bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase III study of androgen deprivation therapy (ADT) with enzalutamide (ENZA) or placebo (PBO) in metastatic hormone-sensitive prostate cancer (mHSPC): The ARCHES trial.
Authors: Armstrong Andrew J. , Szmulewitz Russell Zelig , Petrylak Daniel Peter , Villers Arnauld , Azad Arun , Alcaraz Antonio , Alekseev Boris Y. , Iguchi Taro , Shore Neal D. , Rosbrook Brad , Sugg Jennifer , Baron Benoit , Chen Lucy F. , Stenzl Arnulf 
Published: March 2019

687 Background: ENZA, a potent androgen receptor inhibitor, has demonstrated benefit in men with metastatic and nonmetastatic castration-resistant prostate cancer (CRPC). Efficacy of ENZA with ADT in men with mHSPC is unknown. Methods: ARCHES is a multinational, double-blind, phase 3 study (NCT02677896). Patients (pts) with mHSPC were randomized 1:1 to ENZA (160 mg/day) + ADT or PBO + ADT, stratified by disease volume (CHAARTED criteria) and prior docetaxel therapy. Primary endpoint was radiographic progression-free survival (rPFS) assessed centrally or death within 24 weeks of treatment discontinuation. Secondary endpoints included time to prostate-specific antigen (PSA) progression, PSA and radiographic responses and overall survival (OS). Treatment continued until disease progression or unacceptable toxicity. Results: 1150 men were randomized to ENZA (n=574) or PBO (n=576); baseline characteristics were balanced between groups. Overall, 67% had distant metastasis at initial diagnosis; 63% had high volume disease, 18% had prior docetaxel. Median follow-up was 14.4 mo. ENZA + ADT significantly improved rPFS (Table); similar significant improvements in rPFS were reported in prespecified subgroups of disease volume, pattern of spread, region and prior docetaxel (HRs 0.24–0.53). Secondary endpoints improved with ENZA + ADT (Table); OS data are immature. Grade 3–4 adverse events (AEs) were reported in 23.6% of ENZA pts vs 24.7% of PBO pts with no unexpected AEs. Conclusions: ENZA + ADT significantly improved rPFS and other efficacy endpoints vs PBO + ADT in men with mHSPC, with a preliminary safety analysis that appears consistent with the safety profile of ENZA in previous CRPC clinical trials. Acknowledgements: Medical writing and editing assistance was provided by Stephanie Rippon, MBio, and Lauren Smith from Complete HealthVizion, funded by the study sponsors. This study was funded by Astellas Pharma Inc. and Medivation LLC, a Pfizer Company, the co-developers of enzalutamide. Clinical trial information: NCT02677896. [Table: see text]
Typical hormone deprivation side effects compared to SM-88 therapy for rising PSA.
Authors: Gartrell Benjamin Adam , Del Priore Giuseppe , Retter Avi S. , Sokol Gerald H. , Vandell Alexander G , Roach Mack 
Published: March 2019

79 Background: Treatment for rising PSA non-metastatic prostate cancer (nmPC) includes multifaceted hormone therapies (HT) associated with increasing related toxicity; in aggregate the risk benefit ratio is not ideal. We report on the use before HT, of SM-88, a novel combination therapy (amino acid analogue, CYP3A4 inducer, mTOR inhibitor and catalyst) based on the Warburg effect without known hormone related toxicity. Methods: Prospective ongoing Phase II of SM-88 (230 mg po bid) in recurrent nmPC with rising PSA (PCWG3 definition), no radiographically identified metastases at baseline and detectable CTCs. Results: From Sept 2016 to Dec 2017, there have been 31 consented (34 planned) with 23 evaluable (completed > 1 cycle). Mean age 68.9; BMI 28.7; 38% black and 62% post RT. Mean testosterone (T) rose from 319 to 382 ng/dl (p=.19). Typical HT related side-effects were not observed: 96% of subjects reported no hot flashes, 91% no gynecomastia, 83% interest and 61% activity in sex, 78% excellent or nearly so overall health and 74% excellent QOL on at least 50% of their EORTC questionnaires; weight (-0.2 kg), hct (0%), glu (+2 mg/dl), urinary N telopeptide (-4.2 nmol), MAP (normotensives -2 mmHg, hypertensives -3 mmHg), heart rate (-2.4 beats/min), QTc (-3 ms) with no newly emergent >480 ms, serum Ca++ (-0.006 mg/dL), LDH (+6.4 u/L), bsAlkPhos (+6.2 u/L), triglycerides (-5.2 mg/dL), total protein (0.05 g/dL) and albumin (0.02 g/dL). Neutrophil lymphocyte ratio decreased at the end of cycle 1 in 100% (n=5, median 2.4) of those who progressed to subsequent therapy vs 47% of those who did not (p=.05). AEs occurred in 16 subjects: 1 unrelated Grade (G) 3; 0 G 4; 14/26 G 1-2 possibly related to drug. No AEs were related to T levels. From initial diagnosis of PSA rise (median 9, 3-18 months), 96% (22/23) have remained metastases free and 78% (18/23) remained free of additional HT (p<.05). There were no skeletal or cardiovascular events. Conclusions: SM-88 may be useful in delaying the start of HT. While on SM88 subjects did not report any T or therapy related AEs >G2. SM88 may be useful in prostate cancer patients who are more sensitive or vulnerable to HT related toxicity while maintaining stable PSA values. Prospective trials are planned to confirm its utility. Clinical trial information: NCT02796898.
TheraP: A randomized phase II trial of [177Lu]-PSMA-617 theranostic versus cabazitaxel in progressive metastatic castration-resistant prostate cancer.
Authors: Hofman Michael , Emmett Louise , Violet John A , Lawrence Nicola Jane , Williams Scott , Stockler Martin R. , Francis Roslyn J , Iravani Amir , Zhang Alison Yan , Martin Andrew James , Azad Arun , Yip Sonia , Langford Ailsa , McJannett Margaret Mary , Davis Ian D. ,   Australian and New Zealand Urogenital and Prostate Cancer Trials Group
Published: March 2019

TPS332 Background: Lutetium-177 [177Lu]-PSMA-617 is a novel radiolabelled small molecule that binds with high affinity to prostate-specific membrane antigen (PSMA), which is commonly overexpressed in prostate cancer. This treatment has demonstrated promising activity and tolerability in men progressing after multiple lines of chemotherapy and endocrine therapy. This trial will determine the activity and safety of 177Lu-PSMA-617 compared to cabazitaxel chemotherapy in men with progressive metastatic castrate resistant prostate cancer. Methods: TheraP is an open-label, randomised, two-arm, multi-centre, phase 2 trial comparing the activity and safety of experimental treatment with [177Lu]-PSMA-617 versus standard 2nd line chemotherapy with cabazitaxel. Key eligibility criteria include prior chemotherapy with docetaxel; rising serum PSA; sufficient PSMA avidity according to central reviewed of imaging with PSMA PET/CT and FDG PET/CT; no discordance between FDG PET and PSMA PET. The trial will include 200 participants randomised in a 1:1 ratio to either [177Lu]-PSMA-617 intravenously every 6 weeks, 8.5 GBq for cycle 1, decreasing by 0.5 GBq with each subsequent cycle, up to maximum 6 cycles (experimental group); or, chemotherapy with cabazitaxel (20 mg/m2) intravenously every 3 weeks, for 10 cycles (standard group). In the event of an exceptional response to [177Lu]-PSMA-617, according to centrally-reviewed, post-therapy SPECT imaging, treatment is suspended but can recommence subsequently on progression. The primary endpoint is a 50% or greater reduction from baseline in serum PSA. Secondary endpoints include overall survival, progression-free survival (PFS), PSA-PFS, pain-PFS, radiographic-PFS, health-related quality of life, pain response, and adverse events. The outcomes of patients excluded because of discordant disease on FDG PET and PSMA PET will be reported as a tertiary objective. The study has accrued 79 of 200 planned participants from 29 January 2018 to 23 October 2018. Clinical trial information: NCT03392428.
A phase I clinical trial of PSMA-directed/TGFβ-insensitive CAR-T cells in metastatic castration-resistant prostate cancer.
Authors: Narayan Vivek , Gladney Whitney , Plesa Gabriela , Vapiwala Neha , Carpenter Erica , Maude Shannon L. , Lal Priti , Lacey Simon F. , Melenhorst Jan Joseph , Sebro Ronnie , Farwell Michael , Hwang Wei-Ting , Moniak Michael , Gilmore Joan , Lledo Lester , Dengel Karen , Marshall Amy , Coughlin Christina Marie , June Carl H. , Haas Naomi B. 
Published: March 2019

TPS347 Background: Adoptive immunotherapy with Chimeric Antigen Receptor (CAR)-T cells has transformative potential for the treatment of cancer. However, a primary challenge to the success of these therapies in prostate cancer is the immunosuppressive microenvironment, including high levels of Transforming Growth Factor-beta (TGFβ), encountered by re-directed T cells upon tumor infiltration. Importantly, these immunosuppressive functions of TGFβ can be abrogated in T cells using a dominant negative TGFβ receptor (TGFβRdn), thereby enhancing antitumor immunity. In in vivo disseminated prostate cancer models, co-expression of TGFβRdn on PSMA-redirected CAR-T cells led to increased T cell proliferation, enhanced cytokine secretion, resistance to exhaustion, long-term persistence, and greater tumor eradication. Methods: We initiated a first-in-human phase 1 clinical trial to evaluate the safety and preliminary efficacy of lentivirally-transduced PSMA-directed/TGFβ-insensitive CAR-T cells (CART-PSMA-TGFβRdn) in men with metastatic CRPC. In preliminary dose-escalation cohorts, patients received a single dose of 1-3 x 107/m2 (Cohort 1) or 1-3 x 108/m2 (Cohort 2) CART-PSMA-TGFβRdn cells without lymphodepleting chemotherapy in a 3+3 design. In Cohort 3, patients will receive the MTD of CART-PSMA-TGFβRdn following a lymphodepleting regimen of cyclophosphamide and fludarabine. All patients provide newly obtained metastatic tumor biopsies at baseline, as well as on day +10 following the CAR-T cell infusion and at disease progression. CAR-T expansion and persistence in peripheral blood and trafficking to target tissues is evaluated via quantitative PCR of CART-PSMA-TGFβRdn DNA. Bioactivity of CART-PSMA-TGFβRdn cells is evaluated via multiplex immunoassays. Additional correlative studies include enumeration and phenotyping of circulating tumor cells and DNA. Cohorts 1 and 2 have been completed without observed DLT. Interestingly, a reversible cytokine release syndrome has been observed that is responsive to tocilizumab. Enrollment in Cohort 3 began in September 2018. Cohort expansions will examine serial CART-PSMA-TGFβRdn re-treatment strategies. Clinical trial information: NCT03089203.
Phase II study of sitravatinib in combination with nivolumab in patients with advanced or metastatic urothelial carcinoma (UC) after checkpoint inhibitor therapy (CIT).
Authors: Doshi Gurjyot K. , Vogelzang Nicholas J. , Richards Donald A. , Chong Daniel , Shaffer David R. , Nordquist Luke T. , Picus Joel , Alvarez Delia , Der-Torossian Hirak , Christensen James , Yorio Jeffrey Thomas 
Published: March 2019

TPS498 Background: Combination therapy with agents targeting molecular and cellular mechanisms of CIT resistance is a rational approach to restoring CIT efficacy in patients (pts) with immunotherapy-resistant UC. Sitravatinib is a tyrosine kinase inhibitor (TKI) that targets multiple closely-related receptor tyrosine kinase (RTK) pathways, including the split RTKs VEGFR-2 and KIT, as well as the TAM (TYRO3, AXL, and MER) RTKs. Inhibition of the split RTKs enhances antitumor activity by reduction of immunosuppressive regulatory T cells and myeloid-derived suppressor cells (MDSCs) within the tumor microenvironment (TME). Inhibition of TAM RTKs further restores a more immune-supportive TME by depletion of MDSCs and repolarization of tumor-associated macrophages to the M1 phenotype associated with secretion of pro-inflammatory cytokines. Given these pleiotropic immune-activating effects, the combination of sitravatinib with nivolumab is a rational approach to restoring or enhancing CIT clinical activity in pts with immunotherapy-resistant UC. This combination has been shown to be safe and tolerable in an ongoing Phase 2 study in pts with metastatic non-small cell lung cancer. Methods: This open-label Phase 2 study evaluates tolerability and clinical activity of sitravatinib in combination with nivolumab in pts with advanced or metastatic UC who experienced disease progression on or after CIT as the most recent systemic therapy. Enrollment is stratified by prior receipt of platinum-based chemotherapy. If the initial 2 cohorts are of high interest for efficacy, the protocol allows for addition of new cohorts to include pts previously treated with selected immunotherapies (anti-CTLA-4, anti-OX40 or anti–CD137 therapy) or who are CIT-naïve. The primary objective is Objective Response Rate. A Predictive Probability Design will be applied allowing for expansion to 40 pts per cohort. Sitravatinib is administered orally daily in continuous 28-day cycles at 120 mg; nivolumab intravenously at 240 mg every 2 weeks or 480 mg every 4 weeks. Status: The study is open for enrollment and recruitment is ongoing. Clinical trial information: NCT03606174.
Keynote-676: Phase 3 study of bacillus calmette-guerin (BCG) with or without pembrolizumab (pembro) for high-risk (HR) non–muscle invasive bladder cancer (NMIBC) that is persistent or recurrent following BCG induction.
Authors: Kamat Ashish M. , Shore Neal D. , Hahn Noah M. , Alanee Shaheen , Nishiyama Hiroyuki , Shariat Shahrokh , Nam Kijoeng , Kapadia Ekta , Frenkl Tara L. , Steinberg Gary D. 
Published: March 2019

TPS502 Background: Intravesical instillation of BCG is the standard of care for patients with HR NMIBC. However, many patients have persistent/recurrent HR NMIBC after BCG induction and are at a particularly increased risk for progression, representing a significant unmet need. Programmed cell death ligand 1 (PD-L1) expression in the tumor microenvironment may attenuate responses to BCG. KEYNOTE-676 is a randomized, comparator-controlled, phase 3 trial to evaluate the efficacy and safety of the PD-1 inhibitor pembro plus BCG in patients with persistent/recurrent HR NMIBC after BCG therapy. Methods: Adult (≥18 years) patients with histologically confirmed persistent/recurrent HR NMIBC of the bladder after adequate BCG induction therapy are eligible. Patients are required to have undergone cystoscopy/transurethral resection of bladder tumor within 12 weeks prior to randomization, to have no concurrent extravesical disease, and to have ECOG performance status score 0-2, adequate organ function, and tissue for biomarker analysis. Patients will be randomly assigned 1:1 to continue on BCG therapy alone or receive BCG plus pembro 200 mg every 3 weeks. Treatment will be stratified by carcinoma in situ (CIS) histology (presence/absence), PD-L1 combined positive score (≥10/˂10), and timing of NMIBC persistence/recurrence (0 to ≤6, ˃6 to ≤12, or ˃12 to ≤24 mo). Primary end point is complete response rate in participants with CIS. Secondary end points will include event-free survival, patient-reported outcomes, and safety. Responses will be assessed by cystoscopy and blinded independent central review of urine cytology and biopsy (as applicable) every 12 weeks for years 1-2 and every 24 weeks for years 3-5 and by computed tomography urography every 18 months through year 5. Treatment will continue with pembro for up to 2 years and BCG for 3 years or until pathology-confirmed HR NMIBC persistence, recurrence, or disease progression, unacceptable toxicity, or patient/physician decision to withdraw. Recruitment will begin November 2018 and will continue until ~550 patients are enrolled. (NCT03711032). Clinical trial information: NCT03711032.
Phase II trial of nivolumab (nivo) plus ipilimumab (ipi) in patients with SMARCB1-deficient kidney malignancies.
Authors: Msaouel Pavlos , Slack-Tidwell Rebecca , Tannir Nizar M. 
Published: March 2019

TPS677 Background: The potent tumor suppressor SMARCB1 (also known as INI-1, hSNF5, or BAF47) is inactivated in all cases of renal medullary carcinoma (RMC) and renal cell carcinoma unclassified with medullary phenotype (RCCU-MP), as well as most malignant rhabdoid tumors (MRT) of the kidney. Although rare, these kidney malignancies are highly lethal and often occur in young patients. The role of immune checkpoint inhibitor therapy remains to be prospectively defined in tumors harboring SMARCB1 defects. Although a case report noted efficacy of single-agent Nivo in a patient with RMC (Beckermann et al J Immunother Cancer, 2017), there were no durable responses in subsequent cases (Sodji et al. J Immunother Cancer, 2017). We hypothesize that the combination of anti-PD1 (Nivo) with anti-CTLA4 (Ipi) immune checkpoint inhibitor therapy will lead to more potent antitumor responses compared to those reported with single-agent Nivo. Methods: This single-arm phase II trial will test the efficacy of Nivo + Ipi in up to 30 patients with SMARCB1-negative RMC, RCCU-MP, and adult-onset kidney MRTs. Any number of prior therapies is allowed. Patients will be treated with Ipi 1 mg/kg + Nivo 3 mg/kg every 3 weeks x4 doses followed by maintenance Nivo 480 mg every 4 weeks for up to 2 years. Ongoing monitoring for safety and futility will be implemented per the method of Thall et al. (Stat Med, 1995; 14:357-79) using cohorts of 10 patients each. The primary endpoint is objective response rate (ORR) and the trial objective is to achieve a similar or greater ORR compared with the historical ORR of 29% achieved in our institution using conventional cytotoxic chemotherapies. Secondary endpoints include progression-free survival, overall survival, and disease control rate. To evaluate potential biomarkers for treatment response, correlative analyses will be performed in tumor tissue and peripheral blood samples obtained i) pre- treatment (baseline) up to 6 weeks (42 days) prior to initiation of treatment on Day 1, ii) after completion of the combination therapy (Nivo + Ipi) phase, and iii) upon disease progression. At the time of the abstract submission, 2 patients have been enrolled on this study. Clinical trial information: NCT03274258.
RENAVIV: A randomized phase III, double-blind, placebo-controlled study of pazopanib with or without abexinostat in patients with locally advanced or metastatic renal cell carcinoma.
Authors: Aggarwal Rahul Raj , Thomas Scott , Hauke Ralph J. , Nordquist Luke T. , Munster Pamela N. 
Published: March 2019

TPS681 Background: Abexinostat is a pan-histone deacetylase (HDAC) inhibitor that has shown promising activity in prior pre-clinical studies and early phase clinical trials. A phase 1b study of pazopanib plus abexinostat (Aggarwal et al. J Clin Oncol 2017) demonstrated strikingly durable responses in patients (pts) with clear cell renal cell carcinoma (RCC), including one patient with previously refractory disease with ongoing response for > 5 years’ duration. Induction of histone acetylation in peripheral blood mononuclear cells (PBMCs) was associated with durable treatment response. We hypothesize that the addition of abexinostat to pazopanib will significantly improve outcomes in patients with clear cell RCC. Methods: RENAVIV is a global, randomized, double-blind, placebo-controlled, two arm phase 3 study of pazopanib plus abexinostat versus pazopanib plus placebo, in pts with locally advanced or metastatic RCC with clear cell component. Up to one prior line of immunotherapy is allowed. Prior VEGF-targeting tyrosine kinase inhibitor treatment is prohibited. Stratification factors include: 1) Prior immunotherapy (yes/no) and 2) prognostic group (good, intermediate, poor). Pts randomized to pazopanib + placebo have the option of crossing over to receive pazopanib plus abexinostat at the time of disease progression. The primary endpoint is PFS by independent review committee. Secondary endpoints include PFS by investigator assessment, overall survival, safety, objective response rate (ORR), duration of response, patient-reported quality of life, and outcomes in cross-over population. Planned correlative studies include association between histone acetylation and HDAC expression in PBMCs with clinical outcomes. The total planned accrual is 413 pts, estimated to provide 90% power to detect a hazard ratio of 0.67 in the comparison of PFS between experimental versus control arms, with an overall two-sided type I error rate of 0.025. A pre-specified minimum of 50% of patients are required to have received prior immunotherapy. The first patient was enrolled in October 2018. Clinical trial information: NCT03592472.
Phase Ib (COSMIC-021) trial of cabozantinib (C) in urothelial carcinoma (UC) or C in combination with atezolizumab (A) in patients (pts) with UC, castrate resistant prostate cancer (CRPC) or renal cell carcinoma (RCC).
Authors: Pal Sumanta K. , Vaishampayan Ulka N. , Castellano Daniel E. , Necchi Andrea , Van Herpen Carla M.L.- , Ramsingh Giridharan , Loriot Yohann , Agarwal Neeraj 
Published: March 2019

TPS683 Background: C is an inhibitor of tyrosine kinases involved in tumor growth, angiogenesis, and immune regulation, including MET, VEGFR, and TAM kinases (Tyro3, AXL, MER). Preclinical and clinical studies suggest that C promotes an immune-permissive tumor environment which may enhance response to immune checkpoint inhibitors (ICI) such as the anti-PD-L1 mAb, A. C is approved for pts with advanced RCC and has shown encouraging clinical activity in combination with a PD-1 targeting mAb in RCC, UC, and CRPC (Nadal et al 2017). A is approved for pts with advanced UC after prior platinum-containing chemo and for chemo-naïve pts with platinum ineligible UC or PD-L1+ cisplatin ineligible UC. Combination of C with A may enhance treatment efficacy in pts with genitourinary (GU) cancers. Here, we present the study design of an ongoing phase 1b trial of C + A which includes cohorts with advanced RCC, UC, and CRPC. Methods: This global multicenter, phase 1b, open-label trial will assess the safety, tolerability, activity, and pharmacokinetics of C or C + A (NCT03170960). The study comprises a dose-escalation stage and an expansion stage. The dose-escalation stage (3+3 design) is completed. C 40 mg qd + 1200 mg A q3w is the recommended dose for the expansion stage. In the expansion stage, 18 cohorts (each 30 pts) will be enrolled including 7 cohorts with GU cancers: (1) treatment naïve clear cell RCC; (2) non-clear cell RCC, treatment naïve or following systemic anticancer therapy; (3) UC after prior platinum-based therapy; (4) treatment naïve cisplatin-ineligible UC; (5) treatment naïve cisplatin-eligible UC; (6) UC after prior ICI therapy and (7) CRPC after prior enzalutamide and/or abiraterone. In addition, an exploratory cohort (30 pts) will evaluate single agent 60 mg C in pts with UC after prior ICI therapy. Pts will continue treatment as long as they experience clinical benefit per investigator or until unacceptable toxicity. The primary objective of the expansion stage is the objective response rate per RECIST 1.1 per investigator for each cohort. Secondary objectives will assess safety including immune related AEs. Clinical trial information: NCT03170960.