bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase I study of CC-90010 in patients with advanced solid tumors and relapsed/refractory non-Hodgkin lymphoma (R/R NHL).
Authors: Moreno Victor , Braña Irene , Sepulveda Sanchez Juan Manuel Manuel , Villar Maria Vieito , Hernandez-Guerrero Tatiana , Doger Bernard , Saavedra Omar , Ferrero Olga , Sarmiento Rafael , Arias Marina , De Alvaro Juan , DiMartino Jorge F. , Zuraek Marlene , Sánchez Pérez Tania , Filvaroff Ellen , Aronchik Ida , Lamba Manisha , Hanna Bishoy , Nikolova Zariana G.
Published: May 2019

3015

Background: Bromodomain and extra-terminal (BET) proteins are epigenetic readers that control expression of genes involved in cell growth and oncogenesis. CC-90010 is an oral, potent and reversible BET inhibitor that showed promising activity in lymphoma and solid tumor cell lines and reduced tumor growth in xenograft models. Methods: CC-90010-ST-001 (NCT03220347; 2015-004371-79) is a phase I, first-in-human study of CC-90010 in patients (pts) with advanced solid tumors and R/R NHL. Three schedules and 11 dose levels were evaluated (Table). Primary objectives were to determine safety, maximum-tolerated dose and/or recommended phase II dose (RP2D). Secondary objectives were the identification of early activity signals, pharmacokinetics and pharmacodynamics (PD). Results: As of 10 Dec 2018, 69 pts were enrolled, 67 with solid tumors and 2 with R/R NHL. Data shown are from all pts (N = 69). The median age was 57 y (range, 21–80), 38 (55%) were male, and the median number of prior systemic anticancer regimens was 3 (range, 1–9). The RP2Ds were dose cohorts 3A and 4B. Dose-limiting toxicities (n = 6) occurred in dose cohorts 3A, 3C, and 4B. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 17 pts (25%), most commonly (≥2 pts) thrombocytopenia (7%), platelet count decreased (4%), fatigue (3%), and increased alanine aminotransferase (3%). No deaths from toxicity occurred. Two pts (endometrial carcinoma and astrocytoma) had a partial response (PR); 1 occurred after the data cutoff. Seven pts had prolonged stable disease (SD) > 9 mo. Exposures and PD marker regulation increased with dose in each dosing schedule; terminal half-life was ~ 73 h. Conclusions: Most of the TRAEs observed were mild or moderate in severity, reversible, and manageable by dose adjustments and/or supportive care. Promising ongoing anticancer activity with prolonged SD and PRs were observed. The preliminary clinical data provide the rationale for dose expansion of CC-90010 in pts with selected advanced malignancies. Clinical trial information: NCT03220347. [Table: see text]
Risk of QTc interval prolongation among cancer patients treated with tyrosine kinase inhibitors.
Authors: Abu Rmilah Anan Abdelmoti , Lin Grace , Herrmann Joerg
Published: May 2019

3033

Background: QTc interval prolongation can lead to life-threatening complications such as torsade de pointes (TdP), ventricular tachycardia (VT), and sudden cardiac death (SCD). It can occur with various tyrosine kinase inhibitors (TKIs) but comparative analyses on the incidence and complication rates are scarce. We thus conducted a comprehensive analysis of TKI use and QTc prolongation in clinical practice. Methods: We retrospectively reviewed the electronic medical records of all cancer patients who were treated with TKI between 01/2005 and 12/2018 at our institution. QTc prolongation was defined as a QTc ≥ 450 ms or 460 ms among male or female patients, respectively. For each type of TKIs, we determined the administration rate and incidence of QTc interval prolongation. We also studied the frequency of QTc prolongation ≥ 500 ms, rate of increase of the QTc interval by ≥ 60 ms, and the development of complications (VT, TdP and SCD). Results: In the present study, we analyzed the data of 685 cancer patients (431 male and 254 female), including 299 patients with RCC, 188 with chronic leukemia, 55 with acute leukemia, 65 with thyroid cancer, 48 with lung cancer and 39 with GIST. These patients received 902 TKI administrations and QTc prolongation was reported in 1/3 of these (289 administrations). The highest frequency was seen with imatinib, nilotinib and dasatinib (30, 40 and 50%). Among cases of QTc prolongation, a QTc interval ≥ 500 ms was documented in 53 (18.3%) and QTc progression ≥ 60 ms in 72 (25%). Complications were found in 14 cases (5%) including VT in 9, TdP in 2 and SCD in 3 administrations. Conclusions: The current findings suggest that TKI therapy leads to QTc prolongation in 1/3 of patients on average and most commonly with the Bcr-Abl TKIs, imatinib, nilotinib and dasatinib. While SCD is rare (1%) it can still evolve and in 5% of all QTc prolongations with TKIs are potentially life-threatening. These data support recommendations for serial ECGs in cancer patients undergoing TKI therapy. [Table: see text]
A prospective study tracking longitudinal changes in genome-wide cell-free DNA (cfDNA) methylation to identify early nonresponders to cancer treatment.
Authors: Davis Andrew A. , Iams Wade Thomas , Chan David , Oh Michael S , Lentz Robert William , Srivas Rohith , Lambert Nicole , Robertson Alex , Peterman Neil , Shah Abhik , Wilson Timothy , Close Jason , George Peter , Wood Haleigh , Tezcan Ayse , Yalamanchili Ram , Nesmith Ken , Spinosa John C , Tezcan Haluk , Chae Young Kwang
Published: May 2019

3042

Background: Methylation is an epigenetic modification linked to cancer pathogenesis. The aim was to determine if changes in cfDNA methylation patterns before and after initiation of treatment could predict non-response to treatment prior to routine imaging and clinical follow-up. Methods: We prospectively collected clinical data and blood from 28 patients with metastatic malignancies (13 lung, 11 breast, 4 other). Blood was drawn prior to start of a new treatment, after first cycle (median 30 days), and/or second cycle (median 57 days). We performed whole-genome (WG) bisulfite sequencing (median depth 18X) on plasma cfDNA to determine methylation levels. By tracking how methylation levels deviate from unaffected individuals, from baseline to subsequent timepoints, we classified patients as either progressors (greater deviance) or non-progressors. Treatment response at first follow-up imaging (FUI) was determined by RECIST 1.1. Study endpoints were agreement with first FUI and progression-free survival (PFS) by cfDNA classification. Results: The cohort consisted of 68% females and the median age was 70. Main treatment regimens were chemo- (N = 12), immuno- (6), endocrine (5), or targeted-therapy (5). PFS was significantly shorter (log-rank p = 8 x 10-7) in patients classified as progressors by cfDNA (N = 8; median: 62 days) compared to non-progressors (N = 20, median: 263 days). For patients classified as progressors, the cfDNA assay preceded imaging and clinical evaluation by a median of 34 days. 7 out of 8 patients classified as cfDNA progressors were later confirmed to progress at first follow-up evaluation (88% positive predictive value). The one patient who was classified as progressor based on cfDNA was stable based on FUI (day 93 of treatment) but was later confirmed as progression on day 128 by FUI. For the remaining patients, 18 of 20 did not progress (90% negative predictive value). Thus, sensitivity for the assay for identifying progression was 78% and specificity was 95%. Conclusions: Our results show that WG cfDNA methylation change is a novel signature with potential to identify patients whose treatment regimen is ineffective prior to imaging.
Circulating bacterial DNA as a tool towards noninvasive biomarkers for colorectal adenocarcinoma and adenoma.
Authors: Ding Ke-Feng , Xiao Qian , Kong Xiangxing , Hu Yeting , Lu Wei , Wang Ao , Liu Kaihua , Bao Hua , Yuan Ying , Chen Jiaqi , Wang Da , Wang Xiaonan , Wu Xue , Shao Yang
Published: May 2019

3045

Background: The gut microbiota is closely associated with the progression of colorectal neoplasia. While most metagenomics studies utilized fecal samples, circulating bacteria DNA in colorectal adenocarcinoma (ADC) or adenoma (ADM) patients remain unexplored. This study aimed to characterize microbiota DNA in plasma samples and build a machine-learning model for ADC and ADM early detection. Methods: In this proof-of-concept study, we performed whole genome sequencing (~30X) of plasma samples from 25 ADC patients, 10 ADM patients, and 22 healthy controls (HC). Significant biomarkers were identified in the discovery cohort (12 ADC and 11 HC) and built into a random-forest model which was tested in the validation cohort (13 ADC and 11 HC). These biomarkers were further examined in ADM and tested for abundance difference with ADC and HP. Results: In the discovery cohort, 111 species had increased relative abundance in ADC compared to HC and 165 species had decreased relative abundance. Alteration in several species such as Flavobacterium and Ruminococcus torques were consistent with previously published results in faecal and gut microbiome samples. The random forest-recursive feature elimination model selected 28 significant species from the discovery cohort (mean AUC = 0.98, repeated 2-fold cross-validation) and yielded an AUC of 1 in the validation cohort. Interestingly, most biomarker species in ADM patients, with abundance intermediate between ADC and HC, were distinguished from HC. To further test the clinical utility of this model, sequencing data were randomly down-sampled to 1X and the model performance remained robust (AUC = 1) at distinguishing ADC and ADM from HC. Conclusions: This study is the first effort to characterize circulating bacteria DNA in patients with ADC and ADM. Our findings revealed significant difference in relative abundance of several bacterial species between ADC, ADM and HC. A predictive model constructed with selected microbial features accurately distinguished ADC and ADM from HC. Circulating bacteria biomarkers represent potential non-invasive tools for early diagnosis of colorectal neoplasia.
First-in-human phase I and pharmacological study of TAS-119, a selective Aurora A (AurA) kinase inhibitor, in patients (pts) with advanced solid tumors.
Authors: Robbrecht Debbie , Eskens Ferry , Calvo Emiliano , He Xiaomin , Hirai Hiroshi , Soni Nital , Cook Natalie , Dowlati Afshin , Fasolo Angelica , Moreno Victor , De Bono Johann S.
Published: May 2019

3063

Background: AurA is a serine threonine kinase regulating cell division and cell cycle progression and has a role in carcinogenesis. This clinical trial investigated safety, pharmacokinetics and -dynamics and antitumor activity of the selective oral AurA kinase inhibitor TAS-119. Methods: Pts with advanced solid tumors were enrolled into 6 dose escalation cohorts (70-300 mg BID 4 days on/3 days off; every 3 out of 4 weeks; or the same schedule in a continuous weekly schedule). In the expansion phase (intermittent schedule), pts with small-cell lung cancer (SCLC), breast cancer, or MYC-amplified/B-catenin mutated (MT) tumors were enrolled, and pts with other solid tumors in a basket cohort. Results: Overall, 34 pts were enrolled to the escalation (median age 67 years; 45.3% > 2 prior therapies); DLT was observed in 5 (16.1%) of 31 DLT evaluable pts; 1/10 at 150 mg, 1/6 at 200 mg, 1/5 at 250 mg, and 2/2 at 300 mg BID (fatigue, nausea, dry eyes, corneal epithelial microcysts). The maximum tolerated dose (MTD) was 250 mg BID and recommended Phase 2 dose (RP2D) was 200 mg BID. The most frequent treatment-emergent adverse events were diarrhea (28.3%), eye disorders (27%), fatigue (22.9%), and decreased appetite (14.8%). Grade 3 ocular toxicity were corneal epithelial microcysts in 1 pt (300 mg cohort) and punctate keratitis (expansion breast cancer cohort) in 1 pt. Toxicity grade ≥ 3 in ≥ 10% of pts were diarrhea (escalation part only), and increased lipase. Plasma exposure was dose-proportional and accumulation ratio was low. Pharmacodynamic data demonstrated target inhibition. Overall, 40 pts were enrolled to multiple expansions (10 SCLC, 9 breast cancer, 13 MYC-amp/B-cat MT tumors, 8 other; median age 60 years; 72.5% > 2 prior therapies). Median delivered relative dose intensity was 89.1% (47.9% - 100%). Stable disease was reported in 37.8% of patients but no complete or partial responses. Conclusions: TAS-119 demonstrated favorable safety and tolerability. Low-grade eye toxicity was a dose-dependent toxicity. Preliminary anti-tumor activity of monotherapy TAS-119 is limited. A Phase 1 trial combining TAS-119 with paclitaxel was conducted in parallel. Clinical trial information: NCT02448589.
An artificial intelligence approach to variant calling of ALK resistance mutations.
Authors: Lennerz Jochen K , Chin Emily , Rooney Marguerite , Zomnir Michael , Dominguez Meneses Enrique , Lipkin Lev , Iafrate A. John , Le Long P. , Shaw Alice Tsang
Published: May 2019

3079

Background: ALK tyrosine kinase inhibitors (TKIs) are effective in treating advanced anaplastic lymphoma kinase (ALK) fusion-positive non-small-cell lung cancers (NSCLC), and specific ALK variants are associated with the development of resistance to specific TKIs. Humans struggle to harness the full potential of the highly complex next-generation sequencing bioinformatics pipeline output. As a consequence, the decision to report a variant remains difficult, and we considered the discrete nature of the data and the binary decision (report vs. not-report) as an ideal setting to apply an artificial intelligence (AI) approach for variant reporting. Methods: We assessed diagnostic performance of an AI model in calling ALK-resistance mutations in n = 50 consecutive ALK fusion positive patients who relapsed on TKI-therapy and underwent repeat biopsy at MGH. The random forest model was derived from independent datasets (training and validation) capturing the reporting decision on > 36,000 variants with ~500 features per variant resulting in a matrix of > 18 million data points. The model output is a contiguous prediction score from 0 (not report) to 1 (report) and a visual drill-down functionality allows exploration of the underlying features that contributed to the decision. Results: Examination of n = 76 tests from n = 50 patients with a total of n = 130 reported variants (and = 115 not reported variants) included a total of n = 31 ALK point mutations: p.1156(n = 2), p.1171(n = 8), p.1174(n = 2), p.1180(n = 2), p.1196(n = 1), p.1198(n = 1), p.1202(n = 8), p.1203(n = 1), p.1204(n = 1), p.1206(n = 1), p.1269(n = 4). Setting a screening threshold of the model at > 10% for reporting showed only one false-negative (p.Ile1171Asn) variant and 96.7% sensitivity. The average model score for ALK variants was 0.664 (range: 0.08–0.98; median 0.8) and did not show significant differences from other reported variants (0.636; 0–1; 0.7; t-test 0.66). The model would have called n = 18 of the non-reported control variants (average 0.07; range < 0.001–0.64; P < 0.0001) and was 84% specific. Review of the drill-down function identified prior call frequency, allelic ratio, and predicted transcript consequences as common model features. Importantly, the model is currently agnostic to the medical literature and does not take clinical parameters (e.g. TKI type) into account, which may further improve performance. Conclusions: Applying artificial intelligence to large discrete datasets is one approach to help identify clinically relevant variants in the setting of ALK resistance in ALK-fusion positive NSCLC.
Determining clinical relevance of genomic heterogeneity in an ethnically diverse cohort of newly diagnosed patients with breast cancer.
Authors: Rajagopal Padma Sheila , Beaubier Nike , Hattori Masaya , Sveen Lise , Khramtsova Galina , Abboushi Taylor , Barber Mathew , Liu Fang , Yoshimatsu Toshio , Zheng Yonglan , White Kevin , Huo Dezheng , Olopade Olufunmilayo I.
Published: May 2019

3084

Background: The trajectory from early breast cancer to distant metastasis has not been precisely characterized. We are building an ethnically diverse, longitudinal cohort of prospectively ascertained breast cancer patients with integrated genomic, transcriptomic, epidemiological and clinical data, with the goal of identifying biomarkers that can improve on clinical predictors. Methods: Our goal is 500 histologically confirmed invasive cases with a minimum follow-up of 5 years. To date, Tempus Labs, Inc. has completed xT assays (595-gene panel DNA-seq and full-transcriptome RNA-seq) on 127 cases with matched tumor-normal samples. Clinical information was obtained from electronic health records and our cancer registry. Results: Median age of diagnosis was 51, with 47% African-Americans. 73% had stage 2 or 3 disease (2 patients were stage 4). 24.4% had TNBC; 30% had HER2+ and 62.2% HR+ status. Somatic alterations were identified in 560 genes with most common mutations in TP53 (56%), MCL1 (35%), PIK3CA (30%) and ERBB2 (17%). Somatic mutations in BRCA1 (10%) and BRCA2 (5%) were associated with increased tumor mutation burden (TMB). 2 patients were MSI high; 6 were equivocal. After a median follow-up of 6.5 years, 46 patients died and 38 had recurrent disease. With adjustment for clinical factors, TMB showed a slight nonsignificant negative association with recurrence-free survival (HR: 0.97, 95% CI: 0.91-1.00, p = 0.31). TP53 was associated with recurrence-free survival (HR: 1.76, 95% CI 0.94-3.29; p = 0.08) as was MSI (HR: 0.24, 95% CI: 0.06-1.06, p = 0.06). Conclusions: These data support the importance of integrating tumor sequencing in a diverse cohort with full clinical annotation to assess the diversity of actionable genomic alterations at the time of primary diagnosis to develop interventions for prevention of metastases.
c-AMP/MAPK dysregulation and its impact on survival and response to immunotherapy in advanced melanomas.
Authors: Al-Rohil Rami , Marks Etan , Vasudevaraja Varshini , Kelly Stephen , Snuderl Matija , Johnson Douglas Buckner , Jour George
Published: May 2019

3086

Background: Immunotherapies blocking the interaction of CTLA-4 or Programmed Death 1 (PD-1) with their ligands are the standard of care for advanced MEL although many pts fail to benefit from immunotherapy. Herein, we seek to identify epigenetic and genetic signatures associated with lack of response in patients treated with immunotherapy . Methods: We performed whole exome sequencing of 580 cancer-related genes and whole-genome DNA methylation arrays targeting > 850k CpG sites covering promoters, enhancers, and transcription factor sites in 28 MEL samples from patients treated with PD-1 +/- CTLA-4 inhibitors. Findings were correlated with collected clinical history. Results: Findings are summarized in the table . Unsupervised clustering and multi-parametric analysis showed a distinct methylation signature independent of age, sex, stage, site of metastasis, or type of treatment (adj. p<0.01). Pathway analysis identified c-AMP/MAPK and PI3K-Akt signaling pathways (adj. p=2.10E-05 and 8.19E-06, respectively) enrichment in non-responders . This coincided with significant increase of mutational events in c -AMP/MAPK and PI3K-Akt pathways (p= 0.0001) including deleterious events affecting PDE4DIP (p=0.0002), a negative regulator of mTORC1, in non-responders. C-AMP/MAPK/PI3K genomic alterations were associated with a worse OS and PFS but not worse response rate (p=0.04, p=0.01, and p=0.20). PDE4DIP deleterious events were associated with decreased response rate, worse OS and PFS (p=0.002; p=0.002;p=0.00003). Conclusions: Convergent epigenetic dysregulation of cAMP/MAPK signaling and inactivation of PDE4DIP is associated with worse outcome and lack of response to immunotherapy, respectively. [Table: see text]
Preclinical testing of ultra-rapid FLASH total abdominal irradiation demonstrates survival benefit and decreased gastrointestinal toxicity compared to conventional external beam radiation.
Authors: Levy Karen , Rafat Marjan , Schueler Emil , Eggold Joshua Thomas , Wang Jinghui , Casey Keriann , Koong Albert , Maxim Peter , Loo Billy W. , Rankin Erinn
Published: May 2019

3092

Background: Total abdominal irradiation (TAI) is not widely used in the treatment of ovarian cancer due to high abdominopelvic toxicity. Ultra-rapid FLASH irradiation has been shown to spare the lung, skin and brain from radiation toxicity in preclinical models. Conventional radiotherapy delivers a dose-rate of 3-4 Gy/minute, while our small animal FLASH system uses a linear accelerator to generate a dose-rate of 200 Gy/second. Our data demonstrates that use of FLASH-TAI in a preclinical model protects against death from irradiation and confers gastrointestinal (GI) protection when compared to conventional external beam irradiation. Ongoing studies are evaluating the potential for tumor control in an ID8 mouse model of ovarian cancer. Methods: Female C57BL/6 mice received TAI using FLASH and conventional (CONV) radiation at increasing doses: 8.5 Gy, 10.5 Gy and 12 Gy. Unirradiated controls and irradiated cohorts were analyzed at 5-days and 12 months post-irradiation. Normal tissue toxicity was determined by measuring total body weights, stool counts, laboratory analysis, histological analysis, immunohistochemistry, immunofluorescence microscopy and survival. Results: Solid stool production was preserved in FLASH mice, whereas a 50-63% decrease was observed in the CONV cohorts. Histology demonstrated that FLASH preserves small intestinal architecture. TUNEL analysis demonstrated an increase in apoptosis throughout the small intestine of only the CONV cohort. Exploratory necropsy of all surviving cohorts at 12 months post-irradiation was notable for secondary transmural proximal duodenal adenocarcinomas within the radiation field in 25% of only the aged CONV cohorts. There was no laboratory evidence of long-term hematopoietic, liver or kidney toxicity at 12 months. Survival analysis was notable for death of all 12 Gy CONV mice by 9 days post-irradiation whereas 75% of the 12 Gy FLASH mice were alive at 11 months. Conclusions: FLASH protects against death from TAI, improves small intestine epithelial integrity following TAI, protects against radiation-induced apoptosis and may protect from secondary gastrointestinal tumors in the radiation field. Our discovery that FLASH is a safe strategy to deliver effective doses of total abdominal radiation potentially identifies a new opportunity to utilize FLASH-TAI for treatment of ovarian peritoneal metastases.
First-in-human imaging of nanoparticle entrapped docetaxel (CPC634) in patients with advanced solid tumors using 89Zr-Df-CPC634 PET/CT.
Authors: Miedema Iris H.C. , Zwezerijnen Gerben J.C. , Oprea-Lager Daniela E. , Verheul Henk M.W. , Vugts Danielle J. , Huisman Marc C. , Mathijssen Ron H.J. , Rijcken Cristianne J.F. , Hu Qizhi , Dongen G.a.M.S. van , Menke Catharina Wilhelmina
Published: May 2019

3093

Background: CPC634 is a nanoparticle entrapping docetaxel designed to improve tumor accumulation and tolerability compared to conventionally administered docetaxel by taking advantage of the presumed enhanced permeability and retention (EPR) effect. In vivo imaging with zirconium-89 (89Zr)-desferal (Df)-CPC634 will provide valuable information on its biodistribution and will quantify tumor retention. Methods: Patients with solid tumors not amenable to standard therapy received 37 MBq, 0.1-2mg of 89Zr-Df-CPC634 tracer and whole body PET/CT scans were obtained at 2, 24 and 96h post-injection (p.i.). Patients were administered CPC634 (60mg/m2) two weeks later followed by a second tracer injection and scans at 24 and 96h p.i. Biodistribution was quantified by delineating organs of interest and calculating mean %ID/kg. Visual tumor retention was defined as focal uptake in tumor lesions exceeding local background and quantified as standardized uptake peak values (SUVpeak) in volumes of interest. Results: Five patients were included. Biodistribution of 89Zr-Df-CPC634 showed significant retention in healthy liver, and spleen compared to lung (respectively 2.54, 1.61 and 0.56 mean %ID/kg at 96h p.i.), supporting apparent opsonization of nanoparticles in cells of the reticuloendothelial system. Visual retention was observed in 16/37 evaluable tumor lesions with the highest intensity at 96h p.i, compatible with the assumed EPR effect. Tumor retention showed intra- and interpatient heterogeneity, with a mean %ID/kg of 3.43 [1.14-9.32]. Pre-administering unlabeled CPC634 did not change the mean tumor retention of 89Zr-Df-CPC634 (at 96h p.i. mean 3.50 %ID/kg [1.64-9.97]), however, four additional lesions were visible in comparison to tracer only. Conclusions: The biodistribution of 89Zr-Df-CPC634 was consistent with a prolonged exposure of nanoparticle containing docetaxel. 89Zr-Df-CPC634 showed high retention in tumors confirming the EPR effect of these nanoparticle in humans, and supporting their further development for tumor targeting of therapeutic agents. A Phase II efficacy study in platinum resistant ovarian cancer (NTC03742713) is currently ongoing. Clinical trial information: NCT03712423.
A first-in-human phase I/II trial of SRA737 (a Chk1 Inhibitor) in subjects with advanced cancer.
Authors: Plummer Elizabeth Ruth , Kristeleit Rebecca Sophie , Cojocaru Elena , Haris Noor Md , Carter Louise , Jones Robert Hugh , Blagden Sarah Patricia , Evans T.R. Jeffry , Arkenau Hendrik-Tobias , Sarker Debashis , Danson Sarah , Symeonides Stefan N. , Walter Harriet , Ocen Joanita , Randhawa Manreet , Kowalski Mark Marion , Verdon Ines , Dye Andrew , Banerji Udai
Published: May 2019

3094

Background: SRA737 is a potent, highly selective and orally-bioavailable inhibitor of checkpoint kinase 1 (Chk1). SRA737-01 was designed to investigate the safety and tolerability of continuous, daily dosing with SRA737 and to evaluate preliminary efficacy in expansion cohorts of prospectively-selected genetically-defined subjects with advanced tumors. Methods: The escalation phase employed an accelerated titration design starting at 20 mg administered orally in 28-day cycles. Incremental 100% dose escalations in single-subject cohorts were followed by a rolling-6 design once SRA737-related ≥ Grade 2 toxicity was observed during Cycle 1. The expansion phase enrolled subjects prospectively selected by next-generation sequencing with: high grade serous ovarian, colorectal, metastatic castration-resistant prostate, non-small cell lung, and head and neck cancers. Results: In escalation, 18 subjects received SRA737 in 9 dose level cohorts, from 20 to 1300 mg QD; median treatment duration 62.5 days (range 1 to 226). Of these subjects, 3 experienced dose limiting toxicity (DLT; inability to receive 75% of the planned dose); 2 at 1300 mg QD due to gastrointestinal intolerability and 1 at 500 mg BID due to thrombocytopenia. The maximum tolerated dose (MTD) was established at 1000 mg QD or 500 mg BID. The Cmax and AUC0-24 at 1000 mg QD were 2391 ng/mL and 26795 ng∙h/mL respectively and the Cmin (411 ng/mL) exceeded that determined in preclinical models to be effective. Doses ≥ 300 mg QD also exceeded this level. Of 462 subjects prospectively screened for genetic alterations associated with Chk1 sensitivity, 93 were enrolled in expansion across all tumor types. Overall, the most commonly reported treatment-emergent adverse events were diarrhea (70%), nausea (64%), vomiting (51%), and fatigue (47%); the majority were of mild to moderate severity. Conclusions: In this first-in-human trial of SRA737 monotherapy, the MTD was 1000 mg/day and based on overall tolerability and PK, the recommended Phase 2 dose is 800 mg/day. The successful enrollment of prospectively-selected genetically-defined subjects will allow response data to be correlated with genomic profiles hypothesized to confer sensitivity to Chk1 inhibition. Clinical trial information: NCT02797964.
A randomized phase 0 trial of the mitochondrial inhibitor ME344 or placebo added to the antiangiogenic (Aa) bevacizumab in early HER2-negative breast cancer (E-HERNEBC).
Authors: Quintela-Fandino Miguel , Morales Serafin , Salgado Alfonso Cortes , Manso Luis , Apala Juan V , Cortes Javier , Guerra Juan Antonio , Caleiras Eduardo , Mulero Francisca , Mouron Silvana Andrea
Published: May 2019

3100

Background: We have shown that when Aas induce vascular normalization (VN), tumors escape upregulating mitochondrial metabolism. Mitochondrial inhibition with ME344 induced synergy with various Aas. We also found that VN could be traced by showing a 10% decrease in tumor FDG-PET SUV from day (d) 0 to d8 of Aa. We studied the activity of adding ME344 or placebo to Bev (Ki67 decrease) in E-HERNEBC in a phase 0 randomized trial. As a secondary objective we measured the activity of the combination in patients (Pts) showing VN according to FDG-PET. Methods: Untreated E-HERNEBC Pts with T > 1cm, any N, M0 underwent a baseline FDG-PET (d1) and received a single dose of Bev (15mg/kg) prior to randomization (1:1) to arm A (FDG-PET on d8 followed by ME344 10 mg/kg IV on d8, d15 and d21) or Arm B (FDG-PET on d8 followed by placebo on d8, d15 and d21). Tumors were biopsied on d0 and 28. A 40 Pts sample size was powered to detect a 30% relative difference between arms in digitally acquired Ki67 decrease from d0 to d28 (alpha 0.05, beta 0.2). Results: Arm A: 20 Pts; Arm B: 21 Pts. Baseline characteristics were in arm A vs B: age 58.4(41.5-75.3) vs 53.6(39-82.8); T1(30%)/T2(60%)/T3(10%) vs T1(52%)/T2(48%)/T3(0%); N0(80%)/N1(20%) vs N0(81%)/N1(19%); ER+(75%)/TNBC(25%) vs ER+(71.4%)/TNBC(28.6%); Ki67 31.6% (3.6%-70%) vs 25.2% (1.2% - 81.5%). PET-SUV decreased > 10% from d0 to d8 in 6/20 (arm A) and 6/21 (arm B) Pts. Two G3 adverse events (blood pressure) were reported (1/arm) and deemed related to Bev. Results of the primary endpoint: table. Conclusions: ME344 showed significant biologic activity, enhancing the effect in Ki67 decrease vs placebo when added to Bev in E-HERNEBC. The activity was greater in TNBC. A trend for greater activity in patients experiencing VN according to FDG-PET was observed. Clinical trial information: NCT02806817. [Table: see text]
A phase I dose-escalation study of two cycles carboplatin-olaparib followed by olaparib monotherapy in patients with advanced cancer.
Authors: Geenen Jill J.J. , Dackus Gwen , Schouten Philip C. , Pluim Dick , Marchetti Serena , Sonke Gabe S. , Huitema Alwin , Beijnen Jos H. , Schellens Jan H. M. , Linn Sabine C.
Published: May 2019

3118

Background: The PARP-inhibitor olaparib has single-agent activity in BRCA mutated breast and ovarian cancer. Preclinical studies show synergistic effects when combining PARP-inhibitors and platinum drugs in BRCA1/2 mutated cancer cell models. A formulation change from olaparib capsules to tablets initiated a new dose finding study of olaparib tablets BID continuously with carboplatin. Methods: Patients were included in a 3+3 dose-escalation schedule in the following dose-levels: olaparib 25mg BID and carboplatin AUC 3 d1/d22, olaparib 25mg BID and carboplatin AUC 4 d1/d22, olaparib 50mg BID and carboplatin AUC4 d1/d22, olaparib 75mg and carboplatin AUC 4 d1/d22 and olaparib 100mg BID and carboplatin AUC 4 d1/d22. After two cycles patients continued olaparib 300mg BID as monotherapy. Primary objective was to assess the Maximum Tolerable Dose (MTD). Secondary objectives were to investigate the preliminary response rate, pharmacodynamics and systemic exposure. Results: In total 24 patients were included with breast cancer (n = 18), ovarian cancer (n = 3), melanoma (n = 1), colorectal cancer (n = 1) and esophageal cancer (n = 1). Nineteen out of 24 patients had a germline BRCA mutation (79%). Most common AEs were nausea (46%), fatigue (33%) and platelet count decrease (33%). The majority of AEs (83%) were grade 1/2 in severity. Because two dose-limiting toxicities (consisting of ≥ 7 days dose delay of cycle 2 or missing ≥ 5 doses of olaparib due to hematologic toxicity) occurred in dose-level 4, dose-level 3 (olaparib 75mg and carboplatin AUC 4; n = 6 patients) was determined to be the MTD. Fourteen out of 24 patients (56%) had a partial response as best response, according to RECIST 1.1. Systemic exposure of the olaparib tablet formulation appeared comparable to the previous capsule formulation with an olaparib tablet AUC0-14 of 16.3 μg/ml*h at MTD. PARP activity in PBMCs was decreased by 98.7% ± 0.14% at day eight compared to day one for dose-level 3. Conclusions: Olaparib tablets 75mg BID and carboplatin AUC 4 for two cycles preceding olaparib monotherapy is a feasible and tolerable treatment schedule with encouraging clinical antitumor activity. Clinical trial information: NCT02418624.
Pharmacodynamics of PI3K, MEK, and AKT inhibitors through isoform-specific measurements of MEK, ERK, AKT, and ribosomal protein S6 in needle biopsies.
Authors: Herrick William , Kilpatrick Casey , Esposito Dominic , Stotler Howard , Hollingshead Melinda G. , Doroshow James H. , Parchment Ralph E. , Srivastava Apurva K.
Published: May 2019

3134

Background: The success of drugs targeting the MAPK or PI3K pathways in cancer has been slowed by insufficient pathway suppression or onset of resistance through rebound or cross-pathway activation. Isoform-specific measurement of key signaling molecules and a pathway convergence marker ribosomal protein S6 (RPS6), may provide valuable pharmacodynamic (PD) evidence to assess drug effectiveness. Methods: We developed Luminex multiplex assays to measure total and phosphorylated forms of RPS6, ERK1, ERK2, MEK1, MEK2, AKT1, AKT2, and AKT3 from a single tumor biopsy. Fit-for-purpose validation was performed with three drugs currently in clinical trials. A SW620 (KRAS G12V) model was tested with selumetinib (NSC741078, 20 mg/kg), MK2206 (NSC756656, 24 mg/kg), and two PTEN-null models (PC3 & HCC70) with AZD8186 (NSC777572, 25 & 50 mg/kg). Tumors were collected at multiple timepoints after single and repeated dosing, processed by a validated method (PMID 27001313) and data analyzed relative to vehicle control (n = 4-5/grp). Results: The multiplexed assays demonstrated satisfactory analytical performance. Treatment of the SW620 model with a single dose of selumetinib suppressed pERK1/2 ( > 90%), MEK1/2 (50%) and pRPS6 (40-60%) up to 4 h (last time point tested) which was reversed by 24 h. AKT inhibitor, MK2206, suppressed pAKT1/2 (75%) and pAKT3 (50%) 2 h post-dose with reversal at 24 h but did not significantly suppress pRPS6, implying limited downstream modulation. Dosing selumetinib for 21 days had no added effect on pERK isoforms. In both PTEN-null models, AZD8186 suppressed all pAKT isoforms by 40-75% up to 4 h post-dose. The pAKT remained suppressed at 7 h in HCC70 but both pAKT and pRPS6 rebounded by 7 h in PC3. The basal pERK1/2 levels were low and unaffected by AZD8186 in PC3 and HCC70. Conclusions: We established the fitness of PD assays to provide critical evidence regarding the duration of on-target effects, timeline of biomarker reversal and effectiveness of pathway suppression for three distinct classes of drugs. The PD assays are ready for an ongoing clinical trial of AZD8186 and to support clinical development of FGFR inhibitors. Funded by NCI Contract HHSN261200800001E.
Mutation and treatment profiles of patients with concurrent EGFR and ALK actionable mutations (muts).
Authors: Zhao Jun , Liu Caixia , Liu Hui , He Yong , Rao Liqiang , Hao Jiqing , Liu Xiang , Xie Zefeng , Chen Rongrong , Xia Xuefeng
Published: May 2019

3138

Background: Actionable muts in EGFR and ALK define two molecular subtypes sensitive to EGFR-TKIs and ALK-TKIs, respectively. Although generally mutually exclusive, they did co-exist in some cases. However, when and how do they co-exist are not well understood. Methods: Pts with concurrent actionable muts in ALK and EGFR were selected from our database. Their mutation profiles and treatment histories were analyzed. PFS was estimated using Kaplan-Meier method. Results: Among 341 ALK-positive ( ALK-pos) and 3804 EGFR-positive ( EGFR-pos) pts, 9 (2.6% of ALK-pos, 0.2% of EGFR-pos) had concurrent EGFR and ALK actionable muts, including 3 EX19Indel + EML4-ALK, 2 EX19Indel + STRN-ALK, 2 L858R + L1152R, 1 L858R + EML4-ALK, and 1 G719C + S768I + STRN-ALK. All 9 pts had lung cancer. One pt with EX19Indel + EML4-ALK was treatment naïve. The other 8 pts have taken ≥ 1 EGFR-TKIs. The mPFS of these pts on first-generation EGFR-TKIs was 22 mo (95% CI: 11 - NR). Except for 1 pt who progressed on Gefitinib and subsequently on Osimertinib had a T790M+C797G, the other 7 EGFR-TKI resistance pts had no common known resistance muts. 3 pts ordered NGS tests before taking EGFR-TKIs. None of them had ALK muts at that time. Later, 1 pt (19Indel) gained an STRN-ALK after 15 mo on Osimertinib, 1 pt (L858R) gained an EML4-ALK after 5 mo on Gefitinib, and 1 pt (L858R) gained an L1152R after 10 mo on Afatinib. Therefore, ALK muts were likely developed as resistance mechanisms during EGFR-TKIs therapies in these 3 pts. Unfortunately, with no information on ALK status before EGFR-TKI therapies, we can not tell if the ALK muts were also developed during and conferred resistance to EGFR-TKI therapies in the other 5 pts. Both STRN-ALK and ALK L1152R were recorded 4 times in our database, and they concurred with EGFR actionable muts in 3 and 2 of the 4 records, respectively. Conclusions: ALK and EGFR actionable muts concurred at a relatively low frequency in our pts. In some cases, ALK muts were developed during EGFR-TKI therapies. Developed either together or sequentially, some combinations of EGFR and ALK muts, such as L858R with L1152R and EX19Indel with ALK fusion, may form more easily or may be preferable than other combinations for the development or evoluation of tumors.
Validation of the Immunoscore prognostic value in stage III colon cancer patients treated with oxaliplatin in the prospective IDEA France cohort study (PRODIGE-GERCOR).
Authors: Pages Franck , Andre Thierry , Taieb Julien , Vernerey Dewi , Henriques Julie , Borg Christophe , Marliot Florence , Ben Jannet Rim , Louvet Christophe , Mineur Laurent , Bennouna Jaafar , Desrame Jérôme , Faroux Roger , Duval Alex , Laurent-Puig Pierre , Svrcek Magali , Hermitte Fabienne , Catteau Aurelie , Galon Jerome , Emile Jean-François
Published: May 2019

3513

Background: The Immunoscore (IS), which has been shown to prognostically classify Stage I-III colon cancer (CC) patients, was assessed in the IDEA France cohort study evaluating 3 versus 6 months of oxaliplatin-based adjuvant chemotherapy in Stage III CC patients. Methods: Densities of CD3+ and cytotoxic CD8+ T cells in the tumor and invasive margin of each patient were quantified by digital pathology and converted to IS using pre-defined published cut-off. The performance of IS to predict disease-free survival (DFS) was assessed in the modified intention-to-treat population, in each study arm, and was adjusted with relevant clinical features in multivariable Cox models. Harrell’s C-statistics was used to investigate the IS performance. Results: 1322 patients were included; 82 were excluded due to pre-analytical non-conformity. IS was successfully analyzed in 1062 (85.6%) eligible patients. In a 2-category IS analysis, Low and (Int+High) IS were observed in n=599 (43.6%) and n=463 (56.4%) patients, respectively. IS was significantly correlated with T stage, T/N stage (T1-3 and N1 versus T4 and/or N2), and microsatellite instability status. The study met its primary objective of validating that Low IS identifies patients with higher-risk of relapse or death [HR=1.54; 95%CI 1.24-1.93, p=0.0001]. The 3-year DFS rates were 66.80% [95%CI 62.23-70.95] and 77.14% [95%CI 73.50-80.35] for Low IS and (Int+High) IS, respectively. In multivariable analysis, IS remained independently associated with DFS (p<0.0012) when combined with T/N stage. The addition of IS to the T/N stage significantly improved the model discrimination capacity [bootstrap C index mean difference, 0.022; 95%CI 0.005-0.04]. In addition, IS in 3 categories (Low, Int, High) and as a continuous variable were also both significantly associated with DFS (all p<0.001). In univariable analysis, IS was also associated with DFS in 6 months arm (p<0.0001); a similar trend was observed in 3 months arm (p=0.09). Conclusions: IS was confirmed as a prognostic factor of DFS in Stage III CC patients in the prospective IDEA France cohort study. Clinical trial information: NCT03422601.
Screening patients for fluoropyrimidine-related toxicity risk.
Authors: Capitain Olivier , Seegers Valérie , Metges Jean-Philippe , Faroux Roger , Stampfli Claire , Ferec Marc , Matysiak-Budnik Tamara , Senellart Helene , Rossi Valerie , Blouin Nadege , Boisdron-Celle Michele , Dauve Jonathan , Campone Mario
Published: May 2019

3529

Background: Severe, sometimes fatal, toxicity can occur during the 1st or 2nd course of chemotherapy using fluoropyrimidines (FPs), and poses a serious public health problem. FPs carry a 3-5% risk of grade ≥ 3 early toxicities and 0.2% risk of death linked to Dihydropyrimidine Dehydrogenase (DPD) deficiency. Methods: Of 29,000 patients screened since July 2000, 472 were referred to us due to severe toxicity during 1st round 5-FU, or because pre-screening was done too late. Toxicity evaluation was performed according to the NCI scale of adverse reactions to cancer drugs (0=none, 5=death). Patients were previously 5-FU naïve, had different cancers, and received various protocols, eg. 5FU or Capecitabine; bolus±continuous or per os. The reliability of the following 4 pre-treatment screening tests to predict grade≥ 4 toxicity was assessed: 1) DPYD genotype mutation (*2A,*2B,*7, 13, HapB3) 2) Plasma uracil (U) level, 3) Plasma dihydrouracil/uracil ratio (UH2/U) 4) a multiparametric approach with genotyping, UH2/U ratio and key patient factors (age, sex, etc.). McNemar’s test with Bonferroni correction was used for statistical analysis. Results: Of the 472 referred patients, 169 had grade 4 or 5 toxicity, of which 41 died from toxicity. 98 had one or plus DPYD mutation: 42(42.9%)*2A; 43(43.9%)*2B; 3(3%)*7; 4(4%)*13; 8(8.16%) HapB3; 1 was homozygous *2A. Data below compare the 4 screening methods for predicting grade 4-5 toxicity. Conclusions: The multiparametric approach is statistically (p<0.0001) the most efficient in terms of preventing grade 4 and 5 toxicity (death) due to 5-FU treatment. Around 290,000 patients are treated with 5-FU per year in the USA. Assuming a 0.2% mortality rate due to toxicity, around 580 lives could be saved per year using the multiparametric pre-treatment test. [Table: see text]
Efficacy of retreatment with anti-EGFRs in mCRC is not predictable by clinical factors related to prior lines of therapy: A multi-institutional analysis.
Authors: Rossini Daniele , Pagani Filippo , Pellino Antonio , Dell'Aquila Emanuela , Liscia Nicole , Bensi Maria , Germani Marco Maria , Masi Gianluca , Moretto Roberto , Santini Daniele , Salvatore Lisa , Scartozzi Mario , Lonardi Sara , Zucchelli Gemma , Ongaro Elena , Falcone Alfredo , Pietrantonio Filippo , Cremolini Chiara
Published: May 2019

3540

Background: Retrospective analyses and phase 2 studies suggest that administering an anti-EGFR in advanced lines may be effective in mCRC pts who achieved benefit from a 1st-line anti-EGFR containing regimen. The identification of clinical features associated with benefit from anti-EGFR re-treatment (re-tx) in pts experiencing PD during 1st-line anti-EGFR (rechallenge) or after its interruption (reintroduction), is a major clinical need. Methods: A real-life data-base including a total of 5530 pts treated at 6 insitutions from December 2010 to October 2018 was queried. Pts retreated with anti-EGFRs, with RAS/ BRAF wild-type status on tissue samples, who had received a 1st-line anti-EGFR-based tx with at least SD as best response, and at least one further line of therapy before anti-EGFR re-tx, were included. The association with RECIST response (RR), PFS and OS was investigated for the following variables: RR (PR or CR vs SD) and PFS during 1st-line; time from the last anti-EGFR administration to 1st-line PD (i.e. re-introduction vs rechallenge); reason for anti-EGFR discontinuation in 1st-line (PD vs. other); number of anti-EGFR-free lines of therapy before re-tx; anti-EGFR free interval (time between the last anti-EGFR administration in 1st-line and the time of re-tx); primary tumor side; time from the diagnosis of metastatic disease to re-tx (≥ vs. < 18 mos). Results: Data from 86 patients were retrieved, 56 (65%) and 30 (35%) received anti-EGFR rechallenge or reintroduction, respectively. Median anti-EGFR free interval was 15.1 mos. The RR during re-tx was 19.8%, with a DCR of 46.5%. Median PFS and OS were 3.6 and 10.2 mos, respectively. No significant association of investigated features with RR and PFS was observed. No differences in RR or PFS were observed among patients receiving anti-EGFR re-tx as rechallenge or reintroduction (20.4% vs 23.1%, p = 0.99; median PFS: 3.49 vs 4.97 mos, p = 0.61). Patients with left-sided tumors had longer OS (HR: 0.50, 95%CI: 0.26-0.93, p = 0.005). Conclusions: Clinical factors that are generally believed to affect the efficacy of anti-EGFR re-tx are not confirmed in our series. Therefore, clinicians should not rely on those characteristics in their decision-making on anti-EGFR re-tx, and adequate studies for implementing liquid biopsy in clinical practice are urgently needed.
Trifluridine/tipiracil plus bevacizumab in elderly patients with previously untreated metastatic colorectal cancer (KSCC1602): A multicenter, phase II clinical trial.
Authors: Oki Eiji , Makiyama Akitaka , Miyamoto Yuji , Kotaka Masahito , Kawanaka Hirofumi , Miwa Keisuke , Kabashima Akira , Hamanoue Masahiro , Ohchi Takafumi , Kashiwada Tomomi , Shimokawa Mototsugu , Saeki Hiroshi , Akagi Yoshito , Baba Hideo , Mori Masaki
Published: May 2019

3548

Background: Elderly patients are often intolerable in combination of cytotoxic agents. Recently, Trifluridine/tipiracil plus bevacizumab has been shown as good candidate for the vulnerable patients. We aimed to assess the efficacy and safety of trifluridine/tipiracil plus bevacizumab in elderly patients with metastatic colorectal cancer. Methods: Patients aged 70 years and older with previously untreated, unresectable, metastatic colorectal cancer, who were not deemed to be candidates for oxaliplatin-based or irinotecan-based chemotherapy regimens, were included in this trial. Treatment consisted of trifluridine/tipiracil (35 mg/m2 orally a day on day 1-5 and day 8-12) with bevacizumab (5mg/kg intravenously on day 1 and day 15), given every 4 weeks until disease progression. The primary endpoint was progression-free survival (PFS). The secondary endpoints were response rate (ORR), Overall survival (OS) and adverse events (AEs). Results: Between 2017 January and 2018 March, 39 patients were enrolled in this study. The characteristics of patients were male/female : 17/22, median age : 77.5 (range: 70-88) and PS: 0/1 : 31/8. The ORR of 37 patients were assessed by the central review committee. The best response was 40.5(15/37) % (95% CI: 24.8-57.9), and the disease control rate was 86.5 (32/37) % (95% CI: 71.2–95.5). The AEs which were frequent as grade 3 or 4 were leucopenia (71.8 %), neutropenia (48.7 %), anorexia (12.8 %), febrile neutropenia (10.3 %) and fatigue (10.3 %). No treatment related death was reported. Conclusions: The combination of trifluridine/tipiracil plus bevacizumab is an effective and well-tolerated regimen for elderly patients with metastatic colorectal cancer. Hematological adverse events were need for caution. The primary endpoint of PFS will be presented in the end of this year. Clinical trial information: UMIN000025241.