bluuebunny/crossref_metadata_2025_split huggingface dataset:
FDA analysis of patient enrollment by region in clinical trials for approved oncological indications.
Authors: Kanapuru Bindu , Singh Harpreet , Fashoyin-Aje Lola A. , Myers Adrian , Kim Geoffrey , Farrell Ann , Pazdur Richard 
Published: September 2018

2539 Background: Clinical trials are increasingly conducted on a global scale in an effort to accelerate accrual. This analysis attempts to quantify and characterize participants in trials submitted to support approval of drugs for oncology indications by the region of enrollment. Methods: Demographic information was extracted for patients enrolled in clinical trials submitted to the FDA from 2005-2015. Only trials submitted to support approval for malignant solid tumor or hematology indications were included. Countries were grouped into regions for further analysis. A total of 178,024 patients with information regarding age and country were included in this analysis. Results: Forty five percent (80,460) of clinical trial participants were enrolled from Europe, 36% (63,958) from North America (includes U.S.A and Canada) and 8.4% (14,975) from Asia. Countries in Latin America, Middle East/Africa and the Baltic States/Russia enrolled the remainder 10.5% of the patients. Among 99,556 participants < 65 years of age; 38.7% (38,538) were enrolled from North America, 40.5% (40,362) from Europe, 9.7 % (9674) from Asia and 11% from the rest of the regions. Europe enrolled the highest number of cancer patients aged 65 years or older; 51.1% (40,098) compared to 32.4% (25,420) from North America and 6.8 % (5301) from Asia. Conclusions: Majority of patients enrolled into clinical trials submitted for oncology drug approvals were from regions other than North America, with highest number enrolled from Europe particularly in the older age group. While it is interesting to speculate, the reasons for differential enrollment of patients between Europe and North America and the impact of these findings on interpretation of clinical trial results need additional exploration. Analysis of trends over time may be useful to address this issue. [Table: see text]
Safety and pharmacokinetics of crizotinib in patients (pts) with hepatic impairment (HI) and advanced cancer.
Authors: El-Khoueiry Anthony B. , Sarantopoulos John , O'Bryant Cindy L. , Ciombor Kristen Keon , Xu Huiping , O'Gorman Melissa T , Chakrabarti Jayeta , Usari Tiziana , El-Rayes Bassel F. 
Published: September 2018

2552 Background: Crizotinib is a kinase inhibitor approved for treating ALK+ and ROS1+ advanced non-small cell lung cancer. Since crizotinib undergoes hepatic metabolism, this phase 1 study evaluated the pharmacokinetics (PK) and safety of crizotinib in pts with liver dysfunction. Methods: Crizotinib-naïve pts with different types of advanced cancer (ALK and ROS1 status unknown), ≥ 18 yr old, and ECOG PS 0–2 were enrolled. Pts were assigned to groups A1 – D based on liver function: normal (A1/A2) = both AST and TB ≤ the upper limit of normal (ULN); mild impairment (B) = AST > ULN and TB ≤ ULN, or TB > 1.0 – 1.5 × ULN; moderate (C1/C2) = TB > 1.5 – 3 × ULN; severe (D) = TB > 3 × ULN. Starting dose was based on HI. Pts in A1 and A2 were matched for weight, age, gender, race and ECOG PS to pts in B and C2, respectively. Study objectives included PK, safety and antitumor activity. Results: 88 pts were enrolled in A1 (n=11), A2 (n=15), B (n=20), C1 (n=10), C2 (n=16) and D (n=16). The geometric means of PK parameters at steady-state (Cycle 2 Day 1) are shown below. 75% of pts experienced treatment-related AEs (TRAEs), 9 (81.8%), 14 (93.3%), 15 (75.0%), 6 (60.0%), 11 (68.8%) and 11 (68.8%) in groups A1, A2, B, C1, C2 and D, respectively. 25% of pts experienced Grade 3/4 TRAEs, 3 (27.3%), 3 (20.0%), 3 (15.0%), 1 (10%), 7 (43.8%), 5 (31.3%) in groups A1, A2, B, C1, C2 and D, respectively. Three (3.4%) pts, all in A2, experienced treatment-related SAEs. Two pts (10%) in B and 1 (6.3%) in C2 required dose reductions for TRAEs. TRAEs associated with permanent discontinuation of treatment occurred in 1 pt in A1, A2, C2 and D. Overall, 3 pts had partial responses with durations of 96, 17 and 17 wks; 25 pts had stable disease. Conclusions: Systemic exposures of crizotinib in pts with mild HI receiving 250 BID and in pts with moderate HI receiving 200 mg BID are comparable with that of pts with normal hepatic function at 250 mg BID. All TRAEs were manageable across the various levels of hepatic function. Clinical trial information: NCT01576406. [Table: see text]
A phase II study of copper-depletion using tetrathiomolybdate (TM) in patients (pts) with breast cancer (BC) at high risk for recurrence: Updated results.
Authors: Sahota Sheena , Kornhauser Naomi , Willis Amy , Ward Maureen M. , Cigler Tessa , Moore Anne , Andreopoulou Eleni , Fitzpatrick Veronica , Schneider Sarah E. , Wiener Alysia , Rubinchik Anna , Lee Sharrell , Lane Maureen E. , Mittal Vivek , Vahdat Linda T. 
Published: September 2018

2557 Background: The tumor microenvironment (TME) plays a critical role in the spread of tumors. Bone marrow derived VEGFR2+endothelial progenitor cells (EPCs) and copper-dependent lysyl oxidase (LOX) are key in tumor progression. We hypothesized TM-associated copper depletion inhibits tumor metastases by reducing the number of EPCs and other copper dependent (CD) processes in the pre-metastatic niche. These results are an update with longer follow-up. Methods: Phase II study of BC pts at high risk for recurrence, defined as node+ triple negative (TNBC), stage 3 and 4 with no evidence of disease (NED) were enrolled on a trial of CD with TM. Ceruloplasmin (Cp) levels were maintained between 8-16 mg/dl for two years with an extension phase or until relapse. The primary endpoint was change in EPCs measured by flow cytometry before and during treatment. Secondary endpoints included tolerability, safety, PFS and LOXL-2 levels. Results: 75 pts received 2650 cycles of TM on primary and extension study. The median age is 51 years (range 29-66). Forty-five pts have stage 2/3 BC and 30 with stage 4 NED. TNBC pts were 48% and 40% of pts are stage 4 NED. Median Cp level decreased from 28 to 16 (p < 0.0001) after one cycle. Copper depletion was most efficient in TNBC where Cp levels dropped from 23.5 to 13 after one cycle. TM was well tolerated with grade 3/4 toxicities including: reversible neutropenia (2.3%), febrile neutropenia (0.04%), fatigue (0.2%). Five-year analysis showed a decrease in EPC’s (p = 0.004) and LOXL-2 (p < 0.001). At a median follow-up of 6.9 years, the EFS for 75 pts is 75.6%. PFS for 36 pts with TNBC is 79.2%. EFS for stage 2/3 TNBC is 90% and for stage IV TNBC is 66.7%. Conclusions: TM is safe, well tolerated and appears to affect multiple components of the TME creating an inhospitable environment for tumor progression especially in high risk patients such as TNBC. Randomized trials are warranted, especially in patients at high risk for relapse. Clinical trial information: UL1TR000457.
A first in human phase I study of AZD8186, a potent and selective inhibitor of PI3K in patients with advanced solid tumours as monotherapy and in combination with the dual mTORC1/2 inhibitor vistusertib (AZD2014) or abiraterone acetate.
Authors: Hansen Aaron Richard , Shapiro Geoffrey , Do Khanh T , Kumar Rajiv , Martin-Liberal Juan , Higano Celestia S. , Wisinski Kari Braun , Dean Emma Jane , Heath Elisabeth I. , Rathkopf Dana E. , Linch Mark David , Barry Simon T , Brugger Wolfram , De Bruin Elza , Colebrook Steve , Klinowska Teresa , Mitchell Patrick D , Moorthy Ganesh , De Bono Johann S. , Siu Lillian L. 
Published: September 2018

2570 Background: Loss of PTEN function leads to increased PI3Kβ signalling. AZD8186 (AZD) exhibits significant anti-tumour activity in PTEN-deficient preclinical models, particularly when combined with anti-androgens or the dual mTORC1/2 inhibitor vistusertib (AZD2014). Here we report on the dose-finding part of this Phase 1 study. Methods: AZD single agent was administered twice daily (BD) in 3 different schedules (5 days on/ 2 days off, 2 days on/ 5 days off and continuous). Escalating doses of AZD were evaluated in cohorts of 3-6 patients treated until progression, unacceptable toxicity, or consent withdrawal. Accrual is ongoing in the combination arms with vistusertib or abiraterone acetate. Results: As of 16 Jan 2017, 87 patients have received AZD at doses of 30–360 mg BD, with 28 confirmed as PTEN deficient (IHC). The selected RP2D for the 5 days on/2 days off monotherapy schedule is 60 mg BD. PK parameters show that systemic exposures to AZD and its major active metabolite increase in a dose proportional manner. 69 serious adverse events (SAEs) were reported in 31 patients on AZD monotherapy with 23 SAEs considered possibly related to AZD. In the 5/2 schedule: 5 dose limiting toxicities (G3 rash with ≥G2 fever and/or chills) were observed in 5 patients at doses of 120-360mg. Adverse events ≥G1 in > 20% included diarrhoea, nausea, fatigue, LFT elevations and decreased appetite. 20 patients remained on study for > 100 days. Dose-dependent target inhibition has been demonstrated in surrogate tissue (platelets). Evaluation of direct tumour target engagement in paired biopsies is currently ongoing. Preliminary efficacy: Confirmed PRs seen in a CRPC patient (BRCA2 and androgen receptor mutant) treated in combination with vistusertib (on study for 411 days) and in one ongoing monotherapy PTEN-deficient colorectal cancer patient (on study > 329 days). Updated data will be presented. Conclusions: AZD has potential for treatment of PTEN-deficient tumours. Investigation of the safety/tolerability and preliminary efficacy in combination with vistusertib or abiraterone acetate is continuing. Clinical trial information: NCT01884285.
A phase I trial of selective PI3K inhibitor taselisib (tas) plus palbociclib (palb) with and without endocrine therapy incorporating pharmacodynamic (PD) studies in patients (pts) with advanced cancers.
Authors: Lim Joline Si Jing , Asghar Uzma Saddia , Diamantis Nikolaos , Ward Sarah Emily , Parmar Mona , Purchase Beth , Raynaud Florence I. , Swales Karen E , Hrebien Sarah , Hall Emma , Tovey Holly , Bye Hannah , Proszek Paula , Lopez Juanita Suzanne , Turner Alison Joanne , De Bono Johann S. , Banerji Udai , Yap Timothy Anthony , Turner Nicholas C. 
Published: September 2018

2573 Background: The phosphatidylinositol 3-kinase (PI3K) pathway is commonly mutated in cancer. Tas is a selective β-isoform-sparing PI3K inhibitor with improved therapeutic index compared to pan-PI3K inhibitors. Palb is a CDK4/6 inhibitor now standard of care in combination with endocrine therapy (ET) in hormone receptor positive breast cancer. Combination of Tas, Palb and ET is synergistic in preclinical models. Methods: This investigator-initiated study investigated safety and tolerability, pharmacokinetics (PK), PD and antitumor activity of Tas+Palb, with addition of ET in dose expansion. Pts were enrolled in 3+3 dose escalation design. Tas was given continuously or 3-weeks-on, 1-week-off (3/1), Palb was given on 3/1 schedule. PD studies included analyses of platelet-rich plasma (PRP) (n = 20) and paired tumor biopsies (n = 5). Serial circulating tumor DNA was monitored in pts with PIK3CA mutations. Results: 24 pts were treated, 22 with Tas+Palb, 2 with Tas+Palb+fulvestrant(ful); M/F 11/13, median lines prior therapy 4. Treatment was well tolerated with mainly G1-2 toxicities. Most frequent G3 toxicities were neutropenia (5/24), thrombocytopenia (5/24) and rash (5/24), with no G4/5 toxicities. Two pts had dose-limiting toxicities (DLT) at DL2. No DLTs were observed at DL4, although pts experienced delayed neutrophil recovery. PK was linear and comparable with monotherapy. At 125mg Palb, significant decreases in pAKT and pGSK3β in PRP confirmed PI3K target inhibition. Two pts with PI3KCA H1047R mutant breast cancers have ongoing RECIST partial response; 1 pt with PIK3CA E542K colorectal cancer had stable disease for 20 weeks. Conclusions: Tas+Palb is well tolerated with evidence of PD and antitumor activity. Dose expansion including recruitment to triplet Tas+Palb+ful and Tas+Palb+letrozole is ongoing with continuous Tas 2mg QD, and Palb 100mg QD on 3/1 schedule, increasing to 125mg after cycle 1 in absence of myelosuppression. Clinical trial information: NCT02389842. [Table: see text]
First-in-human phase 1 study of ETC-159 an oral PORCN inhbitor in patients with advanced solid tumours.
Authors: Ng Matthew , Tan David SP , Subbiah Vivek , Weekes Colin D. , Teneggi Vincenzo , Diermayr Veronica , Ethirajulu Kantharaj , Yeo Pauline , Chen Deborah , Blanchard Stephanie , Nellore Ranjani , Gan Bong Hwa , Yasin Maryam , Lee Lay Hoon , Lee May Ann , Hill Jeffrey , Madan Babita , Virshup David , Matter Alex 
Published: September 2018

2584 Background: The Wnt signalling pathway is involved in cellular proliferation, differentiation, migration and implicated in stem cell function in several cancers. ETC-159 is a selective small molecule inhibitor of porcupine, an enzyme required for palmitoylation and secretion of all Wnt ligands. In preclinical studies, ETC-159 induced tumour regression in patient-derived xenograft models. Methods: Open-label, multi-centre study to determine safety, maximum tolerated dose, pharmacokinetics, pharmacodynamics (PD) of ETC-159 given orally, once every other day in a 28d cycle. PD was evaluated by AXIN2 mRNA levels in whole blood and hair follicles and bone turnover by radiological and serum markers. Dose escalation was by ordinal continual reassessment method with a dose-limiting toxicity (DLT) period of 28d. Results: As of 18 Jan 2017, 16 patients (pts) were treated in 6 cohorts at 1 mg (2pts), 2 mg (2pts), 4 mg (3pts), 8 mg (4pts); 16 mg (3pts), and 30 mg (2pts). 80% were male, median age (range) was 55yr (19-68). One DLT was seen at 16 mg due to hyperbilirubinaemia. Adverse events (≥ 20%) were vomiting (32%); anorexia and fatigue (31%); dysgeusia and constipation (25%). ETC-159 Cmax increased with dose with a mean t1/2 of 14 hr. Plasma levels of ETC-159 that inhibited colony formation in vitro were attained from 4 mg onwards. Reduction of whole blood and hair follicle AXIN2 mRNA levels and doubling of serum β-CTX levels was first observed at 4 mg and at C1D15 in some patients. PD modulation increased with dose, consistent with on-target modulation of Wnt signalling. Two pts had β-CTX rise > 1000 pg/mL (reference limit) and a ≥ 5% reduction in bone density by C3D1. Both took vitamin D and calcium supplements and were given i.v. bisphosphonates. No responses were seen but 2 pts (2 mg: colorectal and 4 mg: peritoneal carcinoma) had stable disease for 6 and 8 cycles respectively. Dose-escalation is ongoing at 30 mg. Conclusions: ETC-159 inhibits Wnt signalling at doses that are well tolerated. β-CTX levels increased early on, and in two pts were associated with reduced bone mineral density. Early and regular monitoring of bone turnover is indicated. This study was sponsored by D3 which is funded by NMRC, NRF and BMRC Singapore. Clinical trial information: NCT02521844.
Safety and clinical activity of adenosine A2a receptor (A2aR) antagonist, CPI-444, in anti-PD1/PDL1 treatment-refractory renal cell (RCC) and non-small cell lung cancer (NSCLC) patients.
Authors: Fong Lawrence , Forde Patrick M. , Powderly John D. , Goldman Jonathan Wade , Nemunaitis John J. , Luke Jason John , Hellmann Matthew David , Kummar Shivaani , Doebele Robert Charles , Mahadevan Daruka , Gadgeel Shirish M. , Hughes Brett Gordon Maxwell , Markman Ben , Riese Matthew John , Brody Joshua , Emens Leisha A. , McCaffery Ian , Miller Richard Alan , Laport Ginna 
Published: September 2018

3004 Background: Adenosine production in the tumor leads to immunosuppression through A2aR on infiltrating immune cells. CPI-444 is an oral A2aR antagonist with single agent(SA) anti-tumor activity in pre-clinical models. This phase 1/1b clinical trial uses a 2-step adaptive design to evaluate CPI-444 as a SA and in combination (combo) with the anti-PDL1 antibody, atezolizumab (atezo). We report results of RCC and NSCLC cohorts. Methods: Primary objectives: safety, efficacy and to identify optimal dose/schedule. Step 1 utilized 3 SA and 1 combo cohort to select dose/schedule. Step 2 included disease-specific expansion cohorts including RCC and NSCLC. Eligible pts had selected advanced cancers and failed standard therapies including checkpoint inhibitors. Results: 34 pts have enrolled and 25 pts were evaluable for response (Table 1). Median prior regimens: 3 (range,1-5) and most pts were resistant/refractory to anti PD1/PDL1 therapy (R/R). Most common AEs were Gr 1 nausea (n = 3) and pyrexia (n = 3); Gr 3 tachycardia was the only possibly related SAE. The selected Step 2 doses were CPI-444 100mg BID as a SA and in combo with atezo 840mg IV q2 weeks. The disease control rate (DCR, CR+PR+SD; duration 2 mo to > 8 mo) for pts with RCC and NSCLC cohorts were 86% and 50%, (100% and 43% for R/R pts), respectively. DCRs were similar in the SA and combo cohorts. Of 7 evaluable RCC pts, 1 pt has an ongoing PR (SA cohort, > 4 mo) and 5 have ongoing SD, duration 3 mo to > 8 mo (2 SA, 3 combo). Biopsy of the PR pt showed no detectable tumor and infiltration with CD8+ lymphocytes. In 18 evaluable NSCLC pts, 1 PR (PDL1 negative pt) and 8 SD were seen. PRs and SDs were seen in R/R pts and in PDL1 negative pts in both diseases. Conclusions: CPI-444 is well tolerated and shows anti-tumor activity in RCC and NSCLC pts as a SA and in combo. Pts who are R/R to anti PD1/PDL1 therapy and who are PDL1 negative can also benefit. Clinical trial information: NCT02655822. [Table: see text]
The relationship of pharmacodynamics (PD) and pharmacokinetics (PK) to clinical outcomes in a phase I study of OX40 agonistic monoclonal antibody (mAb) PF-04518600 (PF-8600).
Authors: El-Khoueiry Anthony B. , Hamid Omid , Thompson John A. , Ros Willeke , Eskens Ferry , Doi Toshihiko , Hu-Lieskovan Siwen , Chou Jeffrey , Liao Ken , Ganguly Bishu J , Fleener Catherine , Joh Tenshang , Diab Adi 
Published: September 2018

3027 Background: PF-8600 is a novel fully human IgG2 agonistic mAb against human OX40, a TNF receptor superfamily member expressed primarily on activated T cells. This ongoing phase 1 study (NCT02315066) is investigating the safety, efficacy, PK and PD of PF-8600 in patients (pts) with solid tumors. Methods: PF-8600 (0.01–10 mg/kg) was given IV every 14d. Expression of free/total OX40 receptor, proliferation marker ki67 and activation markers HLA-DR/CD38 were measured in T cell subsets in peripheral blood by flow cytometry in all pts. CD4, CD8, OX40 and FOXP3 were evaluated in paired tumor biopsies (bx), collected from a subset of pts (≥0.1 mg/kg) at baseline (BL) and Wk6, by immunohistochemistry. Results: As of 21Sep2016, 48 pts with melanoma (n = 14), hepatocellular carcinoma (HCC, n = 19), head and neck squamous cell (n = 6) or renal cell carcinoma (n = 9) enrolled in the dose-escalation cohorts (0.01-3 mg/kg). No immune related adverse events (AE) were reported. The most frequent treatment related AEs in > 3 pts were fatigue (27.1%) and nausea and vomiting (8.3% each); all Gr 1-2. 2 pts had a partial response: melanoma at 0.1 (Pt1) and HCC at 0.3 (Pt2) mg/kg. 25 pts had best ORR (BOR) of stable disease (SD; 3 pts ≥24 wks). A majority of pts at 0.1, 0.3, and 3 mg/kg, including Pt1 and Pt2, had increases in ki67 and HLA-DR/CD38 expression in peripheral CD4+ central memory T cells. Pt1, Pt2 and all pts at ≥0.3 mg/kg had full receptor occupancy. Paired bx were only available from pts with BOR of SD or progressive disease. In 10 pts with available paired tumor bx and defined date of radiographic progression (rPD), longer time to rPD correlated with increases in %OX40+ in bx from BL to Wk6, regardless of dose level, tumor type or prior immunotherapy (R2= 0.52, p = 0.0188); no correlation between rPD and CD4+, CD8+ or FOXP3+ expression changes was observed. Updated efficacy, safety, PK and PD data will be presented. Conclusions: PF-8600 is well tolerated with evidence of single agent efficacy. Initial observations of PD markers that change with treatment and correlate with rPD support efforts to confirm these findings as more clinical outcomes and larger sample sizes become available. Clinical trial information: NCT02315066.
Association of changes in T regulatory cells (Treg) during nivolumab treatment with melanoma outcome.
Authors: Weber Jeffrey S. , Ramakrishnan Rupal , Laino Andressa , Berglund Anders E. , Woods David 
Published: September 2018

3031 Background: PD-1 blocking antibodies have significant efficacy in the treatment of melanoma; however, many patients fail to respond and resistance mechanisms remain unknown. We addressed the role of Tregs, an immunosuppressive T-cell population, in patient outcome after treatment with nivolumab. Methods: Peripheral blood mononuclear cells (PBMC) were obtained from patients on trials with nivolumab as adjuvant therapy for resected disease or as treatment for metastatic melanoma. To measure suppression, Tregs were flow-sorted from PBMC and evaluated in allogeneic mixed lymphocyte reactions. Tregs and conventional CD4 T-cells were evaluated for gene expression changes by RNA-sequencing. Treg percentages and phosphorylated STAT3 (pSTAT3) expression were evaluated by flow cytometry. The effects of PD-1 blockade with nivolumab were evaluated in vitro using T-cells from baseline patient PBMC samples. Results: Tregs from responding patients or adjuvant patients without evidence of disease (NED) had reduced suppressive function post-nivolumab (p < 0.05), but no changes were observed in relapsing/non-responding patients; their Tregs were more suppressive than NED/responding Tregs (p < 0.001). NED Tregs had unique gene expression changes and associated pathways post-nivolumab compared to relapsing patient Tregs and conventional CD4 T-cells, including up-regulation of proliferation pathways (q < 8e-19) and downregulation of oxidative phosphorylation (q < 7e-5). NED Tregs had upregulation of pSTAT3 expression post-nivolumab (p < 0.05), which was not observed in relapsing patients. Evaluation of Tregs from patients with active disease also showed upregulation of pSTAT3 in responders (p < 0.05) but not non-responders. The relative increase in Treg pSTAT3 was associated with increased overall survival (R2= 0.49, p < 0.05). In vitro assays using PD-1 blocking antibodies recapitulated the increase in pSTAT3 (p < 0.05) and Treg percentages (p < 0.001), which were diminished with the addition of a STAT3 inhibitor (p < 0.01). Conclusions: These results demonstrate previously unknown roles of decreased Treg suppressive function and induction of STAT3 as biomarkers of patient’s outcome to nivolumab therapy.