bluuebunny/crossref_metadata_2025_split huggingface dataset:
Initial phase 1 study of WT2725 dosing emulsion in patients with advanced malignancies.
Authors: Fu Siqing , Piccioni D. E. , Liu Hongtao , Lukas Rimas Vincas , Aregawi Dawit , Yamaguchi Kenichiro , Whicher Kate , Chen Yu-Luan , Poola Nagaraju , Eddy John , Zhang Ian , Blum David 
Published: September 2018

2066 Background: WT2725 is a Wilms’ tumor (WT1)-derived-oligopeptide vaccine intended to induce WT1 specific cytotoxic T-lymphocytes against WT1 positive tumors in HLA-A*0201+ or HLA-A*0206+. This first in human study of WT2725 was conducted to evaluate the safety, tolerability, and efficacy. Methods: Subjects with progressive or recurrent glioblastoma (GBM), acute myeloid leukemia (AML) (patients in morphologic remission with minimal residual disease determined by WT1 RT-PCR were allowed), non-small cell lung cancer (NSCLC), or ovarian cancer despite standard therapy were treated with 0.3, 0.9, 3, and 9 mg of WT2725 subcutaneously (s.c.) every week for 4 weeks, then every other week for 6 weeks, and every 4 weeks thereafter until progression or other discontinuation event (part 1); and with 18 mg and 27 mg of WT2725 s.c. every week for 8 weeks, then every other week for 10 weeks, and every 4 weeks thereafter until progression or other discontinuation event (part 2). Responses were evaluated by Immune-related Response Criteria (irRC) for solid tumors and modified International Working Group (IWG) for AML. Results: 62 subjects were dosed, the most frequent adverse events were grade 1 injection site reactions (no grade 3 injection site reactions or dose limiting toxicities observed). Of the 21 GBM subjects who were dosed, seven survived for ≥ 1 year (33%). Of these seven subjects, three survived for ≥18 months (14%), and two for ≥2 years (both in complete radiologic remission, 9.5%). One of the seven subjects with ≥1 year survival had previous treatment with bevacizumab. Two subjects continue dosing (1 complete response with no measurable disease >3 years and 1 partial response > 13 months on study). Results in subjects with non-GBM tumors (12 subjects with AML, 21 with ovarian CA, 7 with NSCLC, and 1 other cancer) are not presented here. WT1-specific CTLs and tumor burden was monitored. WT1 specific CTLs were associated with decrease of tumor burden in two patients with low tumor burden. Some patients with high disease burden did not respond. Conclusions: Preliminary data suggests WT2725 is well tolerated with potential antitumor activity in GBM patients, supporting future development of WT2725 for treatment of GBM in selected subjects. Clinical trial information: NCT01621542.
Examination and prognostic implications of the unique microenvironment of breast cancer brain metastases.
Authors: Prince Grace , Deal Allison Mary , McKee Megan Jean , Trembath Dimitri G. , Keith Kevin , Ramirez Juanita , Midkiff Bentley Randall , Blackwell Kimberly L. , Leone Jose Pablo , Hamilton Ronald L. , Brufsky Adam , Morikawa Aki , Brogi Edi , Seidman Andrew David , Ewend Matthew G. , Carey Lisa A. , Moschos Stergios J. , Vincent Benjamin Garrett , Anders Carey K. 
Published: September 2018

2072 Background: Brain metastases (BM) are an increasingly common consequence of breast cancer (BC). Knowledge of the microenvironment in primary BC and its impact on prognosis is evolving. A similar understanding of the microenvironment of BC metastases is lacking, particularly for the brain, where unique immune regulation governs stroma composition. Such features of the peri-tumoral landscape, i.e. high immune infiltrate and low hemorrhage, offer prognostic value in BM from melanoma. This study reports on 4 biomarkers, gliosis (glio), immune infiltrate (immune), hemorrhage (hem) and necrosis (nec), and their prognostic significance in BCBM. Methods: A biobank of 203 patients (pts) who underwent craniotomy between 1989-2013 was created across 4 sites. Glio, immune, and hem (grouped 0 v 1-3) and nec (0-2 v 3) were scored via H&E stain (0-3). Overall survival (OS (years)) from craniotomy was estimated using the Kaplan-Meier method; log-rank tests compared OS. Cox proportional hazards regression was used to evaluate prognostic value of the 4 biomarkers. Results: Mean age at primary BC diagnosis was 48 years (range 26-77). BCBM subtype (n = 158) was 36% HER2+, 26% HR+/HER2-, 38% HR-/HER2- (TN). Across all samples, expression was 82% glio, 45% immune, 82% hem, and 13% nec. Subtype differences were seen for nec (higher in TN, p < 0.01). Across all pts, expression of glio, immune, and hem was associated with improved OS (years): 1.08 v 0.62 (p = 0.03), 1.31 v 0.93 (p = 0.03), 1.07 v 0.92 (p = 0.1), respectively. Nec was associated with inferior OS: 0.38 v 1.12 (p = 0.01). The association with improved OS was maintained for glio in TN (p = 0.02), and immune (p = 0.001) and hem (p = 0.07) in HER2+. In a multivariable model for OS, adding the 4 biomarkers to traditional clinical variables (age, race, subtype) significantly improved the model fit (p < 0.001). Conclusions: Nec is a poor prognostic finding in BCBM across all subtypes. Glio confers superior prognosis in TN, while immune and hem correlate with superior prognosis in HER2+. A deeper understanding of the rich BCBM microenvironment both refines prognostic considerations for this pt population and may lead to future investigations of targeted immunotherapies in select subtypes of BCBM.
Planned interim analysis of PATRICIA: An open-label, single-arm, phase II study of pertuzumab (P) with high-dose trastuzumab (H) for the treatment of central nervous system (CNS) progression post radiotherapy (RT) in patients (pts) with HER2-positive metastatic breast cancer (MBC).
Authors: Lin Nancy U. , Stein Alisha , Nicholas Alan , Fung Anita M. , Kumthekar Priya , Ibrahim Nuhad K. , Pegram Mark D. 
Published: September 2018

2074 Background: There is currently no clear standard of care to address the management of recurring/multiple intracranial metastases post RT in HER2-positive MBC. The ongoing PATRICIA study (NCT02536339) is evaluating the safety and efficacy of P in combination with high-dose h for patients with HER2-positive MBC with CNS metastases who have CNS progression following RT. Reported herein are results from the protocol-specified interim analysis of PATRICIA. Methods: All eligible patients must have measurable (≥10 mm) CNS progression post RT, and stable non-CNS disease. Patients receive P (840-mg loading dose, then 420 mg every 3 weeks) and high-dose h (6 mg/kg weekly). The primary efficacy endpoint is objective response rate (ORR) in the CNS per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. The interim analysis was planned after 15 patients were enrolled and had ≥2 left ventricular ejection fraction (LVEF) measurements, 2 cycles of study drugs, and 2 response measurements. The study would proceed to full enrollment (n=40) if objective response or stable disease in the CNS was observed in ≥1 of 15 patients and <2 of 15 patients develop congestive heart failure (CHF) related to P or H. Results: As of Sept 6, 2016, 15 patients had been enrolled across 9 sites. Median treatment duration was 4.4 (range 1.2−8.3) months. Six patients discontinued treatment (5 for disease progression; 1 for symptomatic deterioration). Range for duration of response was 1.4−3.3 months. There were no new safety signals for P combined with high-dose h treatment. No patients had CHF or a clinically significant drop in LVEF. Conclusions: Based on early evidence of clinical benefit (ORR 20%) and a lack of new safety signals, the safety and futility boundaries for PATRICIA have been passed and study enrollment continues. Clinical trial information: NCT02536339. [Table: see text]
Phase I first-in-man trial of a novel bromodomain and extra-terminal domain (BET) inhibitor (BI 894999) in patients (Pts) with advanced solid tumors.
Authors: Aftimos Philippe Georges , Bechter Oliver , Awada Ahmad , Jungels Christiane , Dumez Herlinde , Huyvaert Nathalie , Costermans Jo , Lee Chooi , Meeus Marie-Anne , Burkard Ute , Musa Hanny , Zhao Yihua , Schoffski Patrick 
Published: September 2018

2504 Background: The BET family (BRD2, BRD3, BRD4) regulates transcription, epigenetic memory and cell growth, emerging as a novel therapeutic strategy. BI 894999 is a highly potent and selective orally available BET inhibitor. Methods: BI 894999 was given once a day, continuously (1 cycle = 3 weeks; Arm A). An intermittent schedule was explored: once a day, D1-14 Q21 days (1 cycle = 3 weeks; Arm B). Bayesian Logistic Regression Model was used to guide dose escalation. HEXIM1, HIST2H2BF and CCR2 gene expressions were used as pharmacodynamic (PD) markers. Results: 28 pts were treated: 21 in Arm A, 7 in Arm B. Median number of cycles was 2 (range: 1-12). Pts were treated at 6 dose levels in Arm A (0.2-5 mg) and 2 dose levels in Arm B (1.5 and 2 mg). The maximum tolerated dose (MTD) was exceeded at 2 mg in Arm A. In Arm B, dose escalation was halted due to the observation of ECG changes in 3 pts and raised serum troponin in 8 pts, pending cardiology review. MTD in Arm A was defined as 1.5 mg. The most frequent (≥10%) treatment-related adverse events were: fatigue (50%), thrombocytopenia (29%), decreased appetite (21%), diarrhea (18%), increased troponin T (18%), dysgeusia (14%), nausea (14%), stomatitis (14%), increased CK (11%), neutropenia (11%) and vomiting (11%). DLTs included: thrombocytopenia grade (G) 4 (n=3), increased troponin G3 (n=1), hypophosphatemia G3 (n=1), multiple G2 events in 1 pt preventing adequate dose intensity in cycle 1. Of 27 evaluable pts, 3 had partial response (PR; one was confirmed) and 1 had stable disease (SD) lasting >4 cycles. Cmax and AUC increased with dose in a greater than linear fashion particularly at higher dose levels. Mean terminal T1/2 was ~1 day with high interpatient variability. PD analyses showed target engagement in all 3 genes at doses ≥1 mg in both schedules. Conclusions: BI 894999 showed target engagement at doses ≥ 1 mg and demonstrated clinical activity (3 PRs and 1 SD lasting >4 cycles). Thrombocytopenia prevented continuous dosing and 1.5 mg was defined the MTD for Arm A, whilst dose escalation was halted in Arm B due to cardiac findings. Mitigating hematological toxicity of BI 894999 via synergistic drug combinations should be explored. Clinical trial information: NCT02516553.
Phase I trial of a novel stapled peptide ALRN-6924 disrupting MDMX- and MDM2-mediated inhibition of WT p53 in patients with solid tumors and lymphomas.
Authors: Meric-Bernstam Funda , Saleh Mansoor N. , Infante Jeffrey R. , Goel Sanjay , Falchook Gerald Steven , Shapiro Geoffrey , Chung Ki Y , Conry Robert Martin , Hong David S. , Wang Judy Sing-Zan , Steidl Ulrich , Walensky Loren D. , Guerlavais Vincent , Payton Marie , Annis D. Allen , Aivado Manuel , Patel Manish R. 
Published: September 2018

2505 Background: ALRN-6924 is a cell-penetrating stapled alpha-helical peptide designed to equipotently disrupt the interaction between the p53 tumor suppressor protein and its endogenous inhibitors, murine double minute X (MDMX) and 2 (MDM2). For TP53 wild-type (WT) tumors, pharmacological disruption of this interaction offers a means to restore p53-dependent cell cycle arrest and apoptosis, resulting in antitumor efficacy via a novel mechanism. Methods: The study evaluated safety, PK, PD and anti-tumor effects of ALRN-6924 in patients (pts) with advanced solid tumors or lymphomas in a standard 3+3 design. Pts received ALRN-6924 IV once weekly for 3 consecutive wks on a 28-day cycle (arm A), or 2/wk for 2 consecutive wks on a 21-day cycle (arm B). Results: As of Dec 2016, 69 pts were enrolled with median age 61 yrs (25-78). Pts received a median of 2 (1-19) cycles in arm A [0.16-4.4 mg/kg] and 3 (1-19) cycles in arm B [0.32-2.7 mg/kg]. ALRN-6924 showed a t1/2 of 5.5 hours, dose-dependent PK, and an increase in serum macrophage inhibitory cytokine-1. Treatment-related AEs seen in 96% of pts were primarily grade 1 and 2; most frequent were GI side effects, fatigue, anemia, and headache. DLTs were G3 fatigue at 3.1 mg/kg, and G3 hypotension, G3 alkaline phosphatase elevation, G3 anemia and G4 neutropenia at 4.4 mg/kg all in 5 pts in arm A. No G3/4 thrombocytopenia was observed. All DLTs resolved with dose hold. Infusion-related reactions were seen in 7 pts, with 3 treatment discontinuations. The RP2D was determined to be at MTD: 3.1 mg/kg QW for 3 wks every 28 days. In 55 pts evaluable for efficacy, disease control rate (DCR) was 45%, including 2 CR (Peripheral T-cell Lymphoma [PTCL], Merkel Cell Carcinoma), 2 PRs (Colorectal Cancer, Liposarcoma) and 21 pts with SD. In WT TP53 pts who initiated ALRN-6924 at ≥0.8 mg/kg, DCR was 57%. 9 pts remain on treatment post data cutoff including 3 pts exceeding 1 year of treatment. Conclusions: ALRN-6924 was well tolerated and demonstrated intriguing anti-tumor activity in this first-in-human phase I trial. An expansion phase IIa cohort in PTCL opened in August 2016 using 3.1 mg/kg (arm A) and is currently enrolling. Clinical trial information: NCT02264613.
A first-in-human dose phase 1 study of LY3009120 in advanced cancer patients.
Authors: Hong David S. , Hollebecque Antoine , Gordon Michael S. , Flaherty Keith T. , Shapiro Geoffrey , Rodon Jordi , Millward Michael , Ramdas Nina , Zhang Wei , Gao Ling , Sykes Amanda , Willard Melinda D. , Yu Danni , Schade Andrew , Flynn Daniel Lee , Kaufman Michael , Peng Sheng-Bin , Conti Ilaria , Tiu Ramon Velasquez , Sullivan Ryan J. 
Published: September 2018

2507 Background: LY3009120, a pan-Raf and dimer inhibitor, demonstrates inhibition of phospho-Mek/Erk and tumor growth inhibition in several non-clinical cancer models with BRAF, NRAS, or KRAS mutations. This is the first-in-human phase 1 study of LY3009120 in patients (pts) with advanced cancer. Methods: The safety and tolerability of LY3009120 was evaluated in pts with cancer aged 18 years or older who had an ECOG performance status ≤1, at least 1 unidimensionally measurable lesion (RECIST 1.1), and adequate organ function (NCT02014116; I6X-MC-JBDA; Eli Lilly & Co.). The study sought to determine a recommended phase 2 dose using the toxicity band method and the safety, pharmacokinetic, and preliminary efficacy of LY3009120. Pharmacodynamic (PD) biomarkers, including pERK, p27 and Ki67, were evaluated in tumor tissue. The dose escalation phase evaluated dosages from 50 mg to 500 mg by mouth twice daily in pts with advanced cancers. Results: 34 pts (3 at 50 mg, 4 at 100 mg, 3 at 200 mg, 15 at 300 mg, 7 at 400 mg, and 2 at 500 mg) in dose escalation and 1 pt in dose expansion (1 at 300 mg) received at least one dose of LY3009120 by January 2, 2016 (median age = 47.4 yrs, range: 26-82 ). Most pts had a gene mutation (BRAF, n = 7; N/KRAS, n = 18); the most common cancer types included colon (n = 9), non–small cell lung cancer (n = 8), and pancreatic (n = 5). There were 6 dose-limiting toxicities in the dose escalation phase: 2 pts at 300 mg (G3 dermatitis acneiform [n = 1] and G2 blurred vision [n = 1]); 2 pts at 400 mg (G2 increased ALT with G3 hyperbilirubinemia [n = 1] and G3 increased ALT [n = 1]); 2 pts at 500 mg: (G3 arthralgia/myalgia [n = 1] and G3 stomatitis/pain [n = 1]). Based on these data, the maximum tolerated dose for LY3009120 was determined to be 300 mg twice daily. Treatment-emergent adverse events related to LY3009120 occurring in ≥10% of pts included fatigue (34%), nausea (31%), decreased appetite (20%), and dermatitis acneiform (20%) (Grade 1,2). A dose proportional increase in exposure was observed, but not at the 400 mg dose. The best response was stable disease in 5 pts. PD effect by rtPCR was not observed in tested paired tumor samples. Conclusions: LY3009120 is well tolerated at doses of 300 mg twice daily. Updated data from dose expansion will be presented in the meeting. Clinical trial information: NCT02014116.
A first-in-human first-in-class (FIC) trial of the monocarboxylate transporter 1 (MCT1) inhibitor AZD3965 in patients with advanced solid tumours.
Authors: Halford Sarah E. R. , Jones Paul , Wedge Steve , Hirschberg Sandra , Katugampola Sidath , Veal Gareth , Payne Geoffrey , Bacon Chris , Potter Sarah , Griffin Melanie , Chenard-Poirier Maxime , Petrides George , Holder Graham , Keun Hector C , Banerji Udai , Plummer Elizabeth R. 
Published: September 2018

2516 Background: A key metabolic alteration in tumour cells is an increased dependency on the glycolysis, resulting in the production of lactate, which is transported out of cells by MCTs. Inhibition of MCT-1 leads to a profound inhibition of cancer cell growth in preclinical models. AZD3965 is a FIC inhibitor of MCT-1, and we report results from the phase I study of this agent. Methods: Patients with advanced solid tumours were treated with oral (po) AZD3965 at total daily doses of 5-30mg given once (od) and twice daily (bd). Exclusion criteria included a history of retinal or cardiac disease due to preclinical toxicology findings in the eye and heart (which express MCT-1). The primary objectives were to determine the safety, dose limiting toxicities (DLT) and maximum tolerated dose (MTD) of AZD3965. Intensive pharmacokinetic (PK) profiling was performed with subsequent modelling for receptor occupancy. Pharmacodynamic profiling included imaging to detect pH changes and tumour glucose uptake; plasma/urine metabolomics and MCT-1 and MCT-4 tumour expression by immunohistochemistry. Results: 35 patients (20M:15F median age 65) were treated at dose levels 5, 10, 20, and 30mg od and 15 and 10mg bd. AZD3965 was generally well tolerated with nausea and fatigue (CTCAE Gr1-2) the most commonly reported side effects. A single DLT of cardiac troponin rise was observed at 20mg od. Asymptomatic, reversible retinal ERG changes were observed in all but the lowest dose levels, with DLTs observed at doses above 20mg od. PK data indicate exposures in the preclinical efficacy range. Metabolomic changes in urinary lactate and urinary ketones correlate with on-target activity. The increase in urinary ketones is likely to be attributable to the role of MCT1 in physiological ketone transport. Conclusions: The MCT1 inhibitor AZD3965 can be administered to patients at doses which engage the drug target, with a MTD of 20mg od po. DLTs seen were primarily dose dependent, asymptomatic and reversible changes in retinal function, which were an expected on-target effect. Investigation of the activity of AZD3965 is ongoing in tumours known to express MCT1. Clinical trial information: NCT01791595.
A phase I study of carboplatin and talazoparib in patients with and without DNA repair mutations.
Authors: Dhawan Mallika Sachdev , Bartelink Imke Heleen , Aggarwal Rahul Raj , Leng Jim , Kelley Robin Kate , Melisko Michelle E. , Ryan Charles J. , Thomas Scott , Munster Pamela N. 
Published: September 2018

2527 Background: Talazoparib is a novel PARP inhibitor (PARPi) in clinical development. Synergistic anti-tumor effects of PARPi and chemotherapy have been observed in preclinical models. Overlapping toxicity may limit tolerability in patients with germline DNA repair defects. Methods: In a dose escalation Phase 1 trial, we tested the safety, tolerability, pharmacokinetics (PK), and efficacy of talazoparib and carboplatin in patients with and without germ line mutations. Results: 24 patients with solid tumors were enrolled in 4 cohorts evaluating talazoparib 0.75 or 1 mg daily and carboplatin AUC 1 or 1.5 mg/mL/min 2 or 3 weeks of a 3-week cycle. Dose-limiting toxicities included grade 3 fatigue and grade 4 thrombocytopenia. Other grade 3/4 toxicities included fatigue (13%), neutropenia (63%), thrombocytopenia (29%), and anemia (38%). Post cycle 2 hematologic toxicities required dose delays/reductions in all patients. One complete and two partial responses occurred in germline BRCA1/2 (gBRCA1/2) patients. Of the 4 patients with stable disease beyond 4 months, 3 had somatic BRCA mutations and 1 had a BRIP1 germline mutation suggesting greater benefit in tumors with DNA repair mutations. PK-toxicity modeling suggests that after 3 cycles of carboplatin AUC 1.5 weekly and talazoparib 1 mg daily, the percent decrease in neutrophil counts from baseline was significantly more pronounced in gBRCA carriers; -78% (95% CI: -87 to -68%) vs. non-carriers; -63% (95% CI: -72 to -55%), p-value < 0.001. This modeling also showed that 2-4 fold dose reductions for each drug are needed to improve tolerability of this combination. Pulse dosing of talazoparib may be more tolerable in gBRCA carriers. Conclusions: The combination of carboplatin and talazoparib showed responses in gBRCA carriers but also had increased hematologic toxicity in gBRCA carriers. PK toxicity modeling was used to determine alternate dosing strategies based on carrier status. Clinical trial information: NCT02317874.
Deflexifol (a novel formulation of 5FU): Phase 1 dose escalation study of infusional and bolus schedules after failure of standard treatment.
Authors: Clingan Philip R. , Ackland Stephen P. , Ranson Marie , Brungs Daniel , Aghmesheh Morteza , Tafreshi Ali , Garg Madhu Bala , Parker Suzanne , Henderson Anne , Jokela Rebecca , De Souza Paul L. 
Published: September 2018

2529 Background: 5-Fluorouracil (5FU) is administered in combination with leucovorin (LV) to enhance clinical activity. However, simultaneous administration is not feasible as 5FU and LV are chemically incompatible, so the maximum possible interaction for benefit is not achieved Deflexifol, an all in one formulation of 5FU/LV with cyclodextrin (HP-β-CD 100mg/ml, 5-FU 15mg/ml & LV 1mg/ml) at physiological pH, was developed to improve efficacy and tolerance. Methods: A phase I dose-escalation trial to assess the safety, tolerability, MTD and DLT of Deflexifol given in two schedules has been completed. Secondary objectives included the pharmacokinetic (PK) profile and efficacy outcomes. Cohorts of patients with advanced malignancy after failure of standard treatment received Deflexifol as 46-h infusion Q2W or bolus weekly x6 in a standard 3+3 phase I design with no intra-patient dose escalation from dose level 1: 375mg/m² bolus or 1200mg/m² infusional up to dose level 5: 575mg/m² bolus or 3600mg/m² infusional. PK sampling of 5FU and dihydroFU was conducted on all patients to assess PK variability and adequacy of dosing. Results: 40 patients (21 infusional, 19 bolus) with breast (7), colorectal (24), other GI (6) & NSCLC (3) received a total 293 courses of treatment. No > grade 1 toxicity was noted at 375-475 mg/m2 bolus, or at 1200-2400 mg/m2 infusion. The DLT in bolus schedule was grade 3 diarrhea and myelosuppression at 575 mg/m2, with no DLT in the infusion schedule at the maximum dose 3600 mg/m2. The MTD have been established for both treatment arms: bolus 525mg/m²; 46-h infusion 3,600mg/m², with no grade IV toxicity observed. Other grade 3 toxicities were nausea, vomiting, and raised liver function tests. 5FU PK in this mixture is similar to 5FU alone. Encouraging efficacy results were seen with partial response in 1 patient and stable disease in 23 patients. Median PFS was (12.3 wks) and OS was (24.8 wks). Conclusions: Deflexifol has little toxicity and is effective in bolus and infusion schedules at doses equal to or greater than those feasible with 5FU and LV infused separately. A first-line phase II study in combination with oxaliplatin is planned. Clinical trial information: 044867.