bluuebunny/crossref_metadata_2025_split huggingface dataset:
A first-in-human trial of selective CDK7 inhibitor Q901, in patients with advanced solid tumors: Interim results of a phase I study (QRNT-009).
Authors: Xie Hao , El-Khoueiry Anthony B. , Alistar Angela Tatiana , Babiker Hani M. , Mahalingam Devalingam , Barve Minal A. , Sohn Joohyuk , Borad Mitesh J. , Lee Jae Cheol , Ahn Jiye , Lee Dayoung , Choi Jinho , Kim Jeongjun , Yu Dong-Hoon , Lee Seung-Joo , Jeon Borami , Proniuk Stefan , Kim Jaeseung , Nam Kiyean 
Published: June 2024

3078 Background: Q901 is a potent, covalently binding CDK7 inhibitor with excellent specificity for CDK7 against other protein kinases. Transcriptional regulation by CDK7 inhibition in cancer cells leads to DNA damage repair response inhibition and increased genomic instability. Q901 also regulates cell cycle checkpoints by inhibiting T-loop phosphorylation and transcriptionally downregulating CDK1, 2 and 4. In preclinical in vivo models, intravenous (iv) administration of Q901 once a week and once every three-week dosing regimen was well tolerated and showed significant antitumor activity. The safety profile, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy data for 18, 36 and 60 mg/m2 are presented. Methods: QRNT-009 (NCT05394103) is an ongoing Phase 1/2 multicenter, open-label, dose escalation and expansion study. Q901 is administered iv once weekly for four weeks, then once every two weeks thereafter in patients with advanced or metastatic ovarian cancer, castration-resistant prostate cancer (CRPC), breast cancer, endometrial cancer, colorectal cancer, small cell lung cancer (SCLC), or pancreatic cancers. Results: As of data cutoff (12Jan2024), 17 patients received Q901 across 3 dose levels: 5 patients at 18 mg/m2, 4 patients at 36 mg/m2, and 8 patients at 60 mg/m2. The median prior lines of systemic therapy were 4 (range 2 - 17). Of 17 patients who received Q901 across all doses, there were no treatment related SAEs, treatment discontinuations, or dose reductions. Most common TRAEs ≥ 15% were nausea (29.4%), anemia (23.6%) and fatigue (23.5%). As of data cutoff, no DLTs were observed. All plasma PK analyses across dose levels showed dose dependent increase of AUC0-last and Cmax. No major metabolite was observed. POLR2A, which is a CDK7 target engagement marker showed biologically effective change starting from 18 mg/m2. 1 patient with pancreatic cancer who received 18 mg/m2 had a partial response with CA19-9 reduction from 4,632 to 219. 2 patients at 18 mg/m2 and 2 patients at 36 mg/m2 had stable disease. Additional safety and efficacy data will be presented. Conclusions: Preliminary data from QRNT-009 study showed that selective CDK7 inhibitor Q901 is well tolerated. Preliminary antitumor activity and pharmacodynamic observations are encouraging. Dose escalation is ongoing to identify MTD or recommended dose for further studies. Clinical trial information: NCT05394103 .
Nivolumab plus ipilimumab (N+I) in patients (pts) with solid tumors with high tumor mutational burden (HTMB): Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study.
Authors: Chan John K , Rothe Michael , Mangat Pam K. , Garrett-Mayer Elizabeth , Cannon Timothy Lewis , Ahn Eugene R. , Swiecicki Paul , Hobbs Evthokia , Nazemzadeh Reza , Bell Maria C , Hosein Peter Joel , Meric-Bernstam Funda , Hinshaw Dominique C. , Gregory Abby , Grantham Gina N. , Halabi Susan , Schilsky Richard L. 
Published: June 2024

3130 Background: TAPUR is a phase II basket study evaluating antitumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results in a cohort of pts with advanced solid tumors with HTMB treated with N+I are reported. Methods: Eligible pts had measurable disease, ECOG performance status (PS) 0-2, adequate organ function, and no standard treatment (tx) options or prior immune checkpoint inhibitor tx. PD-L1 expression testing was not required. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. HTMB was defined a priorias ≥9 mutations/megabase (Muts/Mb) via a qualifying test for TAPUR or approved by the Molecular Tumor Board. Pts received I at 3 mg/kg every 3 weeks (wks) for 4 doses with N at 1 mg/kg IV every 3 wks for 4 doses. N alone was then continued at 240 mg every 2 wks or 480 mg every 4 wks until disease progression. Low accruing histology-specific cohorts with HTMB were collapsed into 1 cohort for analysis. Primary endpoint was disease control (DC) per investigator defined as complete (CR) or partial (PR) response per RECIST v. 1.1, or stable disease (SD) of at least 16 wks duration (SD16+). The hypothesized null DC rate of 15% was evaluated by a 1-sided exact binomial test (α= 0.10; 86% power based on alternative DC rate of 35%). Secondary endpoints were progression-free survival (PFS), overall survival (OS), objective response (OR), duration of response (DOR), duration of SD, and safety. DOR is time from documented OR to progressive disease (PD); duration of SD is time from tx start to PD. Results: 26 pts with 13 tumor types with HTMB were enrolled. Table shows demographics and outcomes. Tissue tumor mutational burden (TMB) ranged from 8 to 374 Muts/Mb (median= 16). 1 CR (small intestine; TMB= 48 Muts/Mb; DOR= 36 wks), 7 PR (biliary tract, site unspecified [3], soft tissue sarcoma, uterus, vagina; median TMB= 17 Muts/Mb; median DOR= 20 wks [range, 5-231]) and 1 SD16+ (pancreas; TMB= 26 Muts/Mb; duration of SD= 26 wks) were observed for a DC rate of 35% (1-sided 90% CI: 22 to 100) and OR rate of 31% (95% CI: 14 to 52). The null hypothesis was rejected (p=0.011). Notably, 1 pt (uterus, 374 Muts/Mb) is still on tx with an ongoing 66-wk PR as of Jan 2024. Most pts, including 8/9 with DC, were microsatellite stable. 10 pts had ≥1 grade 3 tx-related adverse event (AE) or serious AE. Conclusions: N+I showed antitumor activity in pts with advanced solid tumors with HTMB. Additional study is warranted to confirm the efficacy of N+I in pts with HTMB. Clinical trial information: NCT02693535 . [Table: see text]
Cold-inducible RNA-binding protein as a context-specific functional mediator of breast cancer metastasis.
Authors: Dankner Matthew , Ouellet Veronique , Lafon Jakob , Ezzeddine Rima , Annis Matthew G , Siegel Peter M ,   QBCF-TMA
Published: June 2024

3136 Background: Cold-inducible RNA-binding protein (CIRBP) is a stress-induced mRNA-binding protein associated with clinical outcomes in a variety of human disease states. CIRBP’s role as a prognostic biomarker in breast cancer (BC) has yet to be established. Methods: We describe a clinically annotated tissue micro-array cohort of 1406 hormone receptor positive (HR+) and 281 triple negative primary breast cancers (TNBC) stained by immunohistochemistry (IHC) for CIRBP. Statistical analyses were performed with the Kaplan-Meier estimator, as well as univariate and multivariate Cox proportional-hazards models. Multivariate models incorporated tumor size, lymph node status, grade and CIRBP expression levels. Co-primary endpoints were overall survival (OS) and progression-free survival (PFS). MDA-MB-231 TNBC cells and MDA-MB-361 HR+ cells were used for CIRBP knockout (KO) by CRISPR/Cas9, and subsequent mammary fat pad injections were performed in immunocompromised mice. Results: In N=281 primary TNBCs, high levels of CIRBP expression by IHC was associated with poor prognosis in multivariate analysis (OS: adjusted hazard ratio (aHR) 2.05, 95% confidence interval (CI) 1.24-3.41, P=0.005. PFS: aHR 2.46, 95% CI 1.33-4.57, P=0.004). However, in N=1406 HR+ primary BC, CIRBP expression was correlated with favorable prognosis (OS: aHR 0.927, 95% CI 0.88-0.98, P=0.05. PFS: aHR 0.904, 95% CI 0.85-0.96, P=0.002). CIRBP KO had minimal impact on mammary fat pad primary tumor growth in both MDA-MB-231 and MDA-MB-361 cell models. However, CIRBP KO resulted in the inhibition of efficient spontaneous metastasis to the liver and lungs in TNBC MDA-MB-231 cells but not HR+ MDA-MB-361 cells. Conclusions: CIRBP expression is associated with poor prognosis in TNBC but not HR+ BC patients, a finding validated with CRISPR/Cas9 KO in representative model systems. This finding highlights the prognostic significance of CIRBP in TNBC and suggests differential underlying mRNA targets bound and modulated by CIRBP in TNBC and HR+ BC, respectively.
A phase II clinical evaluation of radiofrequency ablation (RFA) combined with regorafenib and toripalimab in patients with colorectal cancer with liver metastases.
Authors: Wang Zhiqiang , Ouyang Hui , Luo Huiyan , Gao Fei , Mie Man , Ren Chao , Li Ji-Bin , Fu Haiyan , Huang Jin Shan 
Published: June 2024

3566 Background: In several clinical studies, the combination of anti-programmed cell death protein 1 (anti-PD-1) antibodies with targeted antiangiogenic agents has demonstrated clinical benefits for patients with metastatic colorectal cancer (mCRC). However, individuals with liver metastases have shown suboptimal responses. Prior preclinical study indicates a synergistic efficacy of radiofrequency ablation (RFA) when employed in conjunction with immunotherapy. The study aimed to explore whether RFA combined with regorafenib and toripalimab (an anti-PD-1 antibody) could provide better outcomes in patients with colorectal cancer liver metastases. Methods: Using Simon's two-stage design, a total of 32 subjects were required for enrollment, with10 subjects included in stage 1. If there were no or less patients having response, the study would be terminated; otherwise, it would proceed to stage 2, enrolling an additional 22 subjects. The cohort consisted of 10 microsatellite stable (MSS) mCRC patients with multiple liver metastases who had previously failed fluorouracil, oxaliplatin, irinotecan, with or without targeted therapy. RFA was performed on a single hepatic lesion, with others designated as target lesions. Treatment with regorafenib and toripalimab commenced one week post-RFA, following a 4-week cycle. Toripalimab was administered intravenously biweekly, and regorafenib was given orally at daily dose of 80 mg (three weeks on, one week off, in a 4-week period). The primary endpoint was response rate. Results: Ten patients (3 women) were enrolled in this study, with ages ranging from 26 to 76 years (median: 52 years), and 60% being 52 years or older.Seventy percent had ECOG performance status (PS) of 0; 60% had primary colon tumors; 90% presented with synchronous liver metastases, and 80% had both intrahepatic and extrahepatic metastases. Half of the participants achieved stable disease; however, none exhibited confirmed partial or complete responses. The median progression-free survival was 3.3 months, and the median overall survival reached 11.3 months. The median number of cycles was two (range: 0.5 to 3), with 60% undergoing at least two cycles. Adverse events (AEs) included hand-foot syndrome, liver dysfunction, fatigue, abdominal distension, and thrombocytopenia. The most frequently reported AE was hand-foot syndrome, occurring in 50% of patients. Serious AEs (grade≥3) potentially related to treatment included hand-foot syndrome and hyperbilirubinemia, each with an incidence of 10%. Notably, one patient experienced hyperprogression during immunotherapy. Conclusions: The combination of RFA, regorafenib, and toripalimab has not shown encouraging efficacy in patients with CRC liver metastases. However, the observed safety profile is acceptable. Clinical trial information: NCT05485909 .
A phase II, multicenter, open-label study of polyPEPI1018 in combination with atezolizumab in participants with relapsed or refractory microsatellite-stable metastatic colorectal (MSS mCRC) cancer (Oberto-301).
Authors: Hubbard Joleen M. , Ahn Daniel H. , Jones Jeremy Clifton , Zhu Mojun , Wittenberger Kathleen , Csiszovszki Zsolt , Somogyi Eszter , Lorincz Orsolya , Molnar Levente , Tóth József , Youssoufian Hagop , Toke Eniko Rita 
Published: June 2024

3594 Background: The efficacy of checkpoint inhibitor immunotherapy in MSI-H mCRC has not been replicated in MSS mCRC. Therefore, additional interventions are needed to convert immunologically “cold” MSS CRC to “hot” tumors resembling MSI-H tumors. PolyPEPI1018 is an off-the-shelf, multi-peptide vaccine containing 12 immunogenic epitopes derived from 7 shared tumor antigens which demonstrated early evidence of clinical activity in first-line MSS mCRC. Methods: Patients with MSS mCRC who have progressed on 2-3 lines of prior chemotherapy regimen received PolyPEPI1018 (1.2 mg, sc) and atezolizumab (1,200 mg, iv) Q3W until disease progression or unacceptable toxicity. The primary endpoint was safety. A Simon 2-stage design was applied. Data on objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and correlation studies will be presented. Results: 18 patients (66 % female) were enrolled for stage 1 of the study. Median age was 54 years (range 38–79), 50% had liver metastases and 67% received at least 3 lines of prior therapies. PD-L1 expression was <1% for 85% of patients. The combination was well-tolerated; most common side effect related to treatment was Grade (Gr) 1-2 local skin reaction (n=22). Gr 2 events (n=2) at least possibly related to treatment were nausea, pyrexia and increased blood alkaline phosphatase. There were no Gr 3-5 events or study discontinuation due to treatment AE. The ORR was 0% and the DCR was 61%. The mPFS was 2.7 months (95%CI 1.4-4.0) and the mOS was not reached (95%CI 8.75 – NE months) at the data cut-off date. Ex-vivo FluoroSpot identified 13/16 subjects with robust, vaccine-specific CD8+ and/or CD4+ T cell responses detected against multiple vaccine antigens. For patients with available biopsy pairs (n=8), both the average PD-L1 expression (IC%, p=0.029) and the density of CD8+ tumor-infiltrating lymphocytes (TILs, p=0.019) were significantly increased, post-treatment. Patients with increased PFS (> 12 weeks) had both higher levels of post-treatment PD-L1 (p=0.007) and TILs (p=0.016) than patients with PFS ≤ 12 weeks. Conclusions: PolyPEPI1018 in combination with atezolizumab was well-tolerated with no Grade 3 AEs observed. Despite no objective tumor responses could be detected, correlative data suggest contribution of PolyPEPI1018-induced immune responses to the modulation of tumor microenvironment and to improved disease control. The study did not proceed to stage 2; it is on-going for the collection of survival data. Clinical trial information: NCT05243862 .
Preoperative (neoadjuvant) therapy with tislelizumab for locally advanced colorectal cancer with high microsatellite instability or deficient mismatch repair: An open-label, single-arm, multicenter phase II study.
Authors: Ding Ke-Feng , Chen Gong , Ye Yao , Liu Yue , Sun Yanlai , Gao Yang , Zhang Jingdong , Wei Shaozhong , Li Cong , Li Dandan , Zhou Yanbing , Liu Mulin , Zhang Juan , Zhang Lilin , Kong Dalu 
Published: June 2024

3599 Background: Tislelizumab (TIS), an anti-programmed cell death protein 1 (PD-1) antibody, demonstrated improved anti-tumor response and tolerable safety in patients (pts) with previously treated, locally advanced unresectable or metastatic microsatellite instability high/deficient mismatch repair (MSI-H/dMMR) solid tumors, including colorectal cancer (CRC; NCT03736889). Recent studies of other anti-PD-1 antibodies indicate potential clinical benefit of neoadjuvant anti-PD-1 therapy in pts with resectable MSI-H/dMMR CRC. Here, we report efficacy and safety outcomes of neoadjuvant TIS from a multicenter phase II trial (NCT05116085) in this population. Methods: Pts aged ≥18 years with stage II/III MSI-H/dMMR CRC, ECOG PS 0-1, evaluable disease per RECIST v1.1, and eligible for R0 (complete) resection were enrolled. Pts received TIS 200 mg IV every 3 weeks for 3 cycles followed by surgical resection within 10 weeks of first TIS dose. The primary endpoint was major pathological response (MPR) rate (proportion of pts with ≤10% residual viable tumor in the surgically resected primary tumor). Secondary endpoints included pathological complete response (pCR) rate (proportion of pts with absence of residual tumor in the surgically resected specimen), and safety. The R0 resection rate was an exploratory endpoint. Results: Overall, 33 pts were enrolled across eight sites in China. The median age of enrolled pts was 52.0 years (range: 23-84), 14 (42.4%) pts were male. Ten (30.3%) pts had rectal cancer and 23 (69.7%) colon cancer. At study entry, clinical tumor (T) stage was reported as T2, T3, and T4 in 1 (3.0%), 7 (21.2%), and 25 (75.8%) pts, respectively, and node (N) stage as N0, N1, and N2 in 6 (18.2%), 14 (42.4%), and 13 (39.4%) pts, respectively. All pts had a metastasis (M) stage of M0. A total of 29 (87.9%) pts underwent surgery and were evaluable for efficacy endpoints. Surgery was not performed in 4 pts, 3 of whom were managed non-operatively (1 pt had progressive disease). MPR and pCR rates were 89.7% and 62.1%, respectively (Table). Any-grade and grade ≥3 TIS-related adverse events (TRAEs) were reported in 20 (60.6%) and 1 (3.0%) pts, respectively. Two (6.1%) pts experienced serious TRAEs; no TRAEs led to death or surgery cancellation. One pt (3.0%) experienced a TRAE (grade 2 hypothyroidism) leading to surgery delay. No grade ≥3 or serious TIS-related surgery-relevant adverse events were reported. Immune-mediated adverse events were reported in 10 (30.3%) pts (all grade 1-2). Conclusions: Neoadjuvant TIS was associated with high MPR and pCR rates and an acceptable safety profile, and did not compromise surgery in pts with resectable MSI-H/dMMR CRC. Clinical trial information: NCT05116085 . [Table: see text]
Neoadjuvant toripalimab plus chemotherapy followed by concurrent chemoradiotherapy in locally advanced esophageal squamous cell carcinoma (GASTO 1071).
Authors: Qiu Bo , Liu FangJie , Wang DaQuan , Luo QiaoTing , Wu YingJia , Guo JinYu , Zou YingYi , Rong YuMing , Luo GuangYu , Liu Hui 
Published: June 2024

4077 Background: The combination of immune checkpoint inhibitor and concurrent chemoradiotherapy (CCRT) has been under investigation in patients with unresectable, locally advanced esophageal squamous cell carcinoma (ESCC). We explored the efficacy and safety of neoadjuvant toripalimab plus chemotherapy followed by CCRT in patients with locally advanced ESCC. Methods: This phase II, non-randomized, 2-cohort study enrolled patients with unresectable, stage T1-4N0-3M0-1 ESCC (M1 only includes patients with lymph node metastasis in the supraclavicular region). All patients were aged 18–80 years with an Eastern Cooperative Oncology Group performance status of 0–1. Patients in both cohorts received neoadjuvant therapy comprised of paclitaxel-albumin, nedaplatin and toripalimab 240 mg every 3 weeks, for 2 cycles, followed by CCRT (total dose 60Gy in cohort A, 50 Gy in cohort B, combined with oral capecitabine). The primary endpoint was progression-free survival (PFS) from enrollment. The trial is registered with ClinicalTrials.gov, NCT04844385. Results: Between February 26, 2021, and June 20, 2023, a total of 63 patients were enrolled in cohort A (54 men [85.7%]; median [interquartile range] age, 63 [58-65] years; 57 [90.5%] patients had stage III to IVB disease), and 61 patients were enrolled in cohort B (43 men [70.5%]; median [interquartile range] age, 65 [57-69] years; 52 [85.2%] patients had stage III to IVB disease). The objective response rate assessed 2 months after CCRT was 93.7% in cohort A and 93.4% in cohort B. At data cutoff (January 31, 2024), the median (range) follow-up duration was 31.3 (2.5-47.1) months in cohort A, and 17.0 (5.7-38.7) months in cohort B. The 12-month and 18-month PFS rates were 78.3%, 64.4% in cohort A, and 75.7%, 63.6% in cohort B. Median PFS was not reached in either cohort. Locoregional recurrence was observed in 19.0% (12/63) of patients in cohort A, and 24.6% (15/61) of patients in cohort B. Distant metastasis was observed in 12.7% (8/63) of patients in cohort A, and 3.3% (2/61) of patients in cohort B. Grade 3 and 5 pneumonitis occurred in 3.2% (2/63) and 1.6% (1/63) in cohort A, respectively, while no grade 3+ pneumonitis occurred in cohort B. Treatment-related esophageal fistula occurred in 1.6% (1/63) in cohort A and 1.6% (1/61) in cohort B. Conclusions: Neoadjuvant toripalimab plus chemotherapy followed by definitive CCRT demonstrated promising efficacy and acceptable toxicity in patients with locally advanced ESCC. Further study is warranted to confirm this conclusion. Clinical trial information: NCT04844385 .
Adjuvant mFOLFIRINOX (mFFX) for resected pancreatic cancer (PC): Long term clinical and genomic outcomes.
Authors: Keane Fergus , Moss Drew , O'Connor Catherine A , Perry Maria , Chou Joanne F. , Crowley Fionnuala , Saxena Parima , Chan Amelia , Park Wungki , Varghese Anna M. , Yu Kenneth H. , Capanu Marinela , Kingham T. Peter , D'Angelica Michael Ian , Balachandran Vinod P. , Jarnagin William R. , Wei Alice C , Soares Kevin , Balogun Fiyinfolu , O'Reilly Eileen M. 
Published: June 2024

4170 Background: Adjuvant chemotherapy with mFFX is the standard for pts with ECOG 0-1 (1) after pancreatectomy for resectable PC. Herein, we report long-term survival data on an expanded cohort and present comprehensive genomic analyses. Methods: Pts with resected PC who received >1 dose of adjuvant mFFX identified from institutional databases. Primary endpoints: Recurrence Free Survival (mRFS) and Overall Survival (mOS) calculated from start of treatment until recurrence or death. Key secondary endpoints: clinical factors, genomic descriptors ( KRAS status, whole genome doubling (WGD), and homologous recombination deficiency (HRD)) associated with outcome. Kaplan-Meier method used to estimate RFS and OS. Univariate Cox proportional hazards model correlated clinico-genomic characteristics with RFS and OS. Results: N=147 identified between 01/2015-01/2022. Median age: 67 years; N= 22 (15%) > 75 years. Several prognostically unfavorable groups; N=52 (36%) stage III disease/ N2 nodal status; N=115 (78%) lymphovascular invasion (LVI); N=133 (90%) perineural invasion (PNI). Median time from surgery to start mFFX: 1.78m (IQR; 1.45, 2.12). Median CA 19-9 at start mFFX: 21 (range 0-1,124). N=124 (84%) pts completed 12 doses mFFX (+/- 12 doses oxaliplatin). N=98 pts (67%) stopped oxaliplatin early for neuropathy. With the median follow up 35.1m (range 5.1, 73.0), mRFS 27m (95% CI 20, 39) and OS not reached (NR). For >75 cohort, mRFS 12m (95% CI 9.6, NR) and mOS 30m (95% CI 19, NR). mFFX started <8 weeks from resection associated with improved RFS (HR 0.62; 95% CI 0.41, 0.96; p= 0.033) and OS (HR 0.53; 95% CI 0.3, 0.94; p= 0.030). T3 tumors associated with worse RFS (HR 2.82, 95% CI 1.28, 6.20; p=0.010) and OS (HR 5.10, 95% CI 1.45, 18; p=0.011). Genomic variables summarized (Table). KRASmutation (+), WGD (+), and higher KRAS CNV trended to shorter RFS and OS; statistical significance limited by small subgroups. HRD status did not confer differences in OS. Conclusions: Adjuvant mFFX is an effective therapy and results in long-term OS outcome in resected PC in a non-trial setting, including for pts >75 years. Early initiation of adjuvant mFFX may optimize outcome. Trends observed for improved outcome in select genomic subsets, which require large-scale validation. 1. Conroy, JAMA Onc, 2022. [Table: see text]