m2 D1 and 15), followed by cytarabine consolidation (3g/m2/d X2d) [MPV-A arm]. Neither arm included radiotherapy; prophylactic G-CSF and standardized corticosteroids (methylprednisolone 60mg/d D1-5) were given to both arms. The primary endpoint was PFS (one-stage Fleming design; α= 5%; β=10%). Evaluations included neuropsychological testing and quality of life. Results: Accrual has been completed (7/2007- 3/2010), with 98 pts randomized and 95 analyzed (MT: 48 pts; MPV-A: 47). Pre-treatment characteristics were well balanced between the two arms (all pts: median age=72- range 60-85; median KPS= 70; range 40-100). In the MPV-A arm, the CR rate = 62% (vs 45% in MT arm [p=0.11]), objective response rate= 82% (vs 71%; p=0.23), median PFS= 9.5m (vs 6.1m; HR= 1.14- 95% CI [0.72 ; 1.81]; p=0.6) and median OS= 31m (vs 13.8m; HR= 1.4 - 95% CI [0.84 ; 2.34]; p=0.2). The incidence of grades 3-4 toxicities was 72% in the MPV-A vs 71% in the MT arm. Abnormal liver function test was the most common toxicity (MPV-A: 18 pts; MT: 21). Baseline cognitive impairment (MMSE >24 vs ≤24) predicted OS (p=0.04). Conclusions: This is the first randomized PCNSL study testing two different MTX-based combination regimens. In this elderly population, toxicities were frequent but similar in both arms, and all efficacy endpoints tended to favor the MPV-A arm. The MPV-A regimen is recommended for further development in PCNSL. Clinical trial information: NCT00503594.
Imaging biomarkers of ramucirumab and olaratumab in patients with recurrent glioblastoma.
Authors: Blakeley Jaishri O'Neill , Fisher Joy D. , Lieberman Frank S. , Lupo Janine , Nabors Louis B. , Crane Jason , Wen Patrick Y. , Cote Andre , Peereboom David M. , Wen Qiuting , Cloughesy Timothy Francis , Robins H. Ian , Desideri Serena , Grossman Stuart A. , Ye Xiaobu , Nelson Sarah ,   The Adult Brain Tumor Consortium
Published: March 2020

2044

Background: VEGF and PDGF receptors are overexpressed in glioblastoma (GBM). Both receptor families may be important therapeutic targets. We explored early biologic markers of VEGFR-2 or PDGFRa inhibition with functional MRI. Methods: A subset of patients (pts) from a multicenter phase II study of monoclonal antibodies to VEGFR-2 (ramucirumab 8mg/kg IV q2wks) or PDGFRa (olaratumab 20mg/kg IV q2wks) in adult patients with recurrent GBM underwent a standardized MRI brain protocol with dynamic contrast enhanced (CE); diffusion tensor; perfusion weighted and routine sequences at -1d, +1d, +28d and every +56d from treatment initiation. ACRIN performed site qualification and imaging QA. Regions of CE and T2w hyperintensity were manually defined; percent change in volumes and change in normalized image intensities was calculated. Results: 28 patients were evaluable. Pts receiving ramucirumab (n=11; 7 male) had a median age of 54 (43-67), KPS 90 (70-100) and Dex dose 2mg (0-8). Pts receiving olaratumab (n=17; 14male) had a median age of 58 (24-72), KPS 80 (70-100) and Dex dose 2mg (0-4mg). KPS and Dex were stable over time. Conclusions: Preliminary results show that within 1 day of ramucirumab, CE volume, relative CE intensity and blood volume decreased and by 28 days, T2 volume and ADC decreased suggesting a potent antiangiogeneic effect. PDGFRa inhibition had no effect on lesion volume, but reduced relative CE intensity and blood volume at 28 days. Clinical efficacy results are anticipated in mid-2013. Clinical trial information: NCT00895180. [Table: see text]
Final results from a large prospective Italian population study on glioblastoma and correlations with MGMT status: The Project of Emilia-Romagna Region in Neuro-oncology (PERNO).
Authors: Brandes Alba Ariela , Ermani Mario , D'Alessandro Roberto , Albani Fiorenzo , Franceschi Enrico , Cavallo Michele , Valentini Antonella , Cremonini Anna Maria , Mucciarini Claudia , Faedi Marina , Crisi Girolamo , Fainardi Enrico , Marcello Norina , Pisanello Anna , Agati Raffaele , Michiara Maria , Pasini Giuseppe , Giombelli Ermanno , Servadei Franco , Baruzzi Agostino
Published: March 2020

2048

Background: The impact on the general population of temozolomide concurrent with and adjuvant to radiotherapy (RT/TMZ) was assessed in the context of the Registry of the Project of the Emilia-Romagna Region in Neuro-Oncology (PERNO), the first Italian prospective observational population-based study in the field of neuro-oncology. Methods: Patients (pts) meeting the following inclusion criteria were evaluated: age ≥18 years; PS 0-3; histologically confirmed GBM, no previous or concomitant non-glial tumoral disease, residence in the Emilia Romagna region. The data were collected prospectively. Results: Study accrual, started on January 1 2009, was closed, as planned, on December 31 2010. Two hundred sixty-eight pts (F=111, M=157; median age, 63.5 [range 29-34] years) were studied. mOS was 10.7 months (95%CI: 9.2 – 12.3). MGMT status, assessed in 186 (89%) of 210 pts who had at least radiotherapy was evaluable in 174 pts (83%), being methylated in 76 (43.7%), and unmethylated in 98 (56.3%) pts. mOS for pts with MGMT methylated status was 18.5 months (95%CI: 14.4-22.6), and 12.4 months for those with MGMT unmethylated status (95%CI: 10.5 - 14.3, p<0.0001). 140 pts <70 years were treated with RT/TMZ; mOS in this group was 16.4 months (95% CI: 14.5 – 18.4). mOS was 20 months in the 59 pts (42%) harboring MGMT methylation (95% CI: 12.8 - 27.2), and 13.5 months in the 73 pts (52%) without MGMT methylation (95% CI: 10.8 – 16.2, p<0.0001). At multivariate analysis, a significant prognostic role was found for performance status (p=0.001), extent of surgery (p=0.009), age (p=0.004), postsurgical treatment (p=0.03), and MGMT status (methylated vs unmethylated, p=0.01). Conclusions: The data from the present large prospective population study are in line with those reported in the EORTC/NCIC randomized trial, confirming that this successful approach has been widely incorporated in daily practice.
Safety interim data from a three-arm phase II study evaluating safety and pharmacokinetics of the oral transforming growth factor-beta (TGF-ß) receptor I kinase inhibitor LY2157299 monohydrate in patients with glioblastoma at first progression.
Authors: Carpentier Antoine F , Brandes Alba Ariela , Kesari Santosh , Sepúlveda Juan Manuel , Wheeler Helen , Chinot Oliver L. , Cher Lawrence , Steinbach Joachim Peter , Specenier Pol M. , Cleverly Ann , Tomlin Irene , Desaiah Durisala , Lahn Michael M. F. , Wick Wolfgang
Published: March 2020

2061

Background: Based on preclinical data suggesting an additive antitumor effect of a TGF-ß inhibitor and lomustine, a phase II study was initiated to evaluate the activity of this combination in patients with glioblastoma after first progression. We here report are the safety and PK interim data. Methods: Lomustine was given every 6 weeks as approved, starting on day 7 of cycle 1. LY2157299 (300 mg/day) was administered as intermittent dosing (each cycle = 14 days on followed by 14 days off). Patients received lomustine with either LY2157299 or placebo thereby blinding for LY2157299, while patients receiving LY2157299 alone were unblinded (randomization 2:1:1). Toxicity was assessed using CTCAE, version 4.0. Results: After 31 patients had completed at least 1 cycle (28 days, 3 weeks of lomustine), 50 patients had received at least 1 dose of study drug (LY2157299 or lomustine). Aggregate safety data of the 31 patients are provided: 1 patient died on treatment due to multi-organ failure, not considered related to study treatment. At least 3 patients had the following TEAEs with severity, of grade 3 or 4, and drug relatedness (DR, specific drug not indicated): vomiting (n = 5, 4 DR), fatigue (n = 5, 3 DR,1gr 3), dysphasia (n = 4,1 gr 3), other nervous system disorder (n = 4, 3 gr 3), constipation (n = 3), nausea (n = 3, 3 DR), confusion (n = 3, 1 gr 3). Other grade 3/4 TEAEs observed were: abdominal pain, allergic reaction (DR), fall, syncope, pain, lymphocytes, ANC and thrombocytopenia (all DR) and alanine aminotransferase – in 1patient each. No difference in the LY2157299 concentrations between LY2157299 monotherapy and combination arms was observed. Conclusions: The combination of lomustine with LY2157299 or placebo is consistent with the known profile of lomustine with no unexpected clusters of adverse events and similar to a previous phase I study (Azaro et al. abstract 2042, J Clin Oncol. 30, 2012). The phase II study continues after the first interim assessment on safety. Clinical trial information: NCT01582269.
Heterogeneity in the geographic distribution of diffuse grade II and III gliomas in France.
Authors: Bauchet Luc , Darlix Amelie , Zouaoui Sonia , Virion Jean Marc , Rigau Valerie , Mathieu Daude Helene , Blonski Marie , Reyes-Botero German , Bessaoud Faiza , Tretarre Brigitte , Bauchet Fabienne , Capelle Laurent , Fabbro Michel , Kerr Christine , Figarella-Branger Dominique , Duffau Hugues , Taillandier Luc ,   Societe Francaise de Neurochirurgie, Societe Francaise de Neuropathologie, and ANOCEF
Published: March 2020

2067

Background: Diffuse WHO grade II and III gliomas (DGII/IIIG) are rare tumors (incidence ≤ 2/105person-years). Specific epidemiological studies are very rare. The main objective of this work is to study the geographical distribution of all newly diagnosed and histologically confirmed DGII/IIIG in metropolitan France. Methods: The methodology is based on a multidisciplinary national network already established by the French Brain Tumor DataBase. Personal addresses at the moment of the surgical procedure for all DGII/IIIG cases were collected for the years 2006-2009. For each area, the incidence of DGII/IIIG was analyzed and standardized on age and sex distribution of the French population (pop). Results: The total number of patients with newly diagnosed and histologically confirmed DGII/IIIG was 4790 (1220, 1190, 1228, and 1152 for years 2006-2009). The Table shows the number of tumors by histology, sex and median age at diagnosis. The overall crude rate was 19.4/106. To enable international comparisons, standardized rates were calculated as follows: 19.8/106 (reference pop, Europe), 18.8/106 (reference pop, US 2000), and 16.0/106 (reference pop, world). The geographic distribution by regions in France showed significant differences. For example, the standardized rates (for 106person-years, 95% confidence intervals, reference pop: France) for Auvergne, Champagne-Ardenne, and Basse-Normandie, were 30.9 (26.4-35.5), 28.5 (24.0-33.0), and 13.9 (10.9-17.0), respectively. Conclusions: To our knowledge, this work is the first to study the geographical distribution of DGII/IIIG across one entire country, and it shows significant heterogeneity. These results will enable to look for different environmental and genetic factors in these different regions. [Table: see text]
A validation study of graded prognostic assessment index for lung cancer patients with brain metastases.
Authors: Du Lingling , Alva Venur Vyshak , Dahiya Saurabh , Garje Rohan , Osei-Boateng Kwabena , Elson Paul , Suh John H. , Chao Samuel T. , Ahluwalia Manmeet Singh
Published: March 2020

2070

Background: The Graded Prognostic Assessment (GPA) is a commonly used index based on 5 prior randomized trials performed by the RTOG (Protocols 7916, 8528, 8905, 9104, and 9508). The purpose of this study was to validate GPA index in a recent cohort of lung cancer patients with brain metastases (LBM) at a larger tertiary care center. Methods: Cleveland Clinic Brain Tumor and Neuro-Oncology Center's database was used to identify LBM treated in the recent era (2000-12). A proportional hazards model was used to assess overall survival (OS), measured from the date of diagnosis of brain metastases to death or last follow-up. Results: 490 LBM (250 males) median age 61 years (range 35-86) were included. Histology included small cell (64, 13%) adenocarcinoma (289, 59%), squamous (53, 11%), large cell (26, 5%) and unknown (55, 11%). The median number of brain metastases was 1 (range, 1-47). Karnofsky Performance Scale (KPS) was 90-100 in 187 (41%), 70-80 in 238 (52%) and <70 in 33 (7%). Extracranial Metastases was present in 327 patients (67%). OS was 14.1 months (95% C.I. 12.3-15.7). GPA for lung cancer is derived from KPS, the number of brain mets, the presence/absence of extracranial metastases, and age. GPA was 0-1.0 in 83 patients, 1.5-2 in 211, 2.5-3 in 135 and 3.5-4 in 18 patients. Although overall GPA was prognostic for survival (p<.0001), not all of the factors used to derive it were significant (Table). Factors noted to be prognostic for survival included primary controlled (p=<.0001), squamous cell histology (p=.0001), age (p=.0002), KPS (p=.0002). The new index divided the patients into unfavorable, intermediate, favorable that was prognostic for survival in this cohort (p<.0001). Conclusions: New index developed based on a revised set of independent prognostic factors (primary controlled, squamous cell histology, age and performance status) is proposed. [Table: see text]
Tumor perfusion during bevacizumab and irinotecan in recurrent glioblastoma: A multimodal approach.
Authors: Eoli Marica , Di Stefano Anna Luisa , Aquino Domenico , Scotti Alessandro , Anghileri Elena , Cuppini Lucia , Prodi Elena , Finocchiaro Gaetano , Bruzzone Maria Grazia
Published: March 2020

2074

Background: Angiogenesis is a requirement for progression of glioblastoma (GBM) and vascular endothelial growth factor (VEGF) is a mediator of neo-angiogenesis in this tumor. Bevacizumab (Bev), an antibody directed to VEGF, was recently used to treat GBM. However in vivo modifications induced by treatment are still not clearly understood. Aim of this study is to analyze tumor changes induced by Irinotecan (Ir) and Bev, using two different methodologies: relative CBV variation (rCBV) and Difference Perfusion Maps (DPMs). Methods: 42 recurrent GBM patients underwent Bev (10 mg/kg) and Ir (125 or 340 mg/m2) treatment every 2 weeks and were followed up with a radiological protocol, including Dynamic Susceptibility Contrast MRI every 8 weeks. Radiological responses were assessed based on RANO criteria (Wen et al, 2012). Two methods were used to assess perfusion changes. In method A, relative CBV variation after 8 weeks of treatment was calculated through semi-automatic ROI placement in the same anatomic region as in baseline. In method B, relative CBV variations with respect to baseline values were calculated into the evolving tumour region by means of a voxel-by-voxel difference. DPMs were created showing where rCBV significantly increased, decreased or remained unchanged. Results: After a median follow-up of 33.5 months median overall survival (OS) was 35.0 weeks and median progression free survival (PFS) was 20.0 weeks. Method A showed a significant decrease of rCBV for patients with stable disease or partial response after 8 weeks of treatment (p = 0.01) while progressing patients maintained elevated levels of rCBV (p = 0.38). Method B, based on DPMs, showed that patients presenting rCBV increase higher than 25° percentile (corresponding to rCBV increase higher than 18% of tumor volume) had a significantly longer PFS (p = 0.045) and OS (p = 0.016). Conclusions: Using DPM we observed that early increase in global perfusion is related to better survival. This may suggest that Bev, when effective, reduces blood-brain barrier permeability with a higher contrast retention in vessels. If confirmed by further studies this measure could be useful in identifying responders to Bev.
Recurrent glioblastoma: Stratification of patient survival using tumor volume before and after antiangiogenic treatment.
Authors: Huang Raymond , Rahman Rifaquat , Hamdan Alhafidz , Kane Caroline , Chen Christina , Norden Andrew David , Reardon David A. , Mukundan Srinivasan , Wen Patrick Y.
Published: March 2020

2075

Background: Although antiangiogenic therapies can induce a dramatic clinical and imaging response in patients with recurrent glioblastoma, their benefit on overall survival is less pronounced. We assessed whether tumor volume based on magnetic resonance imaging (MRI) before and after treatment with bevacizumab can stratify patients in terms of progression-free survival (PFS) and overall survival (OS). Methods: Baseline and post-treatment MRI scans of 93 patients with recurrent glioblastoma treated with bevacizumab were evaluated for volume of the enhancing tumor, as well as volume of the T2/FLAIR hyperintensity. The Cox proportional hazards model was used in univariate and multivariate settings to identify volume parameters prognostic and predictive for PFS and OS. Results: Our results show that baseline enhancing tumor volume were predictive of PFS (p = 0.047) and OS (p = 0.011). Specifically, patients with pretreatment enhancing tumor volume less than 18 cm3 have a median OS of 45 weeks, while patients with tumor volume greater than 18 cm3 have a median OS of 26 weeks. In addition, enhancing tumor volume 3 to 6 weeks after treatment, as well as percentage change in volume, are independent predictors of PFS and OS. Neither T2/FLAIR volume nor percentage change in T2/FLAIR volume was associated with survival. Conclusions: These results indicate that measurement of enhancing tumor volume can help identify patients more likely to benefit from bevacizumab therapy.
The prognostic value of cognition in patients with glioblastoma multiforme.
Authors: Flechl Birgit , Sax Cornelia , Ackerl Michael , Crevenna Richard , Gaiger Alexander , Dieckmann Karin , Widhalm Georg , Marosi Christine
Published: March 2020

2078

Background: In patients with glioblastoma multiforme (GBM) progressive disease leads sooner or later to cognitive decline. In this study we evaluated if two cognitive assessments performed early in the treatment course have a prognostic significance for predicting progression free survival (PFS). Methods: We assessed the cognition of 35 patients with GBM using the program NeuroCogFX with four subscales: working memory, attention, verbal and figural memory and verbal fluency. Baseline evaluation was done at initiation of radiotherapy (11-57 days after diagnosis) and second evaluation three months later (82-117 days after baseline). Results in subscales were categorized in “declined”, “stable” and “improved”. Tumor progression was based on MRI scans. Results: The patients (12 women, 23 men) were in median 54 years old (21-75 years). The majority (61%) showed stable cognitive results, 22% improved and 14% decreased in the summary scale of cognition. The median PFS was 11 months (2.6-27.4 months). An improvement of attention correlated significantly with longer PFS (p = 0.015) whereas the other three cognitive subscales were not associated with PFS. Conclusions: The present study shows evidence, that an increase or decrease of attention scales measured within the first 5 months of disease has prognostic value for PFS.
Descriptive epidemiology of meningiomas in the United States.
Authors: Villano John L. , Anderson Stephen Todd , Dolecek Therese A.
Published: March 2020

2099

Background: Although meningioma is the most common tumor in the central nervous system (CNS), the incidence, epidemiology, and clinical outcomes have historically been poorly defined. Our analysis follows the implementation of Public Law 107–260, the Benign Brain Tumor Cancer Registries Act mandating collection of non-malignant meningiomas. Methods: Surveillance Epidemiology End Results Program (SEER) 18 registries research data on cases diagnosed during 2004-2009 with meningioma (ICD-O-3 histology codes 9530-9534 & 9537-9539) in brain or CNS primary site (C70.0-72.9, 75.1-75.3 ) were analyzed. Population-based statistics were generated using SEER*Stat 8.0.1 software. Results: A total of 35,302 cases (34,718 non-malignant; 584 malignant) were available providing a rate of 7.18/100,000, with meningioma, NOS (9530/0) the most common histology. Rates increased with age (0.13/100,000, 0-19 years; 37.78/100,000, 75+ years). The annual percentage change in incidence rates showed a statistically significant increase of 2.57% over 2004-2009. Significant increases were also observed for males, females, whites, blacks, non-Hispanics, and older age groups. The gender ratio M:F was 0.35 in the 0-49 age group and 0.48 in the 50+ age. Primary site location included cerebral meninges (83%) with almost 5% in the spinal meninges. 51% of cases were diagnosed pathologically versus imaging. However, diagnosis among 85% of spinal cases was surgically based. Older age and females were less likely to have a surgical diagnosis. 3.4% received radiation therapy (RT) with 97% receiving RT following surgery. For grade III or malignant cases, 22% received RT, and in grade 1 and 2 nearly 97% of cases did not receive RT, with older age groups less likely to receive RT. Overall survival was high, except for grade 3 or malignant cases where 5 year relative survival was 61.7%. Conclusions: Our analysis following Public Law 107–260 demonstrates an increasing incidence of meningiomas and provides new information, including a decrease in the gender difference with age. Clinical diagnosis is common and higher in women and older adults. Use of RT is low, even in malignant meningiomas, and employed following surgery. These observations were similar for white and black cases.
Diffuse intrinsic pontine gliomas (DIPG) in adolescents can have differing presentations but similar outcomes compared to those of middle childhood.
Authors: Warren Katherine E. , Jacoby Elad , Fangusaro Jason R.
Published: March 2020

2101

Background: DIPG are invasive, treatment-resistant, brainstem tumors that generally affect children in middle childhood. The triad of cranial neuropathies, long tract signs, and ataxia are characteristic presenting signs; most patients have a short history of symptoms. Median survival is less than one year, but young children (<3 years) and adults with DIPG may have a better prognosis. Other positive clinical prognostic factors include longer duration of symptoms and absence of cranial neuropathies. We assessed the presentation and outcome of adolescents with DIPG. Methods: Patients were enrolled on an IRB-approved protocol. Clinical data for patients age>10 years and <20 years with a diagnosis of DIPG who were evaluated and treated at the authors’ institutions were reviewed. Results: A total of 46 patients were identified. M:F was 0.77:1. Median age at diagnosis was 13 (range 10-20) yrs. Frequent presenting symptoms included headache (39 %), dizziness (25%), diplopia (27%) and cranial neuropathies (27%). Two were diagnosed as incidental findings. The interval between onset of symptoms and diagnosis ranged from 2 days-5 years, and only 9 of 41 patients (22%) reported symptom duration of less than 2 weeks. The majority (39/42) received radiation therapy, with or without adjuvant chemotherapy. Of patients for whom data is available, 8/22 (36%) did not improve or worsened during radiation therapy and 17 of 27 (63%) remained on steroids at the end of radiation. Two patients are alive with stable disease and 1 is actively receiving initial treatment. Of the patients with progressive disease for whom data is available (n=32), median time to progression was 8 mo (range 2 mo-2.5 yrs). Conclusions: Presenting symptoms of DIPG in adolescents commonly include headache, dizziness and diplopia for several weeks-months. Although the vast majority are treated with radiation therapy, clinical benefit was not observed in a significant number of patients. Overall outcome is similar to those patients diagnosed in middle childhood rather than the adult population.
A phase I study of the safety and pharmacokinetics of DNIB0600A, an anti-NaPi2b antibody-drug-conjugate (ADC), in patients (pts) with non− small cell lung cancer (NSCLC) and platinum-resistant ovarian cancer (OC).
Authors: Gordon Michael S. , Gerber David E. , Infante Jeffrey R. , Xu Jian , Shames David S. , Choi Younjeong , Kahn Robert S. , Lin Kedan , Wood Katie , Maslyar Daniel J. , Burris Howard A.
Published: March 2020

2507

Background: NaPi2b (SLC34A2) is a multi-transmembrane, sodium-dependent phosphate transporter expressed in non-squamous NSCLC and non-mucinous OC. DNIB0600A is an ADC consisting of a humanized IgG1 anti-NaPi2b monoclonal antibody and anti-mitotic agent, MMAE, that shows anti-proliferative activity in xenograft models. Methods: This study evaluated safety, pharmacokinetics, and pharmacodynamics of DNIB0600A (0.2-2.8 mg/kg) given every 3 weeks (q3w) to pts with NSCLC or OC. A traditional 3+3 design was used for dose escalation followed by expansion by disease at the recommended Phase 2 dose (RP2D). Tumor NaPi2b expression was evaluated in archival tissue. Anti-tumor activity was evaluated per RECIST 1.1. Results: As of 10 Dec 2012, 30 dose escalation pts have enrolled (16 NSCLC; 14 OC), median age 61 (range 45-78), PS 0-1, median number of prior regimens 5 (1-12), received a median of 3 (1-17) doses of DNIB0600A. No DLTs occurred at the maximum assessed dose of 2.8 mg/kg; enrollment in the expansion cohort at 2.4 mg/kg is ongoing. The most common related AEs regardless of Grade were fatigue (43%), decreased appetite (37%), nausea (30%), constipation, dysgeusia, vomiting, and peripheral neuropathy (each 17%), and diarrhea (13%). One pt at 1.8 mg/kg experienced a DLT (Grade 3 dyspnea), however, no additional DLTs occurred through the maximally administered dose of 2.8 mg/kg. Expansion at 2.4 mg/kg was selected based on totality of safety data. No accumulation of total antibody, free MMAE, or conjugated MMAE was observed. Exposure of each analyte was dose proportional. Approximately 70% of NSCLCs and 85% of OC expressed high levels (IHC 2+/3+) of NaPi2b. Of the 18 pts treated at dose levels 1.8-2.8 mg/kg (10 NSCLC; 8 OC) 3 pts had a confirmed partial response (PR) with response durations of 8.8+ (OC), 4.4+ (NSCLC), and 1.4+ (OC) months, censored at data cutoff, and 1 additional pt had an unconfirmed PR (OC). Dose expansion data will be presented. Conclusions: DNIB0600A administered q3w has an encouraging safety profile and evidence of anti-tumor activity in both NSCLC and OC. Further studies are planned. Clinical trial information: NCT01375842.
Predictive value of phase I trials for safety and final approved dose in later trials: Analysis of 33,845 patients.
Authors: Fontes Jardim Denis Leonardo , Hess Kenneth R. , LoRusso Patricia , Kurzrock Razelle , Hong David S.
Published: March 2020

2509

Background: Phase I trials (Ph1) use data efficiently from a small number of patients (pts) to define a maximum tolerated dose (MTD) and the safety profile of new agents. It is unclear how well these trials perform in predicting the future approved dose of agents and in assuring the safety of pts in later trials. Here we compared data obtained from Ph1 and registration trials of the respective agents. Methods: We searched the US Food and Drug Administration (FDA) website for drugs approved in non-pediatric cancers between Jan. 1990 and Oct. 2012. Recommended phase II dose (R2PD), dose-limiting toxicities (DLTs) and grade (G) 3 and 4 adverse events from Ph1 were compared with doses and safety in later trials listed on updated package inserts. Proportions from independent groups were compared using the chi-squared test. Multiple logistic regression analysis adjusted these comparisons for potentially confounding factors. Results: A total of 78 Ph1 (3,499 pts) and 88 later trials (33,845 pts) were included. In 60% (n=50) of 84 matched trials in the dose comparison analysis, the dose from the later trial was the RP2D (often derived from the MTD) from a Ph1. In a multivariable analysis, Ph1 of oral drugs were more predictive of the final approved dose (78% adopting the RP2D oral vs. 43% IV drugs, p=0.011). Other Ph1 characteristics (number of pts, dose levels and tumor type) had no influence on the odds of adopting the RP2D. 55% of phase I DLTs were among the 4 most frequent high-grade events in later trials, with a higher frequency for DLTs of cytotoxic agents (p=0.061). Of the 525 clinically significant toxicities in later trials, 70% (n=369) were described in Ph1. There was a clear relationship (p=0.0032) between increasing the number of pts in the Ph1 (up to 60) and the ability to describe future clinically relevant side effects. Among 28,597 pts in later trials with available data the death rate that was possibly related to drug was 1.48%. Conclusions: Dosing based on Ph1 was associated with a low toxicity-related death rate on later trials. The ability to predict clinically significant toxicities correlates with the number of pts on the initial Ph1. However, the final dose in later trials was the exact RP2D of the Ph1 in only 60% of cases.
Integrated genomics and avatar mouse models for personalized cancer treatment.
Authors: Garralda Elena , Paz Keren , López-Casas Pedro P. , Jones Siân , Katz Amanda , Kann Lisa M. , López-Ríos Fernando , Sarno Francesca , Al-Shahrour Fatima , Vasquez David , Bruckheimer Elizabeth , Angiuoli Samuel V. , Diaz Luis A. , Valencia Alfonso , Velculescu Victor E. , Sidransky David , Hidalgo Manuel
Published: March 2020

2511

Background: Every cancer has its unique set of molecular changes and the knowledge of such alterations is enabling an individualized approach to cancer treatment. The great intellectual challenge lies in linking confirmed mutations to protein function. Methods: Using massive parallel sequencing we performed whole exome sequencing analysis of 30 patients (pts) with advanced solid tumors to identify putatively actionable tumor-specific genomic alterations. We used 2 in silico methods (Polyphen and SIFT) to estimate the functional significance of a given confirmed mutation. Avatar models generated by direct engraftment of tumor samples from the patients into immunocompromised mice were used as an in vivo platform to test proposed treatment strategies. Results: Successful exome sequencing analyses has been obtained for 28 pts. Tumor specific mutations (Muts) and copy number variations were identified ranging from 5 to 952 and 0 to 956 respectively. All samples profiled contained relevant genomic alterations. Some of the most relevant actionable alterations were: CHEK1, FGFR2, IGF1R, MET, BRCA1, XPC, NOTCH, CREB3LB, GNA11, SMAD4, NF1, PTPRC, PI3KA, DDR2 and EGFR. An Avatar model was generated for 15 patients. In occasions actionable alterations such as muts in NF1, PTPRC, PI3KA and DDR2 failed to provide any benefit when a targeted drug was tested in the Avatar and accordingly treatment of the pts with these drugs was not effective. So far 13 pts have received a personalized treatment: two, as expected based on the avatar model, did not response; 5 resulted in durable partial remissions. Eight pts are currently on treatment with at least disease stabilization. Bench testing of candidate treatments in Avatar models correlated with clinical response and helped to select empirical treatments in patients with no actionable mutations. Conclusions: The use of full genomic analysis for cancer care is promising but presents important challenges that will need to be solved for broad clinical application. Avatar models are a powerful investigational platform for therapeutic decision making and help to guide cancer treatment in the clinic. While limitations still exist, this strategy should be tested in prospective randomized clinical trials.
A phase I study of carboxyamidotriazole orotate (CTO) in of advanced solid tumors.
Authors: Sandler Alan , Taylor Matthew Hiram , Urba Walter John , Omuro Antonio Marcilio Padula , Anderson Barry Douglas , Hansen Daniel , Fisher Brenda , Claeys Alisa J , Greathouse Amy , McLean Sean , Karmali Rashida A.
Published: March 2020

2518

Background: CTO is an orotate salt of carboxyamidotriazole (CAI), which is an inhibitor of calcium-dependent intracellular and extracellular signal transduction pathways (presumably affecting VEGF and PI3K) and has tumor anti-proliferative and anti-invasive properties. The activity of CTO alone and in combination with temozolomide or 5Efluorouracil was demonstrated in human glioblastoma, melanoma, and colon tumor xenografts. Methods: This study assessed the maximum tolerated dose (MTD), safety, pharmacokinetics and activity of CTO monotherapy in 34 patients (pts) with advanced solid tumors meeting eligibility criteria with adequate organ function. The CTO study NCT01107522 enrolled pts in 8 cohorts receiving continuous daily oral CTO capsules at doses ranging from 50mg- 555mg/m2/day. The MTD has not been determined. Pharmacokinetic (PK) sampling was performed during cycle 1 at each dose level. CT scans were performed at baseline and after 8 weeks to assess anti-tumor effect. Patients remained on study if they achieved stable disease (SD) or tumor response and did not experience dose limiting toxicities (DLT). Results: The most frequently recorded adverse events (Grade 1 and 2) were fatigue, nausea, vomiting, and dizziness. DLTs of grade 3 fatigue (219 mg/m2) and grade 3 creatine kinase elevation (555 mg/m2) occurred in one pt each. No cardiac QTc prolongations have been recorded. PK data demonstrated therapeutically relevant CAI levels beginning at the 219mg/m2 dose. Nine pts continued CTO dosing beyond 2 cycles. Tumor assessments demonstrated SD at different doses of CTO: i) 75mg/m2 renal carcinoma (1, 12 cycles); ii) 219 mg/m2-small cell lung cancer (1, 4 cycles), squamous cell lung cancer with PIK3CA mutation (1, 10 cycles and continuing), and lung adenocarcinoma with EGFR mutation (1, 10 cycles and, continuing); iii) 285 mg/m2-1 colon cancer with BRAFV600E mutation (1, 6 cycles), and squamous cell carcinoma (tonsil) with PI3KCA and NRAS mutations (1, 9 cycles, and continuing). Conclusions: CTO given as monotherapy up to 555mg/m2/day is safe and tolerable and without MTD. Six patients with different malignancies and genomic markers achieved SD; combinatorial investigations in malignant gliomas have started. Clinical trial information: NCT01107522.
A phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of the selective aurora kinase inhibitor GSK1070916A.
Authors: McNeish Iain , Anthoney Alan , Loadman Paul , Berney Dan , Joel Simon , Halford Sarah E. R. , Buxton Emily , Race Amanda , Ikram Mohammed , Scarsbrook Andrew , Patikis Angela , Rockall Andrea , Dobbs Nicola A , Twelves Christopher
Published: March 2020

2525

Background: GSK1070916A is a potent and selective inhibitor of Aurora B and C. This phase I study in collaboration with GlaxoSmithKline was part of the Cancer Research UK Clinical Development Programme. Methods: Patients (pts) with advanced/metastatic solid cancers for whom there was no standard therapy, with adequate performance status and organ function were eligible for GSK1070916A (1 hour i.v. infusion days 1 – 5, every 21 days). The primary objectives were to determine the safety profile, dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of GSK1070916A. The starting dose was 5mg/m2/day, with initial single pt cohorts, followed by “3 + 3” cohorts and expansion at the MTD. DLTs included prolonged (> 5 days) or complicated grade 4 neutropenia; the MTD was the highest dose at which < 1 of 3 - 6 pts experienced DLT. Cycle 1 blood and healthy skin biopsies were obtained for PK and PD assays. The expanded cohort included 6 pts having pre- and post-treatment functional imaging studies (FDG PET-CT and MRI), and a further 6 having paired tumour biopsies for PD studies. Results: Nine single pt cohorts received up to 73mg/m2/day of GSK1070916A with no grade 3 or 4 related adverse events. At 102.2mg/m2/day, 1 pt had a DLT (febrile neutropenia) and 2 pts non-DLT grade 4 neutropenia; this dose was considered unacceptably toxic and 23 pts received a lower dose of 85mg/m2/day; 7/23 pts had prolonged/complicated grade 4 neutropenia, 5 of whom continued GSK1070916A with dose reduction +/- delay. There were no treatment related deaths. A pt with ovarian cancer (102.2mg/m2/day) had a RECIST PR; 19 pts had stable disease for < 223 days. GSK1070916A PK were linear with a strong correlation between exposure (AUC) and reduction in neutrophils (r2 0.91). At the 85 mg/m2 dose, mean day 1 t1/2 was 8.98 hours and Cl 9.2 l/h; AUCinf was 10% higher on day 5 than day 1. PD results in healthy skin (phosphoHistone-H3, Ki 67 and cleaved caspase-3) were inconsistent. Conclusions: The MTD of GSK1070916A as a 1 hour i.v. infusion on days 1 – 5, every 21 days is 85mg/m2/day, with predictable and manageable neutropenia as the DLT and evidence of clinical activity. Serum levels of cytokeratin-18, tumour PD and functional imaging data will be presented. Clinical trial information: NCT01118611.
Phi-53: (NCI#7251): Phase I trial of belinostat (PXD101) in combination with 13-cis-retinoic acid (13c-RA) in advanced solid tumor malignancies—A California Cancer Consortium NCI/CTEP sponsored trial.
Authors: Luu Thehang H. , Frankel Paul Henry , Lim Dean , Cristea Mihaela C. , Beumer Jan Hendrik , Appleman Leonard Joseph , Lenz Heinz-Josef , Gandara David R. , Piekarz Richard , Newman Edward M.
Published: March 2020

2526

Background: Belinostat has a reported maximum tolerated dose (MTD) of 1,000 mg/m2 given days 1 to 5 every 21 days as a single agent, although in one study in hepatocellular carcinoma belinostat was given at 1,400 mg/m2on the same schedule. Pre-clinical evidence suggests HDAC inhibitors enhance retinoic acid signaling with a synergistic impact in a variety of solid tumors. We conducted a phase I study of belinostat and 13c-RA in advanced solid tumors. Methods: Dose limiting toxicity (DLT) was defined as cycle 1 hematologic toxicity: ≥grade 3 that not resolved to <grade 1 within 1 week or non-hematologic toxicity: ≥grade 3. We sought the MTD of belinostat days 1-5 with 13-cRA days 1-14, every 21 days, in patients (pt) with advanced solid tumors. Eligibility criteria included normal organ function and QT/QTc interval; 4 weeks from previous therapy. Results: 51 pt were treated: median age 61 (range 40-80); 29 men; 57% ECOG 0, 41% ECOG 1, 2% ECOG 2; 13 lung, 11 breast, 8 colorectal, 3 pancreatic. 11 dose levels (DL) were tested starting from belinostat 600 mg/m2/day and 13c-RA 50 mg/m2/day to belinostat 2000 mg/m2/day and 13c-RA 100 mg/m2/day. Only two DLTs were observed: a grade 3 hypersensitivity reaction with dizziness and hypoxia at DL 8 (belinostat 1700 mg/m2/day, 13c-RA 100 mg/m2/day); and a grade 3 allergic reaction in a patient with an ECOG PS 2 at DL 11 (belinostat 2000 mg/m2/day, 13c-RA 100 mg/m2/day). The MTD was not reached. Pharmacokinetics of belinostat suggests dose proportionality. Median number of cycles: 2 (range 1–56). 10 patients had SD including: 1 neuroendocrine pancreatic stable for 56 cycles; 1 breast pt for 12 cycles; 1 lung pt 8 cycles. 2 pt had PRs: a keratinizing squamous cell carcinoma (tonsil) and a lung cancer pt. Conclusions: Belinostat 2000 mg/m2 days 1-5and 13-cis-Retinoic acid 100 mg/m2days 1-14, every 21 days, was well-tolerated and an MTD was not reached despite doubling the established single agent MTD. Future studies building on this combination to belinostat are warranted. Support: U01CA062505 and P30CA033572 (City of Hope); U01CA099168 and P30CA047904 (University of Pittsburgh).
Phase I trial of trebananib (AMG 386) plus temsirolimus (Tr + T) in patients (pts) with advanced solid tumors (PJC-008/NCI#9041).
Authors: Tan David Shao Peng , Kollmannsberger Christian K. , Hotte Sebastien J. , Cescon David W. , Diaz-Padilla Ivan , Hedley David W. , Renouf Daniel John , Razak Albiruni R.A. , Gelmon Karen A. , Hirte Hal W. , Wang Lisa , Wizemann Monika , Moscow Jeffrey , Chen Helen X. , Siu Lillian L. , Bedard Philippe L. ,   Princess Margaret Hospital Phase I Consortium
Published: March 2020

2534

Background: Preclinical data suggest that combined Ang1/2 and mTOR blockade has synergistic anti-cancer activity. The combination of Tr (inhibits angiogenesis by preventing interaction of Ang1/2 with Tie2) with the mTOR inhibitor T was evaluated in pts with advanced solid tumors to determine safety, tolerability, maximum tolerated dose (MTD), pharmacodynamics and preliminary antitumor activity. Methods: Pts were enrolled using 3+3 design. Tr and T were dosed on Day 1 (D1), 8, 15 and 22 of a 28-day cycle. Peripheral blood was collected for evaluation of Tie2-expressing monocytes (TEMs) and thymidine phosphorylase (TP) (an angiogenic enzyme increased in TEMs upon Tie2 stimulation) by flow cytometry. Tumor response was assessed every 2 cycles. Results: 13 pts have been enrolled, 6 at dose level (DL) 1 (15mg/kg Tr + 25mg T) and 7 (1 died from disease before DLT assessment) at DL -1 (15mg/kg Tr + 20mg T). Median age was 57yrs, ECOG 0-1, median previous chemotherapy lines 3 (range 1-8). In DL 1, 1/6 pts experienced DLT (Grade (Gr) 2 pneumonitis). In view of frequent Gr2 adverse events (AEs) in DL 1, DL -1 was evaluated with DLTs in 2/6 evaluable pts (Gr3 mucositis and intolerable Gr2 limb edema preventing start of cycle 2 within 14 days). The most common related AEs (all Gr across both DL) were: fatigue (77%), edema (69%), anorexia (62%), and nausea (54%). Common Gr≥3 AEs included lymphopenia (23%) and fatigue (23%). Of 10 evaluable pts, best RECIST responses were: 1 breast cancer pt (ER+/ HER2-/ PIK3CA mutant) with PR (now in cycle 9), 7 pts with SD, and 2 pts with PD. Four pts with ovarian cancer (1 PIK3CAmutant) had SD ≥11weeks with 2/3 pts (1 not evaluable) demonstrating GCIG response (>50% decrease in CA125). In preliminary analyses, TP expression in TEMs was decreased (mean -18%) in 4pts with tumor shrinkage, but increased (+6%) in 1pt with tumor growth, suggesting a trend between reduced TP and tumor response. Conclusions: The MTD was exceeded at 15mg/kg Tr and 20mg T weekly. The safety of 10mg/kg Tr and 20mg T weekly is currently being evaluated. The combination of Tr and T shows early signs of antitumor activity. TP expression in TEMs by flow cytometry as an early marker of treatment benefit warrants further evaluation. Clinical trial information: NCT01548482.
Phase I study of c-Met inhibitor ARQ197 in combination with FOLFOX for the treatment of patients with advanced solid tumors.
Authors: Jones Suzanne Fields , Kurkjian Carla , Patel Manish R. , Infante Jeffrey R. , Burris Howard A. , Greco F Anthony , Hemphill Michael Brian , Mohyuddin Adil I. , Thompson Dana Shelton , Murphy Patrick , Raefsky Eric , Bendell Johanna C.
Published: March 2020

2544

Background: C-Met protein is a receptor tyrosine kinase which is overexpressed or mutated in a variety of tumor types, causing cell proliferation, metastasis, and angiogenesis. Tivantinib is an orally bioavailable small molecule which binds to the c-Met protein. This phase I study was designed to determine the maximum tolerated dose (MTD) of tivantinib in combination with standard dose FOLFOX for the treatment of patients with advanced solid tumors. Methods: Patients with advanced solid tumors for which FOLFOX (5-FU IV 400 mg/m2 day 1; 5-FU CIV 2400 mg/m2 day 1; Leucovorin IV 400 mg/m2 day 1; Oxaliplatin IV 85 mg/m2 day 1) would be appropriate chemotherapy received escalating doses of tivantinib BID (days 1-14) in a standard 3 + 3 design. Dose-limiting toxicities (DLTs), non-dose-limiting toxicities (NDLTs), safety, and preliminary efficacy were evaluated. Results: Fourteen patients (50% colorectal) were treated across 3 dose levels: 120 mg (n=3); 240 mg (n=5); 360 mg (n=6). No DLTs were observed until the 3rd dose level (treatment delay ≥3 days, secondary to grade 3 neutropenia). Common related adverse events (% grade 1/2; % grade 3/4) included: diarrhea (36%; 0%), neutropenia (0%; 29%), nausea (14%; 14%), vomiting (14%; 14%), dehydration (14%; 7%), and thrombocytopenia (14%; 0%). To date, 7 patients have been evaluated for response including 4 (57%) with stable disease evident at the 8-week evaluation (CRC, 2 patients; unknown primary favoring CRC, 1 patient; esophageal, 1 patient) and 3 (21%) with disease progression. The 4 patients with stable disease are continuing on treatment; three (CRC and unknown primary) had received prior FOLFOX. Conclusions: The addition of tivantinib to standard therapy FOLFOX appears tolerated up to its recommended phase II monotherapy dose of 360 mg. Preliminary efficacy is encouraging, and a phase II study is proceeding with this regimen for the first line treatment of advanced gastroesophageal patients. Clinical trial information: NCT01611857.
Effects of gefitinib and vandetanib on human equilibrative nucleoside transporter 1 and on gemcitabine cytotoxicity.
Authors: Damaraju Vijaya L. , Scriver Tara , Mowles Delores , Cass Carol E , Sawyer Michael B.
Published: March 2020

2546

Background: Combination chemotherapy with tyrosine kinase inhibitors (TKIs) and gemcitabine has been attempted with little added benefit to patients. We hypothesized that TKIs that were designed to bind to ATP pockets of growth factor tyrosine kinases also bind to proteins that recognize nucleosides, thereby potentially interfering with gemcitabine pharmacology. Methods: Interaction of TKIs with human nucleoside transporters (NTs) was studied using recombinant NTs produced in yeast. Effects of TKIs on uridine transport, gemcitabine transport and accumulation, regulation of NT activity and cytotoxicity with and without gemcitabine were evaluated in human A549 lung cancer cells. Results: In yeast, vandetanib inhibited two equilibrative NTs (hENT1, hENT2) and three concentrative NTs (hCNT1, hCNT2, hCNT3) with the greatest inhibition seen with hENT1 whereas gefitinib strongly inhibited hENT1 and hCNT1 only. In A549 cells, which possess major hENT1 and minor hENT2 activities, [3H]uridine uptake was inhibited by vandetanib and gefitinib with IC50 values of 16 ± 4 and 5 ± 0.3µM, respectively. Both TKIs also inhibited [3H]gemcitabine transport and accumulation in A549 cells. hENT1 protein levels were decreased during exposures to vandetanib or gefitinib for 24 hours, and cytotoxicity was greatest when gemcitabine was given prior to vandetanib or gefitinib. Conclusions: Vandetanib and gefitinib inhibited human NTs, especially hENT1, resulting in reduced intracellular gemcitabine accumulation. Gefitinib or vandetanib levels achieved in plasma and tumor tissues are sufficient to inhibit hENT1 activity. Because TKIs can block uptake of nucleoside chemotherapy drugs in cultured cancer cells, attention must be paid to TKIs and nucleoside pharmacokinetic properties when scheduling TKIs and nucleoside chemotherapy.