bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tolerability and preliminary efficacy of BXQ-350 for refractory solid tumors and high-grade gliomas: First-in-human, first-in-class phase I trial.
Authors: Rixe Olivier , Morris John Charles , Wesolowski Robert , Yilmaz Emrullah , Curry Richard , Wise-Draper Trisha Michel , Puduvalli Vinay K. 
Published: May 2020

3505 Background: BXQ-350 is a first-in-class agent comprised of Saposin C (SapC) and dioleoyl phosphatidylserine (DOPS). SapC, a multifunctional lysosomal-activator glycoprotein that preferentially interacts with tumor cell phospholipids, has demonstrated anti-tumor effects in both in vitro and in vivo preclinical models. The tolerability and preliminary efficacy of BXQ-350 in the first-in-human study are summarized here. Methods: Eighty-six refractory solid tumor (ST) or high-grade glioma (HGG) patients age ≥18 (36F:50M, age 24-81) were enrolled in a 3-part first-in-human trial (NCT02859857) from 2016-2019 and received at least one dose of BXQ-350. Doses were administered via intravenous infusion during 28-day cycles until disease progression occurred. The previously reported part 1 dose escalation portion of the study (9 HGG, 9 ST patients) established the highest planned dose of 2.4mg/kg as safe but did not identify a maximum tolerated dose. The part 2 expansion cohort treated 37 patients (18 HGG and 19 ST) and an additional part 3 cohort treated 31 ST gastrointestinal (GI) patients, both at the 2.4 mg/kg dose level. Preliminary antitumor activity was evaluated (RECISTv1.1 or RANO). Results: There were no BXQ-350-related serious adverse events, dose limiting toxicities or withdrawals with the exception of 1 allergic type reaction. Three patients (Glioblastoma, Ependymoma, Appendiceal) demonstrated a partial response per RECIST/RANO. Two HGG patients with progressive radiologic enhancement were seen to have treatment effect at surgery, and hence considered to have stable disease. Seven patients (2 HGG, 3 GI, 2 other ST) remain on study and have received treatment for 9+ to 41+ months, with 5 patients treated for > 1 year. A continuing treatment protocol is planned in order to allow these patients to remain on BXQ-350 treatment. Conclusions: BXQ-350 was well tolerated with no significant dose-limiting toxicities at the highest planed dose level. Preliminary results indicate this novel agent demonstrated possible anti-tumor activity in refractory solid tumors and HGG. Clinical trial information: NCT03967093) .
Phase Ib study of a novel bivalent IAP antagonist APG-1387 in combination of pembrolizumab for patients with advanced solid tumors.
Authors: Rasco Drew W. , Lakhani Nehal J. , Tang Yuefen , Wang Hengbang , Ji Jiao , Chen Jason , LIANG ZHIYAN , Amaya Alex , Yang Dajun , Zhai Yifan 
Published: May 2020

3508 Background: APG-1387 is an IAP (inhibitor of apoptosis proteins) antagonist that has strong antitumor activity in multiple xenograft cancer models and acts as a host immune modulator, supporting its exploration for use in combination with checkpoint inhibitors for cancer therapy. Methods: This “3+3” dose escalation and dose expansion study evaluated APG-1387 combined with pembrolizumab in patients with refractory or intolerant advanced solid tumors (NCT03386526). APG-1387 was administered IV once weekly with pembrolizumab 200 mg on day 1 of a 21-day cycle. Study aims were to assess safety/tolerability, recommended phase 2 dose (RP2D), pharmacokinetics (PK), pharmacodynamics (PD), and efficacy. Results: As of December 25, 2019, total 28 patients had been treated in 3 dose cohorts of APG-1387: 20 mg (n = 4), 30 mg (n = 3), and 45 mg (n = 21, 18 in dose expansion). The median line of prior systemic cancer therapies was 3.0 (1-12). No dose-limiting toxicity was observed. The most common treatment-related adverse events (TRAEs; ≥10%) were fatigue (28.6%), arthralgia (14.3%), headache (14.3%), and tumor pain (10.7%). One patient in the 45-mg cohort had grade 2 Bell’s Palsy. G3+ TRAEs were autoimmune colitis, hypoxia, increased lipase, mucosal inflammation, pneumonitis, and tumor pain in 1 patient each (3.6%). Treatment-related SAEs were 1 G3 autoimmune colitis, 1 G2 myocarditis, and 1 G3 pneumonitis. The maximum tolerated dose (MTD)/RP2D for APG-1387 was 45 mg. Among 25 efficacy-evaluable patients, 1 with ER+, HER2‒ breast cancer receiving APG-1387 30 mg after failing 5 lines of therapy (PD-1 treatment-naïve, microsatellite stable) achieved confirmed PR (-79.2%) for 6 cycles but discontinued due to pneumonitis; another patient with PD-L1‒ non‒small-cell lung cancer treated at 45 mg had confirmed PR (-65.0%) for 6 cycles (ongoing). Other 11 patients had SD for 2-11 cycles. The disease control rate was 52%. Preliminary PK data showed a dose-proportional increase in APG-1387 exposure from 20 mg to 45 mg. Preliminary PD data showed that APG-1387 induced rapid degradation of cellular IAP1 and X-linked IAP in peripheral blood mononuclear cell samples; Increased serum release of interleukins (IL-12, IL-10) and monocyte chemotactic protein 4 was dose and time dependent. Conclusions: APG-1387 combined with pembrolizumab is well tolerated. Encouraging antitumor effects were observed in patients with several tumor types. The ongoing study will further evaluate the efficacy of this combination. Clinical trial information: NCT03386526 .
Safety and efficacy of pyrotinib in patients with NSCLC and other advanced solid tumors with activating HER2 alterations: A phase I basket trial.
Authors: Li Bob T. , Li Tianhong , Johnson Melissa Lynne , Waqar Saiama Naheed , Zhu Viola Weijia , Ou Sai-Hong Ignatius , Lin Jessica Jiyeong , Wang Ding , Shapiro Geoffrey , Wang Judy Sing-Zan , Liu Dazhi , Ye Yuqing , Kosar Hana , Hee Angela , Berk Greg , Zhang Sean , Wang Junsheng , Patel Manish R. 
Published: May 2020

3510 Background: Pyrotinib is a potent, irreversible tyrosine kinase inhibitor (TKI) that blocks signal transduction through the erythroblastic leukemia viral oncogene homolog (erbB) receptors, which has previously demonstrated promising antitumor activity in patients (pts) with breast cancers. We studied the safety and efficacy of pyrotinib in pts with non-small cell lung cancer (NSCLC) and other solid tumors with activating human epidermal growth factor receptor 2 ( HER2, ERBB2) alterations. Methods: This is an open-label, multicenter phase 1 dose expansion basket trial of pyrotinib given 400mg oral daily at 28-day cycles. Expansion cohorts included pts with HER2-mutant NSCLC and advanced solid tumors with HER2 mutation or amplification. HER2 testing was conducted using next generation sequencing or fluorescence in situ hybridization. Primary endpoints included toxicities as evaluated by NCI CTCAE v5.0, and overall response rate (ORR) as evaluated by RECIST v1.1. Secondary objectives included progression-free survival (PFS). Results: A total of 62 pts were enrolled. The median age was 67 (range 40 – 86 years), 61% were female and the median lines of prior systemic therapy was 3 (range 1-11). There were no treatment related deaths. The most common adverse events were diarrhea (96.8%), nausea (82.3%) and vomiting (41.9%). The only ≥ grade 3 treatment related toxicity was diarrhea (24.2%). Prophylactic anti-diarrhea treatment was introduced to facilitate continuation of pyrotinib. At the Jan 13, 2020 cut-off, 24 pts with HER2-mutant NSCLC (20, i.e. 65% of which were the A775_G776insYVMA mutation) and 18 pts with HER2-mutant or amplified solid tumors completed end of Cycle 2 imaging scan and were evaluable for tumor responses. The ORR was 19% (8/42, 95% CI 7-31%); confirmed responses include a complete response (CR) and 3 partial responses (PRs) in HER2-mutant NSCLC, and 4 PRs in HER2-amplified cholangiocarcinoma, ovarian, endometrial and salivary gland carcinomas. There were 7 stable disease ≥ 6 months. Median progression-free survival was 5.4 months (95% CI 4.4-7.3). Conclusions: Pyrotinib demonstrated a manageable safety profile and encouraging efficacy in pts with heavily pre-treated HER2-mutant NSCLC. Furthermore, it is the first TKI to produce durable responses in pts with HER2-amplified biliary tract, ovarian, endometrial and salivary gland cancers. These results warrant further clinical development of pyrotinib. Clinical trial information: NCT02500199 .
CodeBreak 100: Phase I study of AMG 510, a novel KRASG12C inhibitor, in patients (pts) with advanced solid tumors other than non-small cell lung cancer (NSCLC) and colorectal cancer (CRC).
Authors: Hong David S. , Kuo James , Sacher Adrian G. , Barlesi Fabrice , Besse Benjamin , Kuboki Yasutoshi , Dy Grace K. , Dembla Vikas , Krauss John C. , Burns Timothy F. , Kim June , Henary Haby , Ngarmchamnanrith Gataree , Li Bob T. 
Published: May 2020

3511 Background: Kirsten rat sarcoma viral oncogene homolog ( KRAS) p.G12C mutation occurs in approximately 13% of NSCLC and 1%–3% of CRC and other solid tumors. AMG 510 is a first-in-class small molecule that specifically and irreversibly inhibits KRASG12C. Previously, AMG 510 showed preliminary antitumor activity and favorable tolerability in pts with KRAS p.G12C mutant NSCLC or CRC in the phase 1, first-in-human trial. Here, we report results in pts with other tumor types from the same trial. Methods: This study evaluates AMG 510 in pts with locally-advanced or metastatic KRAS p.G12C mutant solid tumors. Key inclusion criteria: KRAS p.G12C mutation via local testing and prior systemic anticancer treatment (tx). Oral daily doses of 180, 360, 720, and 960 mg were tested in the dose escalation, and 960 mg was selected for expansion. Primary endpoint is safety; key secondary endpoints include pharmacokinetics and objective response rate as assessed per RECIST 1.1. Response is assessed every 6 weeks (wks) for 24 wks then every 12 wks thereafter. Results: As of January 8, 2020, 25 pts (9 female, median age 60 years [range: 40–75]) with tumor types categorized by investigators as histology other than NSCLC and CRC were enrolled and dosed (10 pancreatic cancer, 4 appendiceal cancer, 2 endometrial cancer, 2 unknown primary cancer, 1 bile duct cancer, 1 sinonasal cancer, 1 ampullary cancer, 1 small bowel cancer, 1 melanoma, 1 small cell lung cancer, and 1 esophageal cancer). 23 pts received 960 mg dose. 20 pts (80.0%) had ≥2 prior lines of tx. At data cutoff, 13 pts (52.0%) remained on tx; 9 (36.0%) and 3 (12.0%) pts remained on tx for ≥3 and ≥6 months, respectively. Median follow up was 4.3 months (range: 0.1–12.6). Tx-related adverse events (TRAEs) occurred in 9 pts (36.0%). 2 pts (8.0%) had grade 3 TRAEs, including diarrhea (1/25) and pneumonia (1/25, serious AE). No dose-limiting toxicities, grade ≥4, or fatal TRAEs were reported. No TRAEs led to tx discontinuation. 3 pts had not been followed up for ≥7 wks by the data cutoff. 22 pts were followed up for ≥7 wks, and their best overall responses were: 3 confirmed partial response (1 appendiceal, 1 melanoma, and 1 endometrial), 13 stable disease (6 pancreatic, 2 appendiceal, 1 ampullary, 1 bile duct, 1 endometrial, 1 sinonasal, and 1 unknown primary), and 6 progressive disease. Conclusions: AMG 510 was well tolerated and demonstrated clinical activity in pts with advanced KRAS p.G12C mutant solid tumors other than NSCLC and CRC. Clinical trial information: NCT03600883 .
Intratumoral exposure levels of pentaglutamated pemetrexed following treatment with LEAF-1401 and pemetrexed.
Authors: Kim Gwangseong , Nyinawabera Angelique , Xu Zhenghong (Hannah) , DeFuria Jason , Sezibera Alvin , Cui Yanyan , Geng Bolin , Khalifa Khaniz , Dhindsa Navreet , Niyikiza Clet , Moyo Victor M. 
Published: May 2020

3524 Background: The activity of pemetrexed is highly dependent on the intracellular enzyme folypolyglutamate synthase (FPGS) which adds glutamates to pemetrexed and yields very potent pemetrexed polyglutamates. Pemetrexed pentaglutamate (tetraglutamated pemetrexed) is 80-fold more potent than pemetrexed in inhibiting thymidylate synthase. Yet it is a poor drug candidate because it cannot readily cross the negatively charged cell membrane due to its own negative charge. We are developing LEAF-1401, a novel nanoliposomal encapsulation of gamma L-pentaglutamated pemetrexed. Because liposomes can readily be taken up by tumor cells, for its anti-tumor effect, LEAF-1401 can directly deliver pentaglutamated pemetrexed into tumor cells, bypassing the need for transmembrane folate carriers and FPGS which are both downregulated in resistant tumors. Methods: To measure drug levels in tumor, blood and various tissues (biodistribution), in vivo testing of LEAF-1401 and pemetrexed was conducted in a CT-26 murine colorectal carcinoma xenograft model. Animals were treated with a single dose of either LEAF-1401 (80mg/kg; equivalent to 32 mg/kg pemetrexed) or pemetrexed (118mg/kg). Tumor growth inhibition and clinical assessments were conducted. Animals were sacrificed: 5 mice per timepoint in each group and tumor, blood, liver, spleen and other tissues were harvested. Pentaglutamated pemetrexed levels were quantitatively analyzed by LC/MS/MS. Results: Compared to pemetrexed, LEAF-1401 treatment resulted in a 19-fold increase in exposure levels of pentaglutamated pemetrexed in the tumor and significant tumor growth inhibition. Plasma levels of pentaglutamated pemetrexed were high with LEAF-1401, but undetectable with pemetrexed. Like other liposomes, LEAF-1401 also resulted in accumulation of pentaglutamated pemetrexed in the liver and spleen (See Table below). Treatment appeared to be generally well tolerated. Conclusions: LEAF-1401, given at approximately a quarter of the equivalent pemetrexed dose, resulted in a 19-fold increase in pentaglutamate pemetrexed in tumor tissue compared to regular pemetrexed. LEAF-1401 represents a promising new class of novel nanoliposomal antifolates, that enhance the intratumoral delivery of potent polyglutamate antifolates, and improve antitumor activity while retaining an acceptable safety profile. [Table: see text]
Liquid biopsies to enable non-invasive real-time functional chemoresistance profiling in solid organ cancers.
Authors: Akolkar Dadasaheb B , Crook Timothy , Page Raymond , Patil Darshana , Limaye Sewanti , Datta Vineet , Schuster Stefan , Sims Cynthe , Patil Sanket , Apurwa Sachin , Mhase Vishakha , Pawar Sushant , Gawai Ashok , Bodke Harshal , Srinivasan Ajay , Datar Rajan 
Published: May 2020

3525 Background: Despite the development of targeted therapy agents and immune checkpoint inhibitors (ICI), cytotoxic anticancer agents remain the mainstay of treatment in several solid organ cancers. However, instances of innate and acquired resistance towards these anticancer agents can lead to treatment failures, which remain undetectable until clinical or radiological manifestation of symptoms suggestive of disease progression. There are presently no viable means or markers to detect or monitor for chemoresistance in real time. Owing to this unmet need, cancer treatment strategies face risks of failure and poor outcomes. Methods: We obtained 15 mL blood from 3,662 patients with various solid organ cancers, of various states and including treatment-naïve and pretreated patients. Circulating Tumor Associated Cells (C-TACs) were enriched and harvested from PBMCs using an epigenetically activating medium that is cytotoxic towards non-malignant epithelial and hematolymphoid cells in blood, but confers survival benefit on apoptosis resistant cells of tumorigenic origin (Circulating Tumor Associated Cells, C-TACs). In a subset of patients, fresh tumor tissue was also obtained from which viable tumor derived cells (TDCs) were obtained. Viable TDCs and C-TACs were treated with a panel of anticancer agents and the surviving cell fraction estimated to determine chemoresistance. Results: Among the 1,325 therapy naïve patients, resistance towards treatment agents was observed in C-TACs from 56.3 % of samples. Among 2,201 pretreated patients’ samples, resistance towards treatment agents was observed in C-TACs from 77.8% of samples. The increased resistance in C-TACs from pretreated patients indicated that the C-TACs had been resistance-educated by prior therapies. In a subset of patients, Chemoresistance profile of C-TACs was observed to be 96.9% concordant with that of tumor derived cells (TDCs) which were concurrently obtained from tumor tissue indicating that C-TACs accurately represent chemo-antecedents of the tumor. Conclusions: Non-invasive chemoresistance profiling of C-TACs is a viable strategy to monitor treatment efficacy in real time. Adoption of this strategy in the clinic will not only guide treatment selection with reduced risk of failure, but will also enable timely therapeutic course correction upon detection of acquired chemoresistance.
Exploitation of treatment induced tumor lysis to enhance sensitivity of ctDNA analysis: A first-in-human pilot study.
Authors: Breadner Daniel Adam , Vincent Mark David , Correa Rohann Jonathan Mark , Black Morgan , Warner Andrew , Qu Melody , Logan Diane , Sanatani Michael Susmoy , Younus Jawaid , Yaremko Brian P , Rodrigues George , Blanchette Phillip S. , Laba Joanna , Bhat Vasudeva , Morris Clive D. , Green Emma , Jones Greg , Allan Alison L , Palma David A. , Raphael Jacques 
Published: May 2020

3530 Background: Blood based liquid biopsies examining circulating tumour DNA (ctDNA) have increasing applications in non-small cell lung cancer (NSCLC). Limitations in sensitivity remains a barrier to ctDNA replacing tissue-based testing. There is a paucity of data regarding the dynamics of ctDNA levels in the hours to days following a new treatment. We hypothesize that chemotherapy or radiation will yield an increased abundance of ctDNA in plasma by inducing tumor lysis, allowing for the detection of genetic alterations that were occult in baseline testing. Methods: Two prospective cohorts of 20 patients (pts) with stage III/IV NSCLC were enrolled. Cohort 1 (C1) contained pts starting the first cycle of platinum doublet chemoradiation (C1a, n=10) or the first cycle of platinum doublet cytotoxic chemotherapy ± immunotherapy without radiation (RT) (C1b, n=10). Cohort 2 (C2) contained pts receiving palliative RT alone. Two baseline samples were collected, the first ≤ 14 days prior to starting treatment and one immediately prior to treatment. In C1, subsequent samples were collected 3, 6, 24 and 48 hours post initiation of chemotherapy. Pts in C2 had samples collected immediately prior to RT fractions 2, 3, and 4. Samples were analyzed for ctDNA using the 36-gene amplicon-based NGS Inivata InVisionFirst-Lung assay. Results: Complete results were available for the first 35 of 40 enrolled pts, C1a – 10 pts, C1b – 9 pts, C2 – 16 pts. Detectable ctDNA was present at baseline in 27 pts (77%), 4 additional pts (11%) had detectable ctDNA in post treatment samples. Four of the patients with detectable ctDNA at baseline (15%) had new genetic alterations detected in post treatment samples. A total of 8/35 pts (23%) had new genetic alterations detected in the post treatment samples. Mutant molecule numbers increased with treatment in 23 of 31 (74%) pts with detectable ctDNA, C1 - 13 of 19 pts (68%) and C2 - 10 of 16 pts (63%). ctDNA levels peaked a median of 2.2 hours (IQR: 1.5 – 2.9 hours) after the initiation of chemotherapy and a median of 1 day (IQR: 1-2 days) after radiation was commenced. The percentage increase in ctDNA levels was a median of 29% (IQR: -18 to +112%) in C1. C2 had a median increase of 16% (IQR: 0 to +131%). Conclusions: ctDNA levels increase in the hours to days after starting treatment. ctDNA testing in the acute post treatment phase can yield results that were not evident in pretreatment testing. Application of this principle could improve ctDNA utility as an alternate to tissue-based testing and improve sensitivity for the detection of treatment-resistant clones.
Clinical potential of ctDNA-based TMB in small cell lung cancer recieving chemoradiotherapy.
Authors: Jin Ying , Chen Yamei , Tang Huarong , Li Qian , Li Pansong , Hu Xiao , Guan Yan-Fang , Xia Xuefeng , Yi Xin , Zhang Jianjun , Chen Ming 
Published: May 2020

3536 Background: Small cell lung cancer (SCLC) is an aggressive tumor with poor prognosis. Chemotherapy and / or radiotherapy is the main choice of SCLC treatment. Circulating tumor DNA (ctDNA) has received substantial attention in recent years owing to the potential of patient stratification and monitoring. Here, we assessed the value of prediction and prognosis using ctDNA in SCLC. Methods: SCLC patients (pts) with limited-stage disease (LD) receiving chemoradiotherapy and extensive-stage disease (ED) receiving chemotherapy were enrolled. Baseline plasma samples were collected for NGS using a 1021-gene-panel. Mutational features and blood-based tumor mutation burden (bTMB) were analyzed using ctDNA. pyClone software was used to cluster the mutations. The mutations in the cluster with the highest cancer cell fraction (CCF) were defined as clonal mutations. Progression-free survival (PFS) was followed. Results: 58 SCLC pts (35 LD and 23 ED) and 58 plasma samples were enrolled. Smoking pts accounted for 84% (49/58). In all samples, recurrent genes were TP53 (86%), RB1 (57%), LRP1B (34%), CREBBP (26%), and MLL3 (22%). The median of bTMB and clone count were 7.9 [0-26] and 7 [0-25]. Significant higher bTMB and clone count were observed in ED pts compared with LD (Mann Whitney test, p = 0.019 and p = 0.041, respectively). Mutated CREBBP (10/23 ED versus 5/35 LD) was enriched in ED (Fisher exact test, p = 0.017 and OR = 0.223). Mutations in NOTCH signaling pathway were enriched in ED (l6/23 ED versus 13/35 LD, p = 0.031, OR = 0.265). In LD group, there were trend toward prolonged PFS in pts with higher bTMB(p = 0.065), and pts with higher clonal bTMB (cbTMB) exhibited significant longer PFS (p = 0.016, HR 0.37, 95% CI [0.12-1.11]). Patients with alteration in PIK3CA showed shorter PFS than wild type (p < 0.001, HR 0.11, 95% CI [0-2.86]). There were no significant difference in median PFS in LD stage pts with any detectable pathway alterations. Whereas, LD pts whose ctDNA contained RTK-RAS signaling pathway alterations exhibited shorter PFS than pts without those alterations (p = 0.135). In ED pts, NOTCH1 gene wild type displayed longer PFS than mutant type (p = 0.036, HR 0.38, 95% CI [0.1-1.53]). There were no difference in PFS between pts with higher and lower bTMB and cbTMB. Conclusions: ctDNA can characterize the mutational feature of SCLC. There are differences in the molecular characteristics between ED and LD pts. Clonal bTMB is a potential prognostic biomarker for LD SCLC chemoradiotherapy. The prognostic marker of ED chemotherapy is different from LD.