bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase 1b, open-label, single-arm study of cofetuzumab pelidotin (a PTK7-targeting antibody-drug conjugate) in patients with PTK7-expressing, recurrent non-small cell lung cancer (NSCLC).
Authors: Schaefer Eric S. , Camidge D. Ross , Yoh Kiyotaka , Zer Alona , Hernandez Guerrero Tatiana , Bar Jair , Okuma Yusuke , Peguero Julio Antonio , De Miguel Maria , Moskovitz Mor Tal , Morgensztern Daniel , Jeffries Shawn , Wang Lan , Lally Satwant , Conn Christopher , Xin Xiaohua , Jeng Edwin E. , Johnson Melissa Lynne 
Published: June 2021

TPS3142 Background: Protein tyrosine kinase 7 (PTK7) is a highly conserved receptor tyrosine kinase involved in the Wnt signaling pathway and is overexpressed in multiple cancer types, including non-small cell lung cancer (NSCLC). Cofetuzumab pelidotin (ABBV-647) is an anti-PTK7 antibody-drug conjugate comprising the hu6MO24 monoclonal antibody, a cleavable cysteine-reactive linker, and Aur0101 (an auristatin microtubule inhibitor). It has shown promising preclinical anti-tumor effects (Damelin et al. Sci Transl Med 2017;9[372]:eaag2611) and clinical activity with a manageable safety profile in a Phase 1 study in patients with advanced solid tumors, with promising anti-tumor activity noted in NSCLC (Sachdev et al. DOI: 10.1200/JCO.2018.36.15_suppl.5565). Methods: This open-label, single-arm, multicenter Phase 1b study (NCT04189614) will assess the anti-tumor activity and safety of cofetuzumab pelidotin in approximately 40 patients with PTK7-expressing, recurrent NSCLC. The primary objective is to assess the objective response rate of cofetuzumab pelidotin according to Response Evaluation Criteria in Solid Tumors version 1.1. Secondary objectives include the duration of response, progression-free survival, overall survival, and safety and tolerability. Pharmacokinetic and biomarker samples will also be collected throughout for analysis. Patients must be aged ≥18 years with an Eastern Cooperative Oncology Group performance status of 0–1 and have recurrent histologically confirmed NSCLC with PTK7-expressing tumor (using a validated immunohistochemistry assay). Patients must have progressed after treatment with a platinum-based chemotherapy doublet and an immune checkpoint inhibitor (for tumors without targetable genetic alterations), or a platinum-based chemotherapy doublet and targeted agent(s) (for tumors with targetable genetic alterations). Patients must also have received ≤2 prior lines of systemic therapy (≤3 prior lines for tumors treated with targeted agent[s] for genetic alterations), including no more than 1 line of systemic chemotherapy. Cofetuzumab pelidotin (2.8 mg/kg) is administered intravenously every 3 weeks until the patient experiences disease progression, intolerable toxicity, or other study treatment discontinuation criteria are met. The study commenced on February 13, 2020 and enrollment is ongoing. Clinical trial information: NCT04189614.
Phase 1/2 study of eprenetapopt (APR-246) in combination with pembrolizumab in patients with solid tumor malignancies.
Authors: Dumbrava Ecaterina Elena , Mahipal Amit , Gao Xin , Shapiro Geoffrey , Starr Jason S. , Singh Parminder , Furqan Muhammad , Ahrorov Afzal , Hickman Denice , Gubits Amy , Attar Eyal C. , Awad Mark M. , Das Satya , Park Haeseong 
Published: June 2021

TPS3161 Background: The p53 pathway has been implicated in antitumor immunity, including antigen presentation and T-cell proliferation. Loss of p53 function can increase resistance to immunotherapy across many tumor types. Eprenetapopt (eprenet) is a small molecule that stabilizes the folded structure of p53, resulting in activation of mutant p53 and stabilization of wild-type (WT) p53. It also targets the cellular redox homeostasis, resulting in induction of apoptosis in tumor cells. In vivo, mice carrying supernumerary copies of the TP53 gene harbor a pro-inflammatory tumor microenvironment, an effect recapitulated in TP53 normal-copy mice treated with eprenetapopt. Combining eprenetapopt and anti-PD1 or anti-CTLA4 therapy resulted in enhanced tumor growth inhibition and improved survival in TP53 WT mice inoculated with B16 melanoma and MC38 colon adenocarcinoma cells . Based on these results, we hypothesized that eprenet-induced p53 stabilization may augment response to immunotherapy. To test this hypothesis, we are conducting a phase 1b/2 study of eprenet in combination with pembrolizumab (eprenet+pembro) in pts with solid tumors. Methods: The primary objectives are to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) and to assess the safety and tolerability of eprenet+pembro in pts with advanced solid tumors. The secondary objectives are to estimate the anti-tumor activity and to describe the pharmacokinetics of the combination. Exploratory objectives include assessing predictive and pharmacodynamic markers of response. The study includes a safety lead-in with a 3+3 dose de-escalation design for pts with advanced solid tumors with known tumor TP53 mutation status ( TP53 WT is acceptable) (max 18 pts), followed by expansion cohorts in pts with NSCLC, gastric/GEJ and urothelial cancer (max 100 pts). In expansion, pts with urothelial and gastric cancers must be naïve to anti-PD-1/ L1 therapy. Eprenet is given IV once daily on Days 1–4 while pembro is administered on Day 3 of each 21-day cycle. The RP2D of eprenet+pembro is considered the dose at which ≤ 1 of 6 pts in a cohort has a dose-limiting toxicity (DLT). Primary endpoints are occurrence of DLTs, adverse events (AEs) and serious AEs with eprenet+pembro. Key secondary endpoints are best objective response, progression free survival and overall survival. Exploratory endpoints include gene mutations by next generation sequencing (including TP53), mRNA expression, multiplex immunohistochemistry and transcriptomics, multiplex flow cytometry on peripheral blood mononuclear cells and cytokines in serum. Continuous monitoring of toxicity will be conducted. The trial opened in May 2020 and is actively enrolling patients. Clinical trial information: NCT04383938.
A phase 2, multicenter, open-label study evaluating trastuzumab deruxtecan (T-DXd) for the treatment of solid tumors harboring specific HER2-activating mutations (DESTINY-PanTumor01).
Authors: Li Bob T. , Meric-Bernstam Funda , Puvvada Soham D. , Rowbottom Jacqui , Jolliffe Darren , Gustavson Mark , Mendoza-Naranjo Ariadna 
Published: June 2021

TPS3162 Background: There are substantial data suggesting that a subset of human epidermal growth factor receptor 2 (HER2)–activating mutations induce ligand-independent constitutive HER2 signaling and promote oncogenesis. Direct therapeutic targeting of HER2 has transformed the treatment of patients with HER2-overexpressing breast and gastric cancers. However, currently no targeted treatments are approved for patients with tumors harboring HER2-activating mutations. T-DXd is an antibody-drug conjugate consisting of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a membrane-permeable topoisomerase I inhibitor payload that may be selectively internalized in tumors with HER2 mutations (Li BT, et al. Cancer Discov. 2020;10:674-687). In a phase 1 study (DS8201-A-J101), T-DXd demonstrated preliminary antitumor activity in patients with tumors harboring HER2 mutations, with confirmed responses observed in 9 of 19 patients (47.4%) (Tsurutani J, et al. Cancer Discov. 2020;10:688-701). Here we describe the DESTINY-PanTumor01 trial (NCT04639219). Methods: DESTINY-PanTumor01 is an open-label, multicenter, single-arm, phase 2 study evaluating T-DXd for the treatment of patients with unresectable and/or metastatic solid tumors (excluding non-small cell lung cancer) harboring prespecified HER2-activating mutations. Patients (N≈100) are required to have progressed following prior treatment for advanced or metastatic disease or have no satisfactory alternative treatment options. Prior HER2-targeting therapy is allowed. HER2 mutation status will be determined locally using next-generation sequencing or a validated nucleic acid–based methodology. The primary endpoint is confirmed objective response rate according to independent central review per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary endpoints include duration of response, disease control rate, progression-free survival, investigator-assessed confirmed objective response rate, overall survival, safety, pharmacokinetics, and immunogenicity. Clinical trial information: NCT04639219.
A phase II trial of trastuzumab plus modified-FOLFOX for gemcitabine/cisplatin refractory HER2-positive biliary tract cancer (BTC): Multi-institutional study of the Korean Cancer Study Group (KCSG-HB19-14).
Authors: Lee Choong-kun , Cheon Jaekyung , Chon Hong Jae , Kim Min Hwan , Kim Jin Won , Lee Myung Ah , Park Hyung Soon , Kang Myoung Joo , Jang Joung-Soon , Choi Hye Jin 
Published: June 2021

TPS4161 Background: Biliary tract cancer (BTC), one of the most fatal cancers with limited treatment options, is generally rare in most high-income countries, but is relatively prevalent in South Korea. Recent genomic profilings have provided druggable molecular targets including HER2 amplification, which accounts for about 15% of total BTC patients. Trastuzumab is a humanized monoclonal antibody against HER2 with known efficacy in patients with HER2-positive breast and gastric cancer, and has not been tested prospectively in patients with HER2-positive BTC. The modified-FOLFOX regimen is currently being tested as a second-line therapy of BTC in phase III ABC-06 trial. This phase II study is investigating the combination of trastuzumab and modified-FOLFOX as second- or third-line treatment in HER2-postivie BTC. Methods: This study (KCSG-HB19-14; NCT04722133) is a phase II, multi-institutional, single arm trial to evaluate the efficacy and safety of trastuzumab plus modified-FOLFOX in gemcitabine/cisplatin refractory patients with HER2-positive BTC. The main inclusion criteria are HER2-positive (defined as IHC3+, or IHC2+/ISH+; ISH+ defined as HER2/CEP17 ≥2.0, or ERBB2 gene copy number ≥ 6.0 by NGS) BTC (intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, gallbladder cancer and ampulla of vater cancer) patients who progressed on gemcitabine/cisplatin containing chemotherapy (one or two previous cytotoxic chemotherapy lines permitted), ECOG 0 or 1, and adequate organ function. Patients receive trastuzumab-pkrb 4mg/kg (after 6mg/kg load) D1, oxaliplatin 85mg/m2 D1, leucovorin 200mg/m2 D1, 5-FU 400mg/m2 bolus D1, and 5-FU 2400mg/m2 infusion D1-2 every 2 weeks until unacceptable toxicities or disease progression. The study has a Simon's two-stage design, with objective response rate (ORR) per RECIST v1.1 as primary endpoint. Secondary endpoints included progression-free survival, disease control rate, overall survival, safety, quality of life and correlative biomarker exploration. Additional patients were to be recruited if pre-specified thresholds for ORR are met at the first stage. The study will enroll up to 34 patients and is currently recruiting at eight sites in South Korea. As of February 2021, 16 patients have been enrolled. The pre-specified activity goal for the first stage of accrual was met; second stage accrual began in February 2021. Clinical trial information: NCT04722133.
DNA-damage response-umbrella study of the combination of ceralasertib and olaparib, or ceralasertib and durvalumab in advanced biliary tract cancer: A phase 2 trial-in-progress.
Authors: Yoon Jee Sun , Kim Jin Won , Kim Ji-Won , Kim Tae-Yong , Nam Ah-Rong , Bang Ju-Hee , Seo Hye-Rim , Kim Jae-Min , Oh Kyoung Seok , Mortimer Peter G. , Smith Simon , Oh Do-Youn 
Published: June 2021

TPS4166 Background: Ceralasertib (AZD6738) is a selective ATR inhibitor that causes stalled replication forks to collapse, leading to accumulation of double-strand DNA breaks, which is expected to have synergistic anti-tumor effects with immune checkpoint inhibitors (ICI) or PARP inhibitors. First, accumulation of DNA damage by ceralasertib induces tumor cell death, leads to the release of tumor-specific antigen, changing the tumor microenvironment to promote antigen presentation and enhances the anti-tumor effect of ICI. Second, by simultaneously inhibiting two DNA-damage response (DDR) pathways downstream of PARP and ATR, cancer cells are unable to repair damaged DNA, leading to cell death. Ceralasertib has demonstrated promising anti-tumor activity and manageable toxicity in combination with durvalumab or olaparib in solid tumors in a phase 1 study (NCT02264678). In preclinical studies, ceralasertib has shown potent anti-tumor effects in biliary tract cancer (BTC) as a monotherapy and in combination with chemotherapy (Nam, et al, 2019). Methods: This is an open-label, phase 2 umbrella study assessing the efficacy of ceralasertib in combination with durvalumab or olaparib in patients with advanced BTC. Eligible patients have histologically confirmed BTC (including intrahepatic or extrahepatic cholangiocarcinoma, gallbladder cancer, or ampullary cancer), have failed at least one chemotherapy and have ECOG performance status of 0-1. Patients who have received prior ICI, ATR or PARP inhibitor are excluded. Each cycle consists of 4 weeks. In ceralasertib /durvalumab cohort, 37 patients will receive durvalumab 1.5g on day 1 and ceralasertib 240mg twice daily on days 15-28. In ceralasertib /olaparib cohort, 37 patients receive ceralasertib 160mg once daily on days 1-7 and olaparib 300mg twice daily on days 1-28. The primary endpoint is disease control rate, with key secondary endpoints including overall response rate, progression-free survival, overall survival, and safety. Tissue and blood samples are being collected for translational biomarker studies. Clinical trial information: NCT04298021.
KEYNOTE-B15/EV-304: Randomized phase 3 study of perioperative enfortumab vedotin plus pembrolizumab versus chemotherapy in cisplatin-eligible patients with muscle-invasive bladder cancer (MIBC).
Authors: Hoimes Christopher J. , Bedke Jens , Loriot Yohann , Nishiyama Hiroyuki , Fang Xiao , Kataria Ritesh S. , Homet Moreno Blanca , Galsky Matt D. 
Published: June 2021

TPS4587 Background: Standard of care for MIBC is neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy and pelvic lymph node dissection (RC+PLND); however, in time, patients experience disease recurrence or progression. Enfortumab vedotin (EV) is a Nectin-4–directed antibody–drug conjugate comprising a fully human, monoclonal antibody and the microtubule-disrupting agent monomethyl auristatin E. The KEYNOTE-869/EV-103 phase 1/2 study (NCT03288545) showed that the PD-1 inhibitor pembrolizumab + EV had encouraging antitumor activity and acceptable safety as first-line treatment for cisplatin-ineligible patients with metastatic urothelial cancer (Rosenberg JE et al. J Clin Oncol. 2020;38[15 suppl]:5044). Based on these data, investigating EV + pembrolizumab in an earlier setting such as MIBC and in a perioperative fashion is appropriate. KEYNOTE-B15/EV-304 (NCT04700124) is a randomized, open-label, phase 3 study to evaluate the efficacy and safety of perioperative EV + pembrolizumab versus neoadjuvant chemotherapy using gemcitabine/cisplatin in cisplatin-eligible patients with MIBC. Methods: Patients must have histologically confirmed urothelial cancer/MIBC (clinical stage T2-T4aN0M0 or T1-T4aN1M0) with predominant (≥50%) urothelial histology, have nonmetastatic disease (≥N2 disease and/or M1 excluded) confirmed by blinded independent central review (BICR), have ECOG PS 0 or 1, and not have previously received systemic therapy for MIBC. Approximately 784 patients will be randomly assigned 1:1 to receive either 4 cycles of neoadjuvant EV + pembrolizumab followed by 5 cycles of adjuvant EV + 13 cycles of adjuvant pembrolizumab after RC+PLND or 4 cycles of neoadjuvant cisplatin-based chemotherapy followed by observation after RC+PLND. Neoadjuvant and adjuvant pembrolizumab 200 mg + EV 1.25 mg/kg will be administered intravenously every 3 weeks (Q3W), and neoadjuvant chemotherapy will consist of gemcitabine 1000 mg/m2 + cisplatin 70 mg/m2 Q3W. Randomization will be stratified by centrally determined (pathology or imaging) initial T and N stage (T2N0 or T3/T4aN0 or T1-T4aN1), PD-L1 combined positive score (CPS ≥10 or CPS < 10), and geographic region (United States or Europe or most of world). Imaging (CT or MRI) will be performed ≤6 weeks before cystectomy and 6 weeks after cystectomy. After postcystectomy imaging, additional imaging will be performed Q12W up to the end of year 2 (week 96) and at discontinuation. In year 3 and beyond, imaging will be performed Q24W. Primary end points are pathological complete response and event-free survival by BICR. Secondary end points are overall survival, disease-free survival, pathological downstaging, and safety and tolerability. Clinical trial information: NCT04700124.
KEYNOTE-B61: Open-label phase 2 study of pembrolizumab in combination with lenvatinib as first-line treatment for non-clear cell renal cell carcinoma (nccRCC).
Authors: Lee Chung-Han , Li Chenxiang , Perini Rodolfo F. , Hoehn Daniela , Albiges Laurence 
Published: June 2021

TPS4595 Background: Most RCCs contain clear cell histology; the remainder of cases are summarized as nccRCC. nccRCC is a heterogeneous group of tumors and, with advanced metastases, survival is uniformly worse than with clear cell RCC (ccRCC) because of the aggressiveness of these cancers and a lack of effective systemic treatment options. Because data are limited for patients with nccRCC, the role of various agents in the treatment of nccRCC is poorly defined and there is no standard of care; treatment guidelines recommend clinical trials as preferred strategy. Inhibition of the PD-1/PD-L1 pathway is an effective treatment option for nccRCC, and pembrolizumab monotherapy has shown efficacy with an acceptable safety profile as first-line treatment. The VEGF TKI lenvatinib has also shown efficacy with a tolerable safety profile as combination therapy with everolimus for nccRCC. Also, in the phase 3 KEYNOTE-581 study (NCT02811861), the combination of lenvatinib + pembrolizumab as first-line therapy showed antitumor activity in patients with metastatic ccRCC, suggesting this combination might be an excellent therapeutic option for nccRCC. The phase 2, open-label, single-arm, KEYNOTE-B61 study (NCT04704219) is being conducted to evaluate pembrolizumab in combination with lenvatinib as first-line treatment for nccRCC. Methods: Patients with centrally confirmed nccRCC, locally advanced/metastatic measurable disease per RECIST v1.1 per blinded independent central review (BICR), no prior systemic therapy for nccRCC, and KPS score ≥70 will be enrolled. Approximately 152 patients will receive pembrolizumab 400 mg every 6 weeks and lenvatinib 20 mg once daily. Pembrolizumab treatment will continue for up to approximately 2 years or until a discontinuation criterion is met (disease progression, unacceptable toxicity, or withdrawal of consent); lenvatinib treatment can continue beyond 2 years or until one of the same discontinuation criterion is met. Participants who discontinue one of the treatments can continue to receive the other treatment as monotherapy. A second-course treatment phase is available for patients who meet specific criteria. CT/MRI will be performed at 12 weeks from the start of treatment, every 6 weeks until week 54, and every 12 weeks thereafter. Adverse events will be monitored throughout the study and graded using CTCAE, version 5.0, guidelines. The primary end point is objective response rate based on RECIST v1.1 per BICR. Secondary efficacy end points for this study are clinical benefit rate, disease control rate, duration of response, progression-free survival, overall survival, and safety. Tertiary/exploratory end points are biomarker analysis and association with clinical response/disease etiopathogenesis. Clinical trial information: NCT04704219.
A phase 3, randomized, double-blind, adaptive, placebo/paclitaxel-controlled study of AVB-S6-500 in combination with paclitaxel in patients with platinum-resistant recurrent ovarian cancer (GOG-3059/ENGOT OV-66/AVB500-OC-004).
Authors: Fuh Katherine Cynthia , Herzog Thomas J. , Moore Kathleen N. , Myers Tashanna K. N. , Rimel BJ , Liu Joyce F. , Secord Angeles Alvarez , Hamilton Erika P. , Reid Thomas J. , Lewin Sharyn Nan , Mullen Mary M , Mills Kathryn A. , Anderson Randy , Rangwala Reshma A. 
Published: June 2021

TPS5605 Background: The AXL receptor and its activating ligand, GAS6, are important drivers of metastasis and therapeutic resistance in human cancers. This signaling axis represents an attractive target for therapeutic intervention, but the strong picomolar binding affinity between endogenous GAS6 and AXL and the promiscuity of small molecule AXL inhibitors have presented a barrier to specific and potent inhibition of AXL. AVB-S6-500 is a highly sensitive and specific inhibitor of AXL, with ̃200-fold higher affinity than wild-type (WT) AXL. AVB-S6-500 binds GAS6, the sole ligand of AXL, inhibiting its interaction with AXL thereby dramatically reducing AXL signaled invasion and migration of highly metastatic cells in vitro and inhibiting metastatic disease in nonclinical models of aggressive human cancers. A Phase 1b study in platinum resistant ovarian cancer showed no dose limiting toxicities and established a recommended Phase 2 dose of 15mg/kg administered every 2 weeks. Longer progression free survival (PFS) and overall survival (OS) times were observed in patients who had not been previously treated with bevacizumab. Furthermore, retrospective analyses demonstrated that serum soluble AXL to GAS6 ratio may identify patients more likely to respond to this therapy. Methods: Patients with high grade serous, platinum resistant ovarian cancer, who have received no more than 4 prior therapy regimens will be randomized 1:1 to AVB-500 + PAC or PAC + placebo. Patients will be stratified by recurrence after last platinum regimen (<3, 3-6 months), prior lines (1-2, 3-4), and prior bevacizumab (yes, no). The primary endpoint is PFS by RECIST v 1.1 as assessed by the investigator, with OS a key secondary endpoint. The study design is adaptive; with two interim analyses addressing conditional power in the bevacizumab treated subset, and in a serum soluble AXL, GAS6 biomarker subset, respectively, with interim results used to define the final target population. Simulations confirm a nominal one-sided type 1 error below 0.025, and show >90% statistical power for PFS under the following assumptions of PFS medians. Study recruitment began in Q1. Clinical trial information: NCT04729608.