bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I study (BLOOM) of AZD3759, a BBB penetrable EGFR inhibitor, in EGFRm NSCLC patients with leptomeningeal metastasis (LM) who progressed after other anti-cancer therapy.
Authors: Cho Byoung Chul , Ahn Myung-Ju , Lee Jong-Seok , Kim Dong-Wan , Kim Sang-We , John Tom , Kao Stephen Chuan-Hao , Goldman Jonathan Wade , Su Wu-Chou , Natale Ronald B. , Ahn Jin Seok , Kim HyeRyun , Kim Tae Min , Lin Chia-Chi , Overend Philip , Yang Zhenfan , Yang James Chih-Hsin 
Published: September 2018

2069 Background: AZD3759 is the first EGFR inhibitor primarily designed to effectively cross the blood brain barrier (BBB) to treat central nervous system (CNS) metastases. A phase I study is ongoing to assess AZD3759 in EGFRm NSCLC patients with leptomeningeal metastasis (LM) who progressed after other treatment (NCT02228369). Methods: The primary objective is safety and tolerability, and secondary objectives include anti-tumor efficacy. Two dose levels of AZD3759, 200 mg and 300 mg BID, were assessed. Results: As of24 September, 2016,38 patients were recruited into the expansion cohorts of this phase I study. Of those, 18 were TKI pre-treated EGFRm NSCLC patients with LM. 10 and 8 patients were in the 300 and 200 mg BID cohorts, respectively. No DLTs were observed at either dose, while AZD3759 was better-tolerated at 200 than 300 mg BID during > 2 month treatment. The longest duration on treatment was > 9 months. Most common AEs included skin rash and diarrhea. 67% (12 out of 18) patients had drug-related dose interruption and/or reduction, however, there were no drug-related discontinuations.The Ctrough free plasma and CSF exposure were above pEGFR IC90at the two doses. 40% of patients (4 out of 10) had > 50% inhibition of pEGFR in CSF tumor cells at C1D8, and 70% of patients (7 out of 10) had reduced EGFR copy numbers in CSF at C3D1. 53% of evaluable patients (9 out of 17) had confirmed improved/stable LM MRI imaging. 2 out of 3 patients with concomitant measurable BM lesions achieved confirmed/unconfirmed partial CNS response. Among 18 patients with measurable extracranial lesions, 6 (33%) had confirmed stable extracranial disease as best response. 3 patients achieved clearance of tumor cells in CSF by two consecutive assessments. After 6 months follow-up, 29% patients (5 out of 17 evaluable) were still surviving, plus 5 surviving patients with less than 6 months follow-up. Conclusions: AZD3759 was well-tolerated, achieved sufficient CNS exposure for target inhibition and demonstrated promising anti-tumor activity in patients with LM who progressed after multiple lines of treatment. Updated clinical data will be shared at the meeting. Clinical trial information: NCT02228369.
Neurocognitive function testing and health related quality of life in stage IV lung cancer patients with and without brain metastases.
Authors: O'Kane Grainne M. , Tse Brandon C , Tam Vivian , Brown M Catherine , Lu Lin , Borean Michael , Tse Tiffany , Labbe Catherine , Naik Hiten , Mittman Nicole , Tam Emily , Doherty Mark , Leighl Natasha B. , Bradbury Penelope Ann , Shepherd Frances A. , Howell Doris , Liu Geoffrey 
Published: September 2018

2073 Background: Survival in stage IV lung cancer (S4LC) patients (pts) continues to improve, highlighting the importance of assessing health related quality of life (HRQoL). Lung cancer, involvement with brain metastases (BM), and systemic or brain-specific treatment can all impact neurocognitive function (NCF) and HRQoL. We evaluated the relationship between NCF and HRQoL in S4LC pts by BM status. Methods: S4LC pts with BM (BM+) were frequency distributionally-matched to pts without BM (NBM). NCF was measured using the Hopkins Verbal Learning Test – Revised (HVLT-R), the Controlled Oral Word Association Test (COWAT) and Trail Making Tests (TMT-A/B); scores were correlated with health utility score (HUS) data from EQ5D-3L surveys (Pearson Coefficient, R). Results: BM+ (n = 54) and matched NBM (n = 40) pts had similar demographics. The overall median age was 61years; 59% were female; of 89% that were adenocarcinomas, half had EGFR/ALK alterations; mean time since diagnosis was 2.6 years; mean time since BM were diagnosed in BM+ pts was 0.5 years. Mean HUS (mHUS) were similar between groups: 0.77 for BM+ vs. 0.78 for NBM; p = 0.86. However, pts with stable BM had higher HUS than those with progressive BM (mHUS: 0.80 vs 0.69; p = 0.045). Of BM+ pts, 44% had received whole brain radiation (WBRT). Correlations of NCF and HUS specific for BM+ pts were observed for several HLVT scores, including Total Recall (TR), which was correlated with HUS in BM+ (R = 0.35, p = 0.01) but not in NBM (R = 0.04, p = 0.84) and Recognition Discrimination Index (BM+: R = 0.32, p = 0.03 vs NBM: R = 0.13, p = 0.51). In contrast, TMT-A/B NCF test results had slightly stronger associations with HUS in NBM pts. COWAT was least associated with HUS in BM+ or NBM pts. In BM+ pts treated vs untreated with WBRT, HLVT scores were better in untreated patients (TR, p < 0.0001; delayed recall, p = 0.006; retention, p = 0.089), associations not seen with either TMT-A/B or COWAT. Mutation status had no bearing on these associations. Conclusions: NCF impacts HUS in S4LC pts and should be considered in treatment planning. HVLT scores are useful to assess specifically the impact of BM and WBRT in S4LC pts, and is reflected in associations with HRQoL.
A phase I study of PF-06647263, a novel EFNA4-ADC, in patients with metastatic triple negative breast cancer.
Authors: Garrido-Laguna Ignacio , Krop Ian E , Burris Howard , Hamilton Erika Paige , Braiteh Fadi S. , Weise Amy , Abu-Khalaf Maysa M. , Zopf Christopher , Lakshminarayanan Mani , Holland Jaymes S. , Baffa Raffaele , Hong David S. , Hassan Raffit 
Published: September 2018

2511 Background: PF-06647263 is an anti-Ephrin-A4 (EFNA4) antibody drug conjugate (ADC) composed of a humanized mAb, a hydrazone cleavable linker, and calicheamicin, a potent DNA damaging agent. Higher levels of EFNA4 expression have been shown in tumor versus normal tissue, including in two thirds of triple negative breast cancers (TNBC). In vivo preclinical studies demonstrate PF-06647263 induced tumor regression in TNBC models. Methods: In Part 1 of a dose escalation, cohorts of 2-12 patient (pts) with solid tumors that were unselected for EFNA4 expression received escalating doses of PF-06647263 once every 3 weeks (Q3W, Cohort A) or weekly (QW, Cohort B). Escalations were based on mTPI design. An expansion cohort enrolled TNBC patients (n=12) unselected for EFNA4 expression. Efficacy, safety, EFNA4 RNA expression, pharmacokinetic (PK) and anti-drug antibody development were assessed. Results: Part 1 (dose escalation):A total of 48 pts (25 in A and 23 in B) wereenrolled. The most common treatment related adverse events (AE) were fatigue (65%), and nausea (60%), thrombocytopenia (40%), and decreased appetite (38%). DLTs were observed in 6 and 2 pts in the Q3W and QW regimens, respectively. One confirmed VOD and one suspected VOD were observed in two patients in the Q3W schedule. The maximum tolerated dose (and RP2D) was determined to be 0.015 mg/kg QW. Confirmed partial responses (PR) were observed in 5 pts (3 Ovarian Ca and 2 TNBC). Part 2 (TNBC dose expansion at RP2D)data are available on 10 of 12 pts treated (2 ongoing). The most common adverse events (AE) were nausea (40%), asthenia (30%), vomiting (30%) and mucosal inflammation (30%). No objective RECIST response was observed; there was no dependency with duration of treatment relative to EFNA4 expression. Conclusions: In Part 1 of this study, PF-06647263 was generally well-tolerated in the QW schedule and some anti-tumor activity was observed in heavily pretreated pts with EFNA4 unselected advanced malignancies. However, in the expansion cohort (Part 2) at RP2D in TNBC no objective responses were observed regardless of EFNA4 expression. Final safety, efficacy, expression and PK data will be reported at the meeting. Clinical trial information: NCT02078752.
GMI-1271, a novel E-selectin antagonist, in combination with chemotherapy in relapsed/refractory AML.
Authors: DeAngelo Daniel J. , Jonas Brian Andrew , Liesveld Jane , O'Dwyer Michael , Bixby Dale , Advani Anjali S. , Marlton Paula , Magnani John , Thackray Helen M. , Becker Pamela S. 
Published: September 2018

2520 Background: GMI-1271 is a novel antagonist of E-selectin (E-sel) that down-regulates cell survival pathways and enhances chemotherapy response. We assessed GMI-1271 plus salvage chemotherapy with mitoxantrone, etoposide, and cytarabine (MEC) for the treatment of patients (pts) with relapsed/refractory (R/R) AML. Methods: A phase (Ph) 1trial in pts with R/R AML escalated GMI-1271 across pharmacologically active doses from 5-20 mg/kg combined with MEC. Safety, tolerability and anti-leukemia activity were assessed. GMI-1271 was given 24 hrs prior, then every 12 hrs during and for 48 hrs post induction/consolidation. Eligible pts had an ECOG score 0-2, received ≤2 prior inductions, WBC < 20K ( < 40K after 2 dose levels), no active CNS disease, and adequate renal/hepatic function. E-sel expression was assessed. After confirming safety and tolerability, a Ph 2 study of GMI-1271 at 10 mg/kg plus MEC was initiated. Results: To date, 47 pts have enrolled (Ph 1 = 19; Ph 2 = 28 of planned 47). The recommended Ph 2 dose is 10 mg/kg based on drug exposure, time over IC50 for E-sel binding, lack of DLT, and clinical outcomes. Ph1/Ph2 combined median age was 55yrs (range 26-84) with 70% male pts. Prior AML history included 26% primary refractory, 36% CR1 < 6 mos; 17% prior SCT; 55% unfavorable cytogenetics (by SWOG). Common Gr 3/4 AEs were febrile neutropenia (36%), sepsis (26%), bacteremia (13%), hypoxia (13%). 30 and 60 d mortality were 0 and 7%, respectively. ORR (CR/CRi/MLFS/PR) was 21/42 evaluable (50%). Remission rate (CR/CRi) was 45%. Observed/expected remission (CR/CRi) ratio was > 2.75 (Estey, Blood 1996). With a median follow-up of 11 mos, the Ph 1 median Leukemia Free Survival was not reached and Overall Survival was 7.6 mos. The median E-sel ligand binding at baseline was 35% of blasts (range, 1-75%) and was higher in those achieving remission. Conclusions: The addition of GMI-1271, a novel E-sel antagonist, to MEC chemotherapy is well tolerated with a high ORR, low induction mortality, and promising initial survival outcomes in pts with R/R AML. Furthermore, the baseline expression of E-sel ligand is predictive of response. Clinical trial information: NCT02306291.
Results of a phase Ib study of ARQ 092 in combination with carboplatin (C) plus paclitaxel (P), or with P in patients (pts) with solid tumors.
Authors: Lakhani Nehal , Tolcher Anthony W. , Rasco Drew W. , Patnaik Amita , O'Rourke Timothy J. , Schwartz Brian E. , Abbadessa Giovanni , Kazakin Julia , Savage Ronald , Wang Yunxia , Chai Feng , Papadopoulos Kyriakos P. 
Published: September 2018

2524 Background: ARQ 092 is an oral, potent AKT inhibitor with single agent antitumor activity. P or P+C is the standard therapy or the therapy of choice for pts with various solid tumors. ARQ 092 potentiated antitumor activity of P in in vivo xenograft models, providing the rationale for this study. Methods: This is an open-label, phase Ib study of ARQ 092+C+P (CP Arm) or ARQ 092+P (P Arm) in pts with advanced solid tumors to determine safety and tolerability of these 2 combinations. Blood samples are collected for PK. Results: Enrollment into CP Arm has been completed with 13 pts (15% male; median age 62 years, 4 ovarian, 9 others) being treated in 2 dose cohorts (see table and results below). Enrollment into P Arm is ongoing. Data from P Arm (80 mg/m2 weekly) will be presented during the meeting. In CP Arm, 3 DLTs were observed in 2 pts (both received ARQ 092 at 200 mg BID, 1 day/week) including grade (G) 4 neutrophil count decreased, G 4 thrombocytopenia and G 3 diarrhea. ARQ 092-related adverse events (AEs) in ≥10% pts included diarrhea 69%, fatigue 54%, hyperglycemia 31%, maculopapular rash 31%, nausea 23%, mucosal inflammation 23%, anemia 15%, platelet count decreased 15% and hypokalemia 15%. Paclitaxel- and/or carboplatin-related AEs in ≥10% pts included fatigue 77%, alopecia 62%, thrombocytopenia 39%, platelet count decreased 39%, nausea 31%, lymphocyte count decreased 31%, neutrophil count decreased 31%, white blood cell count decreased 31%, anemia 23%, mucosal inflammation 23%, hypomagnesaemia 23%, peripheral sensory neuropathy 23%, neutropenia 15%, vomiting 15% and hypokalemia 15%. Two ovarian pts previously treated with CP achieved complete response (mutant AKT) and partial response (AKT mutation unknown) respectively and 3 pts (Gastroesophageal, pancreatic, ovarian mixed mullerian) experienced stable diseases for >12 weeks. PK data will be presented during the meeting. Conclusions: Encouraging anticancer activity was demonstrated in heavily pretreated ovarian cancer pts, but full dose CP was not tolerated by most patients. Clinical trial information: NCT02476955. [Table: see text]
Phase 1/2a trial of daily oral BAL101553, a novel tumor checkpoint controller (TCC), in advanced solid tumors.
Authors: Kristeleit Rebecca Sophie , Evans T.R. Jeffry , Ingles Garces Alvaro Henrique , Slater Sarah , Drew Yvette , Devlin Michael-John , Haris Noor R Md , Diamantis Nikolaos , MacDonald Julie , Bachmann Felix , Hannah Alison L. , Anderson Stephanie , Lane Heidi A , Schmitt-Hoffmann Anne , McKernan Phil , Engelhardt Marc Frederick , Greystoke Alastair , Miller Rowan , Plummer Elizabeth R. , Lopez Juanita Suzanne 
Published: September 2018

2532 Background: BAL101553 (prodrug of BAL27862) is a small molecule TCC that binds microtubules and promotes tumor cell death by activation of the spindle assembly checkpoint. In a previous study (NCT01397929, Lopez et al. JCO 34, 2016; abstr 2525), 2-h IV infusion on Days 1, 8, 15 (q28d) of BAL101553 up to 80 mg/m2 (maximum administered dose, MAD) showed vascular toxicities, including transient hypertension, which appeared to be Cmax related. The recommended Phase 2 dose (RP2D) was 30 mg/m2 weekly IV. Based on nonclinical models, antiproliferative effects of BAL27862 are driven by AUC. This trial explores whether once daily oral administration of BAL101553 reduces Cmax-related toxicity and improves the therapeutic window (NCT02490800). Methods: Patients (pts) with advanced solid tumors who failed standard therapy, received QD oral BAL101553 (28-d cycles) in a 3+3 dose-escalation design to determine the MTD. Adverse events were assessed by CTCAEv4 grade (G); tumor response by RECIST 1.1; serial PK on Day 1 of Cycles 1 and 2. Results: In the ongoing study, 19 pts (9M/10F; median age 67 y) received doses of 2, 4, 8, 16 or 30 mg oral BAL101553 QD. The MAD was 30 mg with DLTs of reversible G2 hallucination and asymptomatic, reversible G3 electrolyte imbalances. No DLTs were observed at ≤ 16 mg. Dosing is ongoing between 16 and 30 mg QD to determine the MTD. BAL27862 exposures after oral QD dosing of BAL101553 compared to weekly 2-h infusions suggested high relative oral bioavailability. The BAL27862 weekly AUC at the oral MAD (30 mg QD) compared to the RP2D of 30 mg/m2 for 2-h IV was more than 5-fold higher (19,656 vs 3,584 ng*h/mL) and Cmax was 1.5-fold lower (171 vs 266 ng/mL). Both Cmaxand AUC were dose-proportional, with low/moderate variability. Oral BAL101553 had no effects on blood pressure and showed no vascular toxicity. 5 pts had stable disease (2 pts [cholangiocarcinoma, neuroendocrine pancreatic cancer] > 4 cycles). Conclusions: Daily oral BAL101553 enables higher weekly exposures of BAL27862 with lower Cmax levels compared with a 2-h weekly infusion, due to the absence of Cmax related vascular toxicity. Doses up to 16 mg QD are well tolerated. The MAD has been identified as 30 mg QD; definition of the MTD is ongoing. Clinical trial information: NCT02490800.
Whole exome sequencing (WES) of multiple spatially distinct biopsies from single metastatic lesions to evaluate tumour heterogeneity and identify actionable truncal mutations (ATMs) in patients (pts) with advanced solid malignancies using a radiologically-guided single-pass percutaneous technique.
Authors: Heong Valerie , Wee Bernard , Goh Shane , Tay Darwin , Lee Xiao Wen , Soo Ross A. , Lim Joline Si Jing , Sundar Raghav , Chee Cheng Ean , Lee Soo-Chin , Ow Samuel Guan Wei , Goh Boon C. , Yong Wei-Peng , Wong Andrea Li Ann , Gopinathan Anil , Lim Diana , Pang Brendan , Feroz Mohammad , Soong Richie Chuan Teck , Tan David Shao Peng 
Published: September 2018

2550 Background: Genomic profiling of single core biopsies (bx) are confounded intratumoral heterogeneity, resulting in sampling bias. We explored the use of a novel technique to obtain multiple bx from single metastatic lesion in pts to evaluate heterogeneity and identify therapeutic ATM. Methods: 15 pts (5 NSCLC; 3 ovarian; 2 colon, 2 uterine and 1 breast, cervix and HCC) with biopsiable lesions were identified. Using a single pass radiologically guided percutaneous bx technique, we obtained multiple spatially distinct core bx samples from a single metastatic lesion. Each bx underwent DNA extraction and WES using the NextSeq500. Results: Median of 4 core bx were obtained from each lesion. Complication rate utilizing this technique was 0%. 2 pts were omitted from analysis due to poor quality DNA with 13 pts successfully sequenced. In 1 pt, only 2 of 4 cores were successfully sequenced. The median amounts of total and non-synonymous variants were 137 (27-1286) and 66 (10-649) respectively. The median (range) filtered variants detected in 1/4, 2/4, 3/4, and 4/4 bx cores was 63(16-91)%, 5(1-65)%, 4(0-30)% and 26(0-63)% respectively, suggesting significant subclonal diversity within a single lesion. ATMs were identitified in 8/13 pts. 4/13 pts (31%) had no ATM across all 4 cores. 3 pts received therapy with inhibitors targeting ATMs. A pt with AKT1_E17K ATM received an AKT inhibitor with 21% tumour shrinkage and PFS 6.1 mths. 2 NSCLC pts harbouring an EGFR_T790M ATM were treated with an EGFRT790M specific TKI. 1 withdrew due to toxicity after 2mths and another had PFS > 16.5 mths. Tumour mutational burden (TMB) was consistent across multiple bx from each lesion. A NSCLC pt with the highest TMB received a checkpoint inhibitor with ongoing > 4 mths stable disease. Conclusions: Utilizing a single pass radiologically guided techniqueto obtainmultiple bx is feasible, safe and informative. This allows reconstruction of a tumour’s subclonal genomic architecture, providing insights into mutational heterogeneity and help guide therapy.
Phase I study of the combination of balixafortide (CXCR4 inhibitor) and eribulin in HER2-negative metastatic breast cancer (MBC) patients (pts).
Authors: Gil-Martin Marta , Gomez Pardo Patricia , Lopez-Tarruella Sara , Manso Luis , Perez-Fidalgo Jose Alejandro , Ademuyiwa Foluso Olabisi , Mayer Ingrid A. , Pluard Timothy J. , Martinez Garcia Maria , Kaufman Peter A. , Vahdat Linda T. , Hooftman Leon W. , Romagnoli Barbara , Hernando Cristina , Weilbaecher Katherine N. , Ciruelos Eva M. , Martin Miguel , Pernas Simon Sonia , Cortes Javier 
Published: September 2018

2555 Background: Balixafortide (POL6326) is a cyclic peptide and a potent, selective antagonist of the chemokine receptor CXCR4. Evidence suggests that CXCR4 inhibition interferes with the tumor-protective microenvironment and sensitizes tumor cells to chemotherapy. The combination of balixafortide (B) and eribulin (E) was safe with early signs of efficacy in the dose escalation part of this study. Methods: The expanded cohort of thisopen label phase I study was designed to assess the anti-tumor activity, safety and pharmacokinetics of the addition of the recommended phase 2 dose (RP2D) of B to E in pts with MBC and with any CXCR4 expression level at the tumor site. Patients received E (1.4 mg/m2) on days 2 and 9, flanked by B (5.5 mg/kg) on days 1-3, and 8-10 of 21-day cycles. Results: 24 pts with relapsed MBC (median age 59 [33-82]) were enrolled in the expanded cohort. Median number of prior chemotherapies for MBC was 2 (range 1-3). 20/24 (83%) pts were ER and/or PR positive; 3/24 (13%) pts had TNBC. Objective response rate (ORR) was 33%. 8/24 (33%) pts achieved a partial response and 4/24 (17%) pts had meaningful (≥ 6 months) stable disease for a Clinical Benefit Ratio of 50%. Median duration of treatment was 15.3 weeks (range 5-40) with 11 pts still on treatment. The most common Gr 3-4 adverse events were neutropenia (9/24, 38%) and leucopenia (3/24, 13%); 2 pts had febrile neutropenia and 1 patient died from sepsis. 15/24 (63%) pts experienced histamine-like infusion reactions related to B that were manageable with anti-histamines. Conclusions: The therapeutic activity of this treatment regimen appears promising with an ORR of 33% in patients with advanced MBC. B (5.5 mg/kg) can be combined safely with E (1.4 mg/m2) and the safety profile resembles E monotherapy as previously reported. This is the first study of the treatment combination of E with B in relapsed MBC pts. Further confirmatory studies are being considered. Clinical trial information: NCT01837095.
Exposure-efficacy and safety analysis of durvalumab in patients with urothelial carcinoma (UC) and other solid tumors.
Authors: Jin Chaoyu , Zheng Yanan , Jin Xiaoping , Mukhopadhyay Pralay , Gupta Ashok Kumar , Dennis Phillip A. , Ben Yong , Roskos Lorin , Narwal Rajesh 
Published: September 2018

2568 Background: Durvalumab is a human monoclonal antibody that binds to PD-L1 and blocks its interaction with PD-1 and CD-80. The objective of this analysis was to evaluate the relationship between durvalumab PK exposure with efficacy and safety following 10 mg/kg Q2W durvalumab. Methods: Data from Study 1108 (Phase 1/2; all tumor types) and ATLANTIC (Phase 2; NSCLC) were used for exposure-safety analysis for Study 1108 UC cohort, Study 1108 all patients and ATLANTIC patients, respectively, whereas the exposure-efficacy analysis was performed using data from Study 1108 UC cohort. The observed PK exposure metrics included PK concentrations after the first, second or steady state doses. Efficacy endpoints used were objective response rate (ORR) and best percentage change in target lesion from baseline per BICR assessment. Safety endpoints included Grade 3+ AE (any AE, drug-related AE, AESI, and drug-related AESI) and AE leading to treatment discontinuation. Results: Overall, no association of PK exposure with efficacy or safety was observed. Distribution of PK metrics were similar between responders and non-responders. The probability of objective response was similar in all quartiles of exposure (p-value ranged from 0.37 to 0.67; n = 96) with no obvious trends between PK exposures and change in tumor size. For Grade 3+ AE (all types) and AE leading to treatment discontinuation, higher PK exposure was not associated with an increased risk of AE (p-value ranged from < 0.00005 to 0.88; n = 158, 929 and 434 for 1108 UC cohort, 1108 all patients and ATLANTIC all patients, respectively). A few inverse trends were observed, likely due to confounding effect of ECOG or albumin since covariate analysis demonstrated that both variables correlated with PK and AEs. In addition, the association of ECOG and albumin versus PK exposure were also observed in the population PK modeling. Conclusions: The exposure-efficacy and exposure-safety analyses suggested that 10 mg/kg IV Q2W regimen was an appropriate dose for durvalumab as single agent in UC patients. Overall, no relationship of PK exposure with either the efficacy or safety was observed following 10 mg/kg IV Q2W regimen. Clinical trial information: NCT02087423 and NCT01693562.