bluuebunny/crossref_metadata_2025 huggingface dataset:
Continuous daily administration of sunitinib in patients (pts) with cytokine-refractory metastatic renal cell carcinoma (mRCC): Updated results
Authors: Srinivas S. , Roigas J. , Gillessen S. , Harmenberg U. , De Mulder P. H. , Fountzilas G. , Vogelzang N. , Peschel C. , Flodgren P. , Escudier B.
Published: March 2020

5040

Background: Sunitinib malate, an oral, multitargeted tyrosine kinase inhibitor of multiple receptors, showed significant efficacy in 168 pts with cytokine refractory mRCC, with a 42% objective response rate (ORR) and progression-free survival (PFS) of 8.2 months at 50 mg/day (4 weeks on treatment, 2 weeks off) per investigator assessment (Motzer et al. JAMA 2006;295:2516–24). This study was designed to determine the efficacy and safety of single-agent sunitinib when administered in a continuous 37.5 mg/day regimen. Methods: Pts with histologically proven mRCC, refractory to a cytokine-based regimen, were enrolled in this open-label, multicenter, phase II study. Eligibility criteria included measurable disease, ECOG PS 0/1, and adequate organ function. Pts were randomized to receive sunitinib in the morning (AM) or in the evening (PM) at a dose of 37.5 mg/day, with individual doses subsequently titrated based on tolerability. The primary endpoint was RECIST-defined ORR. Secondary endpoints included PFS, adverse events (AEs) and quality of life measures. Results: 107 pts were randomized to AM (54) or PM (53) dosing and have been on study a median of 6.8 months (0.4 to 13.3). As of October 2006, 55 pts have discontinued due to progression (37 pts [35%]), AEs (17 pts [16%]), and 1 consent withdrawal (1%); 47 pts (44%) were dose reduced to 25 mg/day due to grade 2/3 AEs, the most frequent being: asthenia (12%), hand-foot syndrome (8%), and diarrhea (5%). The most commonly reported (=5% of pts) grade 3/4 AEs were hypertension (10%), asthenia (9%), hand-foot syndrome (9%), anorexia (8%), and diarrhea (6%). 31 pts (29%) were maintained on continuous sunitinib at 37.5 mg/day, and 29 (27%) were escalated to 50 mg/day. There were no significant differences between pts who received AM or PM dosing. Quality of life results will be presented. The best response by RECIST per investigator assessment shows an ORR of 19% with 43 pts (40%) with =6 months of stable disease. The median PFS is 8.3 months. Conclusions: Sunitinib 37.5 mg/day continuous dosing has a manageable safety profile and demonstrates promising clinical benefit as second-line therapy in mRCC. This regimen provides alternative sunitinib dosing that can be explored in combination studies.

No significant financial relationships to disclose.
Personalized surveillance and prognostication of patients undergoing kidney cancer surgery: The 15-year UCLA experience
Authors: Belldegrun A. S. , Riggs S. , Zomorodian N. , Pantuck A. J. , Klatte T. , Kabbinavar F. F.
Published: March 2020

5045

Background: Renal cell carcinoma (RCC) is a heterogeneous disease with varying biology, clinical manifestations, and outcome. An evolving understanding of prognostic factors for patients is leading toward individualized surveillance as well as treatment. We reviewed our large single center experience trying to maximize prognostication and surveillance for each patient. Methods: The charts of 1,825 patients with renal masses from 1989–2006 were reviewed and 263 variables/patient were recorded. 1,492 underwent partial or radical nephrectomy with the final histology being RCC. Statistical analysis was performed via Cox regression and concordance models. This enabled us to investigate the Surveillance & Prognosis University of California Integrated Staging System (S&P-UISS), a 3-tiered group system for based on low (LR), intermediate (IR) and high risk (HR) categorization separately for both non-metastatic (NM) and metastatic (M) patients, and to compare its prognostic accuracy with the current TNM classification. Results: Of all patients analyzed 66% were male. A Fuhrman grade of 1, 2, 3 and 4 was assigned to 179 (12.3%), 675 (46.5%), 485 (33.4%), and 114 patients (7.8%), respectively. ECOG performance status was 0, 1, 2 and 3 in 768 (52.1%), 652 (44.3%), 51 (3.5%), and 2 (0.1%), respectively. The disease-specific survival (%) for NM LR (n=326, 22%), IR (n=464, 32%), and HR (n=121, 8%) patients was, respectively, 97, 81, 62 at 5 years; 92, 46, 41 at 10 years; 92, 45, 20 at 15 years. For M LR (n=78, 5%), IR (n=406, 28%) and HR (n=58, 4%) survival was 41, 18, 8 at 5 years; 31, 7, 0 at 10 years; and 31, 0, 0 at 15 years, respectively. Based on concordance statistics, S&P-UISS predicted disease-specific survival better than the 2002 TNM system. Conclusions: The S&P-UISS system is a highly reliable and reproducible predictor of mortality following surgical therapy for localized and metastatic RCC. Surveillance and personal treatments should be individualized for a particular patient based on risk group categorization following surgery for their primary tumor. Accurate prognostication allows personal tailoring for treatments as well as allocation into clinical trials.

No significant financial relationships to disclose.
Clinical factors associated with outcome in metastatic renal cell carcinoma patients treated with VEGF-targeted therapy
Authors: Golshayan A. , Choueiri T. K. , Elson P. , Garcia J. A. , Khaswneh M. , Usman S. , Tamaskar I. , Wood L. , Rini B. I. , Bukowski R. M.
Published: March 2020

5046

Background: Therapy targeted against the vascular endothelial growth factor (VEGF) pathway is a standard of care in metastatic renal cell carcinoma (RCC). Identification of clinical features of patients more likely to benefit from these agents would aid in patient selection and interpretation of clinical trial results. Methods: We reviewed 120 metastatic RCC patients receiving bevacizumab, sorafenib, sunitinib or axitinib on one of eight prospective clinical trials at the Cleveland Clinic Taussig Cancer Center. Clinical features associated with outcome were identified by univariate analysis, and then a stepwise modeling approach based on Cox proportional hazards regression was used to identify independent prognostic factors and form a model for progression-free survival (PFS). A bootstrap algorithm was used to provide internal validation. Results: Forty-one patients (34%) achieved an objective response by RECIST criteria (95% C.I. 27–44%). The median PFS for the entire group was 13.8 months (m) (95% C.I. 10.7–19.0 m). Multivariate analysis identified the following independent adverse prognostic factors (PF) for PFS: time from diagnosis to current treatment <2 years, baseline platelet count >300 K/μL, baseline neutrophil count >4.5 K/μL, baseline corrected serum calcium <8.5 or >10.0 mg/dL and initial ECOG performance status >0. Using these factors three prognostic subgroups were formed based on the number of adverse PF present . Median PFS in patients with 0 or 1 adverse PF was 20.1 m (95% C.I. 19.0–22.3 m) compared to 13 m (95% C.I. 8.6–17.6 m) in patients with 2 adverse PF and 3.9 m (95% C.I. 1.8–7.2 m) in patients with >2 adverse PF. Conclusions: Five independent prognostic factors for predicting PFS were identified and used to categorize patients with metastatic RCC receiving VEGF-targeted therapies into three risk groups. These factors can be readily incorporated to clinical patient care, stratification schema for clinical trials utilizing these novel agents and for interpretation of clinical trial results using VEGF-targeted agents therapy.

No significant financial relationships to disclose.
Prolonged survival in patients with persistently elevated tumor markers after chemotherapy for nonseminomatous germ cell cancer
Authors: He Z. , Sun Z. , Liu G. , Manola J. , Loehrer P.
Published: March 2020

5051

Background: Persistently elevated levels of either AFP or HCG or both after chemotherapy are thought to represent residual viable disease while the normalization of tumor markers predicts favorable outcomes. This study was to evaluate the clinical implication of tumor marker normalization for disseminated nonseminomatous germ cell tumors (GCTs). Methods: This was a retrospective data analysis from two prospective randomized trials (ECOG E4887 and E3887). In E4887, 178 patients with minimal- or moderate-stage disease (Indiana stage) were randomized to receive three cycles of cisplatin plus etoposide with/without bleomycin. In E3887, 304 patients with advanced disseminated GCTs were randomized to receive four cycles of bleomycin, etoposide and cisplatin versus the combination of etoposide, ifosfamide and cisplatin. AFP and HCG were assessed at baseline and after each cycle of chemotherapy. Tumor marker normalization was defined as AFP or HCG normalized after completing chemotherapy. OS and PFS curves were estimated by the Kaplan-Meier method. Multivariate and univariate models, stratified on International Germ Cell Consensus Classification (IGCCCG), were used to assess the impact of marker normalization for patients with abnormal markers at study entry. Results: Median follow-up is 14.8 years. About 40% to 60% of Patients with persistently elevated AFP or HCG after chemotherapy have prolonged PFS and/or OS. In IGCCCG poor risk patients, 35% to 55% of them with persistently elevated AFP or HCG after chemotherapy have prolonged PFS and/or OS. There is a statistically significant difference in OS associated with AFP normalization in both multivariate (p=0.008, HR=0.51 with 95% CI=0.31–0.84) and univariate analysis (p=0.0008, HR=0.43 with 95% CI=0.26–0.71). However, there was no statistically significant difference in OS associated with normalization of HCG in both multivariate analysis (p=0.52, HR=0.84 with 95% CI=0.50–1.41) and univariate analysis (p=0.29, HR=0.76 with 95% CI=0.46–1.26). Conclusions: Patients with persistently elevated AFP or HCG after chemotherapy may still have prolonged PFS and/or OS. Normalization of AFP but not HCG is associated with better OS in patients with disseminated nonseminomatous GCTs.

No significant financial relationships to disclose.
A nomogram predicting survival of patients (pts) with metastatic or unresectable urothelial cancer (UC) treated with cisplatin-based chemotherapy
Authors: Bajorin D. F. , Ostrovnaya I. , Iasonos A. , Milowsky M. I. , Boyle M. , Riches J.
Published: March 2020

5055

Background: Cisplatin-based chemotherapy is the standard of care for pts with metastatic or unresectable UC with phase III studies reporting median survivals of 12–15 months. Even more survival variation exists in phase II studies and this disparity is most frequently due to prognostic factors and not individual regimens. Thus, better tools are needed to predict survival both for individual pts and to balance phase III trials. Nomograms have utility in predicting short- and long-term outcome in muscle-invasive UC treated by surgery but they have not been explored in more advanced UC. Methods: We identified 308 pts with metastatic and/or unresectable UC treated on prospective phase II MSKCC protocols of cisplatin-based therapy containing 3–5 total chemotherapy agents. 203 pts received methotrexate, vinblastine, doxorubicin and cisplatin (MVAC), 45 had ifosfamide, paclitaxel and cisplatin (ITP) and 60 pts received doxorubicin plus gemcitabine (AG) followed by ITP (AG-ITP). Survival distributions were compared across trials. Pre-treatment characteristics were then assessed for impact on survival and a nomogram from a fitted Cox model was created to predict 1-yr, 2-yr, 5-yr and median survival. Results: No difference in median survivals were seen among the 3 regimens; median survival was 14.8 months for MVAC, 18.0 months for ITP and 16.1 months for AG- ITP (p=NS). Median survival for all pts was 12.99 months; 268 pts died and 40 pts were censored. 288 pts had all pre-treatment data. Characteristics most associated with survival included visceral metastases (present versus absent, p=.00001) and Karnofsky poor performance status (≥ 80 versus < 80, p= .0005) followed by hemoglobin (normal versus < normal, p=.01) and albumin (actual values, p<.02). These characteristics were then used to construct a nomogram utilizing all 4 factors to predict probabilities of 1-yr, 2-yr, and 5-yr survival. Conclusions: The number and sequence of drugs utilized in cisplatin-based chemotherapy did not substantially impact survival of pts with advanced UC. A nomogram of pre-treatment clinical factors can predict probability of pt survival at 1 yr, 2yrs, and 5 yrs. This nomogram may also be useful to balance treatment arms in phase III trials.

No significant financial relationships to disclose.
Phase I study of continuous oral dosing of an irreversible CYP17 inhibitor, abiraterone (A), in castration refractory prostate cancer (CRPC) patients (p) incorporating the evaluation of androgens and steroid metabolites in plasma and tumor
Authors: Attard G. , Yap T. A. , Reid A. H. , Parker C. , Barrett M. , Raynaud F. , Dowsett M. , Dearnaley D. , Lee G. , De Bono J. S.
Published: March 2020

5063

Background: Despite androgen deprivation therapy, recent studies indicate high levels of intra-tumor androgens and continued androgen receptor (AR) signalling in CRPC. Methods: A phase I trial to evaluate the safety and tolerability of A administered once daily at 250, 500, 750, 1,000 and 2,000 mg to chemotherapy-naïve CRPC p. Extensive endocrine evaluation and CTC enumeration were undertaken. Tumor biopsies pre- and post-therapy were evaluated for androgen levels and TMPRSS2/ETS gene translocations. To investigate secondary resistance due to activation of a promiscuous AR by raised precursor steroids upstream of CYP17, all p who progressed were offered combination treatment of A with dexamethasone 0.5mg od (D). Results: 15 p were treated in 3-p cohorts with PSA declines >70% in 9/16 p ( table ) and subsequent expansion of the maximum biologically available dose of 1,000mg (19 p treated to date). All p had progressed on LHRH agonists and antiandrogens, 7/15 on diethylstilboestrol and 7/15 on steroids. No dose limiting toxicities were observed and the only = grade 2 toxicity was reversible hypertension (5 pts) due to CYP17 inhibition. Pharmacokinetics were dose-proportional; mean drug clearance was 803L/hour; mean Vd was 11680L; mean elimination half-life was 10.6 hours. At all dose levels, treatment was associated with increased steroid precursor levels upstream of CYP17, including up to a 300-fold rise in corticosterone levels, as well as loss of detection of adrenal androgens. Circulating testosterone levels were in the castrate range (<50 ng/dl) at baseline, rapidly becoming undetectable (<1 ng/dl) in all p. Conclusion: A can be safely administered to CRPC pts with CYP17 suppression and important anti-tumor activity suggesting that at least 60% of CRPC are still hormone driven. Phase II evaluation of 1,000 mg is ongoing.

[Table: see text]

[Table: see text]
Results of a randomized phase II study of irofulven in hormone-refractory prostate cancer patients that have failed first-line docetaxel treatment
Authors: Berger E. R. , Ciuleanu T. , Hart L. , Chi K. N. , Alexandre J. , Oudard S. , Kahatt C. , Weems G. , Cvitkovic E. , MacDonald J. R.
Published: March 2020

5068

Background: Currently, no available treatments demonstrate an increase in survival for patients (pts) with hormone- refractory prostate cancer (HRPC) who have failed treatment with docetaxel-based regimens. Previous monotherapy and combination Phase I/II trials with irofulven (IROF) have shown antitumor effects in pts with HRPC, including those with resistance to docetaxel. A randomized phase II study was undertaken in HRPC pts with documented resistance to docetaxel to evaluate the efficacy and safety of IROF regimens compared to mitoxantrone (MITOX). Methods: Pts with metastatic HRPC with documented progression by RECIST or PSA Working Group criteria during or within 3 months of prior docetaxel were randomized to 1 of 3 arms in a 2:2:1 ratio: Arm A: IROF (0.45 mg/kg, Day [D]1, 8 every [q] 3 weeks [w]) and prednisone (PRED; 10 mg qd); Arm B: IROF (0.4 mg/kg D1, 15), capecitabine (CAPE; 2,000 mg/m2 D1–15 q4w) and PRED; Arm C: MITOX (12 mg/m2 q3w) and PRED. Pts were stratified by baseline pain status. Efficacy endpoints included time to progression (TTP), overall survival (OS), and response. Results: Enrollment of 134 treated pts was completed as of Jan 2006 (Arm A/B/C: 53/54/27). Median age: 64/66/63 years, median KPS: 80/90/80, median baseline PSA (ng/mL): 144/136/243, disease-related pain at baseline: 65%/57%/59%, and median number of metastatic sites: 1/1/2. Median pre-study PSA doubling time (days) was 42/44/50. Efficacy: As of Jan 2007, median OS (mos) was 10.1/9.5/7.4 in Arms A/B/C (based on 73% of pt deaths). Preliminary median TTP (mos) was 2.2/3.8/1.8, based mainly on PSA progression. PSA and RECIST responses were 10%/22%/0% and 10%/10%/13%, respectively. Safety: Treatment was well tolerated in all arms. The most frequent Grade 3–4 toxicities (% pts) were asthenia (8%/15%/0%), and vomiting (4%/11%/0%). Grade 3–4 hematological events included neutropenia (22%/15%/61%) and thrombocytopenia (23%/21%/4%). Conclusions: Results to date indicate longer survival, longer TTP, and greater PSA response for IROF/PRED and IROF/CAPE/PRED compared to MITOX/PRED. Based on these data, a larger randomized trial of irofulven in docetaxel resistant HRPC patients is warranted.

No significant financial relationships to disclose.
A randomized phase II study of OGX-011 in combination with docetaxel and prednisone or docetaxel and prednisone alone in patients with metastatic hormone refractory prostate cancer (HRPC)
Authors: Chi K. N. , Hotte S. J. , Yu E. , Eigl B. J. , Tannock I. , Saad F. , North S. , Powers J. , Eisenhauer E. ,   National Cancer Institute of Canada—Clinical Trials Group
Published: March 2020

5069

Background: Clusterin, a cytoprotective chaperone protein that promotes cell survival, is associated with androgen independent progression and overexpressed in HRPC. OGX-011 (OGX, developed by OncoGenex Technologies/Isis Pharmaceuticals) is a 2’- methoxyethyl modified phosphorothioate antisense that inhibits clusterin expression in humans at doses of ≤640 mg and potentiates chemotherapy activity in prostate xenografts. The objective of this study was to determine the anti-tumor activity of OGX in combination with docetaxel (DOC) in patients (pts) with HRPC. Methods: Chemo-naive pts with metastatic HRPC were randomized to receive DOC 75mg/m2 q3 weeks + OGX 640mg weekly as a 2-hour IV infusion (Arm A) + prednisone or DOC + prednisone (Arm B). Serum levels of clusterin were assessed serially. A single stage randomized phase II design was employed with PSA response rate (RR) as the primary endpoint (Bubley et al, J Clin Oncol 1999;17:3461). Planned sample size was 40 per arm: Arm A the hypotheses (H0:PSA RR<40% vs. H1:PSA RR>60%) could be tested at 10% β and 10% a, Arm B the true PSA RR could be estimated with half-width of the 90% confidence interval <13% if observed PSA RR was 40%. Results: 82 pts (41/arm) were enrolled from September 2005 to December 2006 at 12 centers. Baseline characteristics are similar in both arms (available to date for 63 pts): median age 67 (range: 49–84), PSA 110 μg/L (5.6–1261), hemoglobin 128 g/L (96–158), alkaline phosphatase 133 U/L (47–1294), LDH 193 U/L (120–741). ECOG performance status was 0 in 49% and 1 in 51%; 67% had bone/nodal disease only and 33% had other metastatic sites. To date, 56 pts have received ≥2 cycles. Toxicity due to OGX included grade 1/2 fevers and rigors in 37% and 67% pts respectively, but other adverse events were similar in both arms. PSA response has occurred in 43%, progression in 9%, and 48% have not yet met criteria for response or progression. Conclusions: Combined docetaxel and OGX is well tolerated in pts with metastatic HRPC and PSA responses have been observed. Pt treatment, follow-up and analysis of serum clusterin levels continue. Results by arm will be available by June 2007. Supported by a grant from the NCI-Canada/Canadian Cancer Society.

No significant financial relationships to disclose.
Correlation of 11C-choline PET and PSA values in patients with prostate cancer and biochemical relapse after primary treatments
Authors: Vormola R. , Ortega C. , Montemurro F. , Capaldi A. , Cirillo S. , Gabriele P. , Muto G. , Aglietta M.
Published: March 2020

5073

Background: 11C-choline PET has demonstrated promising results in the evaluation of suspected recurrence after a primary treatment in prostate cancer (PC) patients (pts). However in pts with asymptomatic biochemical relapse (BR), the timing of PET scan is a subject of controversy. Most authors argue against performing PET scan for rising PSA values <5 ng/ml. Aim of our study was to evaluate if there is a PSA cut-off that significatively correlates to 11C-choline PET positivity. Methods: 68 pts with rising PSA after primary treatment underwent 11C-choline PET. Median age was 68 yrs (range 43–84). Median PSA at the time of PET scan was 2.91 ng/ml (range 0.12- 71.60). Primary treatments were: 27 (40%) radical prostatectomy (RP), 22 (32%) external-beam radiation therapy (EBRT), 13 (19%) RP + adjuvant EBRT, 6 (9%) hormonal therapy. Results: 11C-choline PET was positive in 39/68 pts (57%) and negative in 29/68 (43%). Median PSA values were 1.18 ng/ml (range 0.12–6.47) and 5.14 ng/ml (range 1.33–71.60) in pts with negative and positive PET scan respectively. Median PSA values were statistically different in positive and negative 11C-choline PET (Mann-Whitney U Test. p< 0.001). No positive uptake was seen in pts with PSA <1 ng/ml (12/68); all pts with PSA >6.5 ng/ml had a positive finding; for PSA values between 1 and 6.5 ng/ml (33/68), 11C- choline PET showed a pathological uptake in 18 pts. The Receiver Operative Characteristic (ROC) analysis found that a PSA cut-off of 2.31 ng/ml has a sensitivity of 87% and a specificity of 83% in respect of 11C-choline PET positivity. Conclusions: For PSA values > 2.3 ng/ml the probability to have a positive 11C-choline PET is high in order to recommend to perform the exam in clinical practice, even if further data are needed. On the contrary, we can’t suggest to perform PET scan in pts with PSA <1 ng/ml.

No significant financial relationships to disclose.
C-reactive protein as a prognostic marker for men with androgen-independent prostate cancer (AIPC): Results from the ASCENT trial
Authors: Graff J. , Lalani A. S. , Lee S. , Curd J. G. , Henner W. D. , Ryan C. W. , Venner P. M. , Ruether J. D. , Chi K. N. , Beer T. M. ,   ASCENT Investigators
Published: March 2020

5074

Background: Concentrations of blood proteins such as PSA, hemoglobin (HGB), and LDH are associated with survival in men with AIPC. We sought to identify additional blood proteins associated with prognosis in chemotherapy-treated AIPC patients. Methods: Baseline plasma samples were stored (-80°C) from 160 patients enrolled in the ASCENT trial, a randomized placebo-controlled phase 2 trial comparing weekly docetaxel plus DN-101, an oral high-dose formulation of calcitriol, to weekly docetaxel. Multiplex immunoassays measured 16 cytokine/chemokine or cardiovascular/inflammation markers including IL-1a, IL-1β, IL-2, IL-6, IL-8, IL-10, TNFa, MCP-1, EGF, VEGF, PAI-1, MMP-9, sE-Selectin, sICAM-1, sVCAM-1 and C-reactive protein (CRP). Cox’s proportional hazard model was used to assess association between baseline biomarkers and survival or skeletal-related event (SRE)-free survival, and logistic regression for PSA Working Group Criteria response. Results: Baseline characteristics were similar to those of the 90 patients without samples, except for age (mean 68.0 vs. 70.6 yrs) and HGB (12.8 vs. 12.2 g/dL). CRP was the only biomarker that significantly predicted shorter overall survival (HR 1.41, 95% CI 1.20–1.65, p < 0.0001). When CRP (continuous) was entered into a multivariate model using 13 baseline variables (including PSA, LDH, alkaline phosphatase, HGB, ECOG Performance Status, age) only elevated CRP remained a significant predictor (p<0.0001) of shorter survival. When categorized as normal (= 8 mg/L) or abnormal (> 8 mg/L), elevated CRP was a significant predictor of shorter survival (HR 2.96 95% CI 1.52–5.77, p = 0.001) as was HGB (p=0.007). Elevated CRP was also associated with a lower probability of PSA response (OR 0.74, 95% CI 0.60–0.92, p = 0.007) and a shorter SRE-free survival (HR 1.30, 95% CI 1.15–1.48, p < 0.0001). Conclusions: Elevated levels of plasma CRP appear to be a strong predictor of poor survival and development of SREs in AIPC patients receiving docetaxel-based therapy. The use of CRP as a risk marker and its potential as a surrogate marker of treatment effect should be prospectively evaluated in future clinical trials in advanced prostate cancer.

[Table: see text]
Phase II trial of pemetrexed disodium and gemcitabine in advanced carcinoma of the urothelium (E4802): A trial of the Eastern Cooperative Oncology Group
Authors: Li S. , Dreicer R. , Roth B. , Manoloa J. , Cooney M. , Wilding G.
Published: March 2020

5079

Background: Advanced urothelial carcinoma is a moderately chemosensitive disease. Although the gemcitabine/cisplatin regimen has essentially replaced M-VAC as front-line therapy, both regimens are moderately toxic and produce similar response rates and median survival. Pemetrexed is a novel multi-targeted antifolate with single agent activity in advanced urothelial cancer. We evaluated pemetrexed in combination with gemcitabine in untreated pts with advanced urothelial cancer. Methods: Patients with TCC or mixed histologies received pemetrexed 500 mg/m2 IV over 10 minutes followed by gemcitabine 1,000 mg/ m2 IV over 30 minutes on day 1, with gemcitabine repeated on day 8 of a 21-day cycle. Dose reductions were mandated for grade 3/4 toxicities. Patients remained on treatment until disease progression or unacceptable toxicity or a maximum of 6 cycles of therapy. Standard RECIST criteria were used to assess response. Results: Total accrual was 46 pts. Two pts never started therapy and were excluded, leaving 44 pts included in the analysis. The pt cohort was 36 (82%) male and 42 (95%) Caucasian. Twenty-two pts (50%), 21 (48%) and 1 (2%) had 0, 1 and 2 MSKCC risk factors respectively. Seventy-five percent of pts had distant metastatic disease at study entry including 7 (16%) with liver, 3 (7%) bone and 14 (32%) lung metastases. A median of 4 cycles were administered (range, 1–6). The most common reasons for discontinuing treatment were progressive disease (27%) and toxicity (20%). Eighteen pts experienced grade 4 toxicities, including leukocytes (n=5), neutrophils (n=18), cardiac arrest, fatigue, infection with grade 3 or 4 neutropenia (n=1 pt each). Two pts died from grade 5 toxicities while receiving treatment: one death was from neutropenia and the other pt died from infection without neutropenia following sepsis and subsequent cardiac arrest. Response information is available for 39 pts. There has been 1 complete response and 10 partial responses with an overall response rate of 28% (90% CI: [17%, 42%]). Eleven pts had stable disease for at least 6 weeks. Conclusions: Pemetrexed/gemcitabine has modest activity in patients with previously untreated advanced TCC of the urothelium, but at the cost of significant toxicity.

[Table: see text]
Outcomes of surveillance in unselected patients with clinical stage I testicular germ cell tumors: Results of a modern single institution series
Authors: Moore C. J. , Daneshmand S. , Hayes-Lattin B. , Stott W. , Nichols C. R.
Published: March 2020

5085

Background: Orchiectomy is curative in 50–80% of patients (pts) with clinical stage I testicular germ cell cancer (CSITC) and modern chemotherapy at the time of relapse is nearly always curative. Traditional management in the US and Europe, which includes retroperitoneal lymph node dissection (RPLND) or adjuvant radiation or chemotherapy, imposes a significant treatment burden on all patients with CSITC. This study investigated outcomes of active surveillance in all pts with CSITC, with additional post-orchiectomy therapy reserved for only those pts who recur. Methods: Since 1998, Oregon Health & Science University’s institutional policy has been to recommend active surveillance alone to all CSITC pts after orchiectomy, independent of known risk factors. We retrospectively identified and reviewed the charts of 90 pts with CSITC treated between 1998 and 2006. Prognostic factors for relapse, time to relapse, post-orchiectomy treatment required, and overall survival rates were tabulated. Results: Of the 53 pts with CSI nonseminoma, complete data are currently available for 36. 12 (33%) relapsed at a median of 6 months (range 3–48) and all received 3 cycles of bleomycin, etoposide, and cisplatin (BEP). 2 pts (5.5% of total population) required RPLND post-chemotherapy for residual teratoma. No additional relapses have been seen, and all 36 pts are alive at a median follow-up of 51 months. Of 37 pts with CSI seminoma, complete data are available for 28. Seven pts (25%) experienced abdominal relapse, at a median of 10 months (range 3–14 months) after orchiectomy. All 7 pts were treated with abdominal radiation. Two pts subsequently relapsed and were cured with chemotherapy. All CSITC pts are alive without disease at a median follow-up of 60 months. Complete data on all 90 pts will be available this spring. Conclusion: This, the largest modern US series of surveillance alone after orchiectomy, resulted in uniformly excellent outcomes suggesting that primary active surveillance reduces the global burden of treatment for pts with CSITC and is appropriate for all pts with clinical stage I disease, independent of clinical risk factors or pathological subtype.

No significant financial relationships to disclose.
The long term side effects of adjuvant carboplatin for stage 1 seminoma
Authors: Powles T. , Oliver T. , Ostrowski M. , Levay J. , Shamash J. , Williams M.
Published: March 2020

5089

Background: Radiotherapy is associated with an increase of second cancer and cardiovascular disease. Because of difficulties in detecting recurrence on surveillance which can occur out to 10 years, this unit has developed Carboplatin as the treatment for these patients and this abstract summarises late events in these 3 cohorts. Methods: Radiation therapy consisted of para-aortic and pelvis treatment (3,000 cGy). This occurred between 1960 and 1978. Surveillance began in 1980 and Carboplatin studies in 1984 with 2 courses of 450 mg/m2 being standard until 1987 when 1 course AUC × 7 was introduced and with increased confidence became standard. Results: Seventy-eight patients were treated with radiotherapy (median follow up 17 years). Overall mortally was 24% at 20 years compared with expected 10%. Death from germ cell cancer was 4.0%, deaths from 2nd non-germ cell cancer were 13%, and deaths from other causes was 7.0%. For surveillance (n=110, median follow up 9.8 years) there were 1.7% deaths, with no germ cell or non-germ cell cancer related deaths., and 1.7% deaths due to non cancer. Carboplatin (n=186, median follow up 9.5 years 97>10 yrs, and 38 >15 yrs) was associated with 98% survival at 10 years with 0 deaths due to GCC (3% relapse all before 3 years) 1% due to second non-GCC cancer and 1% to other causes. Conclusion: The numbers of cases are too small to be absolutely confident of these figures. However, this data suggests there are no late relapses and no excess of cancer or cardiovascular deaths in the single agent carboplatin cohort.

No significant financial relationships to disclose.
Phase II study of the angiogenesis inhibitor AZD2171 in first line, progressive, unresectable, advanced metastatic renal cell carcinoma (RCC): A trial of the PMH Phase II Consortium
Authors: Sridhar S. S. , Hotte S. J. , Mackenzie M. J. , Kollmannsberger C. , Haider M. A. , Pond G. R. , Chen E. X. , Srinivasan R. , Ivy S. P. , Moore M. J.
Published: March 2020

5093

Background: AZD2171 is an oral, highly potent inhibitor of VEGFR1, VEGFR2, with activity also against cKit, PDGFRβ and Flt-4. We conducted a two-stage, phase II trial of AZD 2171 in first line advanced RCC, with a planned sample size of 37 pts, and a primary endpoint of tumor control rate (PR+SD). Methods: Pts had progressive, unresectable, advanced RCC, measurable disease, a performance status of ≤ 2 and no prior cytokine or antiangiogenic therapy. Pts received AZD2171 45 mg orally, daily, continuously (1cycle = 4wks) as monotherapy. Disease was evaluated with cross-sectional imaging every 8 wks. Functional DCE-MRI imaging was performed at baseline, 24h and 28d after the first dose. Pharmacokinetic studies were performed on day 8, 15 and 28. Results: From January- November 2006, 24 pts median (range) age 62 (44–80), were entered on study. Sixteen pts evaluable for response, 7 too early; 23 pts evaluable for toxicity; 1 pt inevaluable due to withdrawal. There have been 6 confirmed PR (6/16=38%), 1 unconfirmed PR, 5 SD, 4 PD. Tumor control rate 12/16=75%. Seventeen patients remain on treatment, 6 now off due to PD and 1 off due to consent withdrawal. Eighteen patients had dose reductions due to toxicity. Most common toxicities (any grade) were fatigue (21pts), voice alteration (14pts), hypertension (12pts), diarrhea (15pts), and increased creatinine (10pts). Common (>5% of cycles) grade 3+ adverse events were hypertension (5pts), joint pain (4pts), fatigue (7pts), dyspnea (2pts), increased ALT (2pts) and anorexia (3pts). Preliminary pK analysis is available on 6 patients: median (range) Tmax: 2hr (2- 6hr), Cmax: 107.8± 29.8 ng/ml, T1/2: 12.1 ± 2.2hr. Conclusion: AZD2171 is an active agent in first line, progressive, unresectable, advanced RCC with a partial response rate of 38% and tumor control rates of 75%. Accrual is ongoing with pharmacokinetics, functional imaging, and correlative studies. This agent warrants further investigation.

No significant financial relationships to disclose.
The Advanced Renal Cell Carcinoma Sorafenib (ARCCS) expanded access trial: Long-term outcomes in first-line patients (pts)
Authors: Ryan C. W. , Bukowski R. M. , Figlin R. A. , Knox J. J. , Hutson T. E. , Dutcher J. P. , George J. , Kirshner J. , Humphrey J. , Stadler W. M.
Published: March 2020

5096

Background: Sorafenib (SOR) doubled median progression-free survival (PFS) versus placebo in a phase III study (TARGETs) for previously treated pts with clear cell renal cell carcinoma (RCC). We report on pts who had not received any prior systemic anti- cancer therapy (1st line) for advanced RCC from the ARCCS program in the US and Canada, which enrolled a broad range of pts. Methods: Pts received SOR 400 mg bid in the ARCCS open-label, nonrandomized treatment protocol if they were =15 years old with advanced (unresectable, recurrent or metastatic) RCC and had ECOG PS 0–2. In the US, ARCCS enrollment ended with SOR approval in 12/05, and pts were transitioned to commercial drug with 1st line pts being eligible for an additional 6-mo follow-up in an extension protocol (EP); Canadian enrollment completed in 8/06. Response evaluation (baseline and =1 post-baseline radiologic assessment) was conducted every 4 wks in the main study and every 8 wks during the EP. Pts without a confirmatory scan were classified as unconfirmed PR. The primary efficacy analysis on PFS was pre-specified to be performed only on the EP-enrolled pts. Results: Of the 2,488 pts valid for safety in ARCCS, nearly 50% were 1st line (n=1239) of which 69% were male with median age 65 yrs; 77% had prior nephrectomy and 29% had prior radiotherapy. Time from diagnoses to treatment was <1 yr for 52% and =1 yr 36% in these 1st line pts. Grade 3 and 4 adverse events with >2% incidence included hand-foot skin reaction 7.7%, fatigue 4.7%, hypertension 3.8%, rash/desquamation 5.2%, dehydration 2.9, diarrhea and dyspnea 2.6%. Confirmed responses are reported in the table ; 15% had unconfirmed PRs. For the 224 1st line pts enrolled in the EP, median PFS was 35.1 wks (95% CI; 32.7, 41.9). Conclusions: SOR toxicity in 1st line pts appeared similar to that in both overall and 2nd line populations previously reported in the phase III study. The PFS among patients enrolled in the EP is encouraging, but may be biased by low enrollment and selection for non-progressors.

[Table: see text]

[Table: see text]
Phase I trial of bevacizumab plus sunitinib in patients (pts) with metastatic renal cell carcinoma (mRCC)
Authors: Feldman D. R. , Kondagunta G. V. , Ronnen E. A. , Fischer P. , Chang R. , Baum M. , Ginsberg M. S. , Ishill N. , Patil S. , Motzer R. J.
Published: March 2020

5099

Background: Bevacizumab, an intravenous monoclonal antibody against VEGF, and sunitinib, an oral multi-targeted tyrosine kinase inhibitor of VEGF and PDGF receptors, both have activity in mRCC [NEJM 349:427–434; JAMA 295:2516–2524]. Combining bevacizumab and sunitinib may increase antitumor efficacy by maximizing inhibition of the VEGF pathway. The safety and maximum tolerated dose (MTD) of sunitinib in combination with bevacizumab was assessed in this Phase I trial. Methods: Cohorts of 3–6 pts with mRCC received escalating doses of sunitinib (dose levels: 25, 37.5, and 50 mg po) daily for 4 weeks (wks) followed by 2 wks off with fixed- dose bevacizumab (10 mg/kg iv) every 2 wks continuously. Pre-determined dose-limiting toxicities (DLTs) in the first 6-wk cycle included Grade (Gr) 4 neutropenia, ≥Gr 3 thrombocytopenia of ≥7 days, Gr 4 hypertension or proteinuria, and other Gr 3 non-hematologic toxicity of ≥7 days. Pts who came off study prior to completion of cycle 1 for any reason other than a DLT were replaced. Serum VEGF levels were measured before and during cycles 1 and 2. Results: 16 pts (11 male, 5 female, median age 57) were enrolled. Of 8 patients entered at the first dose level (sunitinib 25 mg, bevacizumab 10 mg/kg), 2 were replaced; 1 never received treatment and 1 did not complete cycle 1 due to rapid progression of disease (PD). No DLTs occurred in the remaining 6 evaluable pts in this cohort. At the 2nd dose level (n =6, sunitinib 37.5 mg, bevacizumab 10 mg/kg), 1 pt receiving low molecular weight heparin had a DLT of Gr 4 hemorrhage. 2 pts have enrolled in the 3rd dose level (sunitinib 50 mg, bevacizumab 10 mg/kg) but are not yet evaluable for toxicity or response. Gr 3/4 toxicities over all cycles included Gr 3 hypertension (n=4), Gr 3 proteinuria (n=2), Gr 3 abdominal pain (n=2), Gr 4 hemorrhage (n=1), and Gr 3 hand/foot syndrome (n=1). 13 pts were evaluated for best response–4 had partial responses, 7 had stable disease, and 2 had PD. Serum VEGF levels decreased during cycle 1 in all pts. Conclusions: The combination of sunitinib and bevacizumab in mRCC pts was tolerable at the first 2 dose levels. Once the MTD is identified, further testing of this combination in phase II trials may be indicated for mRCC as well as other malignancies.

[Table: see text]
Phase II ECOG trial of atrasentan in advanced renal cell carcinoma
Authors: Manola J. , Carducci M. , Nair S. , Liu G. , Rousey S. , Wilding G.
Published: March 2020

5102

Background: Atrasentan, an oral selective endothelin A receptor antagonist, demonstrated activity in patients with RCC included in Phase I studies. Based on these preliminary findings, a phase II study was undertaken in patients with measurable or nonmeasurable (bone only) metastatic RCC. Methods: Patients with locally recurrent or metastatic disease were stratified on disease status (measurable or bone only metastases) and prior immunotherapy. Eligible patients also had no prior chemotherapy, no more than 1 prior immunotherapy, and ECOG PS 0, 1, or 2. Prior nephrectomy was permitted. Patients received atrasentan 10 mg/day po until progression or unacceptable toxicity. Standard RECIST criteria were used to assess response. The primary endpoint was the progression-free rate at 6 months. Rates of 25% among patients treated with prior immunotherapy and 45% among patients with no prior immunotherapy were considered promising. A two-stage design was used for cohorts with no prior immunotherapy. Results: Between July 2003 and July 2005, 98 patients were registered. Four patients were ineligible and 1 withdrew before treatment. Median duration of treatment was 10 weeks (range, 2 to 107 weeks). Toxicities were mild, with 73% of patients reporting no Grade 3 or higher treatment- related adverse events. Grade 4 adverse events included neutropenia (n=3), dyspnea (n=2), thrombosis and supraventricular arrhythmia (n=1 each). Six-month progression-free rates (90% CI) were 14% (6 - 25%), 0% (0 - 39%), 12% (3 - 28%) and 17% (5 - 38%) respectively for patients with prior immunotherapy and measurable disease (n=44), prior immunotherapy and bone metastases only (n=6), no prior immunotherapy and measurable disease (n=25), and no prior immunotherapy and bone metastases only (n=18). Median progression-free survival was 2.3 months (95% CI, 2.0 - 3.5 months). Conclusions: While well-tolerated, atrasentan did not yield 6-month progression-free rates that would support its use as first-line monotherapy in patients with advanced RCC.

No significant financial relationships to disclose.
Benefit from adjuvant trastuzumab may not be confined to patients with IHC 3+ and/or FISH-positive tumors: Central testing results from NSABP B-31
Authors: Paik S. , Kim C. , Jeong J. , Geyer C. E. , Romond E. H. , Mejia-Mejia O. , Mamounas E. P. , Wickerham D. , Costantino J. P. , Wolmark N.
Published: March 2020

511

Background: Trastuzumab is a humanized monoclonal antibody targeted to HER2 protein and currently indicated for HER2-positive breast cancer defined by overexpression of HER2 protein (3+ IHC staining by HercepTest™) or HER2 gene amplification (HER2/CEP17 ratio over 2 by PathVysion® FISH assay). These criteria were determined for advanced disease but have not been formally tested in the adjuvant setting. We examined these tests’ ability to predict benefit from adjuvant trastuzumab in NSABP trial B-31. Methods: All available tumor tissue blocks from the B-31 trial were subjected to HercepTest and PathVysion assay as defined in the B-31 protocol. Formal statistical test of interaction between HER2 levels measured by these two tests and benefit from trastuzumab was performed. Results: 207 of 1,795 cases (11.5%) showed gene amplification as determined by PathVysion, and 255 of 1,662 (15.3 %) showed overexpression as determined by HercepTest. 161 of 1,662 (9.7%) had neither gene amplification nor overexpression. There was a consistent benefit from trastuzumab in every subset defined by IHC or FISH. No statistical interaction was found between DFS benefit from trastuzumab and levels of protein (p=0.26) or HER2 gene copy number (p=0.60). Benefit was observed in patients with tumors that were negative for FISH and had less than 3+ staining intensity on IHC by HercepTest (RR=0.36 [CI: 0.14–0.92] p=0.032). Conclusion: Current definition of HER2 overexpression/gene amplification based on data from advanced disease may need to be modified for the adjuvant setting.

[Table: see text]

No significant financial relationships to disclose.
A validation/evaluation of five postoperative prognostic tools for prostate cancer
Authors: Inman B. A. , Leibovich B. C. , Siddiqui S. A. , Frank I.
Published: March 2020

5117

Background: Prognostic nomograms, scoring tools, and risk tables are rapidly accumulating in the prostate cancer (PCa) literature. It is not always clear to whom these tools should apply and how well they predict the outcomes they were designed to forecast. There is need for independent evaluation of these tools. Methods: We used the Mayo Clinic Radical Prostatectomy Registry, a prospective database of radical prostatectomy (RP) outcomes, to assess tools designed to predict RP outcomes. The validation set included 13,313 RP patients from 1990–2005. There were 3,256 PSA failures, 566 metastases, and 1,599 deaths (301 were due to PCa). We assessed the discrimination, calibration and overall accuracy of prediction tools identified through a structured Pubmed search. Results: Tools varied greatly in terms of complexity, width of prediction interval, and method of presentation. Several tools included non-standard variables and were therefore unevaluable, despite an extensive dataset, leaving the 1999 and 2005 Kattan nomograms, the 1998 and 2001 CDPR scores, and the 2001 GPSM score for analysis. Discrimination (quantitated by the c index) was better for PCa-specific survival and metastases than for PSA failure ( Table ). Kaplan-Meier plots demonstrated clustering of risk groups in most tools, most severely in the higher risk groups of the Kattan nomograms. The calibration plots of most tools (excepting GPSM) had a serious discordance between observed and predicted outcomes in the lower probability ranges. This meant that most tools gravely overestimated the probability of RP failure in high-risk patients, by up to 4- fold. Conclusions: The tools showed moderate discriminatory ability for PSA failure but performed much better for non-surrogate outcomes. Most tools (excepting GPSM) were miscalibrated in high risk patients and dramatically underestimated the efficacy of surgery in this cohort. Prognostic tools may not be as accurate as previously reported.

[Table: see text]

No significant financial relationships to disclose.
Biochemical and immunologic correlates of clinical response in a combination trial of the GM-CSF-gene transduced allogeneic prostate cancer immunotherapy and ipilimumab in patients with metastatic hormone-refractory prostate cancer (mHRPC)
Authors: Gerritsen W. R. , van den Eertwegh A. J. , de Gruijl T. D. , Giaccone G. , Scheper R. J. , Sacks N. , Harding T. , Lowy I. , Stankevich E. , Hege K.
Published: March 2020

5120

Background: A Phase 1 trial is underway to study the GM-CSF-secreting immunotherapy for prostate cancer (GVAX immunotherapy [GVAX IT]) and ipilimumab (ipi) in mHRPC patients (pts). Methods: Twelve pts were treated for 24 weeks (wks) with bi-weekly intradermal injections of GVAX IT and monthly Ipi. Pts were enrolled in cohorts of 3; each cohort received an escalating dose of ipi: 0.3, 1, 3 or 5 mg/kg. Results: Median follow-up is 15.0 months. All pts had GVAX IT injection site reactions. Five of six pts at the higher ipi doses (3 and 5 mg/kg) developed Grade 2 or 3 immune-related endocrinopathy, consistent with hypophysitis manifested by adrenal insufficiency and/or hypothyroidism, all successfully treated with standard hormone replacement. Two pts were tapered off Synthroid within 6 months (m). There was no induction of the alpha-21-hydroxylase auto-antibody that is seen in 90% of cases of auto-immune adrenal insufficiency. One pt in the 5 mg group developed a Grade 3 dose-limiting alveolitis. PSA responses (declines > 50%) were seen in 5/6 treated at the two higher ipi doses with median response duration of 4.9 m (2 on-going at 7.2 m and 12.8 m). These PSA responses were associated with immune-related endocrinopathy but were not consistently correlated with declines in adrenal androgens. One pt had resolution of measurable disease on abdominal CT scan. Immunomonitoring studies showed T cell and dendritic cell activation, more pronounced at higher doses. Biopsies of injection sites showed T cell infiltration. Multiple tumor-reactive antibodies (abs) induced by tx were identified by serologic analysis (SEREX), including abs to filamin B. Screening against 20 defined prostate cancer antigens demonstrated induction of abs to PSMA and NY-ESO-1. Conclusions: The GVAX IT and ipilimumab combination is active in mHRPC. There was an association between PSA response and immune-related adverse events. The PSA responses cannot be accounted for by adrenal insufficiency. The relationship between clinical activity and serologic response to identified antigens is under investigation. Tx of 16 additional pts is planned.

No significant financial relationships to disclose.