bluuebunny/crossref_metadata_2025 huggingface dataset:
TROPHY-U-01: A phase II open-label study of sacituzumab govitecan (IMMU-132) in patients with advanced urothelial cancer after progression on platinum-based chemotherapy and/or anti-PD-1/PD-L1 checkpoint inhibitor therapy.
Authors: Tagawa Scott T. , Petrylak Daniel Peter , Grivas Petros , Agarwal Neeraj , Sternberg Cora N. , Hernandez Chris , Siemon-Hryczyk Peggy , Goswami Trishna , Loriot Yohann
Published: May 2019

TPS3153

Background: Patients (pts) with advanced urothelial cancer (UC) who progress after checkpoint inhibitor (CPI) therapy (following failure of or ineligibility for platinum-based chemotherapy) have limited options. Trop-2 is an epithelial cell surface antigen overexpressed in UC (Avellini. Oncotarget 2017). Sacituzumab govitecan (SG) is an antibody-drug conjugate that targets Trop-2 and delivers the active metabolite SN38 of the topoisomerase I inhibitor irinotecan to tumor cells (Starodub. Clin Cancer Res 2015). In a phase 1/2 trial, pts with advanced cancers received SG on days 1 and 8 of a 21-day cycle. In the UC cohort, 45 evaluable pts received SG 10 mg/kg with a median of 2 (range 1–6) prior therapies. Objective response rate (ORR) was 31%; median duration of response was 12.9 mo. Grade ≥3 adverse events in ≥5% of pts were neutropenia/neutrophil count decreased (38%), anemia (13%), hypophosphatemia (11%), diarrhea (9%), fatigue (9%), and febrile neutropenia (7%). Median progression-free survival (PFS) was 7.3 mo and overall survival (OS) 16.3 mo (Tagawa 2019 ASCO Genitourinary Cancers Symposium). These results warrant further investigation in a dedicated phase 2 trial. Methods: TROPHY-U-01 (NCT03547973) is a single-arm, global phase 2 trial evaluating the antitumor activity of SG (10 mg/kg on days 1 and 8 of a 21-day cycle) in 140 pts with advanced UC and measurable disease. Patients are also required to have an Eastern Cooperative Oncology Group Performance Status score of 0 or 1 and creatinine clearance ≥30 mL/min. The pivotal cohort (Cohort 1: progression after both platinum chemotherapy and CPI) will enroll 100 evaluable pts in a Simon 2-stage design with > 90% power accounting for dropouts to exclude the null hypothesis or ORR < 12%; an exploratory cohort (Cohort 2: 40 pts) includes platinum-ineligible pts who progress after prior CPI. The primary objective is ORR per RECIST 1.1, assessed by central review. Secondary objectives include response duration, PFS, and OS. Adverse events, pharmacokinetics, and tissue correlates will also be assessed. Enrollment began August 2018. Clinical trial information: NCT03547973.
Express study: A trial in progress exploring the association between low level of genomic alteration and exceptional and unexpected response to targeted therapies in patients with solid tumors.
Authors: Le Saux Olivia , Italiano Antoine , Andre Fabrice , Filleron Thomas , Spaeth Dominique , Heudel Pierre-Etienne , Albiges Laurence , Bachelot Thomas Denis , Goncalves Anthony , Pierga Jean-Yves , Barlesi Fabrice , Boige Valerie , Lebbe Celeste , Mortier Laurent , Frenel Jean-Sebastien , Tredan Olivier , Jimenez Marta , Legrand François , Ferte Charles
Published: May 2019

TPS3159

Background: Molecular targeted agents (MTA) resulted in breakthroughs in selected niches. It is often assumed that tumor regression is consecutive to an oncogenic de-addiction effect. An emerging hypothesis suggests that genomic instability may be associated with poor response to MTA. Indeed, the accumulation of defects in multiple oncogenes or tumor suppressor genes may result in the activation of multiple oncogenic pathways. These multiple signaling would mechanically result in a limitation of the oncogenic de-addiction process. Another hypothesis, suggests that tumor heterogeneity could also be associated with poor outcome under MTA. Such heterogeneity could also result from the genomic instability, and be appraised by bioinformatic and functional approaches. In this study, we thought to investigate whether molecular profiles reflecting a low level of genomic alterations in genes causally implicated in oncogenesis could be associated with an exceptional response (ER) to MTA. Methods: This is an exploratory, multicenter, multicohort, prospective trial conducted in 264 adult patients, with advanced breast, lung, colorectal, ovarian, kidney cancers and melanoma, having presented an ER to an approved MTA. ER is defined using the definition chosen by the NCI which combines the three criteria: - complete or partial response, - lasting > 6 months, - and not expected in > 10% of the patients in this drug – organ situation. The primary objective is to assess whether ER can be associated with a low level of genomic instability in the tumor. Low genomic instability is defined by the presence of less than the 5th quantile of genomic alterations (mutations, amplifications, deletions) to be expected in the given tumor type as per TCGA database. For each tumor type, the null hypothesis H0: π = 0.05 will be tested, against the one-sided alternative hypothesis π > 0.05. For each of the 6 cohorts, a sample size of 44 patients is necessary to achieve 80% power at π = 15 with a one-sided level 5% test. Patients presenting an ER will be identified retrospectively, in a nationwide manner, then monthly reviewed and validated for inclusion by a panel of pathology experts. As of February 2019, 75 patients have been included. The identification of molecular traits associated with ER might serve the development of predictive classifiers for precision medicine. This study also represents a unique opportunity to better understand cancer biology. Clinical trial information: NCT02701907.
A phase I, first-in-human, dose-escalation and dose-expansion study of the multitarget kinase inhibitor TT-00420 in patients with advanced solid tumors.
Authors: Piha-Paul Sarina Anne , Wan Qunfang , Xiong Wendy , Peng Peng , Yang Xiaoju , Wu Henry , Ngo Brenda , Wu Frank
Published: May 2019

TPS3168

Background: Multi-target kinase inhibitors have gained increasing attention in the past few years due to their capabilities of simultaneously targeting several hallmarks of cancer. Triple negative breast cancer (TNBC), the most aggressive type of breast cancer, is a highly heterogeneous disease composed of several subtypes with distinct genomic profiles and activating pathways. TT-00420 is a multi-target kinase inhibitor that targets Aurora A/B, receptor tyrosine kinases (RTKs) involved in angiogenesis, and other kinases involved in tumor-associated inflammation and immune escape. Preclinical studies have established signs of efficacy for TT-00420 in TNBC. Targets inhibited by TT-00420 are among the key dysregulated pathways directly involved in the tumorigenesis of TNBC. TT-00420 is efficacious against most subtypes of TNBC cell lines. This anti-TNBC activity is confirmed in both cell line derived xenograft (CDX) and patient derived xenograft (PDX) TNBC model in vivo, in which TT-00420 is active both as first-line and second-line treatment. TT-00420 demonstrated good oral bioavailability and pharmacokinetic properties in mice, rats and dogs, and revealed mechanism-related but manageable toxicities. The IND approval of TT-00420 was granted by the FDA on Sept. 27, 2018. Methods: TT420X2101 is an open-label, first-in-human, multicenter, phase I study including a dose escalation portion in adult patients with advanced solid tumors, followed by dose expansion in two parallel cohorts, TNBC cohort (N=22) and selected advanced tumor (SAT) cohort (N=22). Adverse events will be evaluated per CTCAE v5.0 criteria, and tumor responses will be evaluated per RECIST v1.1 criteria. Patients aged 18-75 with measurable target lesion(s) at baseline and ECOG status of 0 or 1 will be enrolled. Patients are treated with a single daily oral administration of TT-00420 continuously for a 28-day cycle. Dose escalation is driven by Bayesian modeling with over-dose control. Approximately 66 patients are expected to be enrolled and treated in this study. Primary endpoint is to evaluate dose limiting toxicity (DLT) and identify maximum tolerate dose (MTD), if feasible, or establish recommended dose for Dose Expansion. Preliminary efficacy and PK profile will be evaluated as well. Enrollment is currently ongoing. Clinical trial information: NCT03654547.
Phase 1, open-label, dose-escalation study of M3814 + avelumab ± radiotherapy (RT) in patients (pts) with advanced solid tumors.
Authors: Bendell Johanna C. , Shafique Michael Rahman , Perez Bradford , Chennoufi Sarah , Beier Frank , Trang Ky , Antonia Scott Joseph
Published: May 2019

TPS3169

Background: DNA-dependent protein kinase (DNA-PK) regulates a key DNA damage response (DDR) pathway for double-strand break (DSB) repair. DNA-PK inhibition augments DNA DSB damage generated by many antitumor therapies, including RT. DNA damage and repair impact the interaction of tumors with the immune system; combining immune checkpoint inhibitors (CPIs) with RT + DDR-targeted agents may modulate the tumor immune microenvironment, enhancing responsiveness to CPIs. M3814 (small molecule selective DNA-PK inhibitor) has demonstrated monotherapy activity in several tumor cell lines, and M3814 + RT combined with avelumab (programmed death ligand 1 mAb) significantly delayed tumor growth vs either agent alone + RT in MC38 syngrafts. This study will evaluate the clinical utility of M3814 combined with avelumab ± RT in pts with advanced solid tumors. Methods: NCT03724890 is a 2-part first-in-man study in adult pts with advanced or metastatic solid tumors. Part A is enrolling pts with measurable/evaluable solid tumors (RECIST v1.1); Part B will enrol pts with primary or metastatic tumor(s) in the lung which is/are amenable to be irradiated. In Part A, M3814 will be given orally twice daily. In Part B, M3814 + TRT will be given once daily, 5 days/wk for 2 wk. In both parts, pts will receive avelumab iv once every 2 wk from Day 1 until disease progression/unacceptable toxicity. Part B will initiate once the Safety Monitoring Committee declares the first dose level of Part A to have acceptable safety/tolerability. Primary objectives are to define the recommended Phase 2 dose (RP2D) of M3814 when combined with avelumab (Part A) and with avelumab + TRT (Part B) via dose-limiting toxicities (DLTs) occurring during the first 3/4 (Part A/B) wk of treatment. Secondary objectives include safety/tolerability, pharmacokinetics, immunogenicity, preliminary antitumor activity (BOR, PFS, OS). Sample size for each part depends on the number of DLTs/dose levels for M3814; dose escalation will be based on a Bayesian logistic regression model with overdose control. Part A aims to include 6–24 pts (≤4 dose levels), Part B 6–18 pts (≤3 dose levels). Recruitment began in Dec 2018. Clinical trial information: NCT03724890.
A phase II study of TAS-102 in combination with ramucirumab in advanced, refractory gastric or gastroesophageal junction (GEJ) adenocarcinoma.
Authors: Mehta Rutika , Kim Richard D. , Shah Neal , Carballido Estrella M. , Kim Youngchul , Imanirad Iman , Kim Dae Won
Published: May 2019

TPS4149

Background: Patients with advanced gastric cancer experience a 5 year survival rate <10% even with multimodality therapy representing a clear unmet need for improved treatment. In advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma, ramucirumab (a monoclonal antibody against VEGFR2) has demonstrated clinical activity and has been approved as second line therapy in combination with paclitaxel with a response rate of 28% and absolute overall survival benefit of 8 weeks when compared to placebo. However, there are many patients that cannot tolerate paclitaxel due to prior exposure to oxaliplatin causing neuropathy. Therefore, novel combinations with ramucirumab, is highly desirable. TAS-102 is an oral cytotoxic agent with two active components; trifluridine (TFD) which inhibits tumor cell growth by being incorporated into DNA during DNA synthesis and tipiracil (TPI) which inhibits the metabolism of TFD, thereby prolonging its ability to exert effect. TPI also inhibits platelet derived endothelial cell growth factor which plays a key role with VEGF in tumor angiogenesis. The combination of a cytotoxic agent with an antiangiogenic agent has demonstrated a significant anticancer activity in multiple cancers. In a recent Phase III study, TAS-102 significantly prolonged overall survival as compared to best supportive care in patients with GEJ and gastric cancers that had received at least 2 prior lines of treatment. We hypothesize that a combination of TAS-102 and ramucirumab might increase efficacy without causing unmanageable toxicity. Methods: This is a single institutional phase II single arm two-stage design trial using the combination of TAS-102 and ramucirumab in advanced, refractory gastric or GEJ adenocarcinoma. Eligible patients include those with histologically confirmed gastric or GEJ adenocarcinoma that have received at least 1 prior line of treatment with performance status 0 or 1 and preserved organ function. Ramucirumab will be administered 8mg/kg every 2 weeks and TAS-102 at doses of 35 mg/m2 twice daily. Each cycle length will be 28 days. The primary endpoint is 6 month OS and secondary endpoints are safety, objective response rate and PFS. Fifteen patients will be enrolled in the first stage. If ≥ 7 of the 15 are alive at 6 months, an additional 10 patients will be enrolled in the second phase. Enrollment is currently ongoing. Clinical trial information: NCT03686488.
A multi-center phase Ib/II study of nal-irinotecan, 5-fluouracil and leucovorin in combination with nivolumab as second-line therapy for patients with advanced unresectable biliary tract cancer.
Authors: Sahai Vaibhav , Buckley Tyler Howard , Griffith Kent A. , Zalupski Mark
Published: May 2019

TPS4154

Background: Patients (pts) with advanced biliary tract cancers (BTC) have poor prognosis despite systemic chemotherapy, and treatment beyond first-line platinum doublet remains investigational. The immunomodulatory properties of conventional cytotoxic therapy, particularly in regard to the upregulation of PD-L1 expression rendering tumor cells more sensitive to T cell-mediated lysis and neoantigen production, rapid emergence of chemotherapy resistance, and known modest efficacy of single agent PD-1 antibody in BTC provide a rationale for combining chemotherapy and immunotherapy. This multi-center, phase Ib/II, single-arm study is designed to investigate the role of nal-irinotecan, 5-FU and leucovorin in combination with nivolumab as second-line therapy in pts with advanced BTC. Methods: Key eligibility criteria include histologically confirmed advanced, unresectable biliary carcinoma (intra- or extra-hepatic and gallbladder) with progression or intolerance of first-line systemic therapy (excluding irinotecan and PD-1/PD-L1 antibody), measurable disease per RECIST v1.1, ECOG PS 0-1, Child Pugh A or B7, and absence of autoimmune disease or chronic steroid use. Primary objective of the phase Ib portion is to determine the recommended phase 2 dose, and of the phase II portion is to evaluate the median progression-free survival. Secondary objectives include evaluation of objective response rate per immune related (ir)RECIST, median OS and safety in this patient population. Exploratory objectives include identification of biomarker predictors of response and mechanisms of resistance through serial biopsies and blood collection (pre, on and post therapy), including sequential whole exome/transcriptomic analysis and immune cell subset analysis (tissue and blood). Therapy includes nal-irinotecan 70 mg/m2, leucovorin 200 (dose level -1) or 400 mg/m2 (dose level 0), 5-fluouracil 2400 mg/m2 IV over 46 hours, and nivolumab 240 mg on day 1 every 2 weeks for 6 months. In the absence of disease progression, pts may continue therapy for up to 2 years. Accrual goal is 30 evaluable pts. Using a null hypothesis value of median PFS of 2.9 months, and an alternative hypothesis of 5.0 months, this ongoing study has > 80% power, with a two-sided alpha of 0.05 to identify treatment efficacy of study arm. Clinical trial information: NCT03785873.
Infigratinib versus gemcitabine plus cisplatin multicenter, open-label, randomized, phase 3 study in patients with advanced cholangiocarcinoma with FGFR2 gene fusions/translocations: The PROOF trial.
Authors: Javle Milind M. , Borbath Ivan , Clarke Stephen John , Hitre Erika , Louvet Christophe , Mercade Teresa Macarulla , Oh Do-Youn , Spratlin Jennifer L. , Valle Juan W. , Weiss Karl Heinz , Berman Craig , Howland Michael , Ye Yining , Cho Terry , Moran Susan , Abou-Alfa Ghassan K.
Published: May 2019

TPS4155

Background: Cholangiocarcinoma is the most common biliary tract malignancy with approximately 5,000–10,000 new cases annually in the USA. The fibroblast growth factor receptor (FGFR) family plays an important role in cholangiocarcinoma, with FGFR2 gene fusions detected in about 15% of patients with cholangiocarcinoma. Infigratinib is an ATP-competitive, FGFR1–3-selective oral tyrosine kinase inhibitor. First-line treatment with chemotherapy offers only modest benefit and more effective treatment options are needed. Based on preliminary response data of infigratinib in relapsed/refractory cholangiocarcinoma with FGFR2 fusions/translocations (Phase 2 Study CBJG398X2204), the PROOF trial is evaluating infigratinib versus gemcitabine + cisplatin in front-line patients with advanced cholangiocarcinoma with FGFR2 gene fusions/translocations. Methods: Patients with advanced/metastatic or inoperable cholangiocarcinoma are randomized 1:1 to oral infigratinib once daily for 21 days of a 28-day treatment cycle versus IV gemcitabine (1000 mg/m2) + cisplatin (25 mg/m2) on days 1 and 8 of a 21-day cycle. Treatment will continue until confirmed progressive disease by central review, intolerance, withdrawal of informed consent, or death. After 8 cycles of gemcitabine + cisplatin, patients can continue treatment if the investigator considers that they are deriving continued benefit. Patients on the gemcitabine + cisplatin arm who progress can cross-over to infigratinib. The primary endpoint is progression-free survival (PFS, per RECIST v1.1 central review). Secondary endpoints include overall survival, PFS (investigator determined), overall response rate, disease control rate, duration of response, and safety. Quality of life, PK and exploratory genetic alterations/biomarkers will also be measured. Current status: The study was initiated in February 2019 with planned enrollment of 350 patients with confirmed FGFR2 gene fusions/translocations. Clinical trial information: NCT03773302.
A randomized noncomparative phase II study of maintenance therapy with multiepitope vaccine Tedopi (OSE2101) ± nivolumab or FOLFIRI after induction chemotherapy (CT) with FOLFIRINOX in patients (Pts) with advanced pancreatic ductal adenocarcinoma (aPDAC) (TEDOPaM–PRODIGE 63 GERCOR D17-01 study).
Authors: Neuzillet Cindy , Hautefeuille Vincent , Lambert Aurélien , Garcia-Larnicol Marie-Line , Vernerey Dewi
Published: May 2019

TPS4160

Background: FOLFIRINOX (5-fluorouracil [5FU], folinic acid [FA], irinotecan [Iri], and oxaliplatin [Ox]) is a standard 1st-line treatment in fit Pts with aPDAC. Anti-PD-1/PD-L1 as single agents have failed in PDAC so far and new combination immunotherapies are needed. Tedopi (OSE2101) is a multiple neoepitope vaccine restricted to HLA-A2 positive Pts, targeting 5 tumor-associated antigens (CEA, HER2, MAGE2, MAGE3, TP53) that are frequently expressed in PDAC. This study aims to assess the efficacy and safety of Tedopi alone and in combination with anti-PD-1 nivolumab, or FOLFIRI as maintenance therapy in Pts with aPDAC after FOLFIRINOX induction CT. Methods: TEDOPaM - PRODIGE 63 is a 3-arm, Fleming 2-stage, open-label, randomized, non-comparative phase II study. 156 Pts with locally advanced or metastatic, pathologically proven PDAC; ECOG performance status 0-1; HLA-A2 genotype; controlled disease (objective response or stable disease) after 8 cycles of (modified) FOLFIRINOX; and adequate organ functions, are randomized (1:1:1, stratified on center, tumor stage, and best response to FOLFIRINOX) into 3 arms: Clinical trial information: NCT03806309. In Arms B and C, FOLFIRI is reintroduced at disease progression or unacceptable toxicity. Primary endpoint: overall survival rate at M12. Secondary endpoints: progression-free survival (CT-scan Q8W), duration of disease control, safety, objective response rate, RECIST v1.1/iRECIST comparison, HRQoL (EORTC QLQ-C30), Q-TWiST. An interim analysis is planned after inclusion of 20 Pts in each arm. Translational research will be performed on tumor tissue (initial FFPE biopsy and optional re-biopsy at inclusion): RNAseq (cancer and stroma), mutation burden, MMR status, immune infiltrates; and in blood (before and on-treatment): cytokine panel, PBMC phenotyping, vaccine-antigen specific T-cells, TCR repertoire, and extracellular vesicles, to explore biomarkers and pharmacodynamics effects of Tedopi ± nivolumab. Enrollment (12th Feb 2019): 1. ClinicalTrials Registration: NCT03806309.[Table: see text]
Adaptive Dose Escalation Trial of Stereotactic Body Radiation Therapy (SBRT) in combination with GC4419 in pancreatic cancer.
Authors: Holmlund Jon , Brookes Melissa , Colbert Lauren Elizabeth , Moningi Shalini , Bhutani Manoop S. , Katz Matthew H. G. , Varadhachary Gauri Rajani , Thall Peter F. , Herman Joseph M. , Taniguchi Cullen M.
Published: May 2019

TPS4164

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 5-7 Gy/fraction x 5 are constrained by nearby organ tolerance and offer only palliation without improving survival. Safe dose escalation is necessary to improve SBRT efficacy. GC4419, a superoxide dismutase mimetic, selectively converts superoxide (O2•-) to hydrogen peroxide (H2O2) and oxygen. O2•-initiates normal tissue damage due to RT. GC4419 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, ASCO 2018). GC4419 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 GC4419 demonstrated mechanism-dependent synergy with high dose-fraction RT in a human tumor xenograft with inducible expression of catalase (Sishc, AACR 2018). Thus, adding GC4419 to SBRT may increase both the efficacy and the safety of the latter. Methods: 48 patients with localized, unresectable PC without frank duodenal invasion, who have received 3+ cycles of induction chemotherapy, are to be randomized 1:1 to placebo or GC4419, 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 SBRT dose escalation in each arm based on a dual endpoint (Gr 3-4 GI toxicity or death ;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 GC4419 or placebo. Exploratory endpoints include change in tumor radiographic resectability, correlative studies (ctDNA, exosomal DNA, tumor exome/transcriptome sequencing, immune profiling). Supported by Galera Therapeutics, Inc. Clinical trial information: NCT03340974.
A randomized, phase II clinical trial of preoperative stereotactic body radiation therapy versus conventionally fractionated chemoradiation for resectable, borderline-resectable, or locally advanced type a pancreatic adenocarcinoma.
Authors: Hall William Adrian , Tsai Susan , Banerjee Anjishnu , George Ben , Ritch Paul S. , Thomas James P. , Paulson Eric , Christians Kathleen K. , Clarke Callisia , Dua Kulwinder , Khan Abdul H , Knechtges Paul , Hagen Catherine E , Evans Douglas B. , Erickson Beth
Published: May 2019

TPS4167

Background: There is growing consensus for the use of neoadjuvant therapy in patients with potentially operable pancreatic adenocarcinoma (PC). However, there is not consensus on the type and duration of chemotherapy or radiation therapy (RT) dose. Stereotactic body radiation therapy (SBRT) has gained popularity despite the absence of prospective data for its use in the preoperative setting. Furthermore, SBRT preoperatively has not been standardized. At present, there exists no randomized data comparing preoperative SBRT with conventionally fractionated concurrent chemo-RT. We designed this trial to examine differences between pre-op RT dose and fractionation schedules. Methods: This study is a prospective, randomized, two-arm, phase II clinical trial. Eligible patients must have cytologically confirmed PC and be deemed suitable for surgical resection with resectable, borderline resectable, or locally advanced type A disease, based on cross-sectional imaging. Before randomization patients are stratified by clinical node positivity, neoadjuvant chemotherapy, and stage of disease. Patients are then randomized to either 50.4 Gy over 28 fractions with concurrent weekly Gemcitabine vs SBRT to a total dose of 25-35 Gy over 5 fractions. The primary endpoint of the study is pathologic node positivity. We hypothesize that patients treated with neoadjuvant chemotherapy followed by conventionally fractionated chemo-RT will have a lower rate of pathologic node positivity as compared to those patients treated with neoadjuvant chemotherapy followed by SBRT. Secondary endpoints include patient reported quality of life, local recurrence, primary tumor pathologic response, margin status, surgical complications, MR based treatment response, and overall survival. We anticipate a node positivity rate of 37% when using preoperative chemotherapy followed by SBRT. We hypothesize that treatment with chemotherapy followed by conventionally fractionated chemo-RT will reduce the rate of node positivity to 17%. Using a one-sided Type I error rate of 0.1, approximately 88 total patients (44 per arm) provide an 80% power to detect the hypothesized difference in pathologic node positivity between the two arms. To address patient dropout, an additional 14 patients (about 15%) will be enrolled for a total target accrual of 102 patients. The trial opened in November 2018 and 8 of the planned 102 patients have been enrolled. Clinical trial information: NCT03704662.
Niraparib in metastatic pancreatic cancer after previous chemotherapy (NIRA-PANC): A phase 2 trial.
Authors: Kasi Anup , Chalise Prabhakar , Williamson Stephen K. , Baranda Joaquina Celebre , Sun Weijing , Al-Rajabi Raed Moh'd Taiseer , Saeed Anwaar , Kumer Sean , Schmitt Timothy , Foster Carolyn , Pessetto Ziyan Y. , Witek Malgorzata A. , Soper Steven A. , Godwin Andrew K.
Published: May 2019

TPS4168

Background: Attempts to improve therapy for patients with pancreatic adenocarcinoma with traditional chemotherapy have largely failed to meaningfully improve survival. Therefore, there is a critical need for identification of specific molecular changes that define prognosis and potentially guide therapy decisions. Defective DNA damage response pathways in pancreatic cancer represent a targeted opportunity for treatment. PARP inhibitors exert activity in tumor cells that may not be effectively able to repair initially single-stranded and cumulatively double-stranded DNA breaks and can have a heightened susceptibility in tumor cells over normal tissue. This concept is referred to as synthetic lethality. Niraparib is an orally available, potent, highly selective PARP-1 and -2 inhibitor. We are studying the efficacy of Niraparib in pancreatic cancer patients that harbor DNA repair defects. Methods: This study is funded by a research grant from TESARO. Pre-screening of patients to find biomarker positive patients is funded by KU Cancer Center. This is a phase II open label single arm trial in metastatic pancreatic cancer patients with germline or somatic mutations, either already known, or tested after consent to pre-screening tumor tissue analysis in BRCA1/2, PALB2, ATM, NBN, ATR, BRIP1, IDH1/2, RAD51, RAD51B/C/D, RAD54L, CDK12, BARD1, FAM175A, BAP1, CHEK1/2, GEN1, MRE11A, XRCC2, SHFM1, FANCD2, FANCA, FANCC, FANCG, RPA1, ARID1A. Patients are being treated with Niraparib 300mg or 200mg by mouth daily for 28 days (1 cycle = 28 days) (200mg dose is for participants whose baseline weight is < 77 kg [169.756 lbs] or baseline platelet count is < 150,000 µL). The primary objective is to assess antitumor efficacy of niraparib using Objective Response Rate per RECIST 1.1. Secondary objectives include PFS, OS, DCR, DOR, and safety. Eligible patients received > 1 line of therapy, no prior PARP inhibitor(s), have measurable disease, and ECOG PS 0-1. Accrual target enrollment of 18 patients over a period of 24 months with a study duration of 30 months. Correlative studies include assessment of pharmacokinetics, circulating tumor cells and storing samples for future research. The trial is currently enrolling. Clinical trial information: NCT03553004.
A phase 3 randomized study of neoadjuvant chemotherapy (NAC) alone or in combination with nivolumab (NIVO) ± BMS-986205 in cisplatin-eligible muscle invasive bladder cancer (MIBC).
Authors: Sonpavde Guru , Necchi Andrea , Gupta Shilpa , Steinberg Gary D. , Gschwend Juergen E. , Van Der Heijden Michiel Simon , Garzon Nathalie , Elegbe Ayanbola , Raybold Bradley , Liaw Danny , Rutstein Mark , Galsky Matt D.
Published: May 2019

TPS4587

Background: Immuno-oncology (IO) therapies have revolutionized the treatment (tx) of pts with advanced bladder cancer (advBC). For pts with cisplatin-eligible MIBC, the recommended tx regimen is cisplatin-based NAC prior to radical cystectomy (RC). However, since only ≈ 30% of pts achieve a pathologic complete response (pCR) translating to improved long-term outcomes with approved regimens, new therapies are needed. PD-L1 expression is associated with aggressive BC and has been shown to increase in BC after NAC, suggesting that the PD-1/PD-L1 axis is a valid therapeutic target. Additionally, expression of indoleamine 2,3-dioxygenase (IDO) is higher in BC than in normal bladder tissue and is associated with advanced disease and poor clinical outcome. BMS-986205, a selective, potent, once-daily oral IDO1 inhibitor that works early in the IDO1 pathway to reduce kynurenine production, has demonstrated clinical activity in combination with NIVO (anti–PD-1) in pts with IO tx–naive advBC who had ≥ 1 prior line of therapy (ORR, 37%). Taken together, these data provide a rationale for investigating NAC + NIVO + BMS-986205 in MIBC. Here we describe a randomized, partially blinded, phase 3 study evaluating the efficacy and safety of NAC ± NIVO ± BMS-986205 followed by RC and continued IO tx in pts with MIBC (NCT03661320). Methods: Pts aged ≥ 18 years with previously untreated MIBC (clinical stage T2-T4a, N0, M0), creatinine clearance ≥ 50 mL/min, and predominant UC histology who are eligible for cisplatin-based NAC and RC will be enrolled. Pts with evidence of positive lymph node; metastatic BC; or prior systemic therapy, radiotherapy, or surgery for BC other than TURBT are not eligible. Pts will be randomized to receive NAC (gemcitabine/cisplatin; arm A), NAC + NIVO + oral placebo (arm B), or NAC + NIVO + BMS-986205 (arm C) followed by RC (all arms); arms B and C will receive continued IO tx. Primary endpoints include pCR after neoadjuvant tx and event-free survival (arms C vs A; arms B vs A). Secondary endpoints are overall survival and safety. This global study in 28 countries began accrual in Nov 2018 and has a target enrollment of 1200 pts. Clinical trial information: NCT03661320.
ALBAN: An open label, randomized, phase III trial, evaluating efficacy of atezolizumab in addition to one year BCG (bacillus Calmette-Guerin) bladder instillation in BCG-naive patients with high-risk nonmuscle invasive bladder cancer (AFU-GETUG 37).
Authors: Roupret Morgan , Neuzillet Yann , Bertaut Aurelie , Pignot Geraldine , Houede Nadine , Champiat Stephane , Nénan-Le Ficher Soazig , Chausson Maggy , Loriot Yohann
Published: May 2019

TPS4589

Background: The majority of patients with bladder cancer are diagnosed with non-muscle invasive bladder cancer (NMIBC). Trans-urethral resection of bladder tumor (TURBT) followed by Bacillus Calmette-Guerin (BCG) therapy is the standard of care for most patients with high-risk NMIBC, although clinical outcomes remain poor. Data from preclinical and clinical studies suggest that programmed death-ligand 1 PD-L1 inhibition may enhance antitumor activity of BCG therapy. Atezolizumab, an anti–PD-L1 monoclonal antibody, is approved in the United States and the European Union as monotherapy when patients are ineligible for cisplatin or after prior platinum therapy. This approval was based on the results from phase II and III IMvigor210/211 trials. We have designed ALBAN, a phase III trial to evaluate the efficacy and safety of atezolizumab given in combination with BCG versus BCG alone in patients with high-risk NMIBC. Methods: In 30 centers in France, ALBAN (NCT03799835) is enrolling patients with histologically documented NMIBC who have not received prior BCG therapy. Eligible patients have to have high-risk features (T1 staging, high grade, or in situ carcinoma), ECOG PS 0-2, and a tissue sample for PD-L1 testing (by Ventana SP142 immunohistochemistry assay). Patients are randomized 1:1 to: (Arm A) BCG alone (six weekly instillations of BCG, followed by three weekly maintenance instillations at 3, 6, 12 months), or (Arm B) atezolizumab (1200 mg; IV; q3w for up to 1 year) combined with BCG given as in arm A. Treatment with atezolizumab and BCG are continued in the absence of unacceptable toxicity, for 1 year. The primary endpoint is recurrence-free survival in the intent-to-treat population. Secondary efficacy endpoints include overall survival, PFS, complete response, disease worsening, and quality of life. Safety, biomarkers, and other exploratory endpoints will also be evaluated. Enrollment began in December 2018 with a target of 614 pts. Clinical trial information: NCT03799835.
A phase III, randomized, open label, multicenter, global study of first-line (1L) durvalumab in combination with standard of care (SOC) chemotherapy and durvalumab in combination with tremelimumab and SOC chemotherapy versus SOC chemotherapy alone in patients with unresectable locally advanced or metastatic urothelial cancer (UC).
Authors: Galsky Matt D. , Necchi Andrea , Sridhar Srikala S. , Ogawa Osamu , Angra Natasha , Hois Stephan , He Philip , Ghiorghiu Dana C. , Bellmunt Joaquim
Published: May 2019

TPS4590

Background: Despite high response rates to 1L SoC for locally advanced or metastatic UC chemotherapy (gemcitabine + cisplatin or gemcitabine + carboplatin for patients who are cisplatin-ineligible [poor performance status, impaired renal function, comorbidities]), most patients experience disease progression. Novel strategies such as combining chemotherapy and immunotherapy offer hope for improving clinical outcomes. Durvalumab is a selective, high affinity, engineered human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD80. Tremelimumab is a human IgG2 mAb directed against CTLA-4. The mechanisms of action of PD-1 and CTLA-4 are nonredundant, so targeting both checkpoint pathways may have additive or synergistic efficacy compared with monotherapy. Studies of platinum-based chemotherapy combined with checkpoint blockade in other tumor types have yielded improved efficacy with acceptable safety and support exploration of this approach for 1L locally advanced or metastatic UC. Methods: NILE (NCT03682068) is a randomized, open-label, multicenter, global trial that will enroll approximately 1265 patients with histologically or cytologically documented, unresectable, locally advanced, or metastatic transitional cell carcinoma of the urothelium. Patients will be randomized (1:1:1) to durvalumab + SoC chemotherapy, durvalumab + tremelimumab + SoC chemotherapy, or SoC chemotherapy as 1L therapy. Primary endpoints are progression-free survival using blinded independent central review assessments per RECIST 1.1 and overall survival (OS). Secondary endpoints include objective response rate, OS at 24 months, proportion of patients alive and progression free at 12 months, duration of response, disease control rate, time from randomization to second progression, and health-related quality of life. Safety, pharmacokinetics, immunogenicity, and biomarkers will also be assessed. The study opened for enrollment in September 2018. 2019 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2019 Genitourinary Cancers Symposium. Clinical trial information: NCT03682068.
A phase III, randomized, open label, multicenter, global study of efficacy and safety of durvalumab in combination with gemcitabine+cisplatin (G+C) for neoadjuvant treatment followed by durvalumab alone for adjuvant treatment in muscle-invasive bladder cancer (MIBC) (NIAGARA).
Authors: Powles Thomas , Meeks Joshua J , Galsky Matt D. , Van Der Heijden Michiel Simon , Nishiyama Hiroyuki , Al-Ahmadie Hikmat , Gupta Ashok Kumar , Ye Jiabu , Donegan Sarah E. , Ghiorghiu Dana C. , Ferro Salvatore , Catto James WF
Published: May 2019

TPS4592

Background: Management of MIBC includes both surgery and systemic therapy. Neoadjuvant, cisplatin-based combination chemotherapy has demonstrated improved pathologic complete response (pCR), event-free survival (EFS), and OS compared with radical cystectomy alone. Many patients still develop recurrence, including progression to metastasis. Novel strategies such as combining chemotherapy and immunotherapy in a neoadjuvant setting and consolidating response post cystectomy in the adjuvant setting may improve clinical outcomes. Durvalumab is a selective, high affinity, engineered human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD80. PD-L1 inhibition with durvalumab, in combination with a standard neoadjuvant regimen (G+C), may improve immune-mediated antitumor response and increase the rates of pathologic responses and long-term survival. Methods: NIAGARA (NCT03732677) is a Phase 3, randomized, open-label, multicenter, global study that will enroll ~1050 patients randomized (1:1) to durvalumab and G+C combination (Arm 1) or G+C (Arm 2) as neoadjuvant chemotherapy prior to radical cystectomy. Following radical cystectomy and during adjuvant therapy, patients in Arm 1 will receive durvalumab monotherapy for 8 cycles (8 months); patients in Arm 2 will receive no adjuvant treatment. Patients with resectable MIBC (clinical stage T2N0M0-T4aN0M0) with transitional cell histology planning to undergo a radical cystectomy will be included. Primary endpoints are pCR rates at time of cystectomy following neoadjuvant treatment and EFS. Secondary and exploratory endpoints include proportion of patients who achieve pathologic response <P2 (stages Pa, P1, and carcinoma in situ) at time of cystectomy following neoadjuvant treatment, EFS at 24 months, metastasis-free survival, proportion of patients who undergo cystectomy, and OS at 5 years. Safety, patient-reported outcomes, pharmacokinetics, immunogenicity, and biomarkers will also be assessed. Enrollment opened in Dec 2018. Clinical trial information: NCT03732677.
EV-103: Enfortumab vedotin plus pembrolizumab and/or chemotherapy for locally advanced or metastatic urothelial cancer.
Authors: Hoimes Christopher J. , Rosenberg Jonathan E. , Petrylak Daniel Peter , Carret Anne-Sophie , Melhem-Bertrandt Amal , Flaig Thomas W.
Published: May 2019

TPS4593

Background: PD-(L)1-targeted immune checkpoint inhibitors (CPIs), such as pembrolizumab (P), are approved for patients (pts) with locally advanced or metastatic urothelial cancer (la/mUC) who progress after platinum, are ineligible for first-line (1L) cisplatin (PD-L1 positive), or are ineligible for 1L platinum. The ORR for CPI in all treated pts is ~25%, and a combination approach may provide additional benefit. Enfortumab vedotin (EV), an investigational antibody-drug conjugate, delivers the microtubule-disrupting agent monomethyl auristatin E to cells expressing Nectin-4, found in 97% of mUC pt samples (Petrylak ASCO 2017). In a phase 1 study (NCT02091999), EV (1.25 mg/kg) was generally well tolerated with a confirmed ORR of 43% in 112 mUC pts (Rosenberg ASCO-GU 2019). These encouraging results, with the potential for an enhanced immune response, suggest that EV+P may improve response rates and extend response durability. Methods: EV-103, a phase 1b trial for non–resectable la/mUC pts with no prior CPI, added an additional 4 cohorts (Parts 2 and 3) in an Oct 2018 amendment. It is now expected to enroll ~159 pts. Dose escalation pts (EV+P, 1L or 2L) must be ineligible for 1L cisplatin-based chemotherapy or have disease progression during/following treatment with ≥1 platinum-containing regimen. Dose expansion (Part 1) will evaluate EV+P in 1L (Cohort A) and 2L settings (Optional Cohort B). Part 2 will evaluate 1L EV+cisplatin (Cohort D), 1L EV+carboplatin (Cohort E), and 1L or 2L EV+gemcitabine (Optional Cohort F). Part 3 (Cohort G) will evaluate 1L EV+P+cisplatin or carboplatin, depending on pts cisplatin-eligibility. In all cohorts, pts receive EV on Days 1 and 8 of each 3-week cycle. In combination therapies, pts receive P, cisplatin, and carboplatin on Day 1 or gemcitabine on Days 1 and 8 of each cycle. The primary objective is to assess the safety/tolerability of EV+P and/or chemotherapy. Secondary objectives are establishing EV recommended dose for combination therapies, assessing ORR per RECIST for all cohorts and per iRECIST for therapies with pembrolizumab, as well as assessing disease control rate, duration of response, PFS, OS, PK, and biomarkers. The study opened Oct 2017. Clinical trial information: NCT03288545.
PDIGREE: An adaptive phase 3 trial of PD-inhibitor nivolumab and ipilimumab (IPI-NIVO) with VEGF TKI cabozantinib (CABO) in metastatic untreated renal cell cancer (Alliance A031704).
Authors: Zhang Tian , Ballman Karla V. , Choudhury Atish Dipankar , Chen Ronald C. , Watt Colleen , Wen Yujia , Zemla Tyler , Emamekhoo Hamid , Gupta Shilpa , Morris Michael J. , George Daniel J. , Choueiri Toni K.
Published: May 2019

TPS4596

Background: First-line treatment of mRCC has rapidly changed to include IPI-NIVO or CABO, with clinical benefit of each based on the Checkmate 214 and CABOSUN trials. Combination immunotherapy with VEGF therapies have shown benefit in the JAVELIN 101 and KEYNOTE 426 trials over sunitinib. It is yet unclear which patients (pts) benefit most from combination immunotherapy-VEGF inhibitors, and the optimal sequence of drugs. Methods: In an adaptive, randomized, multicenter, phase 3 trial (Alliance A031704, PDIGREE), pts will start treatment with induction IPI 1mg/kg and NIVO 3mg/kg intravenously (IV) once every 3 weeks. Key inclusion criteria include clear cell mRCC, IMDC intermediate or poor risk, Karnofsky performance status >70, and no prior treatments for mRCC. Based on 3-month radiographic assessment (after completing IPI-NIVO combination), pts with complete responses (CR) will undergo maintenance NIVO 480mg IV every 4 weeks, pts with progression of disease (PD) will switch to CABO 60mg oral daily, and pts with non-CR/non-PD will be randomized to NIVO 480mg IV every 4 weeks versus NIVO 480mg IV every 4 weeks with CABO 40mg oral daily. Randomization will be stratified by IMDC risk criteria and presence of bone metastases. The primary endpoint of the study is overall survival (OS). We hypothesize that 3-year OS rate will improve to 70% for NIVO-CABO compared to 60% for NIVO alone; to achieve 85% power with a two-sided alpha of 0.05 and exponential distribution, 696 patients will be randomized. Accounting for 30% patients with either CR or PD, and 5% dropout from toxicity, up to 1046 pts will be enrolled. Key secondary endpoints include PFS, 12-month CR rate, ORR based on RECIST 1.1 and irRECIST criteria, and toxicity profiles. Quality of life will be assessed based on the FKSI-19, PROMIS-fatigue, and EQ5D-5L questionnaires. Biomarkers associated with CR and association of IL-6 with treatment benefit will be assessed. Other tissue-based and plasma-based biomarkers are planned. Enrollment will begin this year. Support from UG1CA189823, U24CA196171; https://acknowledgments.alliancefound.org . Clinical trial information: NCT03793166.
TALAPRO-2: Part 2 (P2) of the placebo-controlled phase 3 study of talazoparib (TALA) with enzalutamide (ENZA) in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Agarwal Neeraj , Shore Neal D. , Dunshee Curtis , Karsh Lawrence Ivan , Sullivan Beth , Di Santo Nicola , Elmeliegy Mohamed , Lin Xun , Quek Ruben G.W. , Czibere Akos Gabor , Fizazi Karim
Published: May 2019

TPS5092

Background: ENZA is approved to treat men with CRPC. TALA is a poly(ADP-ribose) polymerase (PARP) inhibitor that inhibits PARP1/PARP2 and traps PARP on DNA, preventing DNA damage repair (DDR), and causing cell death in BRCA1/2-mutated cells. TALA is approved in the US to treat germline BRCA1/2-mutated HER2- locally advanced/metastatic breast cancer. A combination of TALA with ENZA in mCRPC may improve clinical outcomes. TALAPRO-2 (NCT03395197) is a 2-part study to evaluate the efficacy, safety, pharmacokinetics and (patient) pt-reported outcomes of the combination treatment. The focus here is on P2 of TALAPRO-2. Methods: Approximately 860 pts are planned to be enrolled in P2 from multinational sites. Pts are aged ≥18 years, have asymptomatic/mildly symptomatic mCRPC, Eastern Cooperative Oncology Group performance status ≤1, no brain metastases, and have not received taxanes/novel hormonal therapy (NHT). P2 is a randomized double-blind study that will evaluate safety, efficacy, and pt-reported outcomes of TALA (0.5 mg QD) + ENZA (160 mg QD) vs placebo + ENZA (160 mg QD). Pts will be randomized to 1 of 2 treatment groups: TALA + ENZA, or matching placebo + ENZA. Randomization will be stratified by prior treatment with NHT for castration-sensitive prostate cancer (CSPC) or prior treatment with taxane-based chemotherapy for CSPC (yes/no) and DDR mutation status (deficient vs. nondeficient/unknown). The primary endpoint is radiographic progression-free survival (rPFS), defined as time to progression in soft tissue per RECIST v1.1 or in bone per PCWG3 criteria or death. The key secondary endpoint is overall survival (OS). Efficacy will be assessed by radiography every 8 weeks up to week 25 and every 8-12 weeks thereafter. The analyses of rPFS will be compared between TALA in combination with ENZA and placebo in combination with ENZA by using a 1-sided stratified log-rank test. OS will be evaluated separately in the all comers and the DDR-deficient populations. Pt recruitment is ongoing. Results: n/a. Conclusions: n/a. Clinical trial information: NCT03395197.