bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase Ib/IIa study of GC1118 in combination with irinotecan or FOLFIRI in patients with metastatic solid tumors.
Authors: Lee Keun Wook , Han Sae-Won , Kim Ji-Won , Lee Dae-Won , Hong Yong Sang , Ahn Joong Bae , Bang Yung-Jue 
Published: May 2020

3592 Background: GC1118 is a novel anti-EGFR monoclonal antibody which has a unique binding epitope and superior ligand inhibition potential. It showed promising antitumor activity as a single agent in the phase I study. This study aimed to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of GC1118 in combination with irinotecan or FOLFIRI in metastatic solid tumors and evaluate the efficacy of GC1118 plus FOLFIRI as a second line therapy for RAS and BRAF wild-type metastatic colorectal cancer. Methods: Phase 1b part was designed to evaluate weekly GC1118 (starting from 3 mg/kg) in combination with biweekly irinotecan (180mg/m2) or FOLFIRI (irinotecan 180mg/m2, leucovorin 400mg/m2, 5-FU 400 mg/m2 bolus, and 5-FU 2400mg/m2 over 46hrs) in a 3+3 design. In the phase 2a part, the RP2D of GC1118 is administered in combination with FOLFIRI in a Simon’s two stage design with objective response rate (ORR) as the primary endpoint. Results: 13 pts were enrolled in phase 1b and received 3mg/kg of GC1118 with irinotecan (N = 6) or FOLFIRI (N = 7). DLT occurred in 2 pts (G4 neutropenia, G2 rash) in irinotecan arm and 1pt (G3 neutropenia) in FOLFIRI arm with 3mg/kg of GC1118 and it was determined as MTD and RP2D. Adverse events (AE) of grade ≥ 3 included neutropenia (61.5 %), skin rash (15.4 %) and diarrhea (15.4%). Dose reductions due to GC1118-related AE were required in 6 (46.2%) patients. Among 10 response-evaluable pts in phase 1b, best overall response was PR in 3 and SD in 6, and median PFS was 12 months. In stage 1 of phase 2a (N = 9), 4 PR and 5 SD were observed (ORR 44.4%, 95% CI 13.7 – 78.8). We moved to stage 2, and are currently enrolling additional 20 pts. AE of grade ≥ 3 included neutropenia (66.7%), skin rash (22.2%) and diarrhea (11.1%). Updated data of the phase 2a part will be presented at the meeting. Conclusions: The MTD and RP2D of weekly GC1118 in combination with irinotecan or FOLFIRI was 3mg/kg. Preliminary results of GC1118 and FOLFIRI as a 2nd line treatment in mCRC suggests promising antitumor activity and acceptable safety profile. Clinical trial information: NCT03454620 .
Safety and efficacy of pemigatinib plus pembrolizumab combination therapy in patients (pts) with advanced malignancies: Results from FIGHT-101, an open-label phase I/II study.
Authors: Gutierrez Martin , Subbiah Vivek , Nemunaitis John J. , Mettu Niharika B. , Papadopoulos Kyriakos P. , Barve Minal A. , Féliz Luis , Lihou Christine Francis , Tian Chenwei , Ji Tao , Silverman Ian M. , Chugh Rashmi , Saleh Mansoor N. 
Published: May 2020

3606 Background: Pemigatinib (INCB054828) is a selective fibroblast growth factor receptor (FGFR) 1–3 inhibitor with demonstrated efficacy as monotherapy in phase 1/2 (FIGHT-101) and phase 2 (FIGHT-201, -202, -203) trials in pts with advanced cancer. Here, we present preliminary safety, efficacy, and pharmacokinetic (PK) data for pemigatinib (PEMI) combined with pembrolizumab (PEMBRO), a programmed cell death protein-1 (PD-1) inhibitor, in pts with refractory advanced malignancies enrolled in the ongoing FIGHT-101 trial (NCT02393248). Methods: FIGHT-101 includes monotherapy (part 1 and 2) and combination therapy (part 3) cohorts. This analysis is based on pts enrolled in the PEMI + PEMBRO combination dose finding (3a) and dose expansion (3b) cohorts. Eligible adults had advanced malignancies who had progressed after prior therapy and for whom PEMBRO treatment was relevant; pts in part 3b had FGF/FGFR alterations. Pts received oral PEMI at 9 mg or 13.5 mg QD on an intermittent dosing (ID) schedule (21-day cycle, 14-day on/7-day off), or 13.5 mg QD on a continuous dosing (CD) schedule, plus PEMBRO 200 mg IV on day 1 of each 21-day cycle. Results: At data cutoff (August 30, 2019), 23 pts had received PEMI + PEMBRO; 22 (96%) had discontinued therapy (disease progression, 70%). Most frequent tumors were NSCLC (n = 3), bladder (n = 3), pancreatic, testicular, and sarcoma (each n = 2). Of 19 enrolled pts with baseline FGF/FGFR data; 5 had FGFR mutations or rearrangements. No dose-limiting toxicities occurred with PEMI + PEMBRO. The recommended PEMI dose combined with PEMBRO was 13.5 mg QD. Most frequent all-cause, all-grade (Gr) adverse events for ID (n = 17) were hyperphosphatemia (n = 14 [82%]; Gr ≥3, n = 0), anemia (n = 9 [53%]; Gr ≥3, n = 3 [18%]), and decreased appetite (n = 9 [53%]; Gr ≥3, n = 0); for CD (n = 6), hyperphosphatemia (n = 5 [83%]; Gr ≥3, n = 0), and dry mouth (n = 4 [67%]; Gr ≥3, n = 0). One pt discontinued, 2 reduced dose, and 13 interrupted dose due to AEs (none for hyperphosphatemia; dose interruption mainly for gastrointestinal AEs [n = 5]). One fatal AE occurred (suicide, not treatment-related). PK parameters for PEMI in the PEMI + PEMBRO combination were comparable with those for PEMI monotherapy. Five pts had partial response (3 had FGFR rearrangements or mutations); 5 pts had stable disease. Conclusions: PEMI + PEMBRO combination therapy was tolerable with no new safety signals, and demonstrated preliminary antitumor activity in pts with advanced malignancies including those with FGF/FGFR alterations. Clinical trial information: NCT02393248 .
Phase I study of afatinib plus selumetinib in patients with KRAS mutation-positive colorectal, non-small cell lung and pancreatic cancer.
Authors: Huijberts Sanne , Brummelen Emilie Van , Van Herpen Carla M.L.- , Desar Ingrid M.E. , Opdam Frans , Geel Robin Van , Marchetti Serena , Steeghs Neeltje , Monkhorst Kim , Thijssen Bas , Rosing Hilde , Huitema Alwin , Beijnen Jos H. , Bernards Rene , Schellens Jan H. M. 
Published: May 2020

3613 Background: Mutations in the KRAS gene result in a constitutively activated RAS-RAF-MEK-ERK (MAPK) pathway. In KRAS mutant tumors, the anti-tumor activity of MEK inhibitors is limited due to intrinsic resistance caused by feedback activation of upstream epidermal growth factor receptors (HER). This upstream activation not only reactivates MAPK, but also the phosphoinositide 3-kinase (PI3K)-AKT pathway in preclinical research. Based on these data, a phase I clinical trial was initiated with the combination of the orally administered pan-HER inhibitor afatinib and the MEK inhibitor selumetinib in patients with KRAS mutant and PIK3CA wildtype colorectal cancer (CRC), non-small cell lung cancer (NSCLC), or pancreatic cancer to determine the recommended phase 2 regimen (RP2R). Methods: In this multicentre study, patients received escalating doses of afatinib and selumetinib according to a 3+3 design starting with 20 mg afatinib once daily (QD) continuously and 25 mg selumetinib twice daily (BID) in a 21 days on/7 days off schedule. Continuous and intermittent dosing were explored to assess optimal exposure and tolerability. The primary aim was determining the RP2R. Secondary objectives included assessment of anti-tumor activity and the analyses of pharmacokinetic and pharmacodynamic parameters for target inhibition. Clinicaltrials.gov identifier: NCT2450656. Results: In total, 26 mostly heavily pretreated patients with CRC (n=19), NSCLC (n=6) and pancreatic cancer (n=1) were enrolled among 5 dose-levels. Dose-limiting toxicities (DLTs) occurred in 6 patients and consisted of grade 3 diarrhea (n=3), decreased appetite (n=1), nausea/vomiting (n=1), dehydration (n=2) and mucositis (n=1). Clinical efficacy was limited with no responses according to RECIST v1.1 and stable disease for 221 days in a patient with NSCLC as best response. Conclusions: The RP2R was determined at 20 mg afatinib QD continuously and 25 mg selumetinib BID 21 days on/7 days off for continuous dosing. The 3 patients treated in the escalation cohort of the ongoing intermittent dose-level with 20 mg afatinib QD and 25 mg selumetinib BID 5 days on/2 days off, experienced no DLTs. Pending the latest safety results of the expansion cohort for this ongoing dose-level, the RP2R of intermittent dosing has not been established at the moment. Clinical trial information: NCT2450656 .
BET inhibitor molibresib for the treatment of advanced solid tumors: Final results from an open-label phase I/II study.
Authors: Cousin Sophie , Blay Jean-Yves , Braña Garcia Irene , De Bono Johann S. , Le Tourneau Christophe , Moreno Victor , Trigo Jose Manuel , Hann Christine L. , Azad Arun , Im Seock-Ah , Ferron-Brady Geraldine , Datta Antara , Wu Yuehui , Horner Thierry , Kremer Brandon Edward , Dhar Arindam , O'Dwyer Peter J. , Shapiro Geoffrey , Piha-Paul Sarina Anne 
Published: May 2020

3618 Background: Molibresib is an orally available, small molecule bromodomain and extra-terminal domain (BET) protein inhibitor under investigation for treatment of advanced solid tumors. Methods: This was an open-label, single- and repeat-dose, 2-part, Phase 1/2 study including patients (aged ≥16 years) with advanced solid tumors. Part 1: patients received different oral doses of molibresib (2–100mg QD; amorphous free-base formulation) to determine recommended Phase 2 dose. Part 2 (expansion cohort): patients with various tumor types received the bioequivalent besylate formulation (75mg) to explore clinical activity at recommended dose. Safety and efficacy (response rate [RR] based on RECIST 1.1 criteria, progression-free survival [PFS], and overall survival [OS]) were evaluated for the total cohort (patients from Part 1 and 2). Safety, pharmacokinetic, pharmacodynamic, and efficacy per tumor type were evaluated in Part 2. Results: Part 1 only data have previously been reported. Overall, 196 patients were included in the total cohort (1 patient in Part 1 was counted twice). In the all treated population, 195 patients (median age 58 years; 46% male) received ≥1 dose of molibresib (Part 1: n = 93; Part 2: n = 102). Adverse events (AEs) were experienced by 193/196 (98%) patients; 180/196 (92%) had a treatment-related AE (TRAE). AEs led to permanent treatment discontinuation in 38/196 (19%) patients. Of different tumor types in Part 2, NUT carcinoma (NC) had the lowest frequency of TRAEs (10/12 [83%]) and AEs leading to permanent treatment discontinuation (1/12 [8%]). In total cohort, 3/31 NC patients and 1/35 with castration-resistant prostate cancer (CRPC) achieved a confirmed partial response. A further 67/196 (34%) achieved stable disease (SD). In Part 2, RR in 12 NC patients was 8% (CI: 0.2–38.5); 50% had SD and median PFS was 4.8 months with median OS of 5.0 months. In CRPC patients, RR was 4% (CI: 0.1–21.9); 22% had SD; median PFS was 8.0 months with median OS of 9.1 months. Plasma concentrations for molibresib and active metabolites were similar between different tumor types. Gene expression analysis from pre- and post-dose biopsy samples collected from 10 mCRPC patients showed transcriptional downregulation of Myc target genes upon treatment with molibresib. Conclusions: Molibresib demonstrated a manageable safety and tolerability profile with single agent activity observed in selected patients with NC and CRPC. Clinical trial information: NCT01587703 .
Targeting G1-S phase cell-cycle alterations with CDK4/6 inhibitor-based genomically matched personalized therapy approach.
Authors: Adashek Jacob J. , Kato Shumei , Okamura Ryosuke , Khalid Noor , Lee Suzanna , Nguyen Van Thomas , Sicklick Jason K. , Kurzrock Razelle 
Published: May 2020

3623 Background: Although CDK4/6 inhibitors are established as a standard treatment option for hormone receptor-positive, HER2-negative metastatic breast cancer patients, its benefit in other solid tumors is unclear. Moreover, no clear biomarker exists that predicts the response to CDK4/6 inhibitors. Herein, we investigated the factors associated with clinical outcomes from CDK4/6 inhibitor-based therapy, used alone or in combination with other therapies targeting genomic co-alterations, among diverse cancer patients with potentially sensitizing alterations in G1-S phase cell-cycle alterations (defined as CDK4/6 amplifications, CCND1/2/3 amplifications or CDKN2A/ B alterations). Methods: We interrogated molecular profiles of 2,457 patients with diverse solid tumors for G1-S phase cell-cycle alterations and co-altered genes using clinical-grade next generation sequencing (182-465 genes). Results: G1-S phase cell-cycle alterations occurred in 20.6% (507/2,457) of patients with 99% of those with cell cycle alterations (N = 501/507) harboring at least one characterized co-alteration (median, 4; range, 0-24). Significant improvement in median PFS was observed when CDK4/6 inhibitor-based therapies matched a larger proportion of tumor alterations, often by being given together with other drugs that were matched to genomic co-alterations, hence achieving a high Matching Score (high Matching Score [≥50%] vs. low Matching Score [ < 50%]: all cohorts including breast cancer [N = 58]: PFS: 6.2 vs. 3.2 months, P = 0.001; non-breast cancer cohort [N = 40]: PFS 6.2 vs. 2.0 months, P < 0.001 [multivariate]). (Matching Score roughly equivalent to number of alterations targeted divided by total number of characterized alterations). In contrast, targeting CDK4/6 alone in patients harboring cell-cycle pathway alterations along with other co-alterations, without targeting the genomic co-alterations, did not improve PFS even in patients who received matched CDK4/6 inhibitors as part of a combination regimen. Representative cases that were successfully treated with a matched combination strategy will also be presented. Conclusions: Most patients with G1-S phase cell-cycle alterations harbored co-genomic alterations. Our current study suggests that targeting co-alterations along with cell cycle molecular alterations may be necessary to achieve better clinical outcome. Further clinical investigation with larger numbers of patients are required.
Modeling differentially expressed genes in patient tumors to guide expression-based biomarker development.
Authors: Liu Derek , He Meng Xiao , Bi Kevin , Van Allen Eliezer Mendel , Liu David 
Published: May 2020

3627 Background: Differential gene expression (DGE) methods, initially developed for analyzing bulk RNA changes in pure tumor cell lines under experimental settings, are commonly used to identify biomarkers in and infer biological differences between patient tumor samples, which are admixtures of tumor and non-tumor components. Methods to sensitively and accurately detect cell type-specific expression differences in admixed patient samples are not well characterized but may greatly affect emerging targeted and immunotherapy biomarker strategies. To address this issue, we developed a simulation framework to benchmark our ability to detect changes in tumor-intrinsic gene expression. Methods: Pseudobulk RNAseq melanoma cohorts were simulated by sampling from melanoma single cell RNAseq data. Simulation parameters were optimized to maximize concordance of gene expression means and variances (Spearman r = 0.81, 0.68, respectively) between the TCGA SKCM cohort (n = 462) and matched simulated cohort, and then validated in two independent melanoma cohorts (n = 42, 129; means Spearman r = 0.80, 0.78; variances Spearman r = 0.68, 0.63). Using this simulation framework, we benchmarked the effect of sample size, magnitude of differential expression, and differences in cell type proportions on the sensitivity and positive predictive value (PPV) of detecting true differentially expressed genes in the tumor-intrinsic compartment. Results: Reference cohorts of 50 total tumors (n = 10) were simulated to contain a 2 standard deviation tumor-intrinsic expression change in 50 randomly selected genes and a 11% difference in mean purity between two equally sized 25-tumor subgroups. DGE analysis using DESeq2 with an FDR q-value threshold of 0.1 yielded a sensitivity of 0.37 and PPV of 0.29. DGE analysis of the same simulated cohorts using a non-parametric Mann-Whitney U test with an FDR q-value threshold of 0.1 yielded a sensitivity of 0.13 and PPV of 0.76. Conclusions: Commonly used DGE methods for existing expression-based biomarker strategies have poor sensitivity and PPV in admixed tumor samples, limiting our ability to find meaningful transcriptional biomarkers in clinical cohorts. We are currently developing methods to more accurately detect true differentially expressed genes in admixed bulk RNAseq samples and applying these approaches for biomarker discovery in immunotherapy-treated patient cohorts and other clinical tumor cohorts.
Olaparib monotherapy in pretreated patients with BRCA1/2 alterations: Results of a DRUP trial cohort.
Authors: van der Wijngaart Hanneke , Hoes Louisa Rose , van Berge Henegouwen Jade Maxime , van Der Velden Daphne Liselotte , Zeverijn Laurien , Roepman Paul , Nguyen Luan , van Werkhoven Erik D. , de Leng Wendy W.J. , Jansen Anne M.L. , Mehra Niven , Robbrecht Debbie , Gelderblom Hans , Voest Emile E. , Verheul Henk M.W. 
Published: May 2020

3633 Background: Extensive molecular profiling in cancer regularly reveals targets for which approved drugs are available in tumor types outside the registered label. Efficacy of off-label use of these drugs is unavailable. Access to these drugs for pts is challenging. In the Drug Rediscovery Protocol (DRUP, Van der Velden et al, Nature 2019), pts are treated based on their tumor molecular profile. Here, we present the results of the successful cohort “Olaparib for tumors with BRCA1/2 alterations”. Methods: Twenty five adult cancer patients (pts) who exhausted all treatment options and had BRCA1/2 loss of function (LoF) mutations (found in routine diagnostics) were included. No pts were eligible for on-label treatment with PARP inhibitors. Pts were treated with olaparib until disease progression or unacceptable toxicity. The primary endpoint was clinical benefit (CB: objective response or stable disease (SD) ≥ 16 weeks). Pts were enrolled using a Simon-like two-stage model, with 8 pts in stage 1 and up to 24 pts in stage 2 if at least 1 pt had CB in stage 1. A fresh frozen biopsy was obtained from each pt for whole genome sequencing (WGS) and target confirmation. Results: Fourteen pts (56%) had CB. The objective response rate was 32%. Nine different cancer types were included: prostate (n=11), breast (n=4), ovarian (n=2), pancreatic (n=3), colorectal (n=2), biliary tract (n=2), kidney (n=1), adrenal gland (n=1) and endometrial (n=1). WGS could be performed on 58% of baseline tumor biopsies, confirming the original BRCA1/2 mutations in 86%. CB was observed in pts with both somatic and germline BRCA alterations and across tumor types. CB was only observed in cases with biallelic loss of BRCA1/2 in the tumor and when classified as HRD by a pan-cancer homologous recombination deficiency classifier (CHORD), which relies on genome-wide SNV, indel, and SV mutational footprints for HRD detection. No evidence of complete BRCA loss and HRD was observed in 5 pts with PD, while 4 patients with effective BRCA complete loss and HRD also had PD. WGS analysis of these pts suggested resistance mechanisms due to other oncogenic drivers (e.g FGFR1 amplification, CTNNB1 stabilization, KEAP1 inactivation). Conclusions: Olaparib seems to be an effective treatment option for pts with BRCA1/2 LoF mutated malignancies, regardless of histology, for both germline and somatic alterations, which needs confirmation in an independent cohort. CB of olaparib was observed in malignancies showing biallelic loss of BRCA1/2 and when classified as HRD, indicating the importance of the BRCA/HRD signature status. Clinical trial information: NCT02925234 .
Total neoadjuvant therapy with mFOLFIRINOX versus preoperative chemoradiation in patients with locally advanced rectal cancer: Final results of PRODIGE 23 phase III trial, a UNICANCER GI trial.
Authors: Conroy Thierry , Lamfichekh Najib , Etienne Pierre-Luc , Rio Emmanuel , FRANCOIS Eric , Mesgouez-Nebout Nathalie , Vendrely Veronique , Artignan Xavier , Bouché Olivier , Gargot Dany , Boige Valerie , Bonichon-Lamichhane Nathalie , Louvet Christophe , Morand Clotilde , De La Fouchardiere Christelle , Juzyna Beata , Rullier Eric , Marchal Frédéric , Castan Florence , Borg Christophe 
Published: May 2020

4007 Background: PRODIGE 23 investigated the role of neoadjuvant mFOLFIRINOX before preoperative (preop) chemoradiation (CRT), with TME-surgery and adjuvant chemotherapy (CT) in resectable locally advanced rectal cancer. Methods: PRODIGE 23 is a phase III multicenter randomized clinical trial. Eligible pts had cT3 or cT4, M0 rectal adenocarcinomas <15 cm from the anal verge, age 18-75 years, and WHO PS ≤1. Randomization was stratified by center, T stage, N status, tumor location, and perirectal fat extramural extension. Primary endpoint was 3-yr disease-free survival (DFS). Main secondary endpoints were ypT0N0 rate, overall survival (OS) and metastasis-free survival (MFS). 460 pts were required to observe 136 events to show a gain in 3-year DFS from 75% to 85% (HR=0.56) with a 2-sided α=0.05 and 90% power. HR and 95% CI were estimated by a stratified Cox proportional hazard model. Arm A pts received preop CRT (50 Gy, 2 Gy/fraction [fr]; 25 fr + capecitabine), surgery, then adjuvant CT for 6 months (mos). Arm B pts received 6 cycles of mFOLFIRINOX (oxaliplatin 85 mg/m², leucovorin 400 mg/m², irinotecan 180 mg/m² D1, and 5-FU 2.4 g/m² over 46 h) every 14 days, followed by the same preop CRT, surgery and 3 mos of adjuvant CT. Adjuvant CT consisted of mFOLFOX6 or capecitabine, depending on the centre’s choice for all pts. Imaging work-up, operative and pathology reports were centrally reviewed. Results: (ITT) Between 6/2012 and 6/2017, 230 and 231 pts were randomly assigned in Arm A/B, respectively by 35 participating centers. Pts characteristics were well balanced. Neoadjuvant mFOLFIRINOX and CRT in both arms were well tolerated. Compliance to CRT and to adjuvant CT was not hampered by neoadjuvant CT. Surgical morbidity did not differ between the 2 arms. The ypT0N0 rate was 11.7 vs 27.5% in Arm A/B (p<0.001). Median follow-up was 46.5 mos. 136 DFS events was reported. 3-yr DFS was significantly increased in arm B (HR 0.69, 95% CI 0.49-0.97, p=0.034): 68.5% (CI: 61.9-74.2) vs 75.7% (CI: 69.4-80.8) in arm A/B. The subgroup analysis showed no evidence of heterogeneity of the effect size of treatment on DFS. 3-yr MFS was also significantly higher in arm B: 71.7 in arm A vs 78.8% (HR 0.64, CI 0.44-0.93, p<0.02) in arm B. 3-yr OS was 87.7 vs 90.8% (HR 0.65, CI 0.40-1.05, p=0.077) in arm A/B, with 54.2% of the pts with recurrence being alive. Conclusions: Neoadjuvant mFOLFIRINOX plus CRT is safe, and significantly increased ypCR rate, DFS and MFS. OS data are not mature. Clinical trial information: NCT01804790 .