bluuebunny/crossref_metadata_2025_split huggingface dataset:
SKB264 ADC: A first-in-human study of SKB264 in patients with locally advanced unresectable/metastatic solid tumors who are refractory to available standard therapies.
Authors: Liu Yongheng , Lian Wei , Zhao Xi , Diao Yina , Xu Jian , Xiao Liang , Qing Yan , Xue Tongtong , Wang Jingyi 
Published: May 2020

TPS3659 Background: Elevated expression of trophoblast antigen 2 (TROP2) is often associated with invasion/aggression, progression, and metastasis of many different tumor types. Efficacies of anti-TROP2 ADC have been demonstrated both pre-clinically and in the clinical trials. SKB264 is being developed as a further optimized TROP2-targeting ADC with a proprietary cytotoxic, belotecan-derived payload and novel stable conjugation chemistry to achieve average DAR (Drug Antibody Ratio) of 7.4. Release of payload upon SKB264 internalization is in a TROP2 expression dependent manner. Extensive preclinical studies demonstrated antitumor activity of SKB264 in vitro, in xenograft and patient-derived xenograft (PDX) animal models. In addition, safety studies have demonstrated a good safety profile to allow SKB264 to be studied in clinical trials. Methods: SKB264-01 is a global open label multicenter study. The study is divided into 2 parts, the phase I is to determine the safety profile, define MTD and/or the RP2D, and characterize DLTs of SKB264. Dose escalation and MTD identification will be directed using a Bayesian logistic regression model (BLRM) with overdose control. The phase II is to evaluate efficacy and obtain clinical activity data of SKB264 as a monotherapeutic agent at the RP2D in each of the designated Phase II cohorts and overall (n = 16 per cohort; n = 48 for entire Phase II part). Objective response rate (ORR) will be continuously evaluated in each cohort using a Bayesian hierarchical model. TROP2 assessments will not be performed prior to enrollment but it will be assessed retrospectively. Confirmation of TROP2 expression by immunohistology or other methods is not required, but the Sponsor will request tissue specimens from archived materials for determination of TROP2 expression. The patient must have, in the judgment of the investigator, historically documented, incurable, locally advanced or metastatic cancer that are refractory to standard therapies of one of the following types: i. ovarian epithelial cancer, ii. gastric adenocarcinoma, iii. pancreatic adenocarcinoma, iv. triple negative breast cancer, v. bladder cancer. Patient will receive study drug as a single IV infusion at the prescribed dose level at each administration. Cycles will continue until disease progression or unacceptable toxicity. Adverse Events (AE) will be graded according to CTCAE V.5.0. Responses will be evaluated according to RECIST V1.1. The enrollment will began in Mar 2020 in USA sites. Clinical trial information: NCT04152499 .
A phase I/II study of PI3Kinase inhibition with copanlisib combined with the anti-PD-1 antibody nivolumab in relapsed/refractory solid tumors with expansions in MSS colorectal cancer.
Authors: Jakubowski Christopher , Collins Natalie B , Sugar Elizabeth Ann , Berg Maureen , Cao Haihui , Giannakis Marios , Jaffee Elizabeth M. , Azad Nilofer Saba 
Published: May 2020

TPS4114 Background: Certain somatic mutations are thought to promote immune evasion and resistance to immunotherapy. PIK3CA was identified in an in vivo genomic screen for mechanisms of resistance to anti-PD1 therapy. MC38 cells (murine colon adenocarcinoma) were engineered to express a library of human cancer-associated mutations from TCGA. Resultant tumors in vivo were exposed to immune pressure with anti-PD1 therapy. Cells that proliferated were then analyzed for mutations that impart immune resistance. Multiple activating mutations in PIK3CA conferred resistance to anti-PD1 therapy. Coadministered PI3K inhibition reversed this resistance. Multiple studies have shown the impact of the phosphatidylinositol 3-kinase (PI3K) pathway on the tumor microenvironment, and 20% of colorectal cancer (CRC) tumors have an activating mutation of PI3K. Methods: A multi-center, open-label, phase I/II study with the combination copanlisib and nivolumab, a PD1 inhibitor, in relapsed/refractory solid tumors with expansions in relapsed/refractory microsatellite-stable (MSS) CRC was developed. Copanlisib is an inhibitor of PI3K and exhibits its most potent inhibitory effect on the isoforms PI3Kα and PI3Kδ. The first phase seeks to determine the maximum tolerated dose (MTD) of copanlisib with fixed dose nivolumab of 480 mg given every 4 weeks. Following determination of the MTD the second phase seeks to determine the 6-month objective response rate of the combination in MSS CRC patients and contains two cohorts 1) PIK3CA wildtype, 2) PIK3CA mutated. The study is planned with 21 evaluable subjects per cohort and allows early termination for lack of efficacy. Tumor assessments will be made using RECIST 1.1. Patients will have a pre-treatment biopsy followed by nivolumab on Day 1 of each 4 week cycle and copanlisib on Day 1, 8 and 15. A second biopsy will occur after six weeks. Eligibility criteria includes completed NGS for PI3K status, and patients must have received at least 2 prior lines of standard therapy. Patients can not have received a prior checkpoint inhibitor or PI3K inhibitor. Secondary and exploratory objectives, in addition to survival and safety outcomes, include exploring immune cell subsets in the local tumor microenvironment and in the peripheral circulation, as well as investigating immune activation and suppressive pathways through RNA expression and additional NGS techniques. The clinical study was activated in January 2019 (NCT03711058). Clinical trial information: NCT03711058 .
A phase Ib/II study of the polo-like kinase 1 (PLK1) inhibitor, onvansertib, in combination with FOLFIRI and bevacizumab for second-line treatment of patients with KRAS-mutated metastatic colorectal cancer (mCRC).
Authors: Ahn Daniel H. , Barzi Afsaneh , Ridinger Maya , Samuelsz Errin , Erlander Mark G. , Bekaii-Saab Tanios S. , Lenz Heinz-Josef 
Published: May 2020

TPS4116 Background: Chemotherapy in combination with targeted agents are standard-of-care options for patients for mCRC with response rates >50% in first line. In the second line setting, efficacy of chemotherapy and targeted agents are much lower with response rates of 5% for FOLFIRI (5-fluorouracil, leucovorin, irinotecan) + bevacizumab (anti-VEGF). New treatment options are urgently needed in particular for the 50 % of patients harboring a KRAS mutation. PLK1 is a serine/threonine kinase, master regulator of the mitotic checkpoint and cell division. PLK1 is overexpressed in CRC and its overexpression is associated with poor prognostic. A genome wide RNAi screen identified PLK1 as a synthetic lethal target in KRAS mutant CRC cells, inducing cell cycle arrest and apoptosis upon inhibition. Onvansertib is an oral, highly selective PLK1 inhibitor that demonstrates single agent and synergistic activity with irinotecan in preclinical CRC models. Additionally, KRAS mutated vs wild-type cells showed higher sensitivity to onvansertib. PLK1 inhibition is a potential target in KRAS-mutated mCRC, and the combination of onvansertib + FOLFIRI + bevacizumab may provide a new second-line treatment option. Methods: The primary objective of this single-arm Phase 1b/2 study is to assess the safety and preliminary efficacy of onvansertib in combination with FOLFIRI and bevacizumab in the second line setting for KRAS-mutated mCRC patients. For the Phase 1b segment, a standard 3 + 3 dose-escalation design is used to determine the maximum tolerated dose or recommended phase 2 dose (RP2D) of onvansertib. As of January 24, 2020, enrollment in the second dose level is ongoing. Efficacy will be determined by objective response rate (ORR) according to RECIST v1.1 (primary endpoint), progression-free survival and reduction in KRAS allelic burden in liquid biopsies (secondary endpoints). In the phase 2, based on a one-sided one sample log-rank test with 10% Type I error, there will be at least 90% power to detect an improvement in ORR from 5% to 20% with 26 patients. Exploratory endpoints include genomic studies of circulating tumor cells and ctDNA to evaluate altered pathways that correlate with patient clinical response. Clinical trial information: NCT03829410 .
The PEGASUS trial: Post-surgical liquid biopsy-guided treatment of stage III and high-risk stage II colon cancer patients.
Authors: Lonardi Sara , Montagut Clara , Pietrantonio Filippo , Elez Elena , Sartore-Bianchi Andrea , Tarazona Noelia , Sciallero Stefania , Zampino M. Giulia , Mosconi Stefania , Muñoz Susana , Lazzari Luca , Luraghi Paolo , Siena Salvatore , Sobrero Alberto F. , Labianca Roberto , Torri Valter , Bardelli Alberto , Tabernero Josep , Marsoni Silvia 
Published: May 2020

TPS4124 Background: Moving stage III Colon Cancer (CC) into the precision medicine space is a priority in view of the lack of molecular markers driving adjuvant treatment. Retrospective studies have demonstrated the tremendous prognostic impact of circulating tumor DNA (ctDNA) analysis after curative intent surgery, and suggested that lack of conversion of ctDNA from detectable to undetectable after adjuvant chemotherapy reflects treatment failure. With these premises, we have designed the PEGASUS trial (NCT04259944). Methods: PEGASUS is a prospective multicentric study designed to prove the feasibility of using liquid biopsy (LB) to guide the post-surgical and post-adjuvant clinical management in 140 microsatellite stable Stage-III and T4N0 Stage-II CC patients. The LUNAR1 test (Guardant Health, Redwood City, CA, USA) will be used for ctDNA determination. For the efficacy analysis, the PEGASUS cohort will be compared with a 3:1 matched cohort of 420 patients from the TOSCA trial (NCT00646607). A LB executed 2-4 weeks post-surgery will guide a “Molecular Adjuvant” treatment: i) ctDNA+ patients will receive CAPOX for 3 months and ii) ctDNA- patients will receive capecitabine (CAPE) for 6 months but will be retested after 1 cycle, and if found ctDNA+ will be switched to CAPOX treatment. At the end of the “Molecular Adjuvant” treatment a further LB will be performed and instruct subsequent treatment. Positive patients (ctDNA+/+ and ctDNA-/+) will receive an up-scaled “Molecular Metastatic” systemic treatment for 6 months or until radiological progression or toxicity: i) ctDNA+/+ patients will be treated with FOLFIRI; ii) ctDNA-/+ patients with CAPOX. These patients will be subjected to a LB after 3 months and at the end of treatment: in case of positivity will be switched to FOLFIRI. ctDNA+/- patientswill receive a de-escalated treatment with CAPE for 3 months. 3 LB will be performed within 3 months and in case of positivity the patient will be switched to FOLFIRI. Patients with ctDNA-/- will be subjected to an interventional follow-up comprising 2 further LB and in case of positivity they will be switched to CAPOX treatment. PEGASUS is piggybacked to AlfaOmega (NCT04120935), a Master Observational Protocol that will follow patients from diagnosis to 5 years or recurrence/death (whichever comes first), collecting clinical data, radio-images and biological samples. AlfaOmega provides a clinical and logistic ecosystem for the seamless integration of PEGASUS clinical results with the biological underpinning of colon cancer. Clinical trial information: NCT04259944 .
Phase I study of proton therapy in adjuvant pancreatic cancer (PROTON-PANC).
Authors: Weinberg Benjamin Adam , Wang Hongkun , He Aiwu Ruth , Villa Nicole , Unger Keith Robert 
Published: May 2020

TPS4663 Background: Pancreatic adenocarcinoma (PAC) has a poor prognosis, with a 5-year survival rate of 10%. The current standard of care for patients with resectable disease is surgical resection followed by 6 months of adjuvant modified FOLFIRINOX (FFX, leucovorin, fluorouracil, irinotecan, and oxaliplatin). As survival outcomes and distant recurrence improve with the use of FFX, locoregional recurrence remains a cause of morbidity and mortality. We seek to integrate adjuvant short-course proton radiation therapy (PRT) to the surgical bed in between cycles of FFX. While there is limited literature on the combination of short course PRT and FFX, there are analogous experiences using 5 fraction SBRT or IMRT following FFX in routine clinical practice. The ongoing Alliance 021501 trial of preoperative chemotherapy vs. chemotherapy plus radiation (IMRT using 5 Gy X 5 or SBRT 6.6 X 5) in borderline resectable pancreatic cancer mandates that radiation starts 5 days or more following the last dose of FFX. Additionally, at the Lombardi Comprehensive Cancer Center, we routinely combine 5 fraction SBRT after a 10-14 day interval from FFX. Methods: This is a phase I, single-arm, open-label study. Eligible pts are ≥ 18 years old, have histologically confirmed, resected PAC of the pancreatic head (R0 or R1) on adjuvant FFX, an ECOG performance status of 0-1, and adequate normal bone marrow and hepato-renal function. Exclusion criteria are prior radiation to the upper abdomen (neoadjuvant chemotherapy is allowed). This study will use a 3+3 dose-escalation design to determine the safety and feasibility of combining 5 fractions of adjuvant PRT with FFX using different intervals between cycle 6 of FFX and PRT: dose level 1 uses a 12 day interval, and dose level 2 uses a 5 day interval. The primary endpoint is to determine the RP2D between the 2 proposed schedules. Using a 3+3 dose-escalation schema, 2-12 patients will be required to determine the RP2D. Enrollment began in Q4 2019. Clinical trial information: NCT03885284 .
Adaptive dose optimization trial of stereotactic body radiation therapy (SBRT) with or without GC4419 (avasopasem manganese) in pancreatic cancer.
Authors: Moser Elizabeth Charlotte , Hoffe Sarah E. , Frakes Jessica , Aguilera Todd Anthony , Karim Mona , Colbert Lauren Elizabeth , Moningi Shalini , Tzeng Ching-Wei David , Thall Peter F. , Pant Shubham , Bhutani Manoop S. , Brookes Melissa , Holmlund Jon , Herman Joseph M. , Taniguchi Cullen M. 
Published: May 2020

TPS4670 Background: Local progression causes up to 30% of deaths from pancreatic cancer (PC) and is also a significant source of morbidity. Stereotactic body radiotherapy (SBRT) offers the potential for improved therapeutic index over standard fractionation, but current regimens of 5 fractions of 5-7 Gy/fraction are constrained by nearby organ tolerance and offer only palliation without improving survival. Safe dose escalation may be necessary to improve SBRT efficacy. Avasopasem, a superoxide dismutase mimetic, selectively converts superoxide (O2•-) to hydrogen peroxide (H2O2) and oxygen. O2•-initiates normal tissue damage due to RT. Avasopasem is in a Phase 3 trial (NCT03689712) to reduce RT-induced oral mucositis in head and neck cancer, based on positive results in a randomized Phase 2 trial for that indication (Anderson, JCO 2019). Avasopasem improved the survival of mice receiving 8.5 Gy x 5 to the upper abdomen. Cancer cells are less tolerant to elevated H2O2, and more tolerant to elevated O2•-, than normal cells, and avasopasem demonstrated mechanism-dependent synergy with high dose-fraction RT in a human tumor xenograft with inducible expression of catalase (Sishc, AACR 2018). Thus, adding avasopasem to SBRT may increase both the efficacy and the safety of the latter. Methods: 48 patients with locally advanced PC, who have completed medically-indicated induction chemotherapy, are randomized 1:1 to placebo or avasopasem, 90 mg IV, prior to each of 5 consecutive daily (M-F) SBRT fractions. A phase I/II Late Onset Efficacy/ Toxicity tradeoff (LO-ET) based adaptive design adaptive model drives assignment of SBRT dose escalation in each arm based on a dual endpoint (Gr 3-4 GI toxicity or death; local stable disease or better) by 90 days post SBRT. The planned dose levels are 10, 11 and 12Gy x 5 fractions (BED10 = 100,112.5 and 132Gy, respectively) as an integrated boost to the gross tumor volume (GTV). Primary endpoint: Maximum tolerated dose of SBRT with avasopasem or placebo. Secondary endpoints progression-free survival, response rate, and acute (90 day) and late (12 month) radiation toxicity with avasopasem vs placebo. Exploratory correlative studies include ctDNA, tumor exome/transcriptome sequencing, and immune profiling. Clinical trial information: NCT03340974 .
Hcrn GU15-215: A phase II trial of atezolizumab (atezo) and bevacizumab (bev) in cisplatin-ineligible patients (pts) with advanced/unresectable urothelial cancer (UC).
Authors: Balar Arjun Vasant , Funt Samuel Aaron , Gupta Shilpa , Dudek Arkadiusz Z. , Boiles Alejandro Recio , Vaena Daniel A. , Kilari Deepak , Rosenberg Jonathan E. 
Published: May 2020

TPS5098 Background: Atezolizumab is a standard of care in selected cisplatin-ineligible pts with advanced UC. VEGF targeted therapies have activity in advanced UC and may lead to immune synergy when combined with anti-PD-1/L1 therapy. This phase II study is investigating the combination of bevacizumab and atezolizumab in untreated cisplatin-ineligible pts with advanced UC. Methods: HCRN GU15-215 (NCT03272217) is a phase 2, multicenter single arm trial to evaluate the efficacy and safety of atezolizumab and bevacizumab in pts with advanced UC. Cisplatin-ineligible pts (defined as any of estimated CrCl < 60 cc/min, Grade ≥ 2 hearing loss or neuropathy, ECOG PS 2 or solitary kidney) with untreated, histologically confirmed locally advanced or metastatic UC irrespective of PD-L1 expression status and with sufficient pre-treatment tumor tissue available for biomarker analysis are eligible. Pts who have received perioperative chemotherapy are eligible, however prior treatment with a checkpoint inhibitor is excluded. Pts with NYHA Class II or greater heart failure, significant cerebrovascular or cardiac disease within 3 months, uncontrolled HTN, persistent gross hematuria, and GI obstruction or perforation within 6 months are excluded. 70 pts will receive treatment with atezolizumab 1200 mg IV plus bevacizumab 15 mg/kg IV every 21 days. All pts will undergo an on-treatment biopsy before cycle 2 if safe and feasible. Peripheral blood samples and stool samples will be collected before treatment and on-treatment for immune-relevant biomarker analyses. Cross-sectional imaging will be performed every 9 weeks on therapy for the first 12 months and then every 12 weeks thereafter to assess for response. Subjects will be eligible to continue treatment until RECIST v1.1 defined progression or unacceptable toxicity for up to 24 months. The primary endpoint is overall survival rate at 1 year and will be analyzed by the Kaplan Meier method. Key secondary endpoints include objective response rate, duration of response, disease control rate, progression-free survival and safety and toxicity as defined by CTCAE version 4.0. Clinical trial information: NCT03272217 .
A randomized phase II study of nivolumab plus ipilimumab versus standard of care in previously untreated and advanced non-clear cell renal cell carcinoma (SUNIFORECAST).
Authors: Ahrens Marit , Escudier Bernard , Boleti Ekaterini , Grimm Marc-Oliver , Gross-Goupil Marine , Barthelemy Philippe , Gravis Gwenaelle , Bedke Jens , Ivanyi Philipp , Panic Andrej , Zschaebitz Stefanie , Negrier Sylvie , Mellado Begona , Biel Anika , Waddell Tom , Maroto Pablo , Retz Margitta , Boegemann Martin , Hartmann Arndt , Bergmann Lothar 
Published: May 2020

TPS5103 Background: Non-clear cell renal cell carcinomas (nccRCC) are a heterogeneous group of tumors accounting for approximately 25% of RCC patients (pts.). Since most clinical trials focus on clear-cell RCC (ccRCC) only, data on treatment strategies for nccRCC are limited. The combination of Nivolumab and Ipilimumab (IO/IO) has recently been approved for treatment in RCC showing a significant improvement in overall response rate (ORR), progression free (PFS), and overall survival (OS) in intermediate and high-risk pts. compared to sunitinib in a phase-III trial. Furthermore retrospective analysis in nccRCC patients have shown promising results for IO/IO as well in these entities. Methods: In this prospective randomized phase-II multicenter European trial adults with advanced or metastatic nccRCC without prior systemic therapy are eligible. Other key inclusion criteria include: available tumor tissue, Karnofsky > 70% and measurable disease per RECIST 1.1. All histological diagnoses are reviewed by a central pathologist. The study plans to randomize ~306 pts. stratified for papillary or non-papillary non-clear cell histology and by the International Metastatic RCC Database Consortium (IMDC) risk score. Pts. will be randomized 1:1 to either i) Nivolumab 3mg/kg intravenously (IV) plus Ipilimumab 1mg/kg IV every 3 weeks for 4 doses followed by Nivolumab fixed dose 240mg IV every 2 weeks or ii) standard of care therapy according to the approved schedule. Treatment will be discontinued in case of unacceptable toxicity or withdrawal of informed consent. Pts may continue treatment beyond progression, if clinical benefit is achieved and treatment is well tolerated. Primary endpoint is the OS rate at 12 months. Secondary endpoints include OS rate at 6 and 18 months, median OS, PFS, ORR and quality of life. The trial is in progress and 122 patients (78 pts with papillary, 37 pts with non-papillary histology) have been enrolled until now. Clinical trial information: NCT03075423 .