bluuebunny/crossref_metadata_2025 huggingface dataset:
CTC versus biopsy tissue sequencing: A concordance analysis of genomic copy number profile from mCRPC patients (pts).
Authors: Scher Howard I. , Lee Jerry , Dago Angel E. , Barnett Ethan , Sutton Ramsay , Carbone Emily , Schreiber Nicole A. , Hullings Melanie , Ebrahim Nadia , Landers Mark Andrew , Wang Yipeng , Solit David B. , Berger Michael F. , Schultz Nikolaus , Dittamore Ryan
Published: May 2019

3050

Background: MSK-IMPACT (Integrated Mutation Profiling of Actionable Cancer Targets), is a high throughput, targeted-DNA-sequencing panel for somatic mutations created by the Department of Pathology at Memorial Sloan Kettering Cancer Center (MSK). The MSK-IMPACT is FDA approved for tumor tissue profiling to guide treatment selection. Recognizing access to tumor tissue in many cancers is difficult and may harbor inter & intra lesional heterogeneity, we sought to evaluate concordance of sequencing single CTCs vs. paired biopsy analyzed by MSK-IMPACT, to assess CTC vs. tumor clonality, and their relationship to outcomes. Methods: 148 biopsy samples from 138 mCRPC pts were submitted for IMPACT analysis and a blood draw within 30-day prior to initiation of a new line of treatment. Blood samples were sent to Epic Sciences for CTC detection. The detected CTCs underwent single cell low pass whole genome sequencing for copy number variation (CNV). For each set of matched samples, DNA copy number profiles from IMPACT and CTC sequencing were compared for similarity. Results: Of the 114 successfully sequenced samples 58 were from lymph nodes, 23 from bone, 25 from liver or lung, and 8 from other soft tissue. Of the 111 patients with CTCs analyzed, a total of 1073 CTCs were sequenced (range 1-27, median = 4 per pt). Of patients with both IMPACT & CTC, >80% pts had multiple subclones with distinguishable CNV. Concordance of genomics clones was found in 63%, and discordant in 37% cases. The clonal concordance between tissue biopsy and CTC was higher when the biopsy was obtained from bone marrow or a visceral site (71% concordance) than from a lymph node (53% concordance). Conclusions: Single CTC sequencing is often concordant to metastatic tissue, but unique CTC clones and the presence of multi-clonal disease highlight the potential to be underrepresented through tissue biopsy, especially when taken from the lymph node.[Table: see text]
Associations between baseline serum biomarker levels and cachexia/precachexia in pretreated non-small cell lung cancer (NSCLC) patients.
Authors: Lobato Gabriela C. , Fidler Mary J. , Fialkoff Jared D. , Multani Maneet , Fughhi Ibtihaj , Wakefield Connor , Basu Sanjib , Batus Marta , Bonomi Philip D. , Borgia Jeffrey Allen
Published: May 2019

3054

Background: We previously reported associations of pretreatment serum biomarkers with clinical outcomes in a cohort of advanced NSCLC patients that progressed on front-line therapy. This study aims to elucidate mechanisms underlying cancer cachexia/ pre-cachexia by evaluating relationships between baseline serum biomarker values and sequential changes in body weight, body mass index (BMI), and neutrophil/lymphocyte ratio (NLR) in NSCLC patients. Methods: We used Luminex immunobead assays to survey 101 protein biomarkers in sera from advanced NSCLC (n = 138) collected prior to their salvage regimen. Serial parameters associated with cancer cachexia included body weight, BMI, and NLR. Outcome variables (progression-free survival (PFS) and overall survival (OS)) were extracted with full IRB-approval. Biomarkers were evaluated as continuous variables with the cachexia surrogates using Pearson correlations, whereas associations of PFS and OS were accomplished with the Cox PH test. Results: High baseline values of BMI and low baseline NLR were associated with both OS and PFS (each p < 0.05), though weight failed to reach significance. PFS and OS were similarly associated with percent changes (relative to baseline) in weight (p < 0.01), BMI (p < 0.01), and NLR (p < 0.001). Thirteen biomarkers were found to be associated (p < 0.05) with baseline BMI values, including positive correlations with leptin, sol.VEGFR2, and c-peptide and inverse correlations with adiponectin, ferritin, ghrelin, IGFBP-1 and IL-8; fifteen biomarkers were associated with baseline NLR (all p < 0.05), including positive correlations with visfatin, insulin, and serum amyloid A and inverse correlations with IGF-II. Fifteen biomarkers were found to be associated (p < 0.05) in common with percent weight and BMI changes, including positive correlations with IGFBP-3 and inverse correlations with insulin, FGF-2, TNF-alpha, and resistin. Only prolactin and placental growth factor were found to be associated (p < 0.05) with percent change in NLR. Conclusions: A series of circulating protein biomarkers primarily connected with metabolic regulation and systemic inflammation/ acute phase response were found to be associated with cachexia/ pre-cachexia in NSCLC patients. Additional cohorts are currently being tested to verify these findings.
Pooled analysis of phase I dose-escalation and dose cohort expansion studies of IMP4297, a novel PARP inhibitor, in Chinese and Australian patients with advanced solid tumors.
Authors: Cao Junning , Zhang Pin , de Souza Paul L. , Gao Bo , Voskoboynik Mark , Ji Dongmei , Shen Weina , Yang Sheng , Zhou Yinglei , Zhang Rong , Lickliter Jason D. , Hoon Siao-Nge , Palmieri David , Cai Suixiong , Tian Ye Edward , Ma Ning , Xu Cong , Yang Stone , Zhang Shuaishuai , Xu Binghe
Published: May 2019

3059

Background: Poly (ADP-ribose) polymerase (PARP) enzymes play critical roles in DNA damage detection and repair. IMP4297 is a novel, potent PARP1/2 inhibitor (IC50 6.27nM/1.57nM) and has demonstrated to be 20-fold more potent than Olaparib in anticancer animal models. Two phase I studies were performed to evaluate and characterize the tolerability and safety, pharmacokinetics, and antitumor activity of single agent IMP4297 in Chinese and Australian patients with advanced ovarian, breast, prostate and other solid tumors. Methods: Dose escalation used a 3+3 design with a modified Fibonacci escalation. Dose cohort expansion was planned after efficacy was observed at the lowest dose level. Patients received IMP4297 monotherapy orally once a day until disease progression or unacceptable toxicity. Results: As of Jan 12, 2019, 56 patients, including 23 BRCA mutation carriers (BRCA+), had been enrolled at 2-100 mg dose level. No DLT was observed. In these two studies, the most frequent treatment-related adverse events (TRAEs) were leukopenia (20%), followed by anemia (18%), nausea (18%) and thrombocytopenia (14%). The majority of TRAEs were grade 1 or 2. Grade 3 TRAEs occurred in five patients (anemia, n=2; vomiting, n=1; thrombocytopenia, n=1; elevated AST, n=1). Only one patient had a dose reduction due to grade 3 thrombocytopenia. No serious TRAEs were observed. In 15 BRCA+ patients who had measurable lesions, the ORR was 33% and the DCR was 80%. There were 4 BRCA+, platinum-sensitive ovarian cancer patients with an ORR of 75% and a DCR of 100%. One patient with somatic BRCA mutated urothelial carcinoma showed a 76% decrease in tumor size. Conclusions: IMP4297 has been well-tolerated with significant anti-tumor activity. The 100 mg daily dose was selected as the RP2D based on safety, pharmacokinetics and clinical activity, and will be further characterized in dose expansion and phase II studies. Tumor response to treatment (RECIST 1.1) in patients with measurable lesions. Clinical trial information: NCT03508011 and NCT03507543. [Table: see text]
Is the optimal biological dose of oncologic molecular-targeted therapies also clinically effective?
Authors: Corbaux Pauline , El Madani Mevidette , Tod Michel , Peron Julien , Maillet Denis , Lopez Jonathan , Freyer Gilles , You Benoit
Published: May 2019

3060

Background: The determination of the optimal biological dose (OBD) defined as the lowest safe dose associated with biological efficacy, appears to be a promising endpoint for defining the recommended phase 2 trial dose (RP2D) of novel oncologic targeted therapies in early-phase clinical trials. However, the clinical relevance of OBD is still unknown. We conducted a review to assess if the OBDs of molecular targeted therapies defined during early phase trials were useful during subsequent drug development and for oncologic drug approvals. Methods: A systematic review was conducted to identify all the molecular targeted therapies approved by FDA in solid and hematological malignancies, and for which early phase trials defined OBDs. The publications of efficacy trials leading to the first FDA approvals were reviewed, as were the FDA approved doses and dosing schedules, which were compared to OBDs found in the early phase trials. Results: OBDs were reported in the early phase trial articles of 39.5% (32/81) FDA approved targeted therapies from 1999 to 2017 (19 small molecules and 13 monoclonal antibodies (mAbs)). The maximum tolerated doses (MTD) had not been reached for 59.4% (19/32) of these drugs. When both MTD and OBD had been defined, OBD were lower than MTD in 84.6% of cases, and equal for the others. The OBDs were chosen as the RP2Ds for 56.3% of the molecules. In that case, the final FDA approved doses were consistent with the OBDs for 83.3% of the drugs. These percentages did not differ in between small molecules and mAbs. OBDs mainly relied on indirect effects on the involved signaling pathway elements for small molecules (11/19, 57.9%), and on involved receptor occupancies for mAbs (6/13, 46.2%). In total, 23.5% of all FDA approved molecular targeted therapies were approved at their OBDs. Conclusions: Although still poorly investigated, OBD may represent a relevant complementary endpoint in in early phase trials of novel anti-cancer targeted therapies, as OBDs are selected as the final FDA approved doses in 83.3 % of cases when chosen as the RP2Ds, which is much higher than the previously reported 58.0 % when MTDs are chosen as the RP2Ds (Fontes-Jardim et al. JNCI 2015).
A phase I multiple-dose escalation study to assess the safety, tolerability, and pharmacokinetics of VEGF-receptor inhibitor telatinib (EOC315) in Chinese patients with advanced solid tumors.
Authors: Pan Hongming , Liu Tianshu , Tsai Jason , Zhao Yapeng
Published: May 2019

3061

Background: Telatinib (EOC315) is a highly selective inhibitor of VEGFR/PDGFR (VEGFR 1-3, PDGFR-β, and c-Kit tyrosine kinases). This phase I study was to assess the safety, tolerability, and pharmacokinetics (PK) of Telatinib in Chinese patients with advanced solid tumors. Methods: Telatinib was administered to Chinese patients with advanced refractory solid tumors as a single agent in 3+3 dose escalation design, starting from 600mg and escalated to 900mg and 1200mg, given orally twice daily. The PK profile, safety, and tolerability were evaluated per protocol. Efficacy was evaluated with RECIST 1.1 criteria every 6 weeks. Results: A total of 15 subjects (6 colorectal cancer, 4 lung cancer, 1 head and neck cancer, 1 melanoma, 1 thymic carcinoma, 1 esophageal carcinoma,1 peritoneal carcinoma) were enrolled per protocol between July 2017 and August 2018, and 13 subjects received at least second line therapies before enrollment. Telatinib was well tolerated in the three dose arms. No dose limiting toxicities (DLTs) occurred during the dose escalation phase. CTC grade 3 AEs observed include hypertension (46.7%, 7/15), fatigue (6.7%, 1/15), transaminase elevation (6.7%, 1/15), hand-foot syndrome (6.7%, 1/15), oral mucositis (6.7%, 1/15), neutropenia (6.7%, 1/15), urobilinogen elevation (6.7%, 1/15), left ventricular systolic dysfunction/decreased ejection fraction (6.7%, 1/15). No CTC grade 4 AE were observed. There were 2 drug related SAEs (hospitalization due to high blood pressure. The PK profile of Telatinib (EOC315) at 600, 900, 1200 mg in Chinese patient cohorts is summarized in Table. For 12 evaluable patients, DCR was 58.3%. For all patients, mPFS was 15 weeks (3.3-34.3w). Conclusions: This study demonstrated the safety and tolerability of Telatinib (EOC315) in a multiple dose escalation design at 600, 900, and 1200 mg PO bid in Chinese patients with advanced refractory solid tumor. Telatinib AUC increased dose-proportionally from 600 mg to 900 mg bid, where 900 mg Telatinib bid is the maximum feasible and recommended dose for future studies in Chinese patients with advanced tumors. Clinical trial information: NCT03175497. [Table: see text]
Modular phase I/II clinical trial evaluating the selective MET-kinase inhibitor OMO-1 in patients with advanced malignancies: Safety and proof of mechanism.
Authors: Lolkema Martijn P. , Plummer Elizabeth Ruth , De Vos Filip Yves Francine Leon , Forster Martin David , Angevin Eric , Libouban Marion , Jansen Ellen , Tjwa Marc , Ciamporcero Eric , Meulemans Ann , Van der Aa Annegret , Perera Timothy Pietro Suren , Clack Glen , Krebs Matthew , Blagden Sarah Patricia
Published: May 2019

3062

Background: MET kinase is a therapeutic target in a range of cancer indications; it is a primary oncogenic driver and a mechanism of therapy resistance. OMO-1 is a highly potent, selective oral inhibitor of MET kinase and Organic Cation Transporter 2 (OCT2). Methods: This study assesses the safety, tolerability, pharmacokinetics (PK) and preliminary activity of OMO-1 in patients (pts) with advanced malignancies (NCT03138083). Module 1 data, evaluating ascending doses of OMO-1 monotherapy, are reported here. Results: As of January 16, 2019, 34 pts were enrolled at 5 twice-daily (BD) dose levels of OMO-1: 100, 200, 250, 350, and 400 mg, including 10 with MET gene amplified or mutated tumours. OMO-1 was generally well tolerated between 100 - 250 mg BD; pts were in the study for an average of 94 days (range: 15-291 days) and 20/34 pts discontinued due to disease progression. Most frequently-reported AEs were nausea (17/34), vomiting (14/34) and fatigue (14/34), mainly G1-2. Notably, no peripheral oedema, cardiovascular events or non-malignancy related LFT abnormalities were observed. A total of 36 SAEs were reported: 17 in 11 subjects were considered related to OMO-1, and included nausea (3/17), vomiting (4/17), chills, diarrhoea, influenza-like illness (2/17), increased blood bilirubin, blood creatinine (3/17) and neutrophil count, and sepsis. A dose of 250 mg BD was determined as the recommended Phase 2 dose (RP2D); doses ≥350mg BD were not in keeping with optimum long-term dosing: at 400 mg BD, 2/3 subjects experienced influenza-like illness (G2 and G3) and at 350 mg BD 2/5 subjects had G2 fatigue and nausea/vomiting. OMO-1 has a half-life of 2.5-3 hrs and plasma exposure is dose-proportional without accumulation. Elevated creatinine was observed across all dose levels, consistent with OCT2 inhibition. IHC analysis on paired tumour biopsies from a MET-mutated NSCLC pt dosed at 200 mg BD showed near-complete inhibition of phosphorylated MET, without affecting total MET. Conclusions: OMO-1 has a favourable safety profile at a RP2D of 250mg BD. Expansion cohorts for MET mutated/amplified tumour types are enrolling. Clinical trial information: NCT03138083.
Rethinking about the dose limiting toxicities (DLTs): They can be equivocal!
Authors: Zhong Wei , Bugarini Roberto , Wang Ling , Basu Cynthia , Beaupre Darrin M.
Published: May 2019

3064

Background: The primary goal of oncology phase I trials is to determine the maximum tolerated dose (MTD) in a small number of patients. Within the standard design methodology currently employed there remains many challenges and one pertains to the variability around defining dose limiting toxicities (DLTs). The pre-specified DLT criteria may not well reflect the clinician’s practical experience with some adverse events, while others may actually be related to the disease status more than the investigational drug and could be misclassified. DLT misclassification seen in testing a small sample size from each dose group could generate a large bias on dose finding and the MTD estimation. Methods: To mitigate the risk of dichotomizing and misclassifying DLTs, we proposed a strategy that introduced the new concept of “equivocal” DLT or AE. A novel dose escalation approach is applied to increase the variability associated with less interpretable AEs so that the model recommendations are more weighted towards the unequivocal AEs/DLTs. To evaluate this novel approach, we established a framework incorporating two types of systematic measurement errors on DLT misclassification, one for the misclassified DLT that is not related to the drug treatment while the other for the non-DLT AE that should be considered severe and relevant to dose finding. In our simulation studies, the Bayesian logistic regression model (BLRM) was used to guide dose escalation in simulated trials to compare the novel weighting approach with the traditional approach. A few numerical examples were also included for method illustration. Results: For different types of measurement errors, simulation studies showed that the weighting approach could successfully improve the trial performance, with higher chance of finding the correct MTD and treating more patients at the MTD level. Conclusions: The DLT weighting strategy provides a flexible but powerful tool that may incorporate the clinician’s valuable experience on some specific DLTs/AEs and improve MTD estimation in oncology phase I dose-escalation trials.
Safety and tolerability of veliparib, an oral PARP inhibitor, and M6620 (VX-970), an ATR inhibitor, in combination with cisplatin in patients with refractory solid tumors.
Authors: Mittra Arjun , O'Sullivan Coyne Geraldine Helen , Do Khanh Tu , Piha-Paul Sarina Anne , Kummar Shivaani , Takebe Naoko , Bruns Ashley , Juwara Lamin , Rubinstein Lawrence , Hogu Murielle , Kinders Robert J. , Parchment Ralph E. , Miller Brandon , Wilsker Deborah , Monge B. M. Cecilia , Khan Sabrina Sharmin , Doyle L. Austin , Doroshow James H. , Chen Alice P.
Published: May 2019

3067

Background: M6620 (M), a potent ATR inhibitor, has synergistic activity with cisplatin (C) in multiple preclinical models, resulting in DNA damage and antitumor activity. We hypothesize that inhibition of both homologous recombination and base excision repair through the combination of M6620 and veliparib (V, a potent inhibitor of PARP1/2) would result in accumulation of lethal double stranded breaks induced by cisplatin and increased antitumor activity and initiated a phase-1 dose escalation trial of this combination in patients (pts) with advanced solid tumors (NCT02723864). Methods: This is a standard 3+3 dose escalation design with 21-day cycles. M is given IV day 2 (D2) and D9; V orally twice daily D1-3 and D8-10; C IV D1 (and D8 from dose level 3 [DL3] onwards) at 40 mg/m2 (with option of holding after cycle 6). Primary objectives: safety; tolerability; maximum tolerated dose (MTD). Secondary objectives: pharmacodynamic (PD) biomarkers; antitumor activity. Dose-limiting toxicity (DLT) evaluated during cycle 1, response using RECIST 1.1. Results: Thirty-seven patients enrolled, median 5 lines of prior therapy (Range 1-12). MTD: V 200 mg, M 210 mg/m2, C 40 mg/m2 (DL6). DLT: grade (gr) 4 thrombocytopenia (DL4), hypophosphatemia (not resolved in 24 hrs., DL3), infusion reaction (DL7). Common gr 3/4 toxicities: anemia (41%), thrombocytopenia (30%), neutropenia (27%), hyponatremia (11%) and hypophosphatemia (8%). Of 34 pts evaluable for response: 2 partial response (PR) (6%, 1 confirmed & 1 transient), 22 stable disease (SD) (65%, median 4 cycles, range 2-11). Of 24 pts with PR/SD, 22 had prior platinum chemotherapy. After July 2018, V was held for gr ≥2 anemia until improved to gr 1, followed by dose reduction. Of 5 pts treated in this period, 3 required V held. PD analysis of circulating tumor cells is underway to elucidate biomarkers of DNA damage and apoptosis. Conclusions: This combination of M6620, veliparib and cisplatin is safe, with activity seen in pts having received prior platinum. The most common toxicity was anemia, which prevented adequate delivery of veliparib. While MTD was established in a heavily pretreated population, consideration should be given to continued dose escalation in pts who have received fewer prior lines of therapy. Funded in part by NCI Contract No. HHSN261200800001E. Clinical trial information: NCT02723864.
[18F] Fluciclatide PET as a biomarker of clinical response to combination therapy of pazopanib and paclitaxel in patients with platinum-resistant or platinum-refractory advanced ovarian cancer: Results of a phase Ib study.
Authors: Sharma Rohini , Valls Pablo Oriol , Inglese Marianna , Dubash Suraiya Rahim , Chen Michelle , Gabra Hani , Montes Ana , Challapalli Amarnath , Tharakan George , Chambers Edward , Cole Tom , Lozano-kuehne Jingky , Barwick Tara , Aboagye Eric
Published: May 2019

3070

Background: Angiogenesis has been shown to be a driver of platinum resistance in ovarian cancer. We assessed the effect of combination pazopanib and paclitaxel followed by maintenance pazopanib in patients with platinum resistant/refractory ovarian cancer. Integrins αvβ3 and αvβ5 are both up-regulated in tumour-associated vasculature. [18F]Fluciclatide is a novel PET tracer that has high affinity for integrins αvβ3/5, and was used to assess the anti-angiogenic effect of pazopanib. Methods: We conducted an open-label, phase Ib study in patients with platinum resistant/refractory ovarian cancer. Patients received 1 week of single agent pazopanib (800mg daily) followed by combination therapy with weekly paclitaxel 80mg/m2. Following completion of 18 weeks of therapy, patients continued with single agent pazopanib until disease progression. Dynamic [18F]Fluciclatide-PET imaging was conducted at baseline and after 1 week of pazopanib. Response (RECIST 1.1), toxicities and survival outcomes were recorded. Circulating markers of angiogenesis were assessed with therapy. Results: Fourteen patients were included in the intention-to-treat analysis. Complete and partial response was seen in 7 patients (54%). Median progression free survival (PFS) was 7.97 months, and overall survival (OS) was 18.5 months. A reduction in [18F]fluciclatide uptake was observed following 1 week of pazopanib, and the reduction in uptake was predictive of long PFS. Elevated baseline circulating angiopoietin and FGF were predictive of greater reduction in SUV60,mean following pazopanib. Kinetic modelling indicated a reduction in K1 and Ki following pazopanib indicating reduced radiotracer delivery and retention. Conclusions: Combination therapy followed by maintenance pazopanib is effective and tolerable in patients with platinum resistant/refractory ovarian cancer. We have shown that [18F]fluciclatide-PET uptake parameters alter with pazopanib therapy indicating an anti-angiogenic response. Clinical trial information: NCT01608009.
Clinical impact of tissue of origin testing and mutation profiling in the Solving Unknown Primary Cancer (SUPER) national prospective study: Experience of the first two years.
Authors: Mileshkin Linda R. , Sivakumaran Tharani , Etemadmoghadam Dariush , Tothill Richard , Fellowes Andrew , Fox Stephen B. , Guccione Lisa , Freimund Alison E. , deFazio Anna , Wilcken Nicholas , Gao Bo , Singh Madhu Sudan , Collins Ian M. , Richardson Gary Edward , Steer Christopher B. , Warren Mark Andrew , Karapetis Christos Stelios , Bryant Cindy , Schofield Penelope , Bowtell David
Published: May 2019

3072

Background: Cancer of unknown primary (CUP) has a poor prognosis with a median survival of less than 12 months. SUPER is a prospective cohort study designed to create a national biobank of patients (pts) with no confirmed primary site following diagnostic work-up. Tumor and blood samples undergo mutational profiling for actionable mutations using the 386 gene PeterMac Comprehensive Cancer Panel (CCP) plus CUPGuide, a microarray gene-expression site-of-origin assay. We aimed to determine the clinical impact of CUPGuide and CCP profiling. Methods: 172 pts were enrolled between 2013-2015. Baseline demographics, treatments, investigations and clinico-pathological characteristics were collected over 12 months. Clinicians completed clinical management questionnaires before and after receiving results. Results: Molecular analysis was performed for 124/172 (72.1%) pts with sufficient DNA and/or RNA. CUPGuide was completed for 97/124 (78.2%); primary site predictions were made in 84/97 patients (86.6%). The most common primary site predictions were lung, gastric, ovary and breast. CUPGuide predictions resulted in a change in management in 10/84 (12%) of cases and confirmed current management already commenced by the clinician in 53/84 (63%). Mutation profiling was completed in 103/124 (83.1%) pts with actionable mutations found in 11 pts, 4 of whom received subsequent targeted therapy. Testing was considered to have a clinical impact in 70/120 cases (58%): either resulting in a change in treatment (n = 14), diagnosis of a pathogenic germline finding (n = 8) or a moderate/high confidence tissue of origin prediction (n = 58). There were two deaths prior to the availability of the CUPGuide results and eleven deaths prior to availability of the CCP results. Conclusions: Molecular analysis for CUP pts has clinical impact in the majority of cases. Timeliness of return of results, drug access and insufficient tissue for testing are barriers to greater impact that need to be addressed to improve the care of pts affected by CUP.
A phase I, open label, multicenter dose escalation study of AZD2811 nanoparticle in patients with advanced solid tumors.
Authors: Johnson Melissa Lynne , Cosaert Jan G. C. E. , Falchook Gerald Steven , Jones Suzanne Fields , Strickland Donald , Greenlees Carol , Charlton Julie , MacDonald Alexander , Overend Philip , Adelman Carrie , Burris Howard A. , Pease Elizabeth J. , Patel Gargi Surendra , Wang Judy Sing-Zan
Published: May 2019

3098

Background: Aurora kinase B (AURKB) represents a potential target for therapy in solid and hematological malignancies. AURKB inhibitor AZD1152 (barasertib) was previously investigated in solid tumor pts in a phase I setting. AZD2811-nanoparticle (np) is a novel, encapsulated slow release AURKB inhibitor offering several advantages over AZD1152 (Ashton S et al., Sci Transl Med 2016). We report the completed dose-escalation safety, pharmacokinetics (PK), preliminary activity and defined maximum tolerated dose (MTD) of AZD2811-np in pts with advanced solid tumors (NCT02579226). Methods: Adult pts with advanced solid tumors received AZD2811-np IV on Day 1 (D1) and 4 (D4) Q4 week (wk) in six cohorts 15-200 mg/infusion without the use of g-csf in cycle 1. D1 Q4wk and Q3wk schedules were investigated up to 600 mg/infusion (including cohorts with mandatory g-csf prophylaxis on day 8). A standard 3+3 design was used. PK was assessed in cycle 1. Results: 50 pts were recruited into 12 cohorts. D1, D4 Q4wk schedule: 24 pts (15, 25,38, 50, 100 mg/infusion (n=3/cohort), 200 mg/infusion (n=9)). All cohorts were tolerated. Transient grade 4 neutropenia was observed in 7/9 pts at 200 mg/infusion, including 1 DLT (gr4 > 7 days) D1 Q4wk: 200 mg(n=3) was tolerated. D1 Q3wk: 23 pts were evaluated (200/400 mg (n=3,7), and 400/600/500 mg with mandatory g-csf (n=3/5/6)). 400 mg without g-csf was not tolerated (1 gr3 mucosal inflammation & 1 gr4 neutropenia > 7 days). 600 mg with g-csf was not tolerated (gr3 febrile neutropenia & gr3 fatigue). 25/50 pts experienced AE ≥gr 3 (21 considered AZD2811-np-related, 19 neutropenia-related, no deaths within-DLT period). AZD2811-np caused transient gr1/2 fatigue, nausea, diarrhoea and mucosal inflammation. AZD2811 total blood PK appears dose proportional with a t1/2 of 30-50 hours irrespective of schedule. Released AZD2811 concentrations ~1% of total. 14 pts (28%) had disease stabilisation. 1 prostate ca. pt had a confirmed partial response (PR) (continued tx to 451 days). Conclusions: The MTD for AZD2811-np is 500 mg D1 Q3wk. AZD2811-np is now being investigated in a small cell lung cancer expansion. Clinical trial information: NCT02579226.
The landscape of RET alterations from 56,970 adult patients with cancer: Clinical implications.
Authors: Andreev-Drakhlin Alexander , Roszik Jason , Subbiah Vivek
Published: May 2019

3106

Background: Activating receptor-tyrosine kinase rearranged during transfection ( RET) mutations and fusions have been recognized as potent drivers of oncogenesis. Recent identification of highly potent and selective RET inhibitors holds great promise in the management of RET-dependent tumors. Here we present a comprehensive analysis of RET alterations in pan-cancer adult malignancies. Methods: We analyzed 59,347 samples from 56,970 patients available from AACR Project GENIE (Cancer Discov. 2017) database for the prevalence of RET fusions, mutations, and copy number alterations in diverse cancer types. Results: A total of 1414 RET alterations were detected, including 91 fusions (6.4%), 1166 missense mutations (82.5%), 136 truncating mutations (9.6%), and 21 in-frame mutations (1.5%). RET fusions were observed in 0.15% of tumor samples and were most commonly identified in non-small cell lung cancer, thyroid cancer, colorectal cancer, prostate cancer, and gastric cancer (62.6%, 18.6%, 5.5%, 4.4%, 3.3% of identified RET fusions, respectively). RET fusions were significantly co-altered with MAPK3/ERK1 (p=0.045), SETD2 (p=1.36E-07 ), and EIF4E (p=0.045), while there was a negative association between RET fusions and EGFR (p=0.009634) , TP53 (p=0.02267), and KRAS (p=2.53E-05) alterations. Most common RET gene upstream partners were KIF5B, CCDC6, and NCOA4 (42.9%, 24.2%, 7.7% of identified RET fusions, respectively). RET missense mutations were found in 2.0% of tumor samples; 136 (11.7%) of identified missense mutations, including 8 RET gatekeeper V804M/L mutations, were characterized as likely oncogenic, 12 (1.0%) as likely benign, and 1018 (87.3%) as variants of unknown significance using OncoKB database. RET amplifications occurred in 1.5% of tested samples. Conclusions: While RET fusions represent extremely rare events in multiple cancers, RET missense mutations occur in 2% of malignancies. Most RET missense variants are described as variants of unknown significance, limiting the impact of precision oncology for the majority of patients with RET alterations. Further functional characterization of RET variants is warranted. MAPK pathway co-alterations in patents with RET fusions may present a strategy for future therapeutic combinations.
Cell-specific upregulation of lung “cancer signature genes” in the small airway epithelium of asymptomatic smokers.
Authors: Rostami Mahboubeh , Zuo Wu-Lin , Crystal Ronald G. , Mezey Jason G.
Published: May 2019

3109

Background: Most lung cancers are derived from the small airway (6th -23rd generations) epithelium (SAE). While a pathogenic mutation in a driver gene is critical to transform a SAE cell to a malignant cell, single cell analysis of lung cancers has demonstrated that individual cancer cells have transcriptional alterations in many “cancer signature genes” (Lambrechts D et al, Nature Med 2018; 24:1277) that are not driver genes, but likely support the malignant state. Based on the concept that dysregulation of many of these genes facilitate the malignant state, we hypothesized that, with the stress of smoking, some of these cancer-supporting transcriptional modifications occur long before the random hit with a driver mutation, providing a soil for the driver mutation. Methods: To assess this hypothesis, we applied drop-seq single cell transcriptome analysis to assess SAE recovered by fiberoptic bronchoscopy and brushing of n = 3 healthy non-smokers and n = 3 healthy smokers. Using unsupervised clustering, 11 cell types were identified including major SAE cell types (basal, intermediate, club, mucous and ciliated), rare epithelial cells (ionocyte, neuroendocrine and undefined NCLhi) and rare immune/inflammatory cell (Tcell, mast, antigen presenting). Results: Comparison of smokers and nonsmokers showed that smoking significantly altered the transcriptome (n = 426 genes upregulated, n = 572 genes downregulated) in different SAE cell types; 21% -56% of smoking-upregulated genes in the major SAE cell population are identified as “cancer signature genes”, where a number have cell-specific smoking regulated patterns within individual cell types including HSPB1 in mucous cells, ADH7 in ciliated, LAMB3 in basal and intermediate cells, MIF intermediate and club cells, ALDH3A1 in all main SAE cell types. Conclusions: These data support the concept that cigarette smoking, long before the development of cancer, reprograms specific SAE cells to provide the biological soil to support driver genes to function.
Integrative analyses of signaling and DNA damage repair pathways in patient-derived xenograft (PDX) models from NCI’s patient-derived models repository (PDMR).
Authors: Das Biswajit , Evrard Yvonne A. , Chen Li , Patidar Rajesh , Vilimas Tomas , McCutcheon Justine N. , Peach Amanda , Nair Nikitha , Jiwani Shahanawaz , Borgel Susanne , Carter John , Divelbiss Raymond , Radzyminski Marianne , Stottlemyer Jesse , Ju Zhenlin , Akbani Rehan , Karlovich Chris Alan , Williams Paul M. , Hollingshead Melinda G. , Doroshow James H.
Published: May 2019

3111

Background: Patient-derived xenografts (PDXs) are increasingly being used in translational cancer research for preclinical drug efficacy studies. The National Cancer Institute (NCI) has developed a Patient-Derived Models Repository (NCI PDMR; pdmr.cancer.gov ) of PDXs with clinical annotation, proteomics, and comprehensive genomic datasets to facilitate these studies. Here, we present an integrative genomic, transcriptomic, and proteomic analysis of critical signaling and DNA damage repair pathways in these PDX models, which represent 9 common and multiple rare tumor histologies. Methods: 304 PDX models from 294 patients were established from various solid tumor histologies from patients with primary or metastatic cancer. Whole Exome Sequencing, RNA-Seq and Reverse Phase Protein Array (RPPA) were performed on 2-9 PDXs per model across multiple passages. An integrative workflow was applied on multiple data sets to detect pathway activation. Results: We profiled 10 signaling and 5 DNA repair pathways in the PDMR dataset. We observed that: (i) a large fraction (40%) of PDX models have at least 1 targetable mutation in the RTK/RAS and/or PIK3CA pathways; (ii) 131 models (45%) have putative driver and oncogenic mutations and copy number variants (CNVs) in the WNT, TGFRb , NRF2 and NOTCH pathways. In addition, 17% of PDX models have targetable mutations in DNA damage repair pathways and 20 PDMR models have a DNA mismatch repair defect (MSI-H). We confirmed activation of the signaling pathways in a subset of PDX models by pathway enrichment analysis on gene expression data from RNASeq and phosphoprotein-specific antibody binding data from RPPA. Activation of DNA repair processes was confirmed by enrichment of relevant mutational signatures and loss of heterozygosity in these PDX models. Conclusions: Genomic analysis of NCI PDMR models revealed that a large fraction have clinically relevant somatic alterations in key signaling and DNA damage repair pathways. Further integrative analyses with matched transcriptomic and proteomic profiles confirmed pathway activation in a subset of these models, which may prioritize them for preclinical drug studies.
A randomized, multicenter clinical trial to determine the efficacy and safety of pegfilgrastim (GEMA BIOTECH) compared to pegfilgrastim (Roche) for prevention of chemotherapy induced neutropenia in patients with breast cancer.
Authors: Richardet Martin Eduardo , Kowalyszyn Ruben Dario , Varela Mirta Susana , Ortiz Eduardo , Micheri Cristian , Zarba Juan Jose , Kahl Susana , Klimovsky Ezequiel , Federico Andrea Alicia , Fein Luis Enrique , Cassini Jorge Horacio , Cortese Gustavo , Visintini Jaime Florencia , Cordeiro Lucas , Lago Nestor Ruben
Published: May 2019

3113

Background: Peg-Neutropine, GEMA BIOTECH SAU biosimilar Peg-Filgrastim, is the first Peg-Filgrastim approved in LATAM for prevention of febrile neutropenia in patients treated with myelosuppressive chemotherapy. Methods: Study population: women with stage 2, 3 or 4 of breast cancer scheduled to receive 4 or 6 cycles of chemotherapy (with Taxane) at 3 weeks interval. Stratification was based on breast cancer stage. Study drug was administered subcutaneously in a 6 mg dose. The study was blind to the assessors. The primary endpoint was Duration of Severe Neutropenia (DSN, Absolute Neutrophil Count-ANC < 500/mm3) in the first cycle of chemotherapy. Secondary endpoints were incidence of severe neutropenia (SN), other efficacy measures, and incidence of ADRs. The non-inferiority margin for DSN was estimated in less than 1 day. Results: A total of 120 subjects were randomized 1:1, 58 were treated with Peg-Neutropine and 62 with Peg-Filgrastim (Roche). Efficacy: SN was developed in 52/283 (18,4%) cycles with Peg-Neutropine in 27 patients and 48/297 (16,2%) cycles with Peg-Filgrastim (Roche) in 20 patients (p=0,4836). In the first cycle, 16 patients with Peg-Neutropine and 11 patients with Peg-Filgrastim (Roche) developed SN. In per protocol analysis mean DNS in the first cycle was 0,78 ± 1,53 days for Peg-Neutropine group and 0,53±1,25 for Peg-Filgrastim (Roche) group (95% IC for the difference -0,26; 0,76). Per ITT analysis the mean DSN was 0,90±1,79 for Peg- Neutropine group and 0,50±1,21 for Peg-Filgrastim (Roche) group , (95% IC for the difference -0,15; 0,95). For all the efficacy secondary endpoints the differences were not statistically significant. Safety: 7 ADRs were developed by 3 subjects with Peg-Neutropine and 31 ADRs were developed by 10 subjects with Peg-Filgrastim (Roche). The most common reaction was myalgia, and other ADRs were arthralgia, asthenia, bone pain and acid sensitive syndrome. Conclusions: Based on the non-inferiority margin established we conclude that Peg-Neutropine is biosimilar to Peg-Filgrastim (Roche). Clinical trial information: NCT03404752.
Correlation between NDRG1 gene polymorphism and neuropathy (N) in metastatic breast cancer (MBC) patients (pts) enrolled in the PAINTER study (Polymorphism And INcidence of Toxicity in ERibulin treatment).
Authors: La Verde Nicla Maria , Damia Giovanna , Garrone Ornella , D'Onofrio Loretta , Fabi Alessandra , Ciccarese Mariangela , Generali Daniele Giulio , Nunzi Martina , Poletto Elena , Pedrazzoli Paolo , Cretella Elisabetta , Scandurra Giuseppa , Meattini Icro , Bertolini Alessandro Stefano , Cavanna Luigi , Romagnoli Emanuela , Legramandi Lorenzo , Guffanti Federica , Bocci Barbara , Farina Gabriella
Published: May 2019

3116

Background: MBC is an incurable disease and therefore treatment focuses mainly on prolonging pts survival and improving quality of life. Eribulin (E) is a microtubule inhibitor that increased overall survival in pretreated pts. E peripheral N is reported in 13.9-35% of cases. PAINTER main objective was to survey tolerability of E in real life in MBC, while secondary endpoints were to investigate the relationships between specific genetic polymorphisms and incidence and severity of peripheral N. Methods: This is a multicenter, interventional, single-arm, phase IV study, that enrolled pts who received E after taxanes and antracyclines (dose 1.4 mg/m2 day 1, 8 every 21 days). PAINTER study follow-up is still ongoing. Genomic DNA was isolated from whole blood samples (Maxwell whole blood DNA kit. Promega). 15 SNPs (Single Nucleotide Polymorphisms) were genotyped by Taqman specific assays. For SNPs analysis, we selected pts with avaliable clinical data and who completed E treatment. N was evaluated by medical examination. The associations between peripheral N (any grade) and the selected polymorphisms were evaluated with Fisher exact test. Results: From May 2014 to June 2018, 180 pts were enrolled in the PAINTER study from 20 Italian hospitals and 135 were analysed for the present report. Pts and tumor characteristics were as follow: median age 62 years (31-85), ductal carcinoma 78.5%, visceral disease 70.4%, luminal type 62.6%, Her2 positive 20.3%, triple negative 17.1%, previous median treatment lines for MBC 5 (0-18), previous N reported in 17.8% of pts (sensory 87.5%, motor 12.5%). N (all grades) were reported in 33.4% of patients (G3-G4: 3%). Among the selected SNPs, one allelic variant (rs2233335 G/G versus G/T or T/T) in NDRG1 gene had a statistically significant association with N (p 0.0010). Conclusions: The data reported demonstrate for the first time that the allelic variant rs2233335 (G/T and T/T) in NDRG1 gene correlates with E induced N. These data, if corroborated, will allow a tailored treatment with E. Clinical trial information: NCT02864030. [Table: see text]
A phase I study of a novel MDM2-P53 antagonist APG-115 in Chinese patients with advanced soft tissue sarcomas.
Authors: Zhang Xing , Wen Xizhi , Yang Chen , Zeng Shan , Men Lichuang , Wang Hengbang , Ma Yuxiang , Zhang Yang , Peng Ruiqing , Weng Desheng , Zhang Li , Ji Jiao , Liu Wenqin , Liang Zhiyan , Huang Yingjie , Yang Dajun , Zhai Yifan
Published: May 2019

3124

Background: APG-115 is a novel and orally active small-molecule MDM2 inhibitor. APG-115 alone or in combination with chemotherapeutic, targeted or IO agents have shown potent antitumor activities in multiple human xenograft tumor models and human cancer patient derived xenograft (PDX) models. Methods: The patients with advanced solid tumors were enrolled in this study in China (CTR20170975). The study objectives were to assess safety, pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activity of APG-115. The patients received APG-115 (ranging 100–200 mg) orally QOD for first 21 days of a 28-day-cycle, until disease progression. Antitumor response assessment was performed every 8 weeks per RECIST v1.1. Archived tumor tissues were collected for analyses of MDM2 and TP53 before treatment. Results: As cut-off on Jan 4 2019, total 13 patients (9 soft tissue sarcomas (STSs), 2 adenoid cystic carcinomas (ACCs) and 2 osteosarcomas) were treated in 3 cohorts of APG-115 (100mg, 150mg, 200mg). The median number of prior systemic anticancer therapies was 2 (range 0-4). Two DLTs were observed in one patient at 200mg including thrombocytopenia and febrile neutropenia. The most common TEAEs (≥50% of pts) included: anemia, thrombocytopenia, vomiting, hypercholesterolaemia, and leukopenia. SAEs occurred in 7 patients (54%), four of which were treatment related. The most common Grade 3 or 4 TRAEs were anemia (38.5%), thrombocytopenia (38.5%), leukopenia (30.8%), and neutropenia (23.1%). One partial response was observed in a liposarcoma patient with MDM2-amplification and TP53-wild type at the 150mg cohort, 5 patients (3 STSs, 2 ACCs) had SD as the best overall response. PK analyses indicated an approximately dose proportional increase in Cmax and AUC0-t following a single or multiple oral administration across dose levels. Preliminary PD data showed that serum MIC-1 increase was exposure dependent within the dose range tested. Conclusions: Preliminary data suggested that APG-115 had promising anti-tumor activity in treatment of patients with MDM2-amplification and TP53-WT liposarcoma. Safety profile and PD effect were consistent with other MDM2 inhibitors. Dosing regimen optimization are ongoing. Clinical trial information: CTR20170975.
A dose escalation pharmacokinetic (PK) and pharmacodynamic (PD) study of mTORC1/2 inhibitor XP-105 (BI 860585) as monotherapy and in combination with exemestane or paclitaxel in patients (pts) with advanced solid tumors.
Authors: De Braud Filippo G. , Wu Wentao Jason
Published: May 2019

3127

Background: Resistance to mTORC1 inhibition may develop through feedback loop leading to upregulation of mTORC2. XP-105, also known as BI 860585, is a potent dual mTORC1/2 inhibitor designed to overcome such resistance. This Phase 1 trial (NCT01938846) was performed to determine the MTD and activity of XP-105 alone or in combination with exemestane or paclitaxel in pts with advanced solid tumors. Methods: A 3+3 escalation design was used; Pts received XP-105 (5–300 mg/day) monotherapy or (40–220 mg/day) combined with fixed-dose exemestane 25 mg/day, or 80–160 mg/day combined with paclitaxel 60 or 80 mg/m2/week. A reduction of pAKT/total AKT ratio was used as a PD marker of target inhibition. Results: 90 pts were treated (41 with monotherapy, 25 and 24 in combination with exemestane, or paclitaxel respectively). XP-105 MTD was defined as 220 mg daily for monotherapy, and 160mg daily with exemestane 25 mg/d or paclitaxel 80 mg/m2/week. In the monotherapy arm, stable disease (SD) was reported in 8 pts (20%), with a median duration of 11 months. In the exemestane combination arm, 4 (16%) partial responses (PR) were reported. In the paclitaxel combination arm, 1 complete response (CR) and 4 PRs were reported (OR rate 21%). Disease control rate (CR/PR/SD) was 20%, 28%, and 58% in the monotherapy, XP-105/exemestane, and XP-105/paclitaxel arms, respectively. A sustained reduction in pAKT/total AKT to < 50% of baseline levels was observed with XP-105 ≥120mg daily. Overall, XP-105 was well tolerated; in the XP-105/paclitaxel combination the most frequent drug-related AEs were diarrhea and fatigue (58.3% each), hyperglycaemia (54.2%), anaemia (50%). Grade ≥3 AEs were hyperglycaemia, fatigue, diarrhea, anaemia, leukopenia. No PK interaction was observed. Conclusions: The MTD for XP-105 monotherapy and in combination with exemestane or paclitaxel was defined as 220 mg and 160mg once daily, respectively. Combination regimens showed higher activity as compared to monotherapy with durable OR in about 20% of pts. The observed safety profile of XP-105 compared favorably to those reported from other mTOR inhibitors. Clinical trial information: NCT01938846.