bluuebunny/crossref_metadata_2025_split huggingface dataset:
A single-arm phase II study of ADT with PD-1 blockade and docetaxel in men with metastatic hormone-sensitive prostate cancer.
Authors: Hawley Jessica , Bowler Timothy Geoffrey , Guo Xinzheng Victor , Dallos Matthew , Lim Emerson A. , Hu Jianhua , Lowy Israel , Drake Charles G. , Stein Mark N. 
Published: February 2020

TPS271 Background: Overall survival of men with de novo metastatic, hormone-sensitive prostate cancer (mHSPC) is improved by treatment intensification with docetaxel and hormone therapy compared to androgen deprivation therapy (ADT) alone. However, castration-resistant prostate cancer (CRPC) invariably develops. Reprogramming the immune system in the mHSPC setting is a novel approach to delay progression to CRPC. In the hormone-sensitive setting, ADT induces a robust and functional immune infiltrate into the tumor microenvironment (TME), with upregulation of immune checkpoint molecules (PD-1 and PD-L1). These effects diminish as castration resistance emerges. Docetaxel causes immunogenic tumor cell death and stimulates antigen presentation. We hypothesize that leveraging the immunogenic effects of ADT with PD-1 blockade and docetaxel will promote antitumor immune killing and improve clinical outcomes. Methods: This is an open-label, single-arm, phase II study of ADT, cemiplimab, and docetaxel in patients with de novo mHSPC (N=20). Subjects will receive continuous ADT, followed by a two-cycle lead-in of cemiplimab prior to the standard six cycles of docetaxel. Cemiplimab will be continued q3weeks for one year or until disease progression or intolerable side effect. The primary endpoint is undetectable PSA at 6 months. Secondary endpoints include time to development of CRPC and radiographic response. Subjects will be monitored for toxicity using a Bayesian adaptive study design with an early stopping rule for toxicity. Correlative studies will determine the effects of ADT and PD-1 blockade on the TME by comparing baseline and on-treatment biopsies using transcriptional data from single-cell RNA-sequencing and standard immunohistochemistry (IHC). Serum samples will also be collected to quantify the effects of therapy on circulating levels of immunosuppressive cytokines. The study is open with 3 patients currently enrolled at the time of submission. Clinical trial information: NCT03951831.
A phase Ib/II, open-label, platform study evaluating the efficacy and safety of AB928-based treatment combinations in participants with metastatic castrate-resistant prostate cancer.
Authors: Wise David R. , Gardner Olivia , Gilbert Houston N. , Rieger Aimee , Paoloni Melissa Constance , Krishnan Kartik 
Published: February 2020

TPS272 Background: The tumor microenvironment contains high levels of immunosuppressive adenosine, which binds to and activates the A2a and A2b receptors (R) on immune cells, resulting in an ineffective anti-tumor immune response. Extracellular adenosine is primarily produced by the enzyme CD73. In prostate cancer (PC), the activity of prostatic acid phosphatase produces additional adenosine. AB928 is the first clinical-stage small molecule dual antagonist of both A2aR and A2bR, which is highly potent, pharmacodynamically active, and has been well tolerated in dose escalation studies as a single agent or in combination with chemo/immunotherapy. Targeting the adenosine pathway in combination with standard of care regimens may have a more profound effect on activating and inducing sustained anti-tumor immunity. Methods: This Phase 1b/2, open-label, multi-cohort platform study will evaluate the efficacy and safety of AB928 combination therapy in participants with metastatic castrate resistant PC (mCRPC). Each cohort will independently assess AB928 plus AB122 (anti-PD-1 antibody) in combination with standard of care (SOC; enzalutamide, docetaxel) or AB928 plus AB680 (CD73 inhibitor) with or without AB122. Cohort eligibility is informed by prior treatment history. In Ph1b, up to 15 participants will receive investigational products at the single-agent recommended dose with SOC per label guidance. Provided safety and activity stopping criteria are not met, further accrual will proceed in Ph2 and, depending on treatment cohort, may involve randomization to enzalutamide or docetaxel; crossover to experimental therapy will be allowed following progression on control treatment. Investigator-assessed antitumor response (radiologic, prostate specific antigen) will follow PCWG3 criteria. Conclusions: This Ph1b/2 study is the first to target the adenosine axis using a dual A2aR/A2bR antagonist (AB928) together with a small molecule CD73 inhibitor (AB680), anti-PD-1 antibody (AB122), and SOC for mCRPC. Study enrollment is proceeding in the United States; results will be shared in upcoming scientific conferences.
A phase II study of sEphB4-HSA in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Burns Michael C. , Sagar Vinay , Jovanovic Borko , Morgans Alicia K. , VanderWeele David James , Quinn David I. , Stadler Walter Michael , Abdulkadir Sarki , Hussain Maha H. A. 
Published: February 2020

TPS274 Background: The EphB4/EphrinB2 pathway is a promising therapeutic target for patients with mCRPC. EphB4 expression is increased in prostate cancer tissue and cell lines, and retained in castration resistant states. EphB4 crosstalks with the PI3K/AKT and MAPK pathways to regulate cell survival and proliferation, and its interaction with the transmembrane ligand EphrinB2 leads to T-cell suppression and immune evasion. A soluble decoy EphB4 receptor-human serum albumin fusion protein (sEphB4-HSA) binds to EphrinB2 and blocks interaction with the cell surface EphB4 receptor to promote immune infiltration and induce tumor cell death. Here we report an ongoing phase II study exploring the preliminary efficacy and safety of sEphB4-HSA in patients with progressive disease after frontline therapy for mCRPC. Methods: Eligibility criteria include mCRPC with disease progression after second generation AR targeted therapy (i.e., abiraterone or enzalutamide), ECOG PS ≤ 2, and adequate renal, hepatic and hematological functions. Pts having received 4 or more prior treatment therapies for mCRPC are excluded. The primary objective is efficacy as reflected by PSA response using PCWG3 criteria. Secondary objectives include safety and tolerability by CTCAE v 5.0, time to PSA progression, overall response by RECIST 1.1 and PCWG3 (bone) criteria, and rPFS. Translational endpoints include expression of EphB4 and EphrinB2 in metastatic tumor samples by immunohistochemistry and correlation with alterations in MYC, PTEN/PI3K, AR, and p53 pathways. sEphB4-HSA is administered as IV infusion over 60 min every 14 days with spacing to every 21 days after 6 cycles. Therapy will continue till disease progression, unacceptable toxicity, treatment delay ≥4 weeks, or patient withdrawal. Preliminary efficacy will be assessed using PSA response rate (PR and CR) with a Simon two stage minimax trial design assuming the undesirable overall response rate (null hypothesis) to be approximately 10% or less, and the alternate hypothesis suggesting success to be approximately 30% or more. Toxicity will be evaluated by the DSMC after the first stage including 15 patients. If 2 or more respond, then an additional 10 patients will be added. Clinical trial information: NCT04033432.
Phase II trial of atezolizumab plus chemotherapy after progression on single-agent PD-1 or PD-L1 inhibitor in cisplatin ineligible patients with advanced urothelial carcinoma HCRN GU17-295.
Authors: Adra Nabil , Hauke Ralph J. , Kaimakliotis Hristos Z. , Gulati Shuchi , Hashemi Neda , Pili Roberto 
Published: February 2020

TPS587 Background: Patients (pts) with cisplatin ineligible metastatic urothelial carcinoma (mUC) who progress after first-line PD1/PDL1 inhibition have limited treatment options. The concept of maintenance therapy with targeted agents and adding onto it at time of progression is a proven effective strategy. Preclinical data indicate that carboplatin+gemcitabine have immunomodulatory effect to potentially augment immune response. We hypothesize that in pts with cisplatin ineligible mUC, the use of atezolizumab+chemotherapy after progression on single-agent PD1/PDL1 inhibitor will result in clinical benefit. Methods: Multi-center, single arm, open label phase 2 trial of atezolizumab+carboplatin+gemcitabine in pts with cisplatin ineligible mUC. Eligible pts are adults with mUC (mixed histology allowed) who progressed after first line PD1/PDL1 inhibitor. Pts should be cisplatin ineligible based on consensus criteria. Neoadjuvant/adjuvant chemotherapy completed ≥12 months prior to enrollment is allowed. Treatment with atezolizumab will continue until disease progression or unacceptable toxicity while carboplatin+gemcitabine can be stopped after 4-6 cycles. Primary objective is progression-free survival per RECIST and secondary objectives are overall response rate, clinical benefit rate, and overall survival (OS). Exploratory endpoints include to compare OS of atezolizumab+carboplatin+gemcitabine in this trial compared to a virtual control arm of carboplatin+gemcitabine in mUC after progression on first-line PD1/PDL1 inhibitors. Other exploratory endpoints include to compare PD-L1 status at time of diagnosis and at time of enrollment (after progression on PD1/PDL1 inhibitor). Using an alternate hypothesis that atezolizumab+carboplatin+gemcitabine will have a median PFS of 9 months compared to historical control of 5 months with a platinum regimen in 2nd line setting, we plan to enroll 33 patients. This study is currently enrolling pts. A protocol amendment is under way that will allow pts with prior platinum-based chemotherapy to enroll on this trial. Clinical trial information: NCT03737123.
Tislelizumab plus cisplatin/carboplatin and gemcitabine versus placebo plus cisplatin/carboplatin and gemcitabine in Chinese patients with advanced urothelial carcinoma: A phase III trial in progress.
Authors: BI Feng , Li Han-Zhong , Zhu Shaoxing , Zou Qing , Tang Jia , Zhang Wei , Ye Dingwei 
Published: February 2020

TPS588 Background: Platinum-based chemotherapy is standard first-line treatment for patients with advanced urothelial carcinoma (UC). Checkpoint inhibitors (ie, anti-PD-1 antibodies) are first-line treatment options for cisplatin-ineligible patients. Combining anti-PD-1 treatment with chemotherapy may have synergistic effects and has demonstrated antitumor activity in a variety of tumor types. Tislelizumab, an investigational monoclonal antibody with high affinity and specificity for PD-1, was engineered to minimize binding to FcγR on macrophages in order to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy. Previous reports showed tislelizumab, as a single agent or combined with chemotherapy, was generally well tolerated and had antitumor activity in patients with advanced UC. Methods: This phase 3, randomized, double-blind, placebo-controlled study (NCT03967977) will compare the efficacy and safety/tolerability of tislelizumab vs placebo, both in combination with cisplatin/carboplatin and gemcitabine. Adult Chinese patients (n≈420) with histologically confirmed, inoperable, locally advanced/metastatic UC who are eligible for (but have not received) systemic anticancer therapy for advanced UC, therapies targeting PD-1/L1, or other antibody/drug targeting T-cell costimulation or checkpoint pathways, will be randomized 1:1 to receive tislelizumab (200 mg Q3W) or placebo (Q3W) plus gemcitabine (1000 mg/m2 administered on Day 1 and 8 of each 3-week cycle) and cisplatin (70 mg/m2) or carboplatin (AUC 4.5) administered on Day 1 or 2 of each 3-week cycle. Patients must provide a fresh biopsy or archival tissue for central assessment of PD-L1 expression. Overall survival (OS) is the primary endpoint. Investigator-assessed overall response rate (RECIST v1.1), duration of response, progression-free survival, and OS rates at Year 1 and 2 are secondary endpoints. Safety/tolerability, assessed by monitoring incidence and severity of adverse events, and health-related quality-of-life measures will also be evaluated. Clinical trial information: NCT03967977.
FIDES-02, a phase Ib/II study of derazantinib (DZB) as monotherapy and combination therapy with atezolizumab (A) in patients with surgically unresectable or metastaticurothelial cancer (UC) and FGFR genetic aberrations.
Authors: Chaudhry Arvind , Sternberg Cora N. , De Santis Maria , Bellmunt Joaquim , Necchi Andrea , Powles Thomas , Cantero Frederique , Marszewska Michalina , Grzyb Michal , McSheehy Paul , Braun Stephan , Siefker-Radtke Arlene O. 
Published: February 2020

TPS590 Background: Deregulation of the FGFR signaling pathway is implicated in various cancers. In UC, FGFR genetic aberrations include FGFR1/2/3 mutations (M) and, less commonly, fusions (F), while the role of amplifications warrants further research. Prognosis of UC patients is overall poor and treatment options are limited. DZB is an oral small-molecule FGFR1/2/3 and CSF1R kinase inhibitor, which demonstrated promising antitumor activity in preclinical studies, including FGFR-driven patient-derived xenograft models. Preclinical data show that DZB reduced CSF1-stimulated CSF1R phosphorylation in macrophages, with a maximal effect similar to the CSF1R inhibitor BLZ945, suggesting DZB could have an effect on tumor-associated macrophage regulation. Thus, DZB+A (PD-L1 immune-checkpoint blockade [ICB]) is a rationale combination for immunogenic tumors like UC. FIDES-02 is a multicenter, multicohort open-label Phase 1b/2 study evaluating the effect of DZB as monotherapy and DZB+A combination. Methods: The study evaluates 300 mg DZB p.o. daily or DZB+A (1200 mg i.v.) in UC patients with FGFR1-3 M/F per liquid or tissue biopsy-based NGS. Cohort 1 (C1) enrolls pts after one or more standard chemotherapy ± ICB regimens (Phase 2; treatment: DZB); C2 enrolls patients with any advanced solid tumor, any FGFR status, any prior treatment (Phase 1b; for RP2D of DZB+A); C3 enrolls first-line patients with cisplatin-ineligible, PD-L1-low UC (Phase 2; DZB v DZB+A); C4 enrolls UC patients resistant to FGFR inhibitor treatment (Phase 2; DZB v DZB+A). Treatment will continue until disease progression, intolerance, withdrawal of informed consent, or death. Using Simon’s two-stage designs, objective response rate (per RECIST 1.1 central review) is the primary endpoint to assess the antitumor activity of DZB or DZB+A in Ph2. Main secondary objectives include evaluation of median PFS, duration of response, safety profile, HR-QoL (incl., QLQ C30, FACT-Bl, EQ-5D), and symptom response from baseline. The study was initiated in July 2019 and C1 (N=71) and C2 (N=24) are currently open for enrollment. Clinical trial information: NCT04045613.
Phase Ib/II umbrella trial to evaluate the safety and efficacy of multiple 2L cancer immunotherapy (CIT) combinations in advanced/metastatic urothelial carcinoma (mUC): MORPHEUS-mUC.
Authors: Drakaki Alexandra , Rezazadeh Kalebasty Arash , Lee Jae-Lyun , Martin-Liberal Juan , Kim Miso , Shin Sang Joon , Shi Jane , Mariathasan Sanjeev , Ci Bo , Degaonkar Viraj , Williams Patrick , Cha Edward , Maltzman Julia , Powles Thomas 
Published: February 2020

TPS591 Background: Although CIT has efficacy against multiple cancers, only subsets of patients (pts) have durable responses with monotherapy. CIT combination treatment (tx) targets multiple immune-evasion mechanisms and may thus be more likely to improve outcomes. However, a large number of potential combinations need to be tested to identify effective combinations. The MORPHEUS platform comprises multiple global, open-label, randomized Phase Ib/II trials to identify early efficacy signals and safety of tx combinations in pts with different cancers. MORPHEUS-mUC is a randomized study of 6 CIT combinations compared with a single CIT control in pts with locally advanced UC/mUC who progressed during or after a platinum-containing regimen. The PD-L1 inhibitor atezolizumab will be combined with agents targeting different mechanisms (via nectin-4, PARP, CD47, CD38, DPP-4 and IL-6R) to simultaneously enhance immune cell priming and activation, tumor infiltration and/or recognition of tumor cells. To accelerate the clinical development of novel combinations, MORPHEUS has the flexibility, via amendment, to allow for the modification of eligibility criteria or the opening of new tx arms to replace arms that demonstrate no signs of clinical activity/unacceptable toxicity. Methods: MORPHEUS-mUC (NCT03869190) has 2 stages. In Stage 1, approximately 130-305 pts with histologically documented, locally advanced inoperable UC/mUC will be randomized to atezolizumab monotherapy (control) or experimental arms: atezolizumab + either enfortumab vedotin, niraparib, magrolimab (Hu5F9-G4), isatuximab, linagliptin or tocilizumab. Safety will be monitored for potential overlapping toxicities. Stage 2 arms will be atezolizumab + either enfortumab vedotin or linagliptin arms, unless these combinations show no activity in Stage 1. Eligible pts who experience unacceptable toxicity or loss of clinical benefit in Stage 1 may enroll in Stage 2 within 3 months. The primary study endpoint is investigator-assessed ORR per RECIST 1.1; secondary endpoints include PFS, OS, DOR, DCR and safety. Biomarkers will also be explored. Clinical trial information: NCT03869190.
Study EV-103: New cohorts testing enfortumab vedotin alone or in combination with pembrolizumab in muscle invasive urothelial cancer.
Authors: Hoimes Christopher J. , Rosenberg Jonathan E. , Petrylak Daniel Peter , Carret Anne-Sophie , Sasse Carolyn , Chaney Marya F. , Flaig Thomas W. 
Published: February 2020

TPS595 Background: Neoadjuvant cisplatin-based chemotherapy is standard of care for muscle invasive urothelial cancer (MIUC) before radical cystectomy (RC) and lymph node dissection in cisplatin-eligible patients (pts). However, many pts are cisplatin-ineligible and while PD-1/PD-L1 inhibitors have had encouraging results in this population, they are not approved for MIUC; new therapies are needed. Enfortumab vedotin (EV), an investigational antibody-drug conjugate, delivers the microtubule-disrupting agent monomethyl auristatin E to cells expressing Nectin-4, which is highly expressed in urothelial cancer. In a phase 2 study, EV monotherapy had a confirmed ORR of 44% in 125 heavily pre-treated metastatic urothelial cancer (mUC) pts (Rosenberg JCO 2019). In the present study, an initial analysis of EV combined with the PD-1 inhibitor, pembrolizumab (P) had a confirmed ORR of 71% in 45 cisplatin-ineligible mUC pts in the first-line setting (Hoimes ESMO 2019). These results suggest that EV and EV+P may be suitable for research in MIUC. Methods: Study EV-103 (NCT03288545) mUC cohorts were described previously (Hoimes ASCO 2019). Sequential cohorts were added to test EV alone (Cohort H, n = 20) and EV+P (Cohort J, n = 20) as neoadjuvant therapy in cisplatin-ineligible pts (stage cT2-T4a, N0, M0) with treatment naive MIUC. Eligible pts are ECOG 0-2, have CrCl ≥30 mL/min, and are medically fit for and scheduled for RC. Cohort H pts receive 3 cycles of EV (1.25 mg/kg) on Days 1 and 8 of each 3-week cycle. Cohort J pts receive 3 cycles of EV as described for Cohort H plus P on Day 1 of each cycle. Following EV or EV+P, pts undergo their scheduled RC. Pathological complete response (pCR) rate per local pathology review is the primary endpoint of the MIUC cohorts. Secondary endpoints include assessment of pCR and pathological response (PaR) rate per central pathology review, PaR per local pathology review, PFS and investigator assessed disease-free survival per RECIST v1.1, OS, and assessment of safety and tolerability, including planned surgeries delayed due to treatment-related adverse events. The ongoing study opened Oct 2017 and was amended to include MIUC cohorts Aug 2019. Clinical trial information: NCT03288545.
NEXT: A phase II, open-label study of nivolumab adjuvant to chemoradiation in patients (pts) with localized muscle invasive bladder cancer.
Authors: Gupta Sumati , Maughan Benjamin Louis , Dechet Christopher B. , Lowrance William Thomas , O Neil Brock , Kokeny Kristine E. , Lloyd Shane , Tward Jonathan David , Boucher Kenneth M. , Agarwal Neeraj 
Published: February 2020

TPS605 Background: In pts with localized muscle invasive bladder cancer (MIBC), trimodality bladder preserving therapy (TMT), with transurethral resection of bladder tumor, radio-sensitizing chemotherapy and definitive radiation, has up to a 50% risk of local and systemic relapse during the 2-year post treatment phase. We hypothesize that by inhibiting immune checkpoints, chemo-radiation induced tumor specific immune response will be enhanced both locally and abscopally, resulting in better failure-free survival (FFS). In the NEXT trial, we evaluate the efficacy of nivolumab after completion of the TMT in this setting. Methods: Pts with localized MIBC who have completed standard TMT are eligible. Pts receive nivolumab 480 mg intravenously every 4 weeks for up to 12 doses. Treatment with nivolumab begins within 90 days of completion of TMT. Subjects undergo surveillance cystoscopic and scan based assessments on study. Archived tumor tissue at baseline and at relapse is obtained for correlative studies. The primary endpoint is 2-year FFS. Secondary endpoints include FFS at 2 years in patients with intact bladder, rate of radical cystectomy (RC), cystoscopic local control, distant FFS in patients with intact bladder and those that undergo RC, overall survival, toxicity and quality of life. Exploratory endpoints include to characterize changes in immune cell subsets that can be correlated with clinical outcome and to assess the correlation of response to PD-L1 expression in pretreatment tumor tissue in the study subjects. The planned sample size for this single arm, open label trial is 28 pts. Kaplan-Meier methods will be used to plot survival endpoints and cystoscopic local control rates. Exact binomial methods will be used to provide 6 months, 1-year and 2-year estimates for these endpoints. The sample size justification is based on the maximum width of a two-sided 95% binomial confidence interval for 2 year FFS. With 28 evaluable subjects, a 95% exact binomial confidence interval, estimated using the method of Clopper-Pearson, will extend no more than 20% from the observed FFS. Clinical trial information: NCT03171025.