bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase II study of sunitinib (SU) for maintenance therapy in metastatic castration-resistant prostate cancer (mCRPC) after response to docetaxel (D).
Authors: Eigl B. J. , Trudeau M. G. , Winquist E. , Chi K. N. , Eliasziw M. , North S.
Published: February 2017

151

Background: After treatment with D based chemotherapy, there is currently no standard therapy although new options are emerging. Due to its mechanism of action, acceptable toxicity profile and simple administration, SU has potential for therapeutic activity in the setting of maintenance therapy for patients with mCRPC who have responded to D based chemotherapy.

Methods: Patients with mCRPC who had evidence of responding or stable disease at completion of D treatment were enrolled in this phase II multicentre trial. Patients received 50mg of SU daily on 4 week on/2 week off cycles. The primary endpoint was effect of SU maintenance on PFS. Because of potential effects of SU on PSA kinetics, clinical progression was defined independent of PSA. PSA response rate was a secondary endpoint. PSA-progression (PSA-P) was defined as a 25% PSA increase over baseline.

Results: Thirteen patients have been enrolled and treated to date. Mean age was 63 years (47-76). ECOG scores of 0, 1, and 2 were reported for 4, 8 and 1 patients respectively. Mean number of prior cycles of D given was 9.5. A total of 28 cycles of SU were administered. A total of 291 adverse events (AEs) were recorded, of which 66%, 27%, and 7% were classified as Grades 1, 2, and 3, respectively. No Grade 4 AEs were seen. AEs were of a type and severity expected for SU. The most frequent grade 3 AEs were fatigue (n=3) and hand foot syndrome (n=3). No PSA responses have been documented. Most patients had immediate PSA increases without evidence of clinical progression. The mean PSAs increased by 159%, 396%, and 853% in Cycles 1, 2, and 3, respectively, corresponding to p-values of 0.18, 0.03, and 0.01 when compared to the PSA-P threshold of 25%. The trial will continue to complete its planned accrual of 26 evaluable patients and updated results, along with PFS, will be presented at the meeting.

Conclusions: SU is well tolerated as maintenance therapy after D in men with mCRPC, with a predictable side-effect profile. PSA values after treatment with SU may not reflect progression in patients with mCRPCas significant increases were observed as early as Cycle 2 without clinical evidence of worsening disease.

[Table: see text]
Prostate-specific membrane antigen antibody drug conjugate (PSMA ADC): A phase I trial in taxane-refractory prostate cancer.
Authors: Petrylak D. P. , Kantoff P. W. , Rotshteyn Y. , Israel R. J. , Olson W. C. , Ramakrishna T. , Morris S.
Published: February 2017

158

Background: The unique expression of PSMA type II transmembrane glycoprotein on prostate cancer cells provides a potentially attractive target for antibody therapy. PSMA ADC, a fully humanized antibody to PSMA linked to the potent antitubulin agent monomethyl auristatin E (MMAE), binds PSMA and is internalized within the prostate cancer cell where cleavage and release of free MMAE occur, causing cell cycle arrest and apoptosis. We report results from an ongoing phase I dose escalation study of PSMA ADC in patients (pts) with taxane refractory metastatic prostate cancer (metCRPC).

Methods: Eligibility requirements included pts ≥18 years with metCRPC after failure of a taxane- containing regimen and ECOG status of 0 or 1. PSMA ADC is administered by IV infusion Q3W for up to 4 cycles. Adverse events, PK, PSA, circulating tumor cells, clinical disease progression and immunogenic response to PSMA ADC continue to be assessed. Serum concentrations of PSMA ADC and total antibody are measured by an enzyme-linked immunosorbent assay (ELISA) method, and free MMAE is measured by liquid chromatography/mass spectrometry/mass spectrometry (LC/MS/MS) method. Dosing cohorts ranged from 0.4 mg/kg to 1.8 mg/kg.

Results: The demographics of 15 subjects enrolled in the four dosing cohorts (0.4, 0.7, 1.1 and 1.8 mg/kg) were similar. Treatment has to date been generally well tolerated and the most common laboratory abnormalities were reversible changes in liver and hematological parameters. Exposure to PSMA ADC and serum half life (t1/2) increased in a dose-proportional manner. Similar PK metrics were observed after the first and third doses. Exposure to free MMAE was also dose proportional and approximately <0.1% of PSMA ADC.

Conclusions: In this first-in-human evaluation, PSMA ADC appears to exhibit dose-proportional PK and limited release of free MMAE. Ongoing enrollment allows for assessment of potential clinical utility of this unique potential treatment of metCRPC.

[Table: see text]
Molecular characterization of neuroendocrine prostate cancer (NEPC) and identification of new drug targets.
Authors: Beltran H. , Rickman D. , Park K. , Sboner A. , Macdonald T. , Tagawa S. T. , Gerstein M. B. , Demichelis F. , Nanus D. M. , Rubin M. A.
Published: February 2017

19

Background: NEPC is an aggressive variant of prostate cancer that can arise de novo or from existing prostate adenocarcinoma (PCA). We sought to better understand the molecular transformation of NEPC and identify new drug targets.

Methods: We used Next Generation RNA sequencing and oligonucleotide arrays to profile 7 NEPC, 30 PCA, 5 benign prostate (BEN), and validated findings on tumors from a large cohort of patients (30 NEPC, 118 PCA, 30 BEN) using IHC and FISH. Functional studies were performed using NCI-H660 (NEPC), VCaP and LnCaP (PCA), RWPE (BEN).

Results: ERG rearrangement was present in 47% of NEPC, but ERG protein expression was absent and corresponded directly with lack of AR expression. 936/25932 genes were differentially expressed in NEPC versus PCA (P<0.001). Aurora kinases (AURKA, AURKB) and N-myc (MYCN) were overexpressed in NEPC (P<0.001) and AURKA and MYCN amplified. Using IHC and FISH, we validated these findings on a large cohort and found majority (>80%) of NEPC showed Aurora overexpression, 35% had AURKA and MYCN amplification. A small subset of PCA (5%) and no BEN were positive. Transfection of MYCN induced AURKA expression and kinase activity in vitro, and MYCN or AURKA could induce expression of neuroendocrine (NE) markers (SYP, NSE). After validating NCI-H660 as model of NEPC, we observed dramatic and enhanced in vitro and in vivo sensitivity to the Aurora kinase inhibitor PHA-739358 in NCI-H660 compared to minimal to no effect in LnCaP and VCaP. Phospho-H3 expression, a downstream marker of Aurora kinase activity, was inhibited in the treated NCI-H660 and not in PCA. Notably, NE marker expression was also suppressed in the treated NCI-H660 xenografts, again supporting a role of Aurora kinase in modulating the NE phenotype.

Conclusions: There is likely clonal origin of NEPC from PCA (with ERG fusion positivity seen in both), but ERG expression is limited to PCA and driven by AR signaling. We discovered significant overexpression and gene amplification of Aurora kinases and N-myc in NEPC and a small subset of PCA, and evidence that that they cooperate and induce a NE phenotype in prostate cells. In vitro and in vivo data confirms that these are novel drug targets for NEPC.

No significant financial relationships to disclose.
Effect of dutasteride on prostate cancer progression and cancer diagnosis on rebiopsy in the REDEEM active surveillance study.
Authors: Fleshner N. , Lucia M. S. , Melich K. , Nandy I. M. , Black L. , Rittmaster R. S.
Published: February 2017

2

Background: The REDEEM (Reduction by Dutasteride of Clinical Progression Events in Expectant Management of Prostate Cancer) study tested whether dutasteride controlled growth of existing low risk, localized prostate cancer (PCa) and hence reduced the need for aggressive therapy in men followed with active surveillance.

Methods: 302 men, aged 48–82, with PSA <11 ng/ml, and Gleason score ≤6 PCa (≤3 cores positive, <50% of any core positive) were randomized to dutasteride or placebo for 3 years. Repeat 12-core biopsies were performed at 18 and 36 months, or for-cause at other times during the study. The primary endpoint was time to progression, defined as the earliest of either pathological progression (Gleason score >6, ≥4 cores positive, or >50% of any core positive) or therapeutic progression (radical prostatectomy, radiation therapy, or hormonal ablation).

Results: 96% of subjects reached the primary endpoint or had a post-baseline biopsy. Dutasteride reduced time to PCa progression (relative risk reduction 38.9%, 95% CI: 12.4–57.4%, P=0.007). The table presents incidence of progression and Gleason score on final biopsy. 23% of men (N=31) in the placebo group and 36% of men (N=50) in the dutasteride group had no cancer detected on their final biopsy. PCa-related anxiety was reduced in the dutasteride arm compared to the placebo arm (P=0.036), based on the Memorial Anxiety Scale for PCa (MAX-PC). Drug-related adverse events were similar to those previously reported for dutasteride.

Conclusions: In men followed with active surveillance, dutasteride delayed the time to PCa progression, increased the percent of men with no detectable PCa, and improved PCa-related anxiety. There was no evidence of increased Gleason score upgrading with dutasteride. Dutasteride may provide a useful adjunct to active surveillance for management of PCa.

[Table: see text]

[Table: see text]
Gemcitabine, paclitaxel, and doxorubicin for patients (pts) with urothelial carcinoma (UC) and renal insufficiency: Preliminary results of a multicenter phase II study.
Authors: Pagliaro L. C. , Munsell M. , Harris D. , Carolla R. L. , Siefker-Radtke A. O.
Published: February 2017

246

Background: The role of cisplatin-based chemotherapy for the treatment of locally advanced or metastatic UC is well established. Pts with impaired renal function cannot receive cisplatin, however, and substitution with carboplatin yielded inferior results. We initiated a phase II study to assess the efficacy of gemcitabine, paclitaxel, and doxorubicin (GTA) treatment for UC in pts with renal insufficiency.

Methods: Eligible pts had metastatic or unresectable UC of bladder, urethra, or upper tract, no prior chemotherapy, glomerular filtration rate < 60 ml/min, ECOG performance status ≤ 2, left ventricular ejection fraction > 40%, and adequate hematopoietic and hepatic function. Pts were excluded if they had brain metastasis, peripheral neuropathy ≥ grade 2, significant heart disease within 6 months of enrollment, or required hemodialysis. Outpatient treatment consisted of 900 mg/m2 gemcitabine, 135 mg/m2 paclitaxel, and 40 mg/m2 doxorubicin on day 1 every 2 weeks. Pegfilgrastim 6 mg sc was given immediately after GTA on day 1, or on day 2 if requested by the pt. Tumor evaluation was repeated every 3 cycles (6 weeks); treatment duration was limited to 9 cycles. A Simon 2-stage design was chosen to detect a target overall response rate of 40% and to reject a response rate of 25% or less.

Results: Twenty-five pts enrolled and 21 could be assessed for response. Median (range) age was 72.8 years (53.4, 89.3) and 8 pts (32.0%) were female. RECIST responses occurred in 12 pts (4 complete; 8 partial), for an overall response rate of 57.1% (95% CI 34.0-78.2). Notable grade 3 and 4 toxicities were anemia (9 pts), thrombocytopenia (3 pts), neutropenia (2 pts), dyspnea (1 pt), mucositis (1 pt), and sepsis (1 pt). No adverse events were attributed to same-day pegfilgrastim and there were no treatment-related deaths. Eleven pts (44.0%) died of progressive disease; the median (range) follow-up time for 14 surviving pts was 5.5 months (2.3, 17.5).

Conclusions: GTA has been well-tolerated in the setting of renal insufficiency, with an observed response rate in advanced UC exceeding the targeted response. The study will continue to a maximum of 72 pts.

[Table: see text]
Phase I trial sunitinib plus everolimus in patients with metastatic renal cell carcinoma (mRCC).
Authors: Molina A. M. , Feldman D. R. , Ginsberg M. S. , Fischer P. , Trinos M. J. , Patil S. , Motzer R. J.
Published: February 2017

311

Background: Sunitinib a targeted tyrosine kinase inhibitor and everolimus an mTOR inhibitor both inhibit hypoxia-induced factor-dependent signaling and have activity in advanced renal cell carcinoma (RCC). The safety and maximum tolerated dose (MTD) of sunitinib in combination with everolimus was assessed in this phase I trial.

Methods: Cohorts of 3–6 patients with mRCC received sunitinib at 37.5 or 50 mg daily for 4 weeks followed by 2 weeks off with everolimus administered either daily (2.5 or 5 mg) or weekly (20 or 30 mg). Dose-limiting toxicities (DLTs) were assessed in the first 6-week cycle to determine MTD.

Results: 20 patients (13 clear cell and 7 non-clear cell RCC) were enrolled in five cohorts. Both patients in the 2nd dose level (everolimus 5 mg daily, sunitinib 37.5mg) experienced grade 3 DLT (thrombocytopenia and mucositis; vomiting). With weekly everolimus dosing, the MTD was everolimus 30 mg /sunitinib 37.5 mg (4th dose level). However, only one of six patients at this dose level tolerated treatment beyond 4 cycles. Grades 3 and 4 toxicities observed with chronic treatment included infection, gastrointestinal hemorrhage, and pulmonary embolism. A total of six patients were treated with everolimus 20b mg weekly/37.5 mg sunitinib (3rd dose level) with better tolerance as chronic therapy. Overall, 5 out of 20 patients achieved a partial response including 3 patients with non-clear cell histology.

Conclusions: Partial responses were observed in both clear cell and non-clear cell histologies. However, due to toxicity the combination of sunitinib and everolimus could not be administered at full doses.

[Table: see text]
A meta-analysis of bevacizumab plus interferon alfa for previously untreated patients with metastatic clear-cell renal carcinoma (mRCC).
Authors: Likun Z. , Ba Y.
Published: February 2017

366

Background: mRCC was highly resistant to conventional chemotherapy. Both CALGB study and AVOREN study failed to detect statistic differences in overall survival (OS). To evaluate the effectiveness and adverse-effect of bevacizumab plus IFN-α for untreated mRCC, we performed a meta-analysis.

Methods: We searched RCTs that compared bevacizumab plus IFN- alpha with other treatments. For trials without heterogeneity, meta-analysis was carried out by using review manager (Revman 4.2) with fixed or random-effects models. Hazard ratio (HR), relative risk (RR), and 95 percent confidence intervals (CI) were calculated. The primary outcome was overall survival. The secondary outcomes were PFS and the adverse effects. Subgroup analyses were performed by MSKCC risk factors.

Results: Two RCTs (CALGB study and AVOREN study) were identified as eligible for inclusion in our meta-analysis. Overall survival: Meta- analysis including 1,381 patients showed a trend in favor of bevacizumab plus IFN-alpha with an HR of 0.89 (95% CI, 0.80-1.00, p=0.05). Meta-analysis of OS which adjusted on stratification factors showed extent improvement in favor of bevacizumab plus IFN-alpha (HR=0.86, 95% CI, 0.76-0.97, p=0.02). Progress-free survival: Meta-analyses showed statistic differences in favor of bevacizumab plus IFN-alpha in both unstratified PFS (HR=0.68, 95% CI, 0.61-0.77, p<0.00001) and stratified PFS (HR=0.67, 95% CI, 0.59-0.75, p<0.00001). Subgroup analysis: There were no statistic differences between bevacizumab plus IFN-alpha and IFN-alpha in MSKCC favorable risk group (HR=0.91, 95% CI, 0.70-1.17, p=0.45) and MSKCC poor risk group (HR=0.79, 95% CI, 0.55-1.14, p=0.21). For MSKCC intermediate risk group, there was statistic difference in favor of bevacizumab plus IFN-alpha (HR=0.85, 95% CI, 0.73-0.99, p=0.04). Adverse effects: There were statistic differences in favor ofIFN-alpha in anorexia, fatigue proteinuria, and bleeding, while no statistic difference in gastrointestinal perforation.

Conclusions: Bevacizumab plus IFN-alpha prolonged both OS and PFS as first line therapy for mRCC, especially for MSKCC intermediate risk group. The toxicity was acceptable and well tolerated.

No significant financial relationships to disclose.
Outcome of patients (pts) with renal medullary carcinoma (RMC) treated in the era of targeted therapies (TT): A multicenter experience.
Authors: Tannir N. M. , Dubauskas Lim Z. , Bekele B. N. , Johnson E. D. , Tamboli P. , Vaishampayan U. N. , Plimack E. R. , Rathmell K. , Jonasch E.
Published: February 2017

386

Background: RMC is a rare, highly aggressive primary neoplasm of the kidney that almost exclusively afflicts young black pts with sickle cell hemoglobinopathies, primarily sickle cell trait. The primary objectives of this study were to evaluate the clinical characteristics and treatment outcome of RMC pts.

Methods: We retrospectively reviewed the medical records of pts diagnosed with RMC at four US institutions between 2000 and 2010. Overall survival (OS) was determined from initial diagnosis to date of death or last follow up (F/U). The time interval from date of metastasis to death or last F/U (OSm) was also determined. Kaplan-Meier methods were used to estimate OS and OSm.

Results: 20 RMC pts were identified. All pts were black; 14 (70%) were males; 18 had sickle cell trait, 1 had sickle thalassemia and 1 not tested. 19 presented with stages III or IV; 7 (35%) had nephrectomy. Nineteen pts had ≥ 2 metastatic sites. Twelve pts had performance status [PS] 0/1; eight pts had PS 2/3. For the OS analysis, data on 16 pts were available and for the OSm analysis, data on 20 pts were available. The median follow up time for the OS analysis was 722 days. Thirteen of 16 pts died with median OS of 421 days [95%CI: 225–546]. Sixteen of 20 pts died in the OSm analysis with median OSm of 378 days [95%CI: 225–487]. Frontline therapy consisted of TT [sunitinib (5), bevacizumab + erlotinib (1), imatinib (2)], chemotherapy (C) [platinum/gemcitabine or taxane (7), gemcitabine/doxorubicin (2)], C + TT [gemcitabine/cisplatinum/bevacizumab (2), imatinib/doxorubicin (1)]. Three pts achieved a partial response (PR) in first-line (2 with C, 1 with C + TT). Twelve pts received second-line systemic therapies; 4 achieved PR (1 with bevacizumab/erlotinib, 2 with C, 1 with C + TT). Among 15 pts who had TT at any time during their treatment course, only 1 pt had PR.

Conclusions: The prognosis of RMC pts remains poor despite initial palliation with systemic therapy. Collaborative multi-institutional efforts are needed to better understand the biology of this disease and improve treatment strategies.

No significant financial relationships to disclose.
Hierarchical clustering analysis of tissue microarray immunostaining data on renal cell carcinomas.
Authors: Antón Aparicio L. M. , Medina Villaamil V. , García Campelo R. , Aparicio Gallego G. , Santamarina Caínzos I. , Haz Conde M. , Valbuena Rubira L. , Grande E. , Valladares Ayerbes M.
Published: February 2017

393

Background: The clinical use of molecular expression profiles could result in more accurate and objective diagnoses of cancers as well as prognoses of disease or response to the treatment. Unsupervised hierarchical clustering (UHC) analysis is a common method to profile the molecular expression of tissue microarray data.

Methods: TM4: a free, open-source system for microarray data management and analysis was used in order to identify expression patterns of interest in our cohort of renal cell carcinomas (RCC) (n=80). We investigated 5 pathological predictors: (a) the histological type, (b) Fuhrman grade, (c) depth of infiltration, (d) metastasis in lymph node, (e) TNM stages, and 27 immunohistochemical molecular predictors involved in different pathways of tumor development and progression including: p53 and VHL tumor suppressor proteins; Bcl-2 and Survivin antiapoptotic proteins; Hif1-alpha and Notch proteins as a transcription factors; EGFR, PDGFR-α and VEGF proteins involved in tumor growth and proliferation; Glut proteins involved in tumor cell metabolism.

Results: Unfavorable prognosis was significantly correlated with pathological predictors. Clear RCC histological subtype had a worse prognosis than the other ones studied to be accompanied by increased expression of Hif1-alpha and CAIX (p<0.001 in both cases) in patients with a number of metastatic nodes weighed (p<0.001). We found in Fuhrman Grade III samples a higher expression of VEGF (p=0.029). UHC analysis was done using average method with Spearman rank test to group the data with different predictor profiles. A preliminary analysis by hierarchical clustering of RCC produced three separate clusters groups.

Conclusions: UHC based on a extended immunoprofile might be a useful, promising and powerful tool for further translational studies and should lead us to define a diagnostic and prognostic signature for RCC. Our laboratory is currently involved in this issue.

No significant financial relationships to disclose.
Improved survival outcomes in clinically relevant patient subgroups from COU-AA-301, a phase III study of abiraterone acetate (AA) plus prednisone (P) in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel-based chemotherapy.
Authors: Scher H. I. , Logothetis C. , Molina A. , Goodman O. B. , Sternberg C. N. , Chi K. N. , Kheoh T. S. , Haqq C. M. , Fizazi K. , De Bono J. S.
Published: February 2017

4

Background: AA is a selective androgen biosynthesis inhibitor that blocks the action of CYP17. Preclinical and early clinical studies suggest that AA potently inhibits persistent androgen synthesis from adrenal and intratumoral sources, thus suppressing an important growth stimulus for mCRPC.

Methods: COU-AA-301 ( NCT00638690 ) is an international, randomized, double blind study of AA (1,000 mg + P 5 mg po BID) vs placebo + P administered to men with mCRPC progressing after docetaxel-based chemo. OS is the primary endpoint. Patients treated with previous ketoconazole or > 2 prior chemo regimens were excluded.

Results: Data are drawn from a planned, stratified interim analysis, unblinded in August 2010, based on significant OS improvement in the AA + P treatment group compared to the placebo + P group [median OS 14.8 vs.10.9 months; HR = 0.646 (0.54-0.77), P < 0.0001]. A subgroup analysis for OS is presented in the table. Mineralocorticoid- related AEs were more common in the AA arm vs placebo: fluid retention 30.5% vs 22.3%, hypokalemia 17.1% vs 8.4%; but grade 3/4 hypokalemia (3.8% vs 0.8%), and grade 3/4 hypertension (1.3% vs 0.3%) were infrequent. LFT abnormalities were observed in 10.4% AA vs 8.1% placebo; and cardiac disorders were observed in 13.3% AA vs 10.4% placebo.

Conclusions: AA significantly prolongs OS in patients with mCRPC who have progressed after docetaxel-based chemo. AA's favorable treatment effect on OS, observed across multiple patient subgroups (HR range 0.59 – 0.74 vs placebo + P), was consistent with the survival benefit for the overall study population.

[Table: see text]

[Table: see text]
Fluorescence-activated cell sorting (FACS) and immunofluorescence (IF) detection and characterization of circulating tumor cells (CTC) from men with castrate-resistant prostate cancer (CRPC).
Authors: Szmulewitz R. Z. , Wyche A. J. , Posadas E. M. , Stadler W. M.
Published: February 2017

41

Background: Men with progressive CRPC have identifiable CTC. The currently available technologies for isolation of these CTC are limited by requiring send out to a central lab, high cost, and relative inflexibility with regards to characterization of the CTC. We hypothesized that modern FACS techniques followed by IF could be utilized for point of care isolation and characterization of CTC from men with CRPC.

Methods: Patients (pts) with progressive CRPC according to Prostate Cancer Working Group 2 criteria were eligible. 15mL of whole blood was collected in BD CPT Vacutainer tubes. The mononuclear cell layer was labeled with primary antibodies against CD45 and EpCAM conjugated to separate flours. The EpCAM+/CD45− population was sorted directly onto a chamber slide, fixed and stained for multiplex IF imaging of markers including: pan-cytokeratin (CK), PSA, and the androgen receptor (AR). Imaged cells were considered CTC if were nucleated and PSA or CK positive. The methodology would be considered feasible if ≥ 5 of the first 15 pts had detectable CTC.

Results: 15 pts with progressive CRPC were accrued to the study. Of these, 14 had documented skeletal metastases and 13 had progressed through docetaxel chemotherapy. 13/15 pts had EpCAM+/CD45− events on flow cytometry; median 94 (range 0–1700). Ten patients had CTC imaged after IF staining. A median of 4 (0–25) CTC were detected, but in 7 pts with >100 events by flow, all had detectable CTC with a median 22 (10–25) (p<0.001 vs. # events <100). A total of 9 contaminating cells (nucleus but no CK or PSA) were observed. All CTC stained positive for AR with variable intensity.

Conclusions: FACS followed by IF is feasible for detection of CTC from men with metastatic CRPC. There is considerable loss of CTC during the processing, however, in men with >100 EpCAM+ events, CTC can be imaged and characterized routinely with these methods. This is a promising technique for utilization in translational research given the relative flexibility, ease and cost. Patients are now being enrolled for pre-analytical validation of IF staining for multiple prostate cancer biomarkers including AR.

No significant financial relationships to disclose.
A double-blind randomized trial of docetaxel plus vandetanib versus docetaxel plus placebo in platinum-pretreated advanced urothelial cancer.
Authors: Choueiri T. K. , Vaishampayan U. N. , Yu E. Y. , Quinn D. I. , Hahn N. M. , Hutson T. E. , Ross R. W. , Rosenberg J. E. , Jacobus S. J. , Kantoff P. W.
Published: February 2017

LBA239

Background: Vandetanib (V) is a novel small-molecule inhibitor that targets key signaling pathways in cancer including VEGF and EGF. V in combination with docetaxel (D) was assessed in patients (pts) who received prior platinum-based chemotherapy for advanced urothelial cancer (UC).

Methods: Patients eligible for this randomized, multicenter, double-blind, investigator-initiated trial had metastatic UC after failure of prior platinum-based chemotherapy. Up to 3 prior therapies were allowed including paclitaxel. The primary objective was to determine whether once-daily oral V (100 mg) + D (75 mg/m2 IV q21 days) prolonged progression-free survival (PFS) vs. placebo (P) + D (80% power to detect 60% improvement in median PFS with 1-sided α=0.05). Patients on D+P, had the option to cross over to single agent V. Overall survival (OS), overall response rate (ORR), stable disease (SD), and safety were secondary objectives.

Results: One-hundred and forty-two pts were enrolled at 16 institutions, 68% men; median age 65y; ECOG PS 0/1: 52%/48%; visceral involvement: 66%. 80% of patients had ECOG PS 1 and/or visceral metastases. 44% of patients had 2 or more prior systemic therapies and 15% had prior paclitaxel. Baseline characteristics were balanced in both arms. Median PFS was 11.1 weeks (wks) for D+V arm vs. 6.9 wks for D+P arm (HR=1.04, p=0.92). Median OS was 25.4 wks for the D+V arm vs. 30.6 wks for the D+P arm (HR 1.21, p=0.35). ORR was 7.1% for the D+V arm vs. 11.1% for the D+P arm (OR=0.6, 90% CI [0.2–1.6]). SD or better rates were 50.0% vs. 37.5% on D+V and D+P, respectively. As of December 2010, 5 pts were on therapy and 70% of pts died. Median follow-up for pts still alive is 7.2 months. Treatment-related grade >3 toxicities for D+V arm was 60% vs. 36% for the D+P arm (p=0.055) and were generally manageable (grade 4, 14% vs. 11%). Grade >3 toxicities that were more commonly seen in the D+V arm were rash/photosensitivity (11% vs. 0%) and diarrhea (7% vs. 0%).

Conclusions: In this platinum-pretreated population of advanced UC, the addition of vandetanib to docetaxel did not result in a significant improvement in PFS, ORR or OS. Toxicities were greater but manageable.

[Table: see text]
Factors associated with surgical resection for pancreatic and periampullary carcinomas in a cancer center in Mexico City.
Authors: Onate-Ocana Luis F. , Bermudez-Benitez Elyzabeth , Ortiz-Toledo Miguel Angel , Ochoa-Carrillo Francisco J. , Aiello-Crocifoglio Vincenzo
Published: February 2017

191

Background: Medical information regarding periampullary neoplasms is scarce in Mexico. Therefore, our aim is to report our experience with pancreatic and periampullary neoplasms, with attention to factors associated to surgical resection in a Cancer Center.

Methods: A retrospective analysis of medical records of all patients with malignant neoplasms located at periampullary region demonstrated by biopsy from January 2005 to December 2010. Factors associated to resectability or survival were calculated employing logistic regression or Cox models.

Results: A total of 464 patients with neoplasms of the periampullary region were identified, 249 women and 215 males (mean age 60.2 years). Pancreatic cancer was reported in 269 cases (58%), ampullary in 91 (19.6%), duodenal in 63 (13.6%), intrapancreatic bile duct in 15 (3.2%), neuroendocrine neoplasms in 13 (2.8%) and other types in 13 (2.8%). Sixty-two pancreatoduodenectomies were performed in this 6-year period (13.4% resectability). Sixty-one patients were stages I or II, and 403 stages III or IV. Age (odds ratio [OR] 0.97; 95% confidence interval [CI] 0.96-0.99) and ampullary carcinoma (OR 6.09; 95% CI 3.4-10.8) were the only factors associated to resectability (p<0.0001). Median overall survival of the cohort was 2.9 months (95% CI 2.4-3.4). Factors associated to overall survival with their estimators of the Cox model (p<0.00001) are shown in the Table.

Conclusions: Resectability is low and advanced stages are frequent. Young age and location in the ampulla defines increased probability of resection. Overall survival is associated to younger age, being female, ampullary carcinoma, neuroendocrine carcinoma and surgical resection.

[Table: see text]
Activity of cabozantinib (XL184) in hepatocellular carcinoma patients (pts): Results from a phase II randomized discontinuation trial (RDT).
Authors: Cohn Allen Lee , Kelley Robin Katie , Yang Tsai-Shen , Su Wu-Chou , Verslype Chris , Ramies David A. , Lee Yihua , Shen Xiaodong , Van Cutsem Eric
Published: February 2017

261

Background: Cabozantinib is an oral, potent inhibitor of MET and VEGFR2. MET over-expression has been observed in advanced hepatocellular carcinoma (HCC). Anti-VEGF pathway agents have shown clinical benefit in pts w/ HCC. Simultaneous targeting of the MET and VEGF signaling pathways with cabozantinib may therefore be a promising treatment strategy.

Methods: HCC pts with progressive measurable disease, per mRECIST received cabozantinib at 100 mg qd PO over a 12 week Lead-in period. Up to one prior regimen was allowed and only pts with Child-Pugh score of A were eligible. Tumor response was assessed every 6 weeks. Treatment beyond Week 12 was based on response: pts with PR continued open-label cabozantinib, those with SD were randomized to cabozantinib vs. placebo, and those with PD discontinued study drug. The primary endpoint was overall response rate (RR) per mRECIST in the Lead-in period, and progression free survival for pts who entered the randomized period.

Results: Enrollment has been completed with 41 pts. Results are available for 34 pts. Median age: 61 years (33 to 83). Males: 24/34 (71%). Asian: 13/34 (38%). HCC etiology: Hepatitis B or C 12/34 (35%); alcohol abuse 5/34 (15%); other 17/34 (50%). Extrahepatic spread was observed in 21/34 (62%). The median number of prior systemic treatments was 1; prior sorafenib: 16/34 (47%). Most common related AEs ≥Grade 3 were hand-foot syndrome (15%), diarrhea (9%) and thrombocytopenia (9%). 3/33 pts evaluable for tumor assessment at 12 weeks achieved PR by original RECIST (RR 9%). One additional pt randomized at Week 12 achieved PR at 18 weeks and treatment remains blinded on study for >1 year. 24/30 pts (80%) with ≥1 post-baseline scan had tumor regression (with no apparent relationship to prior sorafenib therapy). The overall disease control rate (DCR = PR+SD) at Week 12: 71% (Asian subgroup: 77%). Median time on study: 6 mos (1 to 15+ mos). AFP responses (defined as reduction from baseline of >50%) in 21 pts with ≥1 post-baseline result: 9/21 (43%).

Conclusions: Cabozantinib exhibits clinical activity in HCC pts with advanced disease, regardless of prior sorafenib treatment as reflected by tumor reduction, high DCR and time on study.
Multimodality therapy for borderline resectable pancreatic cancer: A single-institution experience.
Authors: Pimiento Jose Mario , Hutchinson Tai , Weber Jill M. , Patel Manish R. , Hodul Pamela Joy , Chuong Michael D. , Springett Gregory M. , Hoffe Sarah E. , Karl Richard C. , Centeno Barbara , Klapman Jason , Shridhar Ravi , Chen Dung-Tsa , Malafa Mokenge Peter
Published: February 2017

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Background: Multimodality therapy has been advocated for borderline resectable pancreatic cancer (BRCP); however, specific regimens vary widely by institution. Outcomes of these interventions need to be examined to inform future investigation of the optimal therapy for these patients. This study represents the experience of multimodality therapy for BRPC at an NCI designated cancer center.

Methods: We identified all patients (pts) with operable pancreatic ductal adenocarcinoma (PDA) from 2006 to 2011. Patients were divided into two groups: resectable group and BRPC group as per the NCCN and AHPBA consensus guidelines. Primary outcomes were resection rate, microscopic negative margin (R0) resection rate, overall survival (OS), and disease free survival (DFS). Fisher's exact and chi-square were used for group comparison while Kaplan-Meier estimates was used for survival analysis.

Results: 160pts were identified with operable PDA. 100 (63%) pts had resectable tumors, and 60 (37%) pts had borderline resectable tumors. Neoadjuvant therapy (NT) was administered to 0% in the group with resectable tumors, and 100% in the group with borderline resectable tumors. The resection rate was 100% in pts with resectable tumors and 58% in pts with borderline resectable tumors. R0 resection rates were 80% in the resectable tumors and 97% in the borderline resectable tumors following NT. Perioperative mortality was <1% (1/125) for resectable tumors and 0% in borderline resectable tumors. Median OS was 22.6 months (m) for pts that had resectable tumors and 13.9m for all pts with borderline resectable tumors (p=0.017); however, the median OS for resected pts with borderline resectable tumors was 21.5m (p=0.6). Improved DFS was seen in patients with resectable tumors when compared with resected borderline resectable tumors (15 vs. 9.5m; p=0.04).

Conclusions: Multimodality therapy leads to high rates of R0 resections in borderline resectable pancreatic cancer; however 42% of patients progressed during NT. The overall survival for patients with resected borderline resectable pancreatic cancer following NT is similar to patients who undergo resection for resectable pancreatic cancer.
Initial experience using percutaneous irreversible electroporation (IRE) in the treatment of locally advanced pancreatic adenocarcinoma (LAPC) with vascular encasement.
Authors: Hosein Peter Joel , Barbery Katuska J , Perez-Rojas Evelyn , Froud Tatiana , Rocha Lima Caio Max S. , Franceschi Dido , Livingstone Alan S , Yrizarry Jose M , Narayanan Govindarajan
Published: February 2017

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Background: Neoadjuvant chemoradiation therapy can convert some patients (pts) with borderline or unresectable LAPC to resectability. Persistent vascular encasement after neoadjuvant therapy usually contraindicates resection. IRE using the Nanoknife is more versatile than other ablative modalities in that tumors abutting vascular structures can be treated with IRE without compromise of the vessels or concern for the heat sink effect of nearby blood flow.

Methods: We examined the records of pts referred for IRE for LAPC. The procedures were all done percutaneously under general anesthesia using a standard protocol. The primary endpoint was safety. Secondary endpoints included survival and resection rate after the procedure.

Results: Between 12/2010 and 8/2011, 8 pts with biopsy-proven PC underwent percutaneous ablation of pancreatic tumors using IRE. The median age was 53 years (range 51-72), the median time from diagnosis to IRE was 8.8 months (range 2.4-29.2) and the median tumor size treated was 2.8cm (range 2.5-6.8). All pts had prior chemotherapy and 7 had prior radiation, with a median of 2 lines of prior therapies (range 1-4). Two pts went to surgery after IRE after 4 and 5 months respectively. Both had margin-negative (R0) resections and one had a pathologic complete response. Both remain disease-free at 1 and 5 months after resection respectively. Among the 6 remaining pts, 2 were lost to follow-up, one had progressive disease after 3 months and 3 remain under follow-up to determine resectability. One of these 3 pts had a negative follow-up PET scan and surgery is planned. The procedure was complicated by a spontaneous pneumothorax during anesthesia in one patient, and another developed pancreatitis; both recovered completely.

Conclusions: Percutaneous ablation of pancreatic tumors appears to be feasible and safe using the IRE modality. In our initial experience, 2 out of 8 pts with unresectable LAPC due to persistent vascular encasement after neoadjuvant therapy achieved a margin-negative resection after IRE. One had a pathological complete response. A prospective neoadjuvant trial in LAPC incorporating IRE is planned.
A phase I open-label, dose-escalation study of intravenous ascorbic acid in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer.
Authors: Littman Susan Joy , Monti Daniel , Newberg Andrew , Bazzan Anthony , Pillai Madhavan V. , Lewis Nancy , Yeo Charles , Levine Mark , Mitchell Edith P.
Published: February 2017

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Background: IV ascorbic acid (vit c) is a prodrug for steady state formation of ascorbate radical (Asc·-) in the extracellular space resulting in sustained production of H2O2 leading to selective killing of tumor cells by a pro-oxidative mechanism. In preclinical models of panc cancer pharmacologic concentrations of Asc·- with gem resulted in a synergistic cytotoxic response. We conducted a Phase I dose escalation study of IV ascorbic acid with gem plus erlotinib chemo as first line therapy in panc cancer.

Methods: Patients with adv panc cancer were enrolled using a standard 3+3+3 design to assess the safety and pharmacology of IV vit c in combo with gem and erlotinib. Cohort 1 received 50 g IV vit c and subsequent cohorts were escalated by 25 g to a final dose of 100 g. Pts were given 3 infusions of vit c per week on separate days for 8 w (1 cycle). IV gem was given on day 1 (1000 mg/m2) and weekly for 7 w followed by a rest week. Oral erlotinib (100 mg) was given daily for 8 w. Trt continued until disease progression or toxicity. Steady state ascorbate PK was assessed in cohorts 2 and 3. AEs were determined using NCI CTCAE v3.0. Tumor responses were assessed per RECIST.

Results: Of 14 pts enrolled, 9 or 3 per cohort completed the study. Median age was 64 years. 5 pts did not complete trt (2 discontinued, 3 died). 9 pts completed at least 24 ascorbic acid trts and 1 cycle of gem/erlotinib therapy. There were 24 AEs. These included 15 non-serious AEs and 8 SAEs. The most frequent AEs were grade 1/2 thrombocytopenia. Other grade 1/2 events included anemia, hyperglycemia, abd discomfort, ascites and infection. SAEs: 2 grade 3 heme, 1 grade 3 GI, 1 grade 3 infectious and 2 grade 4 thrombosis. Plasma asc levels were 25.3 - 31.9 mm/L for pts receiving the 100g dose. 8 of the 9 pts had a reduction in the panc primary with 1 pt having no change at 8 w. For non-target lesions, 2 had PD and 7 had SD per RECIST.

Conclusions: Overall safety data do not reveal AEs other than those expected in patients with metastatic panc cancer and/or treatment with gem and erlotinib. Addition of IV ascorbic acid did not increase toxicity. Preliminary efficacy results are encouraging. A phase II study is planned.
Washington University experience with FOLFIRINOX in pancreatic cancer.
Authors: Peddi Parvin F. , Tan Benjamin R. , Picus Joel , Sorscher Steven , Suresh Rama , Lockhart Albert C. , Menias Christine , Linehan David , Wang-Gillam Andrea
Published: February 2017

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Background: The FOLFIRINOX (5-FU, leucovorin, irinotecan, oxaliplatin) regimen has recently been shown to be an effective treatment with a significant survival benefit in patients with metastatic pancreatic cancer. Concern for treatment-related toxicity, however, has hampered the adoption of this regimen in clinical practice. A FOLFIRINOX registry was created at our institution to document FOLFIRINOX tolerability and efficacy.

Methods: Patients with pancreatic cancer who had received at least one dose of FOLFIRINOX were enrolled in the registry. Demographic information, treatment dosage, adverse events, and efficacy data were obtained. Radiographic response was independently verified by a radiologist.

Results: Between January 2010 and August 2011, 29 patients were identified with a median age of 57 (range 37-71). 26 (92.8%) had ECOG performance status of 0-1. FOFIRINOX was given to 16 patients with metastatic disease, 12 with locally advanced disease, and one with borderline resectable disease. 17 (61%) received the first cycle with a dose reduction in either irinotecan and/or 5-FU dosage. UGT1A1*28/*28 homozygous genotype was found in 4 patients who all received dose reduced irinotecan. 13 patients (46%) were started on G-CSF prophylactically with the first cycle while 5 additional patients (18%) had G-CSF support added in later cycles. Main adverse events were neutropenia (grade 3-4 in 14.2%), and abdominal pain and diarrhea (grade 3-4 in 7% and 4% respectively). One incidence of neutropenic fever was observed. Four patients were hospitalized for treatment-related toxicity while three had therapy discontinued due to intolerance. At present, 19 patients have imaging available to determine efficacy: 5 (26%) had partial response, 12 (63%) stable disease, and 2 (11%) had progression of disease as their best response. For patients with locally advanced disease, 11 out of 12 had clinical benefit on FOLFIRINOX.

Conclusions: In our practice, FOLFIRINOX was well tolerated and was efficacious, consistent with previously published data. It was frequently used in the setting of locally advanced disease and had similar benefit and tolerability in this setting.
Phase II study of sunitinib (SU) in Japanese patients with unresectable or metastatic, well-differentiated pancreatic neuroendocrine tumor (NET).
Authors: Okusaka Takuji , Ito Tetsuhide , Nishida Toshirou , Igarashi Hisato , Mizuno Nobumasa , Hara Kazuo , Morizane Chigusa , Kondo Shunsuke , Hashigaki Satoshi , Kimura Nobuyuki , Okano Kyoko , Tanuma Junichi , Murakami Mami , Sawaki Akira , Yamao Kenji , Imamura Masayuki
Published: February 2017

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Background: SU is an oral, multitargeted, antiangiogenic, tyrosine kinase inhibitor effective in patients (pts) with unresectable, well-differentiated pancreatic NET. This open-label, phase II study examined whether SU is also effective in Japanese pts with this disease.

Methods: Japanese pts received SU 37.5 mg/day on a continuous daily dosing (CDD) schedule (28-day cycle). The primary endpoint was clinical benefit rate (CBR; complete response [CR] + partial response [PR] + stable disease [SD] ≥24 weeks). Secondary endpoints included: objective response rate (ORR; CR + PR), 6-mos progression-free survival (PFS) probability, safety and pharmacokinetics. Tumor assessments were performed at baseline and 8-wk intervals by CT or MRI (RECIST).

Results: Twelve patients were enrolled and received treatment (tx; median age 54 yrs, range 34–79); 9 were ongoing at data cut-off (July 1, 2011). CBR was 75.0% (95% CI 42.8, 94.5), comprising 5 PRs and 4 pts with SD ≥24 weeks. ORR was 41.7% (95% CI 15.2, 72.3). 6-mos PFS probability was 91.7% (95% CI 53.9, 98.8). One PR occurred in a pt with gastrinoma, in whom gastrin levels decreased by 93% and tumor bulk decreased by 45%. All-causality, any-grade (G) AEs included diarrhea (n=9, 75%), HFS and hypertension (both n=8, 67%). Neutropenia was the most common G3 AE (n=5, 42%, all tx-related). Three pts (25%) experienced G4 AEs (herpes encephalitis, convulsion, loss of consciousness [n=1] and lipase increased [n=2], all tx-related).Two pts (17%) experienced serious AEs: convulsion and loss of consciousness (n=1, tx-related), and acute cholecystitis (n=1, unrelated to tx). There were no deaths on study; one death due to disease progression occurred 3 mos after study withdrawal. On day 15 (cycle 1), mean trough plasma concentrations (n=10) for SU, its metabolite, and SU + metabolite were 53.9, 23.7 and 77.5 ng/mL, respectively. SU on a CDD schedule resulted in sustained drug concentrations without accumulation across cycles.

Conclusions: SU 37.5 mg/day on a CDD schedule demonstrated antitumor activity in Japanese pts with unresectable, well-differentiated pancreatic NET. Common AEs were consistent with the known safety profile of SU.
Final results from study 181: Randomized phase III study of FOLFIRI with or without panitumumab (pmab) for the treatment of second-line metastatic colorectal cancer (mCRC).
Authors: Sobrero Alberto F. , Peeters Marc , Price Timothy Jay , Hotko Yevhen , Cervantes-Ruiperez Andres , Ducreux Michel , Andre Thierry , Chan Emily , Lordick Florian , Tian Ying , Sidhu Roger
Published: February 2017

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Background: In the primary analysis of study 181, pmab+FOLFIRI significantly improved progression-free survival (PFS) vs FOLFIRI as second-line therapy in patients (pts) with wild-type (WT) KRAS mCRC. Here, we report the results of a prespecified final descriptive analysis planned for 30 months (mos) after the last pt was enrolled.

Methods: Pts were randomised 1:1 to pmab 6.0 mg/kg Q2W+FOLFIRI (Arm 1) vs FOLFIRI alone (Arm 2). Pts had one prior fluoropyrimidine-based chemotherapy regimen for mCRC and ECOG 0-2. The co-primary endpoints were PFS (central assessment) and OS, and were independently tested. Secondary endpoints included objective response rate (ORR), and safety. KRAS status was determined by a blinded central lab.

Results: 1,186 pts were randomised and received treatment (tx): 591 in Arm 1, 595 In Arm 2. 1,083/1,186 pts (91%) had KRAS results. Adverse event rates were consistent with the primary analysis. Results are shown in the table .

Conclusions: In Arm 1, PFS (standard and on-treatment definition) and ORR were improved, and there was a trend toward improved OS in pts with WT KRAS mCRC. The large proportion of pts receiving post-progression anti-EGFR therapy may have affected the ability to observe a difference in OS between the tx arms. In pts with MT KRAS there was no difference in efficacy. KRAS testing is critical to select appropriate pts for tx with pmab.

[Table: see text]