bluuebunny/crossref_metadata_2025 huggingface dataset:
Radiomic analysis of pseudo-progression compared to true progression in glioblastoma patients: A large-scale multi-institutional study.
Authors: Abrol Srishti , Kotrotsou Aikaterini , Hassan Ahmed , Elshafeey Nabil , Hassan Islam , Idris Tagwa , El Salek Kamel , Elakkad Ahmed , Alfaro Kristin , Weathers Shiao-Pei S. , Moron Fanny E , Huse Jason , Weinberg Jeffrey S , Heimberger Amy B. , Sawaya Raymond , Kumar Ashok J , De Groot John Frederick , Law Meng , Zinn Pascal , Colen Rivka R.
Published: September 2018

2015

Background: Treatment-related imaging changes are often difficult to distinguish from true tumor progression. Treatment-related changes or pseudoprogression (PsP) subsequently subside or stabilize without any further treatment, whereas progressive tumor requires a more aggressive approach in patient management. Pseudoprogression can mimic true progression radiographically and may potentially alter the physician’s judgment about the residual disease. Hence, it can predispose a patient to overtreatment or be categorized as a non-responder and exclude him from the clinical trials. This study aims at assessing the potential of radiomics to discriminate PsP from progressive disease (PD) in glioblastoma (GBM) patients. Methods: We retrospectively evaluated 304 GBM patients with new or increased enhancement on conventional MRI after treatment, of which it was uncertain for PsP versus PD. 149 patients had the histopathological evidence of PD and 27 of PsP. Remaining 128 patients were categorized into PD and PsP based on RANO criteria performed by a board-certified radiologist. Volumetrics using 3D slicer 4.3.1 and radiomics texture analysis were performed of the enhancing lesion(s) in question. Results: Using the MRMR feature selection method, we identified 100 significant features that were used to build a SVM model. Five texture features (E, CS, SA, MP, CP) were found to be most predictive of pseudoprogression. On Leave One Out Cross-Validation (LOOCV), sensitivity, specificity and accuracy were 97%, 72%, and 90%, respectively. Conclusions: 3D radiomic texture features of conventional MRI successfully discriminated pseudoprogression from true progression in a large cohort of GBM patients.
Low grade glioma patients with IDH mutation and 1p19q codeletion: To treat or not to treat?
Authors: Franceschi Enrico , De Biase Dario , Paccapelo Alexandro , Mura Antonella , Tosoni Alicia , Bartolini Stefania , Tallini Giovanni , Pession Annalisa , Danieli Daniela , Rossi Sabrina , Bartolini Daniela , Gardiman Marina Paola , Volpin Lorenzo , Ramponi Vania , Fioravanti Antonio , Foschini Maria Pia , Di Oto Enrico , Minichillo Santino , Pizzolitto Stefano , Brandes Alba Ariela
Published: September 2018

2017

Background: Molecular characterization of low grade gliomas (LGG) is essential for diagnosis and treatment of these diseases. LGG patients (pts) with IDH mutation and 1p19q codeletion (codel) are characterized by a median OS (mOS) longer than 10 years. Thus, the role of treatments and side effects should be carefully evaluated. Methods: We evaluated LGG pts from our data warehouse (n=679 pts) who received surgery and had sufficient tissue to assess biomarkers characterization. Pts with gliomatosis were excluded. IDH1/2 assessment was performed on formalin-fixed paraffin-embedded samples by qPCR. In wild type cases we performed NGS. 1p/19 codel analysis was performed by FISH. Results: 93 consecutive LGG with IDH mutation and codel were included. The median follow up (FU) was 96.1 months. Mean age was 40 yrs (range: 25-66); 8 pts (8.6%) underwent biopsy, 61 pts (65.6%) partial resection, 24 pts (25.8%) complete resection. 84 pts (90.3%) were considered high risk using RTOG criteria (>40 years and/or incomplete resection). Fifty pts (53.7%) received only FU, 17 pts (18.3%) received chemotherapy (CT), 18 pts (19.4%) received radiotherapy (RT), 8 pts (8.6%) received RT + CT. Median PFS (mPFS) was 59.6 months (95%CI: 41.8-77.4) and was significantly longer in pts who received postsurgical treatments (79.5 months, 95%CI: 66.4-92.7) than pts who received FU (46.3 months, 95%CI: 36.0-56.5; P=0.001). mPFS was 50.8 months (95%CI: 17.4-84.3), 103.6 months (95%CI: 11.7-195.6) and 120.2 months (95%CI: 40.5-199.8) in pts treated with CT alone, RT alone and RT + CT, respectively. Multivariate analysis showed that receiving a post-surgical treatment (P<0.001), and the extent of resection (P=0.043) were significantly correlated with PFS. Conclusions: Our study evaluated the role of treatments in LGG pts assessed with NGS and FISH. Post-surgical treatments are crucial to extend PFS in pts with IDH mutation and codel. The choice of post-surgical treatments seems to have a role, being CT alone less effective than RT and RT+CT. Longer FU is needed to provide information about OS.
Association of aggressive resection with survival and progression-free survival in adult low-grade glioma: A systematic review and meta-analysis with numbers needed to treat.
Authors: Brown Timothy J , Bota Daniela Annenelie , Maher Elizabeth A. , Aregawi Dawit Gebremichael , Liau Linda M. , Brown Paul D. , Buckner Jan C. , Weller Michael , Van Den Bent Martin J. , Berger Mitchel S. , Glantz Michael J.
Published: September 2018

2025

Background: Low-grade gliomas (LGG) account for 17-22% of all primary brain tumors. Optimal surgical management consists of optimum safe resection with the goal of complete resection. We performed a systematic review and meta-analysis to quantify the association of extent of resection with likelihood of survival, expressing our results in numbers needed to treat (NNT). Methods: A systematic review and study-level meta-analysis to determine the association of resection with overall survival and progression-free survival in newly diagnosed, supratentorial LGG in adults was performed by querying PubMed. Data were extracted to compare gross total resection (GTR) to subtotal resection (STR) and STR to biopsy (Bx) to determine relative risks (RR) of death and progression at 2, 5, and 10 years. Data were analyzed using a random effects model. NNT were calculated from significant comparisons and rounded up to the nearest whole number. Quality of evidence was determined by American Academy of Neurology criteria. Results: The systematic review resulted in 283 potential studies. Ultimately 29 studies were included in at least one comparison. There were no high quality (class I and II) or prospective studies discovered in the review. Comparing GTR to STR, RR with 95% confidence intervals (CI) of death at 2, 5, and 10 years, and NNT to avoid one death at 2, 5, and 10 years (GTR vs. STR) were 0.29 [0.17-0.52, p < 0.0001, NNT 17], 0.39 [0.29-0.51, p < 0.00001, NNT 6], and 0.50 [0.35-0.70, p < 0.0001 NNT 4]. RR and NNT for progression (GTR vs. STR) at 2, 5, and 10 years were 0.37 [0.24-0.57, p < 0.0001 NNT 7], 0.50 [0.39-0.64, p < 0.0001 NNT 4], and 0.67 [0.53-0.84, p = 0.0005 NNT 4]. Comparing STR to Bx, RR of death at 2, 5, and 10 years were 0.55 [0.34-0.88, p = 0.01 NNT 10], 0.9 [0.61-1.34], and 0.95 [0.73-1.23]. Conclusions: Increasing resection thresholds appear to be associated with improved overall and progression free survival, but the body of literature consists of low quality studies. Prospective studies are required to explore whether extent of resection matters or whether resectable tumors share a favorable biology associated with better outcome.
A cellular platform to enable targeted brain delivery of T cells to glioblastoma.
Authors: Samaha Heba , Pignata Antonella , Fousek Kristen , Byrd Tiara , Lam Fong , Stossi Fabio , Marelli Sean , Shum Thomas , Joseph Sujith , Hegde Meenakshi , Ahmed Nabil M.
Published: September 2018

2053

Background: Poor T cell homing hinders the development of effective cell therapy for central nervous system (CNS) malignancies. Lessons learnt from inflammatory brain diseases can give insight into how to overcome the blood brain barrier (BBB) blockade created by cancer. Activated Leukocyte Cell Adhesion Molecule (ALCAM; CD166) is a pathological adhesion molecule upregulated in the endothelium of a number of inflammatory/infiltrative CNS diseases, such as multiple sclerosis. Antibodies blocking ALCAM decrease leukocyte access to the brain and are currently being tested in a clinical trial for MS. Methods: We studied the difference in the dynamic signature of adhesion molecules in the “anergic” brain tumor endothelium and that of infiltrative brain conditions. Consequently, we mapped the ALCAM minimal binding region to domain 3 (D3) of CD6 and created an artificial molecule with the intent of creating a novel cellular platform to reverse endothelial anergy, through ALCAM specific binding. Results: GBM endothelium fails to launch the second wave of adhesion molecules necessary for firm T leukocyte capture and effective BBB transmigration. Engineered D3 on the T cell crosslinked to ALCAM on endothelial cells in proximity ligation assays (PLA; < 40nm) during TEM. Under shear stress, D3 T cells showed a global improved ALCAM specific trafficking kinetics: higher capture on ALCAM+ endothelium, rolling with slower velocity, and better TEM. In an ex vivo model of BBB, D3 T cells exhibited higher transmigratory ability. We discovered that signaling through the D3 endodomain phosphorylated pZAp70 recruiting Talin that enables LFA-1 (ICAM-ligand) open confirmation, mediating effective TEM. Lastly, in an orthotopic model of GBM, D3 T cells homed more and accumulated at the tumor site compared to NT controls. And, testing Her2 CAR T cells on D3 platform showed an advantageous homing after IV administration which was reflected in tumor control and better survival. Conclusions: We created a cellular platform that enables targeted brain delivery of T cells. This platform serves as a gateway to the effective cellular therapeutics for brain malignancies but potentially as a delivery system for complex biologics for other pathological conditions.
Activity of cabazitaxel in temozolomide refractory glioblastoma: Final results of a phase 2 study (C-GBM study; EudraCT 2013-001550-98 NCT 01866449).
Authors: Heinrich Bernhard , Schlenk Richard F , Brudler Olaf Lothar , Edenhofer Simone , Scheuerle Angelika , Naumann Ralph , Mayer-Steinacker Regine , Bangerter Markus , Bullinger Lars
Published: September 2018

2056

Background: Following progression on Temozolomide (TMZ) glioblastoma (GBM) is a therapeutic challenge with a 6 month survival rate of only ~20-30% and no well-established 2nd line treatments. Methods: We designed a phase II study to assess the efficacy of cabazitaxel, a second generation taxoid, in TMZ-refractory GBM pts (pts). Primary enpoint was response at 12 weeks of treatment. Secondary endpoints were overall survival (OS), quality of life, and pharmacokinetics. The study population were pts with progressive GBM during or within 6 months after TMZ treatment, in whom radiotherapy and surgery was no treatment options. Exclusion criteria were signs of inflammation, an ECOG performance score (PS) > 2, as well as impaired organ function. Patient characteristics: In total, between 2014 and 2016 8 female and 16 male pts were included with a median age of 55 years (range 32-76 years) and a median of 3 previous therapies (range 1-9). Treatment: Cabazitaxel was given at 25mg/m² q3w with G-CSF prophylaxis. Every two cycles response assessment was performed (MRI). Treatment was discontinued in case of i) progressive disease (RANO criteria), ii) PS≥3, or iii) persistent toxicity. Results: Five pts went off study prior to the first MRI assessment due to progressive disease, while 19 of 24 of pts could be evaluated for response after 2 cycles. We did not observe any objective response (i.e. complete or partial remission). In 7 pts a stable disease (SD) was obtained; 12 pts had progressive disease. Of the 7 SD pts, 4 progressed after 4 cycles of treatment and the remaining pts remained in SD for 6, 10 and 12 cycles, respectively. The median OS was 155 days. Toxicity was manageable by G-CSF application in pts with CTC grade 3/4 neutropenia/leukopenia in 12 pts. Non-hematological toxicity CTC grade 3/4 comprised infection (n = 2), diarrhea (n = 2), vaginal bleeding (n = 1) and hypokalemia (n = 1). Conclusions: Cabazitaxel shows only marginal activity in TMZ refractory GBM with a disease stabilization rate following 4 cycles of only 12.5% in heavily pretreated GBM pts and median OS of 155 days. Clinical trial information: NCT 01866449.
Quantifying the benefit of chemotherapy and radiation in low-grade glioma: A systematic review and meta-analysis of numbers needed to treat.
Authors: Brown Timothy J , Bota Daniela Annenelie , Maher Elizabeth A. , Aregawi Dawit Gebremichael , Liau Linda M. , Brown Paul D. , Buckner Jan C. , Weller Michael , Van Den Bent Martin J. , Berger Mitchel S. , Glantz Michael J.
Published: September 2018

2057

Background: The optimal role of chemotherapy and radiation (RT) in adult low-grade glioma (LGG, WHO grade 1 & 2) is unclear. We conducted a systematic review and study-level meta-analysis of the literature on overall survival (OS) and progression free survival (PFS) in patients with LGG. Methods: Pubmed was queried with MeSH terms. All comparative studies of adults with newly diagnosed, supratentorial LGG were included. Comparisons of interest were OS and PFS at 2, 5, and 10 years in chemotherapy versus no chemotherapy and early RT versus delayed or no RT. Data were extracted from studies and synthesized with a random effects model. Quality of evidence was determined by American Academy of Neurology criteria and further analysis was performed, separating high quality (class I and II) from low quality (class III and IV) evidence. Numbers needed to treat (NNT) were determined from the risk difference. Results: 1531 articles were screened; 18 studies were included. Chemotherapy was not associated with a significant survival advantage compared to control. However, an analysis of high quality data revealed a survival advantage at 10 years associated with chemotherapy compared to control with NNT 5 (relative risk death chemo vs control 0.69 [0.56-0.86] p = 0.0006). Furthermore, NNT to prevent one progression with chemotherapy at 5 and 10 years was 6 and 3, respectively. Early RT was not associated with an OS advantage compared to control. However, early RT had progression benefit at all time points, with NNT of 10, 6, and 5 at 2, 5, and 10 years. Conclusions: Further study will be needed to confirm the optimal role of chemotherapy and RT. Caution must be used in interpretation as much of the literature consists of low-quality studies. [Table: see text]
Effect of treating glioblastoma with a cytokine inhibitor, ibudilast, in combination with temozolomide on survival in a patient-derived xenograft model.
Authors: McDonald Kerrie Leanne , Ha Wendy , Sevim Hatice , Matsuda Kazuko , Khasraw Mustafa
Published: September 2018

2062

Background: Recurrence in patients with glioblastoma (GBM) is inevitable, even in patients with O-6-Methylguanine-DNA Methyl Transferase ( MGMT) methylation. We identified increased expression of the inflammatory cytokine, Macrophage Inhibitory Factor (MIF) and its receptor CD74 in patients with recurrent tumors. High levels of MIF and CD74 were associated with poor overall survival in GBM patients. This study aims to determine efficacy of Ibudliast (MN-166; 3-isobutyryl-2-isopropylpyrazolo-[1,5-a]pyridine) to block MIF expression and decrease tumor burden. Ibudilast is an anti-inflammatory drug that was developed for the treatment of bronchial asthma. Methods: The patient derived cell lines (PDCLs) RN1 ( MGMT unmethylated), BAH1 ( MGMT methylated), and HW1 ( MGMT methylated) were treated in vitrowith different concentrations of ibudilast in combination with temozolomide (TMZ). Patient derived xenograft (PDX) models of GBM were developed and treated with the combination of ibudilast and TMZ. Overall survival was calculated. Results: Regardless of MGMT status, significant synergism between ibudilast and TMZ was observed in the PDCLs. Efficacy was associated with significantly decreased expression of its targets, MIF and CD74. Downstream proteins such as Src and Akt were also significantly inhibited. The combination induced apoptosis. RN1 tumors were established intracranially in Balb/c nude mice. Significant increases in survival times of the mice were recorded when treated with the combination. Conclusions: Ibudilast in combination with TMZ resulted in significant blockage of MIF expression, increased apoptosis and longer survival in vivo. A human pilot study for recurrent GBM patients is underway.
The value of 18F-fluordesoxyglucose positron emission tomography (FDG-PET/CT) in the detection of the primary lesion and for staging in brain metastasis (BM) patients with cancer of unknown primary site (CUPS).
Authors: Le Rhun Emilie , Weller Michael , Berghoff Anna Sophie , Rushing Elisabeth Jane , Fuereder Lisa , Petyt Gregory , Leske Henning , Andrastschke Nicolaus , Regli Luca , Neidert Marian Christoph , Stupp Roger , Dummer Reinhard , Frauenfelder Thomas , Roth Patrick , Reyns Nicolas , Kaufmann Philipp Antonio , Preusser Matthias , Wolpert Fabian
Published: September 2018

2076

Background: Brain metastasis (BM) are the first clinical presentation of cancer in around 30% of patients. They are then referred as BM from cancer of unknown primary site (BM-CUPS). The value of 18F-fluordesoxyglucose positron emission tomography (FDG-PET)/CT has not yet be determined for the management of these patients. Methods: A total of 566 patients were operated for BM at the University Hospital Zurich between 2004 and 2014, of whom 127 were identified as BM-CUPS patients. Two cohorts from other independent centers (n = 100 and 120) were used for the validation of data. Results: No difference in determining the localization of the primary lesion was observed between FDG-PET/CT and CT (FDG-PET/CT: 73/78, 93.6%; CT: n = 70/78, 89.7%; p = 0.25, McNemar’s test). The same pattern of primary lesion and other extracranial lesions was observed in 36 of 64 patients (56.3%). Additional suspicious extracranial metastases were identified by FDG-PET/CT in 28 patients (43.7%). The median graded prognostic assessment (GPA) scores were 2.5 determined according to FDG-PET/CT and 3 according to CT alone (p = 3.8x10-5), resulting in predicted survival times of 3.8 versus 5.3 months (p = 6.1x10-5; Wilcoxon’s test). Conclusions: A similar sensitivity of FDG-PET/CT and chest CT was observed for the detection of the primary tumor in BM-CUPS, however, FDG-PET/CT significantly improved the accuracy of staging. FDG-PET/CT should be preferred for the management of BM-CUPS and may help to avoid redundant CT imaging.
Outcomes from 735 patients with breast cancer brain metastases (BM) according to biological subtype, number of BMs, and systemic treatment after local therapy.
Authors: Niwinska Anna , Pogoda Katarzyna , Rudnicka Halina , Jagiello-Gruszfeld Agnieszka Irena , Rybski Sebastian , Nowecki Zbigniew
Published: September 2018

2078

Background: To assess survival when BM is detected according to the biological subtype of breast cancer, number of BMs and systemic treatment after local therapy. Methods: Subjects were 735 consecutive breast cancer patients with BM treated during 2003-2015. Whole brain radiotherapy was undertaken in 97%, neurosurgery -19% and systemic therapy was performed in 74% cases. The biological subtypes: triple-negative (TNBC), HER2+ER/PR-, HER2+/ER/PR+ and ER/PR+HER2- (Luminal) were determined in 714 subjects. Survival after BM detection was assessed in the entire group, in patients with a single BM (1 brain lesion regardless of metastases in other organs) and those with a solitary brain metastasis (1 brain lesion but no metastases in other organs). Factors influencing survival upon detecting BM were assessed by Cox multivariate analysis. Results: The median survivals for all patients with TNBC, HER2+ER/PR-, HER2+/ER/PR+ and Luminal breast cancer BM were respectively 4, 8, 10 and 9 months (p < 0.001). In those both treated and untreated systemically within the TNBC, HER2+ER/PR-, HER2+/ER/PR+ and Luminal subtypes survivals were correspondingly 6, 10, 14, 11 and 2, 3, 2, 2 months (p < 0.001). Median survivals of 171 patients with a single BM treated and untreated systemically were respectively 15 and 5 months (p < 0.001). Median survivals of 70 patients with solitary BM treated and untreated systemically were respectively 28 and 6 months (p < 0.001). In patients with solitary brain metastasis, median survival within the TNBC, HER2+ER/PR-, HER2+/ER/PR+ and Luminal subtypes, with systemic treatment was respectively 16, 28, 28, 28 months and without systemic treatment 6, 7, 7 and 7 months (p < 0.001). Conclusions: Patients with TNBC and BM had the worst prognosis. Systemic treatment performed after local therapy is an important factor prolonging survival of patients with breast cancer BM, even in those with solitary brain metastasis. Based on the present evidence and our recent publication, systemic treatment should be performed in all patients with BM after local treatment, even those with brain metastases as an isolated recurrence.
Initiative for Molecular Profiling and Advanced Cancer Therapy (IMPACT): An MD Anderson precision medicine study.
Authors: Tsimberidou Apostolia Maria , Hong David S. , Cartwright Carrie , Wheler Jennifer J. , Falchook Gerald , Naing Aung , Fu Siqing , Piha-Paul Sarina Anne , Janku Filip , Hwu Patrick , Kee Bryan K. , Kies Merrill S. , Broaddus Russell , Mendelsohn John , Hess Kenneth R. , Kurzrock Razelle ,   ASCO Authors
Published: September 2018

2513

Background: We present outcomes for 637 patients who were referred for phase I trials and were treated under IMPACT. Methods: Patients with advanced, refractory cancer who had tumor genomic analyses were treated with matched targeted therapy (MTT) when available. Results: Overall, 1,179 (82.1%) of 1,436 patients had ≥1 alteration (median age, 59.7 yrs; men, 41.2%); 637 had ≥1 actionable aberration and were treated with MTT (n=390) or non-MTT (n=247). Patients treated with MTT had higher rates of CR and PR (11% vs. 5%; p=.0099) (Table), longer failure-free survival (FFS) (3.4 vs. 2.9 months; p=.0015), and longer overall survival (OS) (8.4 vs. 7.3 months; p = .041) than unmatched patients. Two-month landmark analyses showed that, for MTT patients, FFS for responders vs. non-responders was 7.6 vs. 4.3 months (p<.0001) and OS was 23.4 vs. 8.5 months (p<.0001); for non-MTT patients (responders vs. non-responders), FFS was 6.6 vs. 4.1 months (p=.0005) and OS was 15.2 vs. 7.5 months (p = .43). Patients with both PI3K and MAPK pathway alterations matched to PI3K/Akt/mTor axis inhibitors alone showed outcomes comparable to unmatched patients. Conclusions: Matched versus unmatched patients had significantly better outcomes. For matched responders, median survival reached almost two years. However, matching patients who harbor both a PI3K and a MAPK pathway alteration to only a PI3K pathway inhibitor did not improve outcome. Clinical trial information: NCT00851032. [Table: see text]
Pharmacokinetic-driven phase I study of DCC-2618 a pan-KIT and PDGFR inhibitor in patients (pts) with gastrointestinal stromal tumor (GIST) and other solid tumors.
Authors: Janku Filip , Abdul Razak Albiruni Ryan , Gordon Michael S. , Brooks David Glenn , Flynn Daniel Lee , Kaufman Michael , Pitman Jama , Smith Bryan Douglas , Somaiah Neeta , De Groot John Frederick , Chen Guo , Jennings Julia , Salah Samer , Westwood Deb , Gerstenberger Eric , Rosen Oliver , George Suzanne
Published: September 2018

2515

Background: DCC-2618 is a potent switch control inhibitor of KIT and PDGFR kinases active in a broad range of mutations. GIST is an important disease to achieve a proof-of-concept due to the heterogeneity of KIT resistance mutations, which emerge on treatment with approved KIT inhibitors. Methods: This was a PK-guided dose escalation study of oral DCC-2618 (QD or BID q28 days) in advanced solid tumors. FDG-PET scans were used to assess changes in FDG uptake in GIST pts after 3 wks of therapy. Next generation sequencing (NGS) of plasma cell-free (cf) DNA was performed throughout the study to assess and quantify KIT and other molecular alterations in drug targets and potential mechanisms of resistance. Results: 38 pts were enrolled (30 GIST; 4 glioma; 1 mastocytosis, 3 other carcinoma) to 8 dose levels: BID doses: 20 (4 pts), 30 (4), 50 (5), 100 (6), 150 (6) and 200 mg (3); QD doses: 100 (5) and 150 mg (4). Safety of evaluable pts is as follows: G3 or G4 adverse effects (regardless of attribution and occurring in > 1 pt) included anemia (5), lipase increase (4), hypertension (2). Two of the G3/4 lipase increase at 100 mg BID and 200 mg BID were DLTs. All G3/4 lipase increase were asymptomatic. G1/2 AEs (considered at least possibly related to DCC-2618) and occurring in ≥15% (n > 5) of pts include fatigue (12), alopecia & lipase increase (7), weight decrease (6). Starting with 50 mg BID dose level, trough concentrations of total drug exceeded the IC90 of the least sentivitive KIT mutations. Plasma concentrations > 5μM were achieved starting at 100 mg BID and the selection of the expansion phase dose is being finalized. Of 18 pts with KIT mutant GIST assessed by FDG PET, 14 (78%) had partial metabolic response per EORTC criteria. RANO/RECIST partial responses (PRs) were reported in 3 patients (1 GBM with PDGFRA/KIT amplifications and 2 GIST with Ex 11 & 17 / Ex 11 & 18 mutations, respectively). NGS of plasma cfDNA revealed 44 KIT mutations in baseline samples from 19 of 21 pts with GIST. Conclusions: DCC-2618 is well tolerated with encouraging preliminary activity in GIST pts with a broad spectrum of mutations and prior therapies. PR was also seen in a pt with GBM with PDGFRA/KIT amplifications. Clinical trial information: NCT02571036.
Phase 1 study of ARQ 761, a β-lapachone analog that promotes NQO1-mediated programmed cancer cell necrosis.
Authors: Gerber David E. , Bisen Ajit Kumar , Beg Muhammad Shaalan , Frankel Arthur E. , Fatunde Oluwatomilade , Fattah Farjana , Arriaga Yull Edwin , Dowell Jonathan , Meek Claudia , Bolluyt Joyce D. , Sarode Venetia , Luo Xin , Xie Yang , Schwartz Brian E. , Boothman David A. , Leff Richard
Published: September 2018

2517

Background: NAD(P)H:quinone oxidoreductase 1 (NQO1) is a two-electron oxidoreductase expressed in multiple tumor types at levels 5- to 200-fold above normal tissue. ARQ761 is a β-lapachone hydroquinone analog that exploits the unique elevation of NQO1 found in solid tumors to cause tumor-specific cell death by eliciting a futile redox cycle generating high levels of reactive oxygen species and ultimately PARP1 hyperactivation-dependent cell death. Methods: 3+3 dose escalation study of 3 schedules (weekly, every other week, 2/3 weeks) of ARQ 761 as a 1-hr or 2-hr infusion. Eligible patients had refractory advanced solid tumors, ECOG 0-1, adequate organ function, and central venous access. Blood samples were analyzed for ARQ761 levels and NQO1 polymorphisms. Archival tumor tissue was analyzed for NQO1 staining intensity and prevalence. After 18 patients were analyzed, enrollment was restricted to patients with NQO1-positive tumors (defined as Histo-score ≥200). Results: A total of 42 patients were treated. Median number of prior lines of therapy was 4. For all schedules, the maximum tolerated dose (MTD) was 390 mg/m2 as a 2-hr infusion. DLT was hemolytic anemia. The most common treatment-related adverse events were anemia (79%), fatigue (45%), hypoxia (33%), hemolysis (17%), nausea (17%) and vomiting (17%). Transient grade 3 hypoxia, due to methemoglobinemia, occurred in 26% of patients. Among 31 evaluable patients, the best response was stable disease (n = 11) and progressive disease (n = 19). For the 18 analyzed cases analyzed prior to NQO1 enrollment biomarker, clinical benefit appeared associated with tissue NQO1 expression: disease control rate was 65% in NQO1-positive tumors and 18% in NQO1-negative tumors ( P=0.06). Analysis of all 31 evaluable patients did not show a significant difference in progression-free survival (PFS) according to NQO1 status ( P=0.26), but 3-mo PFS rate was numerically greater among NQO1-positive cases (40% versus 20%). Conclusions: ARQ 761 has clinical activity in NQO1-positive tumors. Principal toxicities include hemolytic anemia and methemoglobinemia. Combination studies are underway.
Effect of target lesions selection on between-reader variability of response assessment according to RECIST 1.1.
Authors: Kuhl Christiane K. , Alparslan Yunus , Sequeira Bruno , Schmoe Jonas , Engelke Hannah , Keulers Annika , Bruemmendorf Tim , Keil Sebastian
Published: September 2018

2528

Background: Response-classification-systems, e.g. RECIST1.1, and dedicated oncology software-tools (DOST) are used to standardize response assessment. Expectation is that different readers should yield the same response-classification for any given patient. We investigated real-life variability between readers who, as in clinical practice, were free to select target-lesions (TL). Methods: Prospective study on 316 patients with metastatic disease who underwent 932 CT-studies, yielding a total 616 follow-up occasions (baseline vs. follow-up) for analysis. All CT-studies were independently evaluated by 3 radiologists who used state-of-the-art DOST (MintLesion). Readers were free to select TL in the respective baseline study, and did so independently. Kappa-statistics were used to analyse agreement for RECIST1.1 response-class-assignment depending on whether readers had selected the same or different TL.To investigate possible impact on treatment decisions, agreement was also determined after aggregating response classes into progressive (PD) vs. non-progressive (CR/PR/SD). Results: Readers used the same TL in 38.6 (238/616), different in 61.4% (378/616). Where readers happened to select the same TL, agreement was “almost perfect” (κ = 0.966 [96%-CI: 0.912–1.00] for assignment of individual response-classes, and 0.977 [0.898–1.0] for the distinction progressive-vs-non-progressive). Where readers had selected different TL, agreement was only “moderate” (0.583 [0.541–0.624] for individual response-class-assignment, and 0.644 [0.587 to 0.701] for distinction progressive-vs.-non-progressive). Choice of the same TL was associated with agreement for distinction between progressive-vs.-non-progressive-disease in 97.7 % [95.4%–100.0%] of patients; choice of different TL was associated with disagreement in 44.7% [37.6%–51.8%]. Conclusions: If different radiologists use RECIST1.1 and DOST for response assessment, they will select different TL more often than not. Just depending on whether TL selection was concordant or not, radiologists will exhibit perfect agreement, or substantial disagreement, even for distinguishing progressive vs non-progressive disease.
Validation of RECIST 1.1 for use with cytotoxic agents and targeted cancer agents (TCA): Results of a RECIST Working Group analysis of a 50 clinical trials pooled individual patient database.
Authors: Litière Saskia , Isaac Gaëlle , De Vries Elisabeth , Bogaerts Jan , Chen Alice P. , Dancey Janet , Ford Robert , Gwyther Steve J , Hoekstra Otto S. , Huang Erich , Lin Nancy U , Liu Yan , Mandrekar Sumithra J. , Schwartz Lawrence HOWARD , Shankar Lalitha , Therasse Patrick , Seymour Lesley ,   RECIST Working Group
Published: September 2018

2534

Background: The Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 were derived from an international collaborative effort supported by data from clinical trials (16 studies, 9147 patients) on cytotoxic chemotherapy (CT), providing a standard tool for response assessment. RECIST’s role has been questioned for TCA. Using a pooled individual patient database (IPD) from clinical trials performed by industry and cooperative groups, we assessed whether modifications to RECIST are required to evaluate antitumor activity of TCA. Methods: Data were collected from phase 2 and 3 clinical trials testing TCA in solid tumors. To study the occurrence of mixed responses, the variability of response of lesions within patients was studied. Furthermore, response was correlated with survival through landmark analyses and time dependent Cox models. Results: Clinical data were obtained from 23,259 patients, mainly with lung (36%), colorectal (28%) or breast cancer (11%). 15,620 patients (67%) received a TCA, mainly transduction or angiogenesis inhibitors, either as single agent (37%) or combined with other TCAs (7%) or CT (56%); 28% received CT only and 5% best supportive care or placebo. Within-patient variability reduced as the number of lesions used for response assessment increased, and did so similarly for TCAs (+/- CT) and CT. Mixed responses seemed to occur similarly across these treatment categories as well. Landmark analyses showed improving overall survival by % tumor shrinkage and a clear distinction between the effect of tumor shrinkage and progressive disease (PD) according to RECIST 1.1. This was confirmed by time dependent analysis. In addition target lesion growth showed no marked improvement in overall survival prediction over and above the other components of RECIST 1.1 PD (new lesions, non-target PD), regardless of treatment (TCA, CT or both) received. Similar results were seen focusing on major tumor types and classes of TCA. Conclusions: Using a large IPD dataset we demonstrated that RECIST 1.1 performs equally well for response assessment of TCA as for CT. No modifications are required.
The Drug Rediscovery Protocol (DRUP).
Authors: Van Der Velden Daphne Liselotte , Hamming Lisanne C. , Verheul Henk M.W. , Bloemendal Haiko , Grunberg Katrien , Huitema Alwin , Lugtenburg Pieternella J. , De Vos Filip Yves Francine Leon , Gelderblom Hans , Voest Emile E. ,   Center for Personalized Cancer Treatment (CPCT)
Published: September 2018

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Background: Bringing precision medicine to cancer patients remains a challenge. For many cancers, the relative contribution of tumor type, mutations or CNV to drug sensitivity remains unknown. In addition, drug access is generally limited to the labeled indication, bypassing rarer disease subgroups for which large trials are not feasible. An innovative trial that facilitates drug access, whilst systematically analyzing treatment outcomes and biomarkers, could help overcome these challenges. Methods: We designed a prospective, non randomized clinical trial in which patients with advanced cancer are treated with targeted or immunotherapy matched to their tumor profile, defined by genetic aberration, microsatellite instability (MSI) or high mutational load (HML). Upon a mandatory pre-treatment tumor biopsy for biomarker research, patients are enrolled in multiple parallel cohorts, each defined by study drug, histologic tumor type and molecular tumor profile. Efficacy is analyzed per cohort, enrolling 8 patients in stage I and 16 more in stage II if ≥1 response is observed in stage I. Study endpoints include objective tumor response (CR or PR), stable disease (SD) at 16 weeks and grade≥3 adverse events. The DRUP is registered at ClinicalTrials.gov (NCT02925234). Results: Since start of recruitment in Sep 2016, 76 patients have been submitted for review (mean per month 15, range 8-17) and 16 (21%) have started treatment in 10 different cohorts, directed at either ATM (n = 1; breast cancer), BRAF (n = 2; salivary duct carcinoma and ACUP), BRCA (n = 1; breast cancer), ERBB2 (n = 2; CRC), HML (n = 2; prostate and CRC), MSI (n = 5; CRC, GBM and urothelial carcinoma), RET (n = 1; NSCLC) or RAS-RAFwt (n = 2; SCC and sarcoma). Out of the 7 patients for whom response evaluation is available, PR (n = 2) or SD at 16 weeks (n = 1) was observed in 3 (43%). Thirteen study drugs (supplied by 6 pharmaceutical companies) are currently available, 6 more are expected soon. Conclusions: Execution of a nationwide multidrug precision oncology trial is feasible. It contributes to oncologists’ education on molecularly targeted therapies and to identification of early signs of activity in rare cancer subsets. Data sharing with similar studies such as TAPUR and CAPTUR will help to enlarge cohorts and affirm conclusions. Clinical trial information: NCT02925234.
Phase I study combining MLN8237 with nab-paclitaxel in patients with advanced solid malignancies.
Authors: Lim Kian-Huat , Lockhart Albert C. , Waqar Saiama Naheed , Govindan Ramaswamy , Morgensztern Daniel , Picus Joel , Tan Benjamin R. , Baggstrom Maria Quintos , Ratchford Emily , Marquez Samantha , Wang-Gillam Andrea
Published: September 2018

2553

Background: MLN8237 is a potent Aurora A kinase inhibitor which synergizes with paclitaxel in preclinical studies for various solid malignancies. Methods: We conducted a two-part, phase 1 study combining MLN8237 with nab-paclitaxel in patient with advanced, refractory solid malignancies (NCT01677559). The part 1, dose-escalation phase utilizes a standard a 3+3 design for determination of maximum tolerated dose (MTD) and dose limiting toxicities (DLTs), starting from nab-Paclitaxel 100mg/m2/week 3 out of a 4-week cycle, and MLN8237 20mg BID D1-3/week (denoted nP/M 100/20). In the part 2, dose-expansion cohort, patients with advanced pancreatic ductal adenocarcinoma (PDAC) or high grade neuroendocrine tumor (pNET) who progressed on standard chemotherapy were enrolled. Results: Totally 33 patients (17 in part 1 and 16 in part 2) with a median age of 61 were enrolled. In part 1, the most frequent treatment-related toxicities (all Grade/Grade 3-4) were: nausea (65%/6%), neutropenia (61%/18%), fatigue (47%/6%), anorexia (47%/0%), oral mucositis (53%/6%) and anemia (35%/18%). Two of 3 patients experienced a DLT at dose nP/M 100/50 (Grade 4 neutropenia; febrile neutropenia). No treatment-related mortality occurred. MTD was set at nP/M 100/40 for part 2. At data cutoff, totally 20 patients from the entire study were evaluable for treatment response. One patient with small cell lung cancer achieved partial response and is in cycle 29. Nine other patients (9/20, 45%) with the following tumor histology achieved stable disease after two cycles: 1 small cell lung cancer, 1 lung neuroendocrine carcinoma, 1 lung squamous cell carcinoma, 1 PDAC and 5 high grade pNET (range: 3 and ongoing ~ 18 cycles). Conclusions: MLN8237 plus nab-paclitaxel has manageable side effect profile with very promising activity in tumors with high grade neuroendocrine features, warranting further testing. Exploratory studies on pharmacodynamic markers are ongoing. Clinical trial information: NCT01677559.
Final report of a phase I study of 2-hydroxyoleic acid (2OHOA) a novel sphingomyelin synthase activator in patients (pt) with advanced solid tumors (AST) including recurrent high grade gliomas (rHGG).
Authors: Azaro Analia , Plummer Elizabeth R. , Urruticoechea Ander , Rodon Jordi , Haris Noor R Md , Veal Gareth , Perier Antoine , Tur Vicenc , Escriba Pablo V. , Busquets Xavier , Alberti Joan , Sicart Elisabet , Collins Dearbhaile , Fernandez Ricardo , Bettenhaussen Evelyne , Klumper Edwin , Lopez Juanita Suzanne
Published: September 2018

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Background: 2OHOA is an orally bioavailable, first-in-class synthetic hydroxylated fatty acid, that activates SGMS1 and modulates the lipid content of cancer cell membranes. This regulates the localization of key signaling proteins, including Ras and PKC at the plasma membrane, leading to inactivation of Ras/MAPK, PI3K/Akt and PKC/cyclin/CDK signaling pathways. A dose escalation (DE) and partial expansion cohorts (EC) results of the phase 1 study have previously been reported. We now present the final results of the study. Methods: 2OHOA was evaluated in a 3+3 DE design (7 cohorts from 500mg/d to 16000mg/d) and 2 EC at 4000mg TID in 21 days cycles. PK profiles were determined after single dose (fasted [D-7] or fed [D1]) and multiple doses (fed [D21]) during DE phase and only on D1 throughout EC.Safety assessments were based on CTCAEv4.Tumor response was measured by RECIST and RANO every 6 weeks. Results: Overall 54 pt (DE: 32 pt; 21AST/11rHGG; EC: 22 pt; 12 AST/10 rHGG) were treated (median age 60, range 19-78 years). During the EC the most common treatment related G1-G2 toxicities were diarrhea (n = 13;11pt),nausea (n = 7;6pt), ALT increase (n = 6;4pt), pruritus in throat (4pt), fatigue (4pt) and vomiting (3pt). No G3-G4 toxicities or DLTs were reported confirming the MTD from the DE at 4g TID. Food intake did not alter oral 2OHOA bioavailability. Steady state was already achieved at D8. Power model showed dose proportionality in terms of AUC and Cmax, after single and multiple BID dosing. Average t1/2 ranged from1-2h to 8-12h with delayed Tmax and longer half-lives at higher doses. One glioblastoma (GBM) pt had sustained partial response ( > 2,5 years) and 4rHGG pt (3 GBM) achieved stable disease for at least 6 months. They had previously received 2 lines of treatment without bevacizumab. Tumor markers were measured and will be presented. Conclusions: 2OHOA is well tolerated at the P2RD of 4000mg TID PO daily. The preliminary antitumor activity including a sustained PR in heavy pretreated rHGG pt warrants further investigation in a Ph2 study Clinical trial information: NCT01792310.
GMI-1271, a novel E-selectin antagonist, combined with induction chemotherapy in elderly patients with untreated AML.
Authors: DeAngelo Daniel J. , Jonas Brian Andrew , Becker Pamela S. , O'Dwyer Michael , Advani Anjali S. , Marlton Paula , Magnani John , Thackray Helen M. , Liesveld Jane
Published: September 2018

2560

Background: The outcomes for elderly patients (pts) with acute myeloid leukemia (AML) remain poor, therefore newer and less toxic therapies are urgently needed. The binding of E-selectin (E-sel), an adhesion molecule expressed in the bone marrow, to the leukemic cell surface activates survival pathways and promotes chemotherapy resistance. GMI-1271, a novel E-sel antagonist, enhances chemotherapy responses and protects from common toxicities in preclinical models (Becker ASH 2013; Winkler ASH 2013 and 2014). We report interim Phase 2 data for GMI-1271 plus chemotherapy in elderly untreated pts with AML. Methods: Pts ≥ 60 yrs with untreated AML, ECOG 0-2, and adequate renal and hepatic function were eligible. Prior treatment of MDS was allowed. GMI-1271 (10 mg/kg) was given 24 hrs prior, during and 48 hrs post induction with infusional cytarabine and idarubicin (7+3). Safety, tolerability, and anti-leukemia activity were assessed. Two cycles of induction were allowed and responders could receive consolidation with GMI-1271 plus intermediate dose cytarabine. Dose-limiting toxicity (DLT), defined as myelosuppression in the absence of disease or related Grade 3 (Gr) non-hematologic toxicity beyond day 42, was assessed in the first 3 pts. Results: 24 pts have been enrolled to date and 17 are evaluable for response. The median age was 68 years (range, 60-79) with 58% male pts, 50% secondary AML (sAML) pts and 25% with high-risk cytogenetics (by SWOG). The first 3 pts had no DLT, allowing enrollment to proceed. Common Gr 3/4 AEs included febrile neutropenia (47%), pneumonia (20%), pulmonary edema (13%) and non-fatal respiratory failure (13%). 2 pts died of sepsis within 60 days. The remission rate (CR/CRi) was 12/17 (71%). CR/CRi rate was 75% for pts with de novodisease and 67% for pts with sAML. E-sel ligand was expressed at high levels on blasts in the majority of pts. Conclusions: The addition of GMI-1271 to anthracycline-based induction chemotherapy in untreated elderly pts with AML demonstrates a high remission rate with acceptable side effect profile and low induction mortality. This study compares favorably to previous studies (Lancet, ASCO 2016). A randomized trial is being planned. Clinical trial information: NCT02306291.
Phase 1 results of PTC596, a novel small molecule targeting cancer stem cells (CSCs) by reducing levels of BMI1 protein.
Authors: Infante Jeffrey R. , Bedard Philippe L. , Shapiro Geoffrey , Bauer Todd Michael , Prawira Amy , Laskin Oscar , Weetall Marla , Baird John , Branstrom Art , O'Mara Edward , Spiegel Robert J.
Published: September 2018

2574

Background: PTC596 is an oral investigational new drug that reduces levels of BMI1, a protein required for CSC survival. PTC596 reduced the number of CSCs in preclinical models and slowed growth rates of tumor xenografts in rodent models. The primary objectives of this first-in-human trial of PTC596 were to determine safety, dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and pharmacokinetics (PK). Secondary objectives included exploratory assessments of biological efficacy, pharmacodynamic changes and anti-tumor activity. Methods: A Phase I multi-center, open-label study was conducted in patients with advanced solid tumors using a modified 3+3 design, followed by a dose-confirmatory 10-patient expansion. PTC596 was administered using bodyweight-adjusted twice-per-week (biw) oral dosing in 4 week cycles. Dose escalation and MTD were based on observed cycle 1 DLTs. Anti-tumor activity was assessed by RECIST 1.1. Results: A total of 31 patients with a broad range of tumor types were enrolled at dose levels of 0.65 (N = 3), 1.3 (N = 3), 2.6 (N = 3), 5.2 (N = 11), 7 (N = 8) and 10 mg/kg (N = 3). Nausea, vomiting, and diarrhea were the most common all grade adverse events, though usually mild and manageable. At 10 mg/kg one patient experienced DLTs of neutropenia, mucositis, and thrombocytopenia. The other two patients at this dose level also experienced poor tolerability with Grade 2 nausea, vomiting, and diarrhea that may be partially due to the overall pill burden and excipients. The recommended dose for the expansion and further study was 7 mg/kg. Over the dosing range, plasma concentrations of PTC596 increased in an approximately dose-proportional manner and at doses of 2.6 mg/kg and above exceeded those associated with activity in vitro and in vivo models. Best response was stable disease in 5 patients including two with minor radiographic reductions in tumor volume. Conclusions: PTC596 is tolerable with manageable gastrointestinal side effects. At 7 mg/kg biw exposures exceeded those associated with preclinical activity and future clinical studies are planned for this first-in class molecule that targets CSCs. Clinical trial information: NCT02404480.
Clinical next generation sequencing for precision oncology in rare cancers.
Authors: Groisberg Roman , Hong David S. , Janku Filip , Tsimberidou Apostolia Maria , Javle Milind M. , Meric-Bernstam Funda , Subbiah Vivek
Published: September 2018

2582

Background: Rare tumors receive little financial support or interest from major drug developers or clinical investigators. They are by nature difficult to study even in a large academic medical center. As such, no standard of care exists for many of these cancers and treatment is often extrapolated. ESMO defines rare tumors as 5/100,000 persons per year. We examined patients with rare tumors for potentially targetable genomic alterations using next generation exome sequencing (NGS). Methods: We reviewed charts of patients with rare tumors per the ESMO definition. Sarcomas were excluded. Patients were referred to investigational therapeutics department and underwent CLIA certified comprehensive genomic profiling (Foundation Medicine). Actionable alterations were defined as targeted by a drug available on-label, off-label, or in clinical trials. Results: Among the 95 patients analyzed median age was 51 years (range 2-75). M:F ratio 46:49. Overall, there were 47 different subtypes in our dataset with the most common being adenoid cystic (13%), cholangiocarcinoma (7%), metaplastic breast (6%), gallbladder (5%), and carcinoid (4%). Eighty-seven out of 96 patients (92%) had at least one genomic alteration identified with mean of 2.6 mutations per patient. Of the patients with identifiable mutations, the most common were TP53 (23%), KRAS (10%), PIK3CA (9%), CDKN2A/B (8%), BRAF (7%), MLL (7%), and ARID1A (6%). Thirty-six patients (38%) had at least one potentially actionable alteration in 21 different tumors (eg: PI3K in metaplastic breast and adenoid cystic carcinomas and BRAFV600Ein Erdheim-Chester disease). Nine patients received targeted therapy. Of these 9 patients, 3 had PR, 4 had SD, and 2 had PD as best response (table). Conclusions: The addition of CGP to management of rare tumors adds a potential line of therapy especially in RAF pathway altered ultra-rare cancers that have no standard of care. [Table: see text]