bluuebunny/crossref_metadata_2025_split huggingface dataset:
A multicenter phase II study of abiraterone acetate (AA) in docetaxel pretreated castration-resistant prostate cancer (CRPC) patients (pts)
Authors: Reid A. H. , Attard G. , Danila D. , Ryan C. J. , Thompson E. , Kheoh T. , Molina A. , Small E. , Scher H. , De-Bono J. S. 
Published: August 2020

5047 Background: Despite castration, androgens remain critical to prostate cancer. Abiraterone acetate (AA) specifically and irreversibly inhibits CYP17, a key enzyme in androgen biosynthesis. Methods: 47 CRPC pts who had failed androgen deprivation therapy and had prior docetaxel chemotherapy received AA orally (1000mg QD) in 28 day cycles. Low dose glucocorticoids were allowed. Results: Patient demographics in table . Total maximal PSA declines with AA at any point on study of ≥30%, ≥50%, and ≥ 90% were observed in 32 (69%), 24 (51%) and 7 (15%) pts respectively. A similar trend in PSA response was seen at wk 12. 35 pts were evaluable by RECIST; 6 (17%) pts had a partial response and 23 (66%) pts had stable disease. 23% of pts showed ECOG improvement (PS 1 to 0 in 10 pts, PS 2 to 1 in 1 pt); 53% of pts maintained PS. Median duration on treatment was 167 days (95% CI 130–201). 17 pts received >6 cycles of AA; 8 pts received ≥ 12 cycles. Toxicities related to mineralocorticoid excess were mainly grade 1–2 (hypokalemia 51%; HTN 17%; edema 13%) and were treated with eplerenone or corticosteroids. Conclusions: AA has anti-tumor activity in these heavily pretreated pts, as evidenced by sustained PSA declines, improvement in PS and RECIST responses. A phase III trial assessing the efficacy and safety of AA and prednisone in CRPC pts who have failed docetaxel chemotherapy is underway. [Table: see text] [Table: see text]
Disseminated tumor cells in primary breast cancer: Evaluation of the percentage of breast cancer stem cells in bone marrow aspirates of patients receiving neoadjuvant chemotherapy
Authors: Reuben J. M. , Lee B. , Lucci A. , Gao H. , Cohen E. N. , Li C. , Krishnamurthy S. , Hortobagyi G. N. , Woodward W. A. , Cristofanilli M. 
Published: August 2020

505 Background: Disseminated tumor cells (DTC) in the bone marrow (BM) are related to poor prognosis of primary breast cancer (PBC). Cancer-initiating stem cells (CSC) have been detected in BM of PBC patients. Downregulation of the Notch pathway leads to murine mammary stem cell expansion and its expression is an early event in breast cancer. We enumerated CSC in BM mononuclear cells (BMC) and assessed the expression of Notch-1, ER, and HER-2 to study the differences between untreated patients and those treated with neoadjuvant chemotherapy. Methods: BM was collected from 90 PBC patients at time of surgery to assess DTC (CD326+CD45-) and CSC (CD326+CD45-CD44+CD24-) by FACS analysis. BM samples were also interrogated for the presence of CSC with ALDH activity using the Aldefluor® detection kit. RNA extracted from 61 BMC was analyzed for Notch-1, ER, and HER-2 transcripts by RT-PCR; the level of each transcript was normalized to that of the housekeeping gene, GAPDH. Results: The median age of patients is 51 years old (range, 27–77 years). A total of 29 patients (32%) received neoadjuvant chemotherapy, including 8 patients with anti-HER-2 targeted therapy. BMC of neoadjuvant-treated patients had a significantly higher median percentage of CSC in BMC (P= 0.046) and a significantly higher proportion of CSC cells within the Aldefluor+ population (P= 0.013) than those of untreated patients. Median level of Notch-1 transcripts in BMC was lower in neoadjuvant-treated patients compared with that of untreated patients (P= 0.07). There was an inverse correlation between the level of Notch-1 transcripts and the percentage of CSC in BMC of untreated (Spearman's rho= -0.519, P < 0.001), but not in neoadjuvant treated (Spearman's rho= -0.483, P= 0.058) patients. Conclusions: Neoadjuvant chemotherapy is associated with expansion of CSC in the BMC of patients with PBC. Untreated patients with higher level of Notch-1 transcripts in the BMC tend to have lower percentages of CSC and suggest that Notch signaling may be crucial for differentiation of CSC. The prognostic value of this finding is under investigation and gene expression profile of CSC may provide indications for novel neoadjuvant therapies. No significant financial relationships to disclose.
Denosumab for prevention of fractures in men receiving androgen deprivation therapy (ADT) for prostate cancer (PC)
Authors: Saad F. , Smith M. R. , Egerdie B. , Tammela T. L. , Feldman R. A. , Heracek J. , Szwedowski M. , Ke C. , Leder B. , Goessl C. 
Published: August 2020

5056 Background: ADT increases bone resorption, reduces bone mineral density (BMD), and increases fracture risk. Previously, we reported that denosumab, a fully human monoclonal antibody against RANKL, increased BMD and reduced the incidence of vertebral fractures in men with PC on ADT. We now describe in further detail the effects of denosumab on fractures at other skeletal sites. Methods: Men receiving ADT for nonmetastatic PC were randomized to receive subcutaneous denosumab 60 mg every 6 months (n = 734) or placebo (n = 734), with daily calcium and vitamin D supplements for 3 years. Men < 70 years old were required to have low BMD or a history of osteoporotic fracture. The primary endpoint was percentage change in lumbar spine BMD at 24 months. Key secondary endpoints were subject incidence of new vertebral fractures and fractures at any site (excluding fractures from severe trauma or pathologic fractures) over 3 years. Here, we evaluate the frequency of all fractures and fractures at key osteoporotic sites. The planned sample size (N = 1226) provided power to differentiate effects of denosumab from placebo for the primary and key secondary endpoints. Results: As previously reported, denosumab reduced the incidence of new vertebral fractures by 62% (p = 0.006), fractures at any site by 28% (p = 0.10), and multiple fractures at any site by 72% (p = 0.006) over 3 years. In a post-hoc analysis, we found a consistent trend showing a positive effect of denosumab on nonvertebral fractures. The occurrence of any fractures (counting all fractures within a subject) over 3 years was lower with denosumab than placebo (43 vs 77, p < 0.01). The subject incidence of fractures at 6 high-risk sites (wrist, humerus, hip, pelvis, leg [excluding patella], and clavicle) was numerically lower with denosumab (15 vs 24 placebo; p = 0.12). Also, fewer subjects in the denosumab arm than in the placebo arm reported fractures at key osteoporotic sites (e.g., 2 for denosumab vs 10 for placebo at the radius). Overall rates of adverse events were balanced between treatment arms. Conclusions: Denosumab significantly reduced the incidence of new vertebral fractures and in a post-hoc analysis, showed a trend toward a positive effect on nonvertebral fractures in men receiving ADT for nonmetastatic PC. [Table: see text]
Phase I/II study of docetaxel and 153Sm for castrate metastatic prostate cancer (CMPC): Summary of dose-escalation cohorts and first report on the expansion cohort
Authors: Morris M. J. , Pandit-Taskar N. , Stephenson R. D. , Hong C. , Slovin S. F. , Rathkopf D. , Solit D. , Carrasquillo J. , Larson S. , Scher H. I. 
Published: August 2020

5057 Background: We previously reported (ASCO 2008) that full doses of docetaxel (Tax) and Sm can be repetitively delivered safely using a schedule of q 3 week (wk) Tax and q 6–9 wk Sm. Here we summarize the dose-escalation cohorts and safety/efficacy data from the expansion cohort of 24 pts. Methods: Cohorts of 3–6 pts with CPMC were defined by: 65, 70, 75, 75, 75 mg/m2 of Tax and Sam 0.5, 0.5, 0.5, 0.75, 1 mCi/kg. Each cycle was 6 wks. The expansion cohort used 75 mg/m2 Tax (q 3 wk) and 1 mCi/kg Sm (q 9 wk). Pts with an ANC of grade 0–1 and platelet count of > 100,000/mm3 at the end of cycle 1 received additional cycles until progression or toxicity. Results: 52 pts have been treated. 28 pts were taxane naïve, 11 received previous taxanes but were not refractory, and 13 were taxane refractory. As anticipated, side effects were primarily hematologic. However, the leading cause for treatment termination was disease progression, involving 16/52 (31%) pts, rather than toxicity. 12/52 (23%) pts came off for thrombocytopenia, and 2/52 (4%) pts experienced neutropenic fever. Cohort 3 tolerated the highest cumulative dose and total number of doses of docetaxel (mean of 8 doses, range 4–12; mean total dose 600 mg/m2, range 300–900 mg/m2). Cohort 5 tolerated the highest exposure to Sm (mean of 3 doses, range 1–5). 50 pts are evaluable for response; 22 (44%) achieved a ≥ 50% decline in PSA. 50% of the taxane naïve patients achieved a significant PSA decline, as did 55% of the taxane exposed, and 23% of the taxane refractory pts. Mean time to progression in the taxane naïve, treated, and refractory groups were: 7.5 (range 1.4–22.6), 5.8 (range 0.7–13.7), and 4.3 (range 0.7–11.2) months. Conclusions: This regimen is safe and appears to be active both in taxane naïve and taxane refractory patients, as reflected by favorable toxicity profiles, and rates of significant PSA declines and times to progression. The optimal phase II dose may differ by the population treated. For studies involving taxane naïve patients, the regimen of cohort 3 maximizes docetaxel exposure; for studies of taxane refractory patients, cohort 5 maximizes Sm exposure. Support: EUSA, NIH CA102544. [Table: see text]
A phase II study of neoadjuvant chemotherapy with docetaxel and bevacizumab in patients (pts) with high-risk localized prostate cancer: A Prostate Cancer Clinical Trials Consortium trial
Authors: Oh W. K. , Febbo P. G. , Richie J. P. , Fennessy F. M. , Scibelli G. , Hayes J. H. , Choueiri T. K. , Tempany C. M. , Taplin M. E. , Ross R. W. 
Published: August 2020

5060 Background: Treatment options for high-risk localized prostate cancer remain inadequate, with the majority of pts relapsing despite surgery or radiation therapy. We conducted a phase II multicenter trial of neoadjuvant docetaxel and bevacizumab prior to radical prostatectomy in pts with high risk localized prostate cancer. Methods: Eligibility included any of the following: PSA > 20 ng/ml or PSA velocity > 2 ng/ml/yr, cT3 disease, any biopsy Gleason 8–10, Gleason 7 with T3 disease by endorectal (er) MRI. Also, >50% biopsy cores involved and either Gleason 7 or PSA >10 or cT2 disease were eligible. Pts were treated with docetaxel 70 mg/m2 q 3weeks x 6 cycles and bevacizumab 15 mg/m2 q 3 weeks x 5 cycles. The primary endpoint was erMRI partial response (PR, defined here as >50% decrease in tumor volume) in a single target lesion after chemotherapy. Results: 42 pts were registered and treated with 220 cycles so far. Median age was 55 yrs (range 41–67). Median Gleason score was 8 (69% with Gleason 8–10 cancer). Median PSA was 10.5 ng/ml (range 2.1–72.5). Clinical stage was T2 in 46% and T3 in 32%. Of 23 evaluable pts to date, the median decline in the maximal tumor volume by erMRI was -45% (range -84% to 110%). 9/23 (39%) patients had PR, and only 1 pt had radiographic progression. Any PSA decline was noted in 22/34 (65%) evaluable pts, with 18% having a >50% decline. Treatment was well-tolerated: 2 pts had grade 3 allergic reactions requiring discontinuation, 3 had febrile neutropenia and 1 had grade 3 hyperglycemia. Mild fatigue was common. Only 1 pt stopped treatment because of a rising PSA. To date, 31 pts have had radical prostatectomy. One had intraoperative bladder neck injury and was treated instead with radiation + hormone therapy. A second pt had an intraoperative rectal injury but completed surgery. Conclusions: Neoadjuvant docetaxel and bevacizumab demonstrates clinical evidence of activity in men with high-risk localized prostate cancer, with a 39% PR rate by erMRI and PSA declines noted in 65%. Treatment was well-tolerated. The study is ongoing and updated data on response, toxicity and pathology will be presented. [Table: see text]
An open-label, multicenter, phase I/II study of AT-101 in combination with docetaxel (D) and prednisone (P) in men with castrate-resistant prostate cancer (CRPC)
Authors: MacVicar G. R. , Greco A. , Reeves J. , Maleski J. , Holmlund J. , Leopold L. 
Published: August 2020

5062 Background: Antiapoptotic Bcl-2 family proteins are overexpressed in CRPC and contribute to resistance to therapy. The oral pan-Bcl-2 inhibitor AT-101 (Bcl-2, Bcl-XL, Bcl-W, Mcl-1) is active as a single agent and in combination in in vitro and in vivo tumor models and as a single agent in CRPC. The Phase 1 portion of the study determined the recommended dose for phase II to be D (75mg/m2 q3weeks) in combination with P (5mg b.i.d. on days 1–21), and AT-101 at 40mg b.i.d. on days 1–3 of each 21-day cycle, and was previously reported. Methods: Men ≥18 years of age with chemotherapy-naïve CRPC (N = 36). Safety (NCI CTCAE v3.0) and efficacy (Bubley Criteria for PSA) were assessed at 3-wk intervals. Radiological assessments were performed at 6-wk intervals for pts with soft tissue disease and bone scans were performed after cycle 6 and at the completion of therapy. Results: 36 patients (pts) have been enrolled in the study. Twenty-four (67%) pts achieved a partial response (PR) (>50% PSA decline), and 26 (72%) pts treated had at least a 30% decrease in PSA level. Nine of 19 pts (47%) with measurable disease had a PR. One PR was unconfirmed per RECIST. Thirteen pts (36%) completed >10 cycles of therapy (range 2–24) thus far. Four pts remains active. Safety data is available for 31 pts. The most common (>20%) Adverse Events (AEs) include: fatigue (68%), nausea (52%), diarrhea (45%), alopecia (32%), constipation and dysgeusia (26%), and neutropenia and vomiting (26%). Neutropenia was the only gr. 4 event occurring in more than one pt (3pts). Serious Adverse Events (SAEs) considered related were reported in 5 pts (16%). The only SAEs reported in 2 or more pts were urinary tract infection (3 pts) and deep vein thrombosis (2 pts) and none were considered related. No ileus has been reported. Conclusions: AT-101 when given in combination with D/P is well tolerated and shows preliminary evidence of efficacy in pts with CRPC. A randomized trial is ongoing. [Table: see text]
A phase I study of CNTO328, an anti-interleukin (IL)-6 monoclonal antibody combined with docetaxel in subjects with metastatic castration-resistant prostate cancer (CRPC)
Authors: Hudes G. , Tagawa S. , Whang Y. , Qi M. , Qin X. , Puchalski T. , Prabhakar U. , O’Brien K. , Eisenberger M. 
Published: August 2020

5063 Background: IL-6 is a potential mediator of prostate cancer morbidity and mortality and may protect prostate cancer cells from chemotherapy-induced apoptosis. CNTO328, a chimeric anti-IL-6 antibody, has been shown to inhibit prostate tumor growth in xenograft mouse models. Methods: Chemotherapy-naïve patients with metastatic CRPC were administered CNTO328 in combination with T (75 mg/m2 q3w) in 3 dose-escalation cohorts (6 mg/kg q2w, and 9 and 12 mg/kg q3w) following an initial run-in cycle of T alone to examine the effect of CNTO328 on T pharmacokinetics (PK). Safety was evaluated prior to each dose escalation. Prostate specific antigen (PSA), radiological response, and C-reactive protein (CRP), the best-known surrogate of serum IL-6 bioactivity, were also assessed. Results: This study is fully enrolled December 2008 with 38 patients. 36 patients with KPS ≥70, median age 66 (range 43–82) received 6 (median) cycles of T (range 1–37). 32 patients received at least one dose of CNTO328 in combination with T and are evaluable. Baseline patient characteristics included: median PSA of 59 ng/mL (range 12–1430) and median CRP was 3.85 mg/L (range <1 to 91.3). One DLT was observed in each cohort (grade 4 neutropenic infection, grade 3 syncope and dehydration, grade 3 GI bleeding), though MTD for the combination was not reached. Most frequent ≥grade 3 adverse events (AE) were neutropenia (69%); leukopenia (63%); lymphopenia (31%); dyspnea (19%); fatigue (16%). One patient died due to AE (sepsis) reported as possible related to T and unlikely related to CNTO328 by investigator. Preliminary data show CNTO328 does not appear to have a major effect on T PK. Preliminary efficacy data is shown in the table . Ongoing evaluation indicates 3/12 partial responses in patients with measurable disease reported thus far. Conclusions: CNTO328 with T is well tolerated and demonstrates biological and clinical activity in CRPC that warrants further study. [Table: see text] [Table: see text]
A phase II study of sunitinib on a continuous dosing schedule in patients (pts) with relapsed or refractory urothelial carcinoma (UC)
Authors: Gallagher D. J. , Milowsky M. I. , Gerst S. R. , Tickoo S. , Ishill N. , Ishill N. , Regazzi A. , Trout A. , Bajorin D. F. 
Published: August 2020

5072 Background: Suntinib has demonstrated activity in the second-line setting for pts with advanced UC when administered on a 4 week on/2 week off schedule. This study was designed to evaluate an alternative 37.5 mg/day continuous dosing schedule for sunitinib in the same setting. Methods: The primary objectives of this single institution phase II study of sunitinib in pts with UC who have failed prior chemotherapy were: 1) to determine the response rate (by RECIST); and 2) to evaluate toxicity. Secondary endpoints include: 1) correlation of response and toxicity with HIF and mTOR pathway marker expression; and 2) phamacokinetics. Pts may not have received >4 prior cytotoxic agents. Pts received sunitinib 37.5 mg/day continuous dosing.. Response was assessed after each of the initial 4 cycles and every other cycle thereafter. A minimax 2-stage design was used (maximal 32 pts). Results: 31 pts (21 M, 10 F) with a median age of 68 yrs and median KPS of 90 were enrolled between 10/15/07 and 12/18/08. Primary sites included bladder (28), and renal pelvis (3). Prior therapy included 1 pt with 1 drug, 19 pts with 2, 7 with 3 and 4 with 4. 25 pts had visceral metastases and 6 pts had lymph node only metastases. 25 pts were evaluable for response after completing at least 1 cycle. One pt achieved PR, 12 pts had SD, 12 had PD, 2 are too early to assess for response, and 4 patients did not complete cycle 1 (2 related to toxicity, and 2 related to non-treatment-related deaths). Radiographic regression was seen in liver, lung, soft tissue and lymph nodes. With a median follow up of 4 months, median progression free survival was 2 months (95% CI, 1 - 4 months) and median overall survival was 7 months (95% CI, 4 months - not achieved). Clinically significant toxicity (Grade 3/4) included: abdominal pain (1), anorexia (1), diarrhea (1), fatigue (4), hand and foot syndrome (2), hemorrhage (2), hypertension (2), mucositis (2), thrombosis (2), and emesis (1). Conclusions: Sunitinib has modest activity when administered on a 37.5 mg continuous dosing schedule to patients with relapsed or refractory UC with a similar toxicity profile to the 50 mg in the 4 /2 schedule. Upcoming trials will evaluate sunitinib in combination with standard chemotherapy in pts with UC. [Table: see text]
Maintenance sunitinib postchemotherapy (CT) in patients (pts) with advanced urothelial carcinoma (UC): A randomized placebo controlled phase II trial
Authors: Bradley D. , Daignault S. , Smith D. C. , Nanus D. , Tagawa S. , Stadler W. M. , Garcia J. , Dreicer R. , Al-Hawary M. , Hussain M. 
Published: August 2020

5073 Background: Although response to CT is common in pts with advanced UC it is rarely durable. Sunitinib is an oral small molecule inhibitor of receptor tyrosine kinases regulating angiogenesis including VEGFR-1, -2, -3, and PDGFR-α, -β with demonstrated antitumor activity in a variety of solid tumors. Inhibition of angiogenesis following CT may delay disease progression. Therefore, we are evaluating maintenance sunitinib in a phase II study. Methods: Pts with advanced UC, > stable disease (SD) after 4–6 cycles of CT, a performance status (PS) 0–2, adequate organ function and < 42 days from last CT dose were randomized to sunitinib 50 mg or placebo; 4 weeks (wks) on 2 off in 6 wk cycles. Pts were stratified by response to CT. Disease was assessed every 12 wks. Pts were unblinded for progression or unacceptable adverse events (AEs), with placebo pts offered open label sunitinib. The primary end point is 6 month progression rate using a modified version of the randomized selection design (Simon 1985). 42 pts/arm are to be accrued to allow selection of the superior arm with 90% probability. Other endpoints include safety, response rate (RR), time to progression, median survival, RR to open label sunitinib and correlation of changes in serum VEGF and sVEGFR-2 levels with outcome. Results: To date, 28 pts have been registered and 26 have completed > 12 wks of therapy. Median age is 69 years (48–81) and PS is 1 (37% PS 0, 52% PS 1). 12% had a complete response (CR) to prior CT, 46% a partial response (PR) and 42% SD. 14 pts have progressed after a median of 2 cycles (range 1–12). 7 pts received open label sunitinib at progression, 1/7 remains on treatment. Median duration on open label therapy is 2.2 months (11 days-15 months). Best response to open label therapy to date is progressive disease (2 pts), SD (2 pts) for 24 wks, PR in 1 pt through 60 weeks and 2 pts have not reached first assessment. Grade 3 AEs on open label sunitinib included: bladder hemorrhage, increased creatinine, fatigue, thrombocytopenia and hand-and-foot syndrome. No grade 4 or 5 AEs were observed. Conclusions: Preliminary results indicate that maintenance sunitinib post CT is feasible in advanced UC pts and is associated with clinical activity. Supported by Pfizer. [Table: see text]
Vascular thromboembolic events in patients (pts) with advanced urothelial cancer (UC) treated with carboplatin/gemcitabine alone or in combination with bevacizumab
Authors: Apolo A. B. , Regazzi A. M. , Milowsky M. I. , Bajorin D. F. 
Published: August 2020

5074 Background: Vascular thromboembolic events (VTE) occur in 13% of UC pts treated with cisplatin-based therapy ( J Urol 160:2021, 1998). Carboplatin-based therapy is used in UC pts intolerant of cisplatin but the frequency of VTE is unknown. Bevacizumab added to chemotherapy increases VTE in non-small cell lung cancer (NSCLC; 5% vs 3%) (Oncologist 12:713, 2007), breast cancer (7.4% vs 5.5%) and colorectal cancer (19% vs 16%) (JAMA. 2008;300:2288). This study evaluated VTE in UC pts treated with carboplatin/gemcitabine alone or with bevacizumab. Methods: Pts with advanced UC treated on a Memorial Sloan-Kettering Cancer Center protocol from June 2006 to September 2008 were analyzed prospectively. Therapy included > 3 cycles of bevacizumab (15 mg/kg on day 1) plus carboplatin (AUC 5 or 4.5 on day 1) and gemcitabine (1000 mg/m2 on days 1,8) every 21 days. Evaluation for VTE on a contemporary UC control group of pts receiving carboplatin plus gemcitabine alone during the exact same time period was conducted retrospectively. VTE were defined as pulmonary embolism (PE), deep venous thrombosis (DVT), myocardial infarctions (MI) and cerebral vascular accidents (CVA). Pts with simultaneous PE and DVT were considered to have one VTE. Results: 89 pts were evaluated. Of the 25 pts treated with bevacizumab plus chemotherapy, 4 pts (16.0%; 95% CI 5–36%) had a VTE of which there were 2 PE alone, 1 DVT alone, and 1 DVT and PE. No MI was observed in bevacizumab-treated pts. Of the 64 contemporary control pts treated with gemcitabine plus carboplatin alone, there were 11 pts (17%; 95% CI 9–29%) who had a VTE of which there were 4 PE alone, 4 DVT alone, 2 DVT and PE, and 1 MI. No CVA were seen in either group. Conclusions: Pts with advanced UC receiving carboplatin plus gemcitabine have a very high rate of VTE (17%). The VTE incidence is similar to colon cancer (16%) and greater than NSCLC (3%) and breast cancer (5.5%). The VTE rate is similar for both cisplatin and carboplatin, suggesting that it is intrinsic to the UC disease state. In this study, the addition of bevacizumab to carboplatin/gemcitabine was not associated with an increase in VTE over that seen for carboplatin/gemcitabine alone. No significant financial relationships to disclose.