bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of serum iron and response to immune checkpoint inhibitors (ICIs) in metastatic clear cell renal cell carcinoma (mccRCC).
Authors: Rathi Nityam , Stenehjem David D. , Agarwal Neeraj , Hahn Andrew W , Sirohi Deepika , Sharma Prayushi , Koh Mei Yee , Maughan Benjamin Louis 
Published: February 2020

723 Background: ICIs have improved survival in mRCC patients (pts), yet response rates (RR) to these treatments are variable. Biomarkers predictive of response to ICIs may improve outcomes for mccRCC pts. Genes that promote tumor-specific iron accumulation such as hepcidin (HAMP) or transferrin (TF) are significantly correlated with decreased overall survival in clear cell RCC (TCGA-KIRC). Iron deficiency in cancer patients is positively correlated with tumor stage and inversely proportional to treatment response (PMID: 23567147). Here, we investigate whether serum iron profile may be associated with response to ICIs in mccRCC pts. Methods: Clinical data was obtained from an mRCC registry at the Huntsman Cancer Institute, University of Utah. Analyses were limited to mccRCC pts who had serum iron studies within 6 months before initiating an ICI and had been assessed for RR. ICIs included nivolumab + ipilimumab, atezolizumab, or nivolumab alone. Responses were defined as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) by RECIST criteria. Clinical benefit (CB) was defined as CR + PR + SD. Descriptive statistics were used to assess associations between iron stores and response to ICIs and IMDC criteria. Results: 36 pts met all aforementioned eligibility criteria (29 were of IMDC intermediate risk, 7 were of IMDC poor risk). 5 pts received a first-line ICI, and the remaining 31 pts received ICIs as salvage therapy. Pts with CB had a significantly higher median serum iron level compared to those with no CB (59 vs 38.5 ug/dL; p=0.024). Furthermore, pts with normal transferrin saturation (TSAT %) were more likely to derive CB from ICIs (p=0.048). No association was found between serum ferritin (a marker of inflammation and tissue iron) and response to ICIs. Conclusions: In this hypothesis-generating study, increased serum iron, and TSAT levels within the normal range are associated with an increased likelihood of response to ICIs in pts with mccRCC. Once validated, these results may establish serum iron profile as a predictive marker of response to ICIs, in addition to providing the rationale for ruling out iron deficiency before starting ICIs.
Soluble PD-L1 as a marker of progressive disease on nivolumab in kidney cancer.
Authors: Mahoney Kathleen Margaret , Ross-Macdonald Petra B. , Shukla Sachet A. , Braun David A. , Song Linan , Veras Eliseo , Wind-Rotolo Megan , Van Allen Eliezer Mendel , McDermott David F. , Hodi F. Stephen , Choueiri Toni K. , Freeman Gordon J. 
Published: February 2020

746 Background: Higher levels of soluble PD-L1 (sPD-L1) are associated with poor prognosis in patients with solid tumors including in renal cell carcinoma (RCC). Here we have tested whether in patients with advanced RCC, sPD-L1 levels are associated with PD-L1 expression on tumor tissue or with clinical outcomes on PD-1 blockade. Methods: Serum from 91 patients with advanced clear-cell RCC on a biomarker study of nivolumab (NCT01358721) obtained at baseline (Day 1), Day 29 and Day 63, was tested by SiMoa™ for sPD-L1 (capture mAb 298.12B1, detection mAb 339.4C10; Freeman laboratory and Quanterix). Tumor PD-L1 (tPD-L1) was assessed on pretreatment biopsies (Dako). Association of sPDL1 and tPD-L1 with clinical outcomes was analyzed, including best overall response by RECIST (BOR), objective response of >20% (OR), progression free survival (PFS), and overall survival (OS). Results quote Wilcoxon Rank Sum test or paired t-test with significance at P < 0.05. Results: Median sPD-L1 was highest in patients with progressive disease (PD) at all timepoints (Table). Compared to baseline, sPD-L1 levels significantly increased in patients with PD on Day 29 and Day 63, while sPD-L1 levels significantly decreased in patients with CR/PR on Day 63. In addition, we found significantly higher baseline sPD-L1 in patients with prior therapy compared to those who were treatment-naïve. High tPD-L1 was weakly associated with favorable OR, but also weakly associated with high baseline sPD-L1. Conclusions: Unlike tPD-L1, sPD-L1 levels may show promise for association with clinical response to nivolumab in RCC. In this exploratory study, sPD-L1 increase on-treatment was significantly associated with lack of OR, and may be of utility as an early marker for PD worthy of future validation. Analysis of RNASeq from patients’ tumor specimen is underway to assess whether high sPD-L1 with PD is associated with immune suppressive signatures.[Table: see text]
Renal biopsy cell cycle proliferation (CCP) score to predict adverse surgical pathology in renal cell carcinoma.
Authors: Tosoian Jeffrey J. , Feldman Adam S. , Abbott Madeline , Mehra Rohit , Tiemeny Placede , Wolf J. Stuart , Wu Shulin , Stone Steven , Wu Chin-Lee , Daignault Stephanie , Taylor Jeremy MG , Morgan Todd Matthew 
Published: February 2020

747 Background: The role of renal mass biopsy (RMB) in risk stratifying patients with renal cell carcinoma (RCC) is unclear. We sought to determine whether the cell cycle proliferation (CCP) score from RMB can improve risk stratification of localized RCC. Methods: We identified patients with RCC who underwent RMB and subsequent partial/radical nephrectomy from 2000-2014. We used multivariable logistic regression to determine the association of patient-level variables and biopsy CCP score with adverse surgical pathology (Fuhrman grade 3-4, pT stage≥3, papillary type II histology, or evidence of metastasis at surgery). Effect size was estimated with odds ratios (OR) and discriminative performance with AUC. Results: Overall, 94 of 202 patients (46%) had adverse surgical pathology. On multivariable analysis, CCP score >0 was associated with 2.38-fold increased odds of adverse pathology (Table). Relative to the model omitting CCP score (AUC=0.70), the addition of CCP score as a continuous (AUC=0.731) or binary (AUC=0.730) variable yielded increased discriminative performance. Similar associations were observed in an analysis limited to patients with low-grade tumors on biopsy (bCCP: OR 2.44, p=0.024; cCCP: OR 1.57, p=0.11). In both models, increased lesion size on imaging was consistently associated with adverse pathology. Conclusions: Among patients with RCC, biopsy CCP score >0 was independently associated with adverse pathology, suggesting this classifier provides prognostic information beyond conventional pathologic data. Biopsy CCP score could be used to better guide patient-specific management.[Table: see text]
Phase II trial of a novel immunotherapy combination of pembrolizumab and HER2 bi-armed activated T cells (BATs) in metastatic castrate resistant prostate cancer.
Authors: Patel Meera , Lum Lawrence G. , Deol Abhinav , Thakur Archana , Heath Elisabeth I. , Chen Wei , Dobson Kimberlee , Fontana Joseph A. , Vaishampayan Ulka N. 
Published: February 2020

97 Background: Immune checkpoint inhibitors (ICI) have demonstrated only modest efficacy in metastatic castrate resistant prostate cancer (mCRPC). Anti-HER2 and Anti-CD3 bispecific antibody armed activated T cells (HER2 BATs) demonstrated efficacy in prostate cancer cell lines, irrespective of HER2 expression status. Safety and preliminary responses in refractory mCRPC were noted in a phase I trial with HER2 BATs. Preclinical synergy was noted in prostate cancer with ICI and BATs. We conducted a phase II study with pembrolizumab and HER2 BATs that would potentially transform immune cells to exhibit cytotoxicity against prostate cancer. Methods: mCRPC patients with 0-1 performance status (PS) and normal liver, kidney and marrow function, pre or post docetaxel chemotherapy were eligible. Primary endpoint was 6 month progression free survival. Patients underwent apheresis for mononuclear cell collection which was shipped to the University of Virginia for manufacturing of HER2 BATs, which were infused twice weekly for 4 weeks. Pembrolizumab was administered every 21 days for a maximum duration of 6 months starting 1 week prior to HER2 BATs infusion. Progression was determined by clinical evaluation, PSA, and radiologic assessment at 3 and 6 months and every 6 months thereafter. Results: Twelve patients have been enrolled on the study of which one withdrew consent. Median age was 69 years (Range 57 to 76 years). Five of 11 patients had prior docetaxel chemotherapy. Eight of 11 patients had bone and lymph node metastases, 1 had lymph node metastases only, and 2 had peritoneal metastasis. Median PSA was 111ng/ml [Range 5.2 - 378 ng/ml]. Five and 6 patients had PS of 0 and 1 respectively. The regimen was well tolerated with no unexpected toxicities. To date 3 of 6 patients have completed study treatment and remain progression free at 6 months, 1 death occurred due to an unrelated cause, and 2 patients progressed at 12 weeks of therapy. Two patients demonstrated an 88% and 36% PSA decline. Immune correlates will be presented. Conclusions: The combination regimen of pembrolizumab and BATs appears to be worthy of future exploration in a larger trial in mCRPC. Clinical trial information: NCT03406858.
MEDI3726, a prostate-specific membrane antigen (PSMA)-targeted antibody-drug conjugate (ADC) in mCRPC after failure of abiraterone or enzalutamide.
Authors: De Bono Johann S. , Fleming Mark T. , Wang Judy Sing-Zan , Cathomas Richard , Williams Marna , Bothos John G. , Balic Kemal , Cho Song Hye , Martinez Pablo , Petrylak Daniel Peter 
Published: February 2020

99 Background: MEDI3726 is an ADC targeting PSMA. Once bound to PSMA and internalized, the released pyrrolobenzodiazepine dimer toxin crosslinks DNA and triggers cell death. This phase 1 study evaluated the safety and efficacy of MEDI3726 in mCRPC after failure of abiraterone and/or enzalutamide and a taxane-based therapy. Methods: The starting dose was 0.015 mg/kg MEDI3726 IV Q3W until disease progression or unacceptable toxicity. Dose escalation used a modified toxicity probability interval algorithm (mTPI). The primary objectives were safety, adverse events (AEs) and dose-limiting toxicities (DLTs) and to determine the maximum tolerated (MTD) or administered (MAD) dose. Secondary objectives included antitumor activity, pharmacokinetics and immunogenicity. The endpoint for activity was composite response: confirmed response by RECIST v1.1, and/or PSA decrease of ≥ 50% after ≥ 12 wks, and/or confirmed conversion in circulating tumor cell count, defined as a decrease from ≥ 5 to < 5 cells/7.5 mL. Efficacy analyses were based on Prostate Working Group Criteria. Mutational profiles were evaluated in ctDNA. Results: As of Sept 27 2019, 33 pts received MEDI3726. Median age was 71.0 yr. Median number of prior regimens was 4. Median follow-up was 5.4 mo. Drug-related AEs occurred in 30 (90.9%), being grade 3/4 in 15 (45.5%), serious in 11 (33.3%) and causing discontinuation in 13 (39.4%). There were no drug-related deaths. One pt at 0.3 mg/kg had a DLT of Grade 3 thrombocytopenia. No MTD was identified per mTPI; the MAD was 0.3 mg/kg. MEDI3726 had nonlinear PK with a short t1/2 (0.3–2 d). Three pts (15.8%) at baseline and 6 (33.3%) post-baseline had antidrug antibodies, with no correlation to PK exposure. Composite response rate across all doses was 2/33 (6.1%). Time to response was 0.3 mo; duration of response was 1.8–3.8 mo. Median progression-free survival was 3.9 mo and median overall survival was 10.6 mo. Conclusions: An MTD was not identified, but drug-related AEs (skin toxicities and effusions) prevented raising the dose over 0.3 mg/kg and limited the number of cycles. Responses were seen at higher doses, but were not durable as pts discontinued due to drug-related AEs. Clinical trial information: NCT02991911.
A phase I study to evaluate PSCA-targeting chimeric antigen receptor (CAR)-T cells for patients with PSCA+ metastatic castration-resistant prostate cancer (mCRPC).
Authors: Dorff Tanya B. , Blanchard Suzette , Carruth Patti , Wagner Jamie , Kuhn Peter , Chaudhry Ammar , Adkins Lauren , Thomas Sandra , Martirosyan Hripsime , Chu Peiguo , Pal Sumanta K. , Forman Stephen J. , Priceman Saul 
Published: February 2020

TPS250 Background: Although treatment options have improved, mCRPC remains highly lethal. Immunotherapy holds potential for durable remissions but not yet in mCRPC. CAR-T cell therapy has yielded cure for patients with refractory hematologic malignancies, and shows promise in solid tumors. Identifying and targeting the optimal antigen will be key to successful translation in solid tumors. Prostate stem cell antigen (PSCA) is highly expressed on prostate cancer cells, especially metastatic foci, and has limited expression on normal tissues. City of Hope has developed a second-generation PSCA CAR-T cell therapy containing an intracellular 4-1BB co-stimulatory domain (PSCA-BBζ) for first-in-human testing in men with mCRPC refractory to standard therapy (NCT03873805). Methods: The toxicity equivalence range (TEQR) design of Blanchard and Longmate will be used to evaluate select doses of PSCA-BBζ cells and determine the maximum tolerated dose (MTD). Doses include Cohort 1 = 100 million (M) CAR-T x 1 alone; Cohort 1b = 100M CAR-T x1 after lymphodepletion; Cohort 2 = 300M after lymphodepletion; Cohort 3 = 600M after lymphodepletion. 12 subjects will be accrued at the MTD. Eligibility: mCRPC treated with either abiraterone, enzalutamide or both; prior chemotherapy and/or radium223 allowed but not mandated. Tumor tissue, primary or metastatic, must stain positive for PSCA by IHC (Abcam 15168) and biopsy is repeated 28 days post infusion. Endpoints: Primary: all toxicities and dose-limiting toxicities defined as grade 3+ toxicity with attribution of possibly related or above, except CRS grade 3 resolved to < grade 2 within 72 hours or grade 3 encephalopathy resolved to baseline within 28 days. Secondary: persistence/expansion of CAR-T, response (soft tissue by RECIST, bone by PCWG3 criteria). Correlative studies include blood (immunophenotyping, cytokines, circulating tumor cell enumeration and PSCA expression), MRI (enhancement/diffusion changes in target lesions) and metastatic core biopsies (PSCA expression and local immune phenotype changes). Progress: 4 subjects have successfully manufactured PSCA-BBζ T cells; 1 completed treatment. Clinical trial information: NCT03873805.
A phase II study of M6620 in combination with carboplatin compared with docetaxel in combination with carboplatin in metastatic castration-resistant prostate cancer.
Authors: Choudhury Atish Dipankar , Xie Wanling , Parikh Mamta , Lee Daniel , Kessler Elizabeth R. , Einstein David Johnson , Kochupurakkal Bose , Mouw Kent William , Van Allen Eliezer Mendel , Doyle L. Austin , D'Andrea Alan D. , Taplin Mary-Ellen , Shapiro Geoffrey 
Published: February 2020

TPS252 Background: Alterations in DNA damage repair genes are common in metastatic castration-resistant prostate cancer (mCRPC), and are implicated in responses to carboplatin, PARP inhibitors and immunotherapeutics. The ATR kinase is involved in the DNA damage response, and ATR inhibitors have been demonstrated in preclinical models to have synergistic activity with platinum compounds due to induction of replication stress. Methods: This is a randomized open-label Phase 2 study of the ATR inhibitor M6620 + carboplatin vs. docetaxel + carboplatin in mCRPC. Patients (pts) previously treated with at least one secondary hormonal therapy and taxane-based chemotherapy undergo mandatory pre-treatment biopsy and are randomized 1:1 to receive Arm A (docetaxel 60 mg/m2 day 1 + carboplatin AUC 4 day 1) or Arm B (M6620 90 mg/m2 days 2,9 + carboplatin AUC 5 day 1) every 21 days. Pts randomized to Arm A who are not candidates for docetaxel receive carboplatin AUC 5 monotherapy. Stratification factors are 1) prior PARP inhibitor (yes vs. no) and 2) evaluable disease by RECIST 1.1 (yes vs. no). Pts on Arm A crossover to Arm B (M6620+carboplatin) at the earlier of PSA or radiographic progression. For the primary endpoint of overall response rate (ORR; PSA reduction by ≥ 50% or radiographic response by RECIST 1.1), with 65 pts on each arm (total N = 130), there will be 80% power to distinguish ORR of 40% vs. 20% using a chi-square test (one sided α = 0.05). 136 pts will be enrolled to account for 5% dropout. Secondary endpoints include time to PSA progression, radiographic PFS, PFS by PCWG3 criteria, safety and adverse events in each arm. Biomarker studies include whole exome sequencing, RAD51 focus formation, and ATM IHC from tumor specimens. Circulating cell-free DNA from pre-treatment and progression plasma specimens will undergo ultra-low pass whole genome sequencing and deep targeted sequencing. The goal of this study is to expand therapeutic options in mCRPC through a novel approach to targeting the DNA damage response, and to identify biomarkers associating with response and resistance to both standard and trial therapy. Enrollment began June 2019 (NCI/ETCTN #10191). Clinical trial information: NCT03517969.
Phase III study of pembrolizumab (pembro) plus olaparib versus enzalutamide (enza) or abiraterone acetate (abi) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) who progressed on chemotherapy: KEYLYNK-010.
Authors: Yu Evan Y. , Park Se Hoon , Huang Yi-Hsiu , Bennamoun Mostefa , Xu Lu , Kim Jeri , Antonarakis Emmanuel S. 
Published: February 2020

TPS256 Background: Pembro, a PD-1 inhibitor, and olaparib, a PARP inhibitor, have some single-agent antitumor activity in mCRPC. The phase 1b/2 KEYNOTE-365 study (NCT02861573) showed promising activity with pembro and olaparib in pts with mCRPC unselected for homologous recombination deficiency, warranting further investigation. Methods: KEYLYNK-010 (NCT03834519) is a phase 3 trial to evaluate efficacy and safety of pembro + olaparib in molecularly unselected enza- or abi-pretreated pts with mCRPC who progressed with taxane chemotherapy. An estimated 780 pts will be randomly assigned 2:1 to receive pembro 200 mg IV every 3 wk plus olaparib 300 mg orally twice daily or abi 1000 mg orally once daily + prednisone/prednisolone 5 mg orally twice daily (enza-pretreated pts) or enza 160 mg/day orally (abi-pretreated pts). Stratification will be by prior treatment (abi/enza) and measurable disease (yes/no). Adults (≥18 y) with histologically confirmed mCRPC who progressed on androgen deprivation therapy ≤6 mo of screening, and an ECOG PS of 0 or 1 are eligible. Pts previously received either abi or enza (but not both) as well as 1 docetaxel-based regimen. Pts are required to provide tumor tissue for biomarker analysis. Responses will be assessed by CT/MRI and radionuclide bone imaging per Prostate Cancer Working Group 3 (PCWG3)–modified RECIST v1.1 by blinded independent central review (BICR) every 9 wk during the first year and every 12 wk thereafter. Treatment will continue with up to 2 y of pembro (35 cycles) and olaparib or abi/enza until disease progression, unacceptable toxicity, or consent withdrawal. Primary end points are OS and rPFS. Secondary end points are time to initiation of subsequent anticancer therapy; ORR, and DOR per PCWG3-modified RECIST v1.1 by BICR; time to PSA progression; time to first symptomatic skeletal event; time to radiographic soft tissue progression; time to pain progression; and safety. Exploratory end points are identification of molecular (genomic, metabolic, or proteomic) biomarkers indicative of response. Accrual began May 2, 2019. Clinical trial information: NCT03834519.
TALAPRO-2: A placebo-controlled phase III study of talazoparib (TALA) plus enzalutamide (ENZA) for patients with first-line metastatic castration-resistant prostate cancer (mCRPC).
Authors: Agarwal Neeraj , Shore Neal D. , Dunshee Curtis , Karsh Lawrence Ivan , Azad Arun , Fay Andre P. , Carles Joan , Sullivan Beth , Di Santo Nicola , Elmeliegy Mohamed , Lin Xun , Quek Ruben G.W. , Czibere Akos , Fizazi Karim 
Published: February 2020

TPS264 Background: TALA is a poly(ADP-ribose) polymerase (PARP) inhibitor that inhibits PARP1/2 and traps PARP on DNA, preventing DNA damage repair (DDR) and causing death of cells with DDR mutations (eg BRCA1/2). TALA is approved in multiple countries for germline BRCA1/2-mutated HER2- advanced breast cancer. ENZA is an established therapy for CRPC. PARP1 activity has been shown to support AR function, suggesting that co-blockade of PARP1 may synergize with AR-directed therapy, regardless of DDR deficiency. A combination of TALA with ENZA in mCRPC may improve clinical outcomes in patients with or without DDR-deficient tumors. TALAPRO-2 (NCT03395197) is a 2-part study to evaluate efficacy, safety, pharmacokinetics, and patient (pt)-reported outcomes (PROs) of the combination. Methods: Enrollment goal is 1037 pts (19 pts, part 1 dose-finding; 1,018 pts, part 2 placebo-controlled). Key eligibility criteria: age ≥18 y, asymptomatic/mildly symptomatic mCRPC, ECOG performance status ≤1, no brain metastases, and no prior life-prolonging systemic therapy in nonmetastatic CRPC or mCRPC state. Prior docetaxel or novel hormonal therapy (excluding novel AR inhibitors) in castration sensitive (CSPC) setting is allowed. The randomized double-blind portion will evaluate safety, efficacy, and PROs of TALA (0.5 mg QD) + ENZA (160 mg QD) vs placebo + ENZA (160 mg QD). Randomization is stratified by prior NHT or docetaxel 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 v.1.1 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. rPFS will be compared between two arms by a 1-sided stratified log-rank test. Pt recruitment is ongoing in multiple regions including US, Europe/Eastern Europe, Israel, South America, South Africa, and Asia Pacific region. This study was sponsored by Pfizer Inc. Clinical trial information: NCT03395197.