bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase 1b/2a study of PLX2853, a small molecule BET inhibitor, in subjects with advanced solid tumors and lymphoma.
Authors: Gordon Michael S. , Carvajal Richard D. , Spira Alexander I. , Huang Marilyn , Watkins Paul , Powell Ben , Inokuchi Kerry , Sterba Michael , Matusow Bernice , Hope Chelsea , Halladay Jason , Zhang Chao , Walling Jacqueline M. , Tsiatis Athanasios C. , Patnaik Amita 
Published: June 2021

3018 Background: PLX2853 is a potent, orally active small molecule BET inhibitor. Its unique pharmacokinetic (PK) profile is associated with less thrombocytopenia and improved tolerability by allowing transient target engagement with a prolonged pharmacodynamic (PD) response and time for recovery after dosing. Methods: We conducted a first-in-human 3+3 Ph1b/2a study of PLX2853 in adults with relapsed or refractory solid tumors and lymphoma to determine the safety, PK and recommended phase II dose (RP2D) (NCT03297424). Secondary endpoints included efficacy and PD. Results: As of 2 February 2021, 44 subjects (median age 65, range 39 - 84) received PLX2853 in escalating doses from 5mg to 120mg QD and 40mg to 60mg BID. Ovarian cancer (n = 11), uveal melanoma, colorectal, and prostate (n = 5 each) were the most represented tumor types. Adverse events (AE) occurring in ≥15% of subjects included nausea (41%), decrease appetite (39%), fatigue (27%), vomiting (25%), diarrhea (25%), dysgeusia (25%), dehydration (23%), anemia (20%), dry mouth (18%), dizziness (16%), abdominal pain (16%), and pyrexia (16%). Thrombocytopenia occurred in 11% of subjects. Most AEs ( > 85%) were grades (G) 1-2. Of all AEs, 40% were related. There were 5 treatment-related serious AEs in 2 subjects (n = 1 G4 thrombocytopenia, G4 ischemic stroke, G3 subarachnoid hemorrhage [SAH], and G3 thromboembolic event; n = 1 G3 vomiting). Dose-limiting toxicities were observed at 120mg QD (G4 thrombocytopenia, G4 ischemic stroke, G3 thromboembolic event, and G3 SAH; asymptomatic G4 thrombocytopenia), 60mg BID (G3 thrombocytopenia with recovery > 7 days), and 40mg BID (dose reduction for transient G3 fatigue). PLX2853 systemic exposure was dose-proportional up to 120mg with a short terminal half-life ( < 3.5 hr). Plasma concentrations were above the IC90 in the MYC-responsive reporter assay for 9 hr at 80mg or higher doses. RNA-seq analyses of peripheral blood mononuclear cells showed a dose-dependent modulation of BET target gene expression. One complete response (ongoing 9+ months) was seen in a patient with DLBCL, two patients had partial responses (1 uveal melanoma, 1 primary peritoneal cancer), and 14 patients had stable disease. The median PFS was 82.5 days (range: 51 – 209 days). Conclusions: PLX2853 shows encouraging signs of clinical activity and is well tolerated at the anticipated RP2D of 80 mg/day. PLX2853 is being evaluated as monotherapy and in combination. Clinical trial information: NCT03297424.
A phase 1 trial of FID-007, a novel nanoparticle paclitaxel formulation, in patients with solid tumors.
Authors: Thomas Jacob Stephen , Habib Diane , Hanna Diana L. , Kang Irene , Iqbal Syma , Nieva Jorge J. , Tsao-Wei Denice , Acosta Francisco , Hsieh Ming , Zhang Yilong , El-Khoueiry Anthony B. 
Published: June 2021

3021 Background: FID-007 (FID) consists of paclitaxel encapsulated in a polyethyloxazoline (PEOX) polymer excipient designed to enhance PK, biodistribution, and tolerability. In addition to allowing the drug to remain in solution until it can enter a cancer cell, the PEOX nanoparticle preferentially delivers paclitaxel to the tumor through the leaky hyperpermeable vasculature. In xenograft studies, FID reduced or limited tumor growth in multiple tumor types including lung, gastric, breast, pancreatic, and ovarian cancer. FID was more effective at lower or comparable taxane doses with fewer side effects. We present the first-in-human trial of FID. Methods: The study is evaluating the safety, PK, and efficacy of FID in pts with advanced solid tumors. The primary objective is to determine the MTD and RP2D. Pts received FID in doses between 15mg/m2 and 125mg/m2 using a standard 3+3 dose escalation design. FID was given IV on Days 1, 8, and 15 of a 28-day cycle. Eligibility included ECOG 0-2, adequate organ function, and no more than 3 prior lines of cytotoxic therapy for advanced disease. Results: Twenty-five pts were treated across 6 dose levels. Median age was 62 (44-76). ECOG PS was 2 in 1 pt and 1 in 64%. Median number of cycles was 2 (1-16). There were 2 DLTs of grade 3 rash at 100 mg/m2. Given the transient nature of the rash and response to topical therapy, DLT definition was modified to exclude grade 3 rash that lasts ≤ 7 days and additional patients were treated at 100 mg/m2 which was deemed tolerable. There was 1 DLT of grade 3 neutropenia at 125 mg/m2. All grade treatment related adverse events (TRAEs) in ≥ 25% of pts were rash (64%), alopecia (52%), pruritus (44%), anemia (44%) leukopenia, fatigue (40% each), dysgeusia, anorexia, nausea (32% each), and neutropenia (28%). Grade 3/4 TRAEs occurring in > 1 pt were anemia (20%), neutropenia, leukopenia, and maculopapular rash (16%). There were no treatment discontinuations due to toxicity. Twenty-two pts were evaluable for response by RECIST 1.1 with a PR rate of 14% (PR in pancreatic, biliary tract and NSCLC) and disease control rate of 59%. PK is linear and dose proportional. There is no paclitaxel accumulation after weekly dosing, and the t1/2 is between 18-26 hours. Conclusions: FID has a manageable safety profile with MTD not reached. Accrual is continuing at 125 mg/m2. PK is linear, dose proportional and comparable to that of nab-paclitaxel. There is preliminary evidence of anti-tumor activity in heavily pre-treated pts across different tumor types. Enrollment in dose escalation continues. Combination studies with immunotherapeutic agents are planned. Clinical trial information: NCT03537690.
Bosutinib in combination with pemetrexed in patients with selected metastatic solid tumors: A phase I study (NCT03023319).
Authors: Abdel Karim Nagla Fawzy , Shoukier Mahran , Eldessouki Ihab , Khaled Ahmed , Morris John 
Published: June 2021

3022 Background: Activation of the Src kinase pathway has been observed in about 50% of cancers of the colon, liver, lung, breast and pancreas. Ceppi, et al, explored that Src inhibitors might be synergistic in combination with pemetrexed. Bosutinib is an approved oral ATP-competitive Bcr-Abl tyrosine-kinase inhibitor with an inhibitory effect on Src kinases. Methods: In this phase 1, dose-escalation study, we enrolled 10 patients with advanced metastatic solid tumors who progressed on standard of care chemotherapy, 9 of whom were evaluable, to receive bosutinib and pemetrexed. Bosutinib was administered once daily in a 3 + 3 dose-escalation study design where the first cohort started at an oral dose of 200 mg daily with I.V. pemetrexed 500 mg/m2 on a three weekly schedule. The primary objective was to determine the dose-limiting toxicity (DLT), and maximum tolerated dose (MTD) of bosutinib with pemetrexed, and the type and frequency of adverse events. Secondary objective(s) were to estimate tumor response rate (RR), progression-free survival (PFS), and overall survival (OS). Results: All patients had progressed on prior chemotherapy and included 9 patients with adenocarcinoma of the lung, and 1 patient with metastatic adenocarcinoma of the appendix. Two patients (22%) had prior pemetrexed exposure. Median age was 62 years (range, 58-44). The median number of bosutinib and pemetrexed cycles received was 2 (range, 1-4). Nine patients were evaluable. The MTD of bosutinib was 300 mg daily in this combination as 2 out of the 3 patients who received 400 mg experienced elevated liver transaminases (>CTCAE Grade 3) and one patient experienced grade 3 fatigue. Two patients (22%) had a partial response, and 6 patients (67%) had stable disease, including 2 patients with prior pemetrexed exposure, and 1 patient had disease progression. The two responders and the subject with the longest stable disease duration demonstrated Src overexpression on immunohistochemical staining of their tumor. Two patients died of sepsis; both had stable disease. Median PFS was 4.1 months (range, 1.2-11.6), and the median OS was 11.9 months (range, 4-36.7). Adverse events included pneumonia/sepsis, diarrhea, fatigue, rash, weakness, transaminitis, hypertension, and thrombocytopenia. Conclusions: The MTD of oral bosutinib was 300 mg daily in combination with pemetrexed 500 mg/m2 every 3 weeks. Despite the limitations of this phase I study there appears potential efficacy of this combination in pretreated patients. We are currently enrolling patients in the expansion cohort. Clinical trial information: NCT03023319.
Circulating tumor DNA as markers of dynamic recurrence risk and adjuvant chemotherapy benefit in resected non-small cell lung cancer.
Authors: Guo Wei , Zhang Fan , Lv Fang , Ji Ying , Peng Yue , Chen Xiaoxi , Bao Hua , Xu Yang , Shao Yang , Tan Fengwei , Xue Qi , Qiu Bin , Gao Shugeng 
Published: June 2021

3028 Background: A significant proportion of non-small cell lung cancer (NSCLC) patients relapse after surgical resection with or without adjuvant therapy. The detection of molecular residual disease (MRD) has great potentials to stratify postoperative risk and facilitate early recurrence diagnosis. Here, we aim to evaluate the clinical utility of serial plasma circulating tumor DNA (ctDNA) in MRD detection, adjuvant therapy guidance, and recurrence risk prediction in resected NSCLC patients. Methods: This prospective cohort study recruited 116 patients with NSCLC following surgery and/or adjuvant therapy. Thirteen patients discontinued, leaving 103 patients for analysis. Tumor samples were obtained at surgery. Plasma samples were collected at baseline, after surgery, after adjuvant therapy and every 3 months thereafter and were analyzed by ultradeep (30000×) next-generation sequencing with molecular barcode and in-silico error correction. Results: Pretreatment ctDNA was detected in 69.8% of patients. ctDNA positivity after surgery and after completion of adjuvant chemotherapy (ACT) were significantly associated with worse recurrence-free survival (RFS) (HR: 4.0; 95% CI: 2.0-8.0; P<.001 and HR:3.2; 95% CI: 1.3-8.2; P <.05, respectively). In stage II-III patients who were positive for ctDNA after surgery, ACT-treated patients had a better RFS than those without ACT ( P<.05), whereas ACT did not confer significant clinical benefits in patients with negative postsurgical ctDNA. During surveillance after definitive therapy, ctDNA positivity was associated with worse RFS (HR: 8.5, 95% CI: 3.7-20, P <.001) and preceded radiological recurrence by a median of 88 days. Using joint modeling of serial ctDNA and time-to-recurrence, we accurately predicted patients’ 12-month and 15-month recurrence status, with areas under receiver-operating characteristics curves (AUROC) of 0.88 and 0.84, respectively. Conclusions: These results indicate that ultradeep ctDNA sequencing could sensitively detect MRD, thus identifying patients with high recurrence risk and guiding the adjuvant therapy decision in resected NSCLC. We also demonstrate that joint modeling of serial ctDNA levels and time to recurrent can provide an accurate dynamic risk prediction for NSCLC patients during surveillance. Clinical trial information: ChiCTR1900024656.
Plasma hPG80 circulating prograstin levels in cancer patients in Nigeria: Prolevcan study.
Authors: Fatiregun Omolara A. , Joubert Dominique , Vire Berengere , Simon-Hart Abigail Anni Frances , Adekeye Olaniyi Andrew , Mahi Younes , Prieur Alexandre 
Published: June 2021

3029 Background: Progastrin is a tumor-promoting peptide which is detectable in the blood of patients with different cancers. hPG80 (circulating progastrin) is produced by cancer cells. Recently it was reported that hPG80 is detected in the blood of cancer patients, suggesting its potential utility for cancer detection. In this Nigerian study, we assessed the performance of hPG80 in diagnosed cancer patients versus healthy volunteers. Methods: Plasma samples of 50 patients with breast (n = 41) and colorectal (n = 9) cancer, aged from 26 to 70 years, were assayed for hPG80 levels with the DxPG80 kit from ECS-Progastrin. The diagnostic performance (ROC AUC) of hPG80 was assessed compared to 50 healthy volunteers aged from 21 to 38 years. Results: Plasma hPG80 levels were significantly higher in cancer patients compared to controls (median values: 4.59 pM (IQR: 2.02-8.27 pM) vs 1.37 pM (IQR: 0-3.11 pM), p < 0.0001). The median value of hPG80level was 3.96 pM (IQR: 1.61-7.89 pM) for breast cancers and 6.43 pM (IQR: 2.80-15.86 pM) for colorectal cancer patients. ROC AUC for all cancers, breast cancer and colorectal cancer were 0.75, 0.74 and 0.82 respectively. There was no correlation between hPG80 blood levels with age or CA15.3 levels. Conclusions: Plasma hPG80 is a simple and relatively affordable blood test, it shows potential utility as a biomarker for cancer detection, monitoring and treatment assessment. Further prospective studies are needed to explore and confirm its potential.
Dynamics of circulating tumor DNA in patients with advanced solid tumors treated with cediranib and olaparib.
Authors: Hu Yiduo , Narayan Azeet , Wolfe Julia , Vu Dennis , Thi Trinh , Kantak Chaitanya , Ivy S. Percy , Eder Joseph Paul , LoRusso Patricia , Kim Joseph W. , Patel Abhijit 
Published: June 2021

3035 Background: Circulating tumor DNA (ctDNA) has emerged as a potential biomarker to monitor treatment response in solid tumors. Our group previously showed that changes in ctDNA levels were predictive of radiographic response and survival in NSCLC patients receiving immunotherapy. Here we evaluated whether ctDNA dynamics could similarly be used to assess response in a PARP inhibitor-based therapy. Methods: A total of 122 patients with NSCLC, TNBC, PDAC or SCLC received cediranib (C) 30mg daily and Olaparib (O) 200mg twice daily in a phase II study NCI9881. Using a multigene NGS assay, ctDNA was measured longitudinally at baseline (T0), after 3 to 7 days of C monotherapy (T1), after 1 week of C+O combination (T2), after 4 weeks of C+O (T3), and every 4 weeks (T4+) thereafter. The first radiographic assessment was done after 8 weeks of C+O and every 8-12 weeks thereafter. CtDNA was quantified by determining the allele fraction of cancer-associated somatic mutations in plasma. We defined an early ctDNA response (e-ctDNA-R) as a >10% decrease in mutant allele fraction from T0 to T2, and an early ctDNA progression (e-ctDNA-P) as a > 10% increase; otherwise, it was stable ctDNA (e-ctDNA-S). Results: In total, 493 samples were analyzed from 94 patients, and 40 unique patients had both T0 and T2 ctDNA measurements, as well as corresponding radiographic assessments. These included 10 NSCLC, 17 TNBC, 3 SCLC and 10 PDAC. Of these patients, 4, 21, and 15 patients had PR, SD, and PD as best overall radiographic response respectively. Twenty-three (57.5%) patients had either e-ctDNA-R (17, 42.5%) or e-ctDNA-S (6, 15.0%), 18 (78.3%) of whom subsequently had either radiographic partial response (PR) or stable disease (SD). Seventeen (42.5%) patients had e-ctDNA-P, 10 (58.8%) of whom then had PD. A fair agreement was observed between e-ctDNA-R/S or e-ctDNA-P and radiographic PR/SD or PD with Cohen’s k 0.38 (70% agreement). The correlation between early ctDNA changes and PFS/OS are summarized in the table. All 25 patients with PR/SD eventually progressed. Of these, 17 (68%) had >10% increase in ctDNA from the nadir prior to disease progression (median 94.6%, 95%CI 38.2%-389.1%). The time between ctDNA progression and ctDNA nadir was significantly shorter (median 21 days, 95%CI 21-28) than the time between radiographic/clinical progression and initial PR/SD (median 107 days, 95%CI 56-204, P=0.0015). Conclusions: Longitudinal ctDNA measurements could enable early assessment of treatment response, resistance, and disease progression in patients treated with PARP inhibitor-based therapy. However, in this study, tumor responses and ctDNA changes were generally not as robust as have been observed with other classes of therapy.[Table: see text]
Advanced imaging to assess longitudinal vascular changes in brain metastases treated with checkpoint inhibition.
Authors: Kim Albert Eusik , Chang Ken , Emblem Kyrre E. , Kalpathy-Cramer Jayashree , Lee Eudocia Quant , Lin Nancy U. , Tolaney Sara M. , Nayak Lakshmi , Chukwueke Ugonma Nnenna , Oh Kevin S. , Shih Helen Alice , White Michael , Lawrence Don P. , Moy Beverly , Cohen Justine Vanessa , Giobbie-Hurder Anita , Cahill Daniel P. , Sullivan Ryan J. , Brastianos Priscilla Kaliopi , Gerstner Elizabeth Robins 
Published: June 2021

3059 Background: Immune checkpoint inhibitors (ICI) have recently been shown to be effective for brain metastases (BM) in melanoma and lung cancer. Several studies demonstrate that 20-50% of BM patients respond to ICI. The reasons behind this wide variability in treatment response is not clear. Therefore, using physiologic imaging, we seek to identify the longitudinal biological changes exerted on BM as a result of ICI administration. Methods: Given the importance of aberrant tumor vasculature in cancer proliferation, we have focused on assessing changes in vascular physiology. We analyzed standard post-contrast and dynamic susceptibility contrast (DSC) MRI to identify characteristic vascular signatures as part of an ongoing Phase 2 study of pembrolizumab for patients with untreated or progressive, previously treated BM from any histology. Tumor volume measurements were calculated by summating all enhancing voxels. As per modified RECIST and RANO criteria for immunotherapy, volumetric increase of > 40% was defined as progressive disease (PD), a decrease of > 60% as partial response (PR), and stable disease (SD) as between -60% and +40%. Results: 35 patients, out of the total cohort of 60, have undergone DSC-MRI analysis. Histologies include 15 with breast cancer, 6 with non-small cell lung cancer, 4 with melanoma, and 10 with other cancers. At baseline, the total number of BM was 1-50+ per patient. Based on summing the entire enhancing intracranial disease burden, best volumetric responses for the 35 evaluable patients include 4 PR, 12 SD, and 19 PD. Thus far, we found that ICI-resistant BM had a 50% increase in cerebral blood flow (CBF), 105% increase in cerebral blood volume (CBV), a 15% increase in mean transit time (MTT), and an 80% increase in vessel caliber at 6 weeks post-treatment. On the other hand, ICI-responsive BM had no change in CBF, a 33% increase in CBV, a 10% decrease in MTT, and no change in vessel caliber. Ongoing analysis to uncover additional vascular changes (e.g. tumor oxygenation, vessel size index) within BM to ICI are pending. Conclusions: Our data provides evidence that effective ICI for BM is associated with unique intra-tumoral vascular physiology. With final analysis, we will uncover other facets of vascular physiology that correlate with ICI response, and may reveal mechanisms of response/resistance within tumors to ICI.
Comprehensive molecular profiling of advanced cancers in a real-world setting using an ultrasensitive amplicon-based next-generation sequencing (NGS) liquid biopsy assay.
Authors: Poh Jonathan , Ngeow Kao Chin , Pek Michelle , Tan Daniel , Lim Jing Shan , Choudhury Yukti 
Published: June 2021

3062 Background: Molecular profiling of circulating tumor DNA (ctDNA) by NGS has demonstrated the value of liquid biopsy in informing treatment decisions and monitoring disease progression in cancer patients. Here we report results from the real-world clinical application of an ultrasensitive amplicon-based NGS liquid biopsy assay for advanced cancers. Methods: Plasma cell-free DNA (cfDNA) from 1,338 consecutive samples (51.3% lung, 15.6% breast, 8.4% colorectal, 26.8% from 18 other cancer types; 86.3% of cancer samples were metastatic) underwent real-world testing in a Singapore-based, CAP-accredited, CLIA-certified laboratory from Jan 2018 – Nov 2020. Genomic alterations were analyzed using an amplicon-based NGS assay that detects alterations in 80 cancer-related genes, microsatellite instability (MSI) and cancer-causing viruses, with previously validated cfDNA detection limits of 0.1% variant allele frequency (VAF) for SNPs and indels, 5% tumor fraction, and 2 IU/mL plasma, respectively. Results: ctDNA was successfully detected in 70.0% of cancer samples (76.3% from metastatic and 24.7% from localized tumors) for a total of 977 unique variants. Across ctDNA-positive samples the median VAF was 1.4%, and 8.5% of all reported variants had VAFs between 0.01 – 0.09%. The most frequently altered genes were TP53 (48.8%), EGFR (36.9%), KRAS (17.4%), PIK3CA (15.3%), and APC (9.5%). In ctDNA-positive lung cancer, 74.6% of samples (66.5% EGFR+) harbored ≥1 actionable target, with 29.9% of patients treated with a first- or second-generation EGFR tyrosine kinase inhibitor harboring an EGFR T790M resistance mutation. Among breast cancers, ESR1 or PIK3CA alterations predicting drug resistance/response were detected in 44.2% of HR+ cases. In colorectal cancer, alterations implicated in anti-EGFR resistance ( NRAS, KRAS, BRAF, ERBB2) were found in 50.0% of samples. Profiling of cfDNA also enabled cancer monitoring, even among cancers with low genetic biomarker prevalence. 50% of nasopharyngeal cancer samples were Epstein-Barr virus-positive while 35.7% of liver cancer samples were Hepatitis B virus-positive, enabling an additional yield of 14.3% and 7.1% respectively, over ctDNA detection. cfDNA profiling of cancers of unknown primary origins informed potential tumor origins via the detection of tumor type-specific alterations such as mutations in AR, ESR1, GNAS, EGFR genes, viral biomarkers, and MSI. Conclusions: The use of a comprehensive pan-cancer liquid biopsy panel with rational inclusion of actionable and driver genes resulted in detection of ctDNA in the vast majority of clinical cases processed routinely. These findings support the utility of ultrasensitive amplicon-based NGS liquid biopsy assays in probing cancer drug sensitivity/resistance, tumor burden monitoring, and molecular characterization of tumors.