bluuebunny/crossref_metadata_2025 huggingface dataset:
The German study group of intravesical hyperthermia-chemotherapy in non-muscle-invasive bladder cancer presents their long-term results in efficacy and tolerability for optimized adjuvant therapy and bladder preservation.
Authors: Lüdecke Gerson , Hasner Florian , Hanitzsch Herbert , Schmidt Matthias ,   German Hyperthermia-Chemotherapy Group
Published: February 2017

268

Background: In NMIBC recurrence and progression in high-risk BC are the dominant aspects for the clinical management. Intravesical chemotherapy and BCG treatment are the techniques to reduce both risks. HTC has a potentiating synergistic action in BC cell death induction. In consequence we proved HTC in the adjuvant indication and the ablativ indication in high-risk BC. Methods: We treated 138 patients in 1,443 treatment sessions in 3 institutions with intravesical hyperthermia-chemotherapy with Mitomycin C applied with the Synergo device. After an initial inductive weekly therapy for 6 to 8 weeks maintenance followed once every 6 weeks 6 times and cystoscopy every 3 month. Results: In the adjuvant indication 52 patients were treated. The over all recurrence free rate was 78.3% over 2.9 years in mean (3.6m – 6.9y). Only 10 patients recurred but none progressed or needed a cystectomy. In the ablative indication 86 patients were treated. For efficacy 69 could be evaluated. 17 patients must be excluded because of protocol violation or extra-vesical TCC or simultanious second malignancy. 85.5% of the patients (58) reached CR and this persited for 26.1 months in mean. 48 patients (69.6%) were tumor free over the hole investigation time. In total 8 patients (11.6%) needed a cystectomy. 3 patient (4.3%) progressed to metastatic disease and the other 5 demonstrated low-risk new tumors again treated transurethral. In total 53 patient (76.8%) achieved organ preservation in high-risk situation. Side effects included allergy, UTI, spasm, difficulties with catheterization and nocturia ascending from 1.4% to 5.6%. Conclusions: HTC is a safe and effective therapy in NMIBC to prevent intermediate risk BC patients for recurrence and to ensure organ preservation in high-risk BC patients in more than 75% with a long lasting efficacy.
Phase I/II clinical trial of ALT-801, a T-cell receptor/IL-2 fusion protein, plus gemcitabine and cisplatin in urothelial cancer.
Authors: Fishman Mayer N. , Hadjenberg Julio , Kuzel Timothy , Mahipal Amit , Rosser Charles Joel , Landau Danny , Gupta Shilpa , Vaena Daniel A. , Agarwala Sanjiv S , Mahoney John Francis , Hoffman-Censits Jean H. , Harris Wayne , Milhem Mohammed M. , Weber Jeffrey S. , Rhode Peter , Schutt Tessa , Hernandez Liza , Huang Bee-Yau , Wong Hing C.
Published: February 2017

271

Background: ALT-801, a T-cell receptor/IL-2 fusion protein, activates NK and CD4+ lymphocytes to secrete IFN-gamma which re-polarizes tumor associated macrophages from M1 to M2 in various murine tumor models. CD8+ memory cells also acquire an innate immune phenotype and become expanded upon ALT-801 activation. Via this novel mechanism, ALT-801 mounted effective immune responses and maintained immunological memory against urothelial cancer in these models. Pretreatment chemotherapy eliminated myeloid-derived suppressive cells, potentiating the anti-tumor effects of ALT-801 (Wong, unpublished data). Previous clinical studies with ALT-801 (advanced malignancy; Fishman 2011 CCR 17:7765) and ALT-801 + cisplatin (melanoma; NCT01029873) showed anti-tumor activity in these settings. Methods: We evaluated co-administration of gemcitabine [G] (1000 mg/m2/dose, day 1 and 8) and cisplatin [C] (70 mg/m2/dose, day 1) with ALT-801 (escalating doses; days 3, 5, 8, 10) for three 21-day cycles, in patients with metastatic urothelial cancer. Those with at least stable disease after 3 courses could receive 4 additional weekly doses of ALT-801 alone. ALT-801 doses were planned at 0.04 to 0.12 mg/kg/dose in 5 cohorts with a 3+3 escalation design. Results: The dose-escalation is completed, with a recommended dose of ALT-801 of 0.06 mg/kg/dose. The best objective response rate (ORR, RECIST v1.1) among 5 chemo-naïve subjects was 100% (2 CR, 3 PR) and among 5 previously treated patients 60% (1 CR, 2 PR), for an overall total of 80% (3 CR, 5 PR, 1 SD, 1 PD). One of 2 patients who underwent radical cystectomy was confirmed pathologically free of tumor. Responding lesions included bulky and extensive liver and pulmonary metastases, and adenopathy. ALT-801 at the 0.06 mg/kg/dose level in this combination was adequately-tolerated. Grade 3/4 toxicities including neutropenia, thrombocytopenia and lymphopenia, appear consistent with known G, C, and ALT-801 effects. Conclusions: ALT-801 is a novel and potentially active immunotherapy for urothelial cancer. More patients are in treatment on the open phase 2 expansion portion of the study (NCT01326871), and updated interim results are anticipated (CA097550). Clinical trial information: NCT01326871.
Brain metastases in patients with urothelial carcinoma.
Authors: Boyle Helen Jane , Lavergne Emilie , Droz Jean Pierre , Bonnin Nathalie , Flechon Aude
Published: February 2017

282

Background: Muscle invasive urothelial cancers are infrequent. Patients (pts) with metastatic disease have poor prognosis. Brain metastases (BM) are rare. The aim of this retrospective study is to analyse the characteristics, the treatment and the evolution of patients with BM treated in a single centre. Methods: Thirty pts with BM were identified among the 1591 pts with urothelial carcinoma seen at the Centre Léon Bérard, between 1994 and 2011. The study population was described, overall survival (OS) from diagnosis of BM was estimated by Kaplan-Meier method and prognostic factors were explored using a Cox model. Results: Twenty seven pts in our series were male. Median age at initial diagnosis was 60 years (range: 33.9-78.9 years). Twenty two pts had primary bladder tumours and 8 upper urinary tract tumours. Twenty four pts underwent surgery for their primary lesion, 2 received chemoradiotherapy and 4 did not receive any radical local treatment. Six pts had metastatic disease at initial presentation: 3 were operated on. Median delay between initial diagnosis and BM was 16.6 months (range: 0-56.4 months), 3 patients had BM at initial presentation. Median time between first metastases and BM was 10 months (range=0-52 months). Eleven patients developed BM as one of the first sites of metastases. BM were symptomatic in 28 pts: specific neurological symptoms (n=25), headaches (n=6), epilepsy (n=2). For the 2 other pts, they were discovered on a systematic brain MRI. Eighteen pts had cerebral metastases only, 5 pts had cerebellar metastases only, 6 had both; the last patient had cerebral, cerebellar and meningeal involvement. Half of the pts had only 1 brain lesion. Five pts were operated on: 4 received postoperative radiotherapy; 19 patients were given radiotherapy alone and 6 did not get any local therapy. In this series, median OS from diagnosis of BM was 3.4 months (IC95% [2.2-10.3]). Only the administration of chemotherapy after the diagnosis of BM was significantly associated with OS; probably because only fit enough patients were offered treatment. Conclusions: Prognosis of patients with urothelial carcinoma and BM is poor; however some patients have long survivals. Treatment is not codified as there is little data in the literature.
Preclinical and correlative studies of cabozantinib (XL184) in urothelial cancer (UC).
Authors: Apolo Andrea Borghese , Lee Young H. , Cecchi Fabiola , Agarwal Piyush K. , Parnes Howard L. , Khadar Kattie , Summerell Amelia , Gulley James L. , Compton Kathryn , Figg William Douglas , Dahut William L. , Bottaro Donald P.
Published: February 2017

314

Background: Mounting evidence supports Met as a target in urothelial cancer (UC). Activated Met can promote angiogenesis and tumor growth by upregulating VEGF and may play a role in UC pathogenesis. Cabozantinib inhibits both VEGFR2 and Met pathways. In this study, we assessed shed Met (sMet) levels in the urine and serum of UC patients (pts) and cabozantinib’s effects on HGF-driven UC cell growth and invasion. Methods: sMet levels in serum and urine samples from 31 pts with UC (23 metastatic, 8 muscle-invasive) were correlated with stage, presence of visceral metastases and urinary source. The effects of cabozantinib on 4 human UC-derived cell lines were studied in vitro. Intact RT4, TCC-SUP, T24M2 and T24M3 cells at 80% confluence were serum deprived 16 h, then left untreated or treated with hepatocyte growth factor (HGF) and/or cabozantinib prior to analysis of Met, phospho- (p)Met, pAkt, Akt, pMAPK and MAPK by immunoassay or immunoblotting. Cabozantinib effects on basal and HGF-induced UC cell invasion, proliferation and soft agar growth were measured. Results: Median serum Met levels were modestly higher in pts with metastatic versus muscle-invasive disease. Urinary Met levels were clearly higher in pts with visceral metastasis (p=0.0111) and in urine from ileal conduits and neobladders compared to normally voided urine, regardless of stage (p=0.0489). Met content in UC cell lines was low in RT4 and higher in T24M2, T24M3 and TCC-SUP. Basal pMet content was universally low, increased significantly by HGF and this was reversed by cabozantinib. HGF-driven increases in pAkt/Akt and pMAPK/MAPK in all 4 cell lines were reversed by cabozantinib, as were HGF-enhanced UC cell invasion, proliferation and anchorage independent growth. Conclusions: Median urinary sMet is significantly higher in pts with visceral metastasis and in specimens from ileal conduits and neobladders relative to normally voided urine. UC cell Met content in culture increased with disease grade; HGF stimulated activation of Met and known effectors, and enhanced invasion, growth rate and anchorage-independent growth; cabozantinib effectively reversed these HGF-driven effects. These data support evaluation of cabozantinib in pts with metastatic UC.
Randomized phase II trial evaluating the optimal sequencing of sipuleucel-T and androgen-deprivation therapy (ADT) in patients (pts) with biochemically recurrent prostate cancer (BRPC).
Authors: Antonarakis Emmanuel S. , Kibel Adam , Tyler Robert Claude , McCoy Candice , Wang Yang , Sheikh Nadeem A. , Drake Charles G.
Published: February 2017

34

Background: ADT is a standard therapy for pts with BRPC after failure of primary therapy, and has known immunomodulatory effects. Sipuleucel-T is an autologous cellular immunotherapy that targets prostatic acid phosphatase (PAP) and is FDA approved for minimally or asymptomatic metastatic castrate-resistant prostate cancer. Here we report interim data from a phase 2 trial evaluating the optimal sequencing of sipuleucel-T and ADT by examining immune response markers in pts with BRPC at high risk for metastases (i.e., PSA doubling time ≤12 mo). Methods: Men were equally randomized to Arm 1: sipuleucel-T followed by ADT (started 2 wk after the final sipuleucel-T infusion); or Arm 2: ADT followed by sipuleucel-T (started after 3 mo of ADT). In both arms pts received 3 infusions of sipuleucel-T and 12 mo of ADT (2 × 45 mg leuprolide injections at 6 mo intervals). The primary endpoint was antigen-specific immune responses (ELISPOT to PA2024 [PAP-GM-CSF]). Secondary endpoints included safety and product parameters (CD54 upregulation, CD54+ and total nucleated cell counts). Results: 68 pts were randomized over 9 mo. Baseline characteristics were balanced across arms. Product parameters, evaluated in 31 and 17 pts in Arms 1 and 2, respectively, were similar between arms at the time of this analysis (26 Sept 2012). Antigen presenting cell activation patterns indicated a prime-boost effect (increased CD54 upregulation at infusions 2 and 3). Analysis of serum samples suggested that there were no differences between the arms in cellular (n=20; n=10) or humoral (n=22; n=13) immune responses to PA2024 or PAP (p>0.05). Similar anti-tetanus titers were seen in both arms, indicating equivalent immunocompetence. To date, the combination of sipuleucel-T and ADT appears to be well tolerated with only 1 serious adverse event seen (vertigo, Arm 2). Conclusions: Preliminary data suggest that in men with BRPC, sipuleucel-T results in a similar prime-boost pattern of immune activation, and antigen-specific cellular and humoral responses, independent of ADT. Sipuleucel-T plus ADT appears to be well tolerated in these pts. Updated results will be presented. Clinical trial information: NCT01431391.
The BEST trial (E2804): A randomized phase II study of VEGF, RAF kinase, and mTOR combination targeted therapy (CTT) with bevacizumab (bev), sorafenib (sor), and temsirolimus (tem) in advanced renal cell carcinoma (RCC).
Authors: McDermott David F. , Manola Judith , Pins Michael , Flaherty Keith T. , Atkins Michael B. , Dutcher Janice P. , George Daniel J. , Margolin Kim Allyson , DiPaola Robert S.
Published: February 2017

345

Background: Single-agent VEGF and MTOR directed targeted therapy have improved outcomes for pts with RCC. Phase I trials suggested that CTT might delay resistance. This randomized phase II trial was designed to find the best CTT regimen in comparison to bev alone for potential comparison to the best available single-agent therapy in a phase III trial. Methods: 361 treatment naïve RCC pts were randomized to receive Bev (10mg/kg Q2wks), Tem (25mg Qwk) + Bev (10mg/kg), Bev (5mg/kg Q2wks) + Sor (200mg po 5d on/2d off), or Sor (200mg QD) + Tem (25mg Qwk) until disease progression or unacceptable toxicity. The study was designed to detect a 67% improvement in median PFS on the combination arms, compared to single-agent bev (median 9 vs. 15 mo). Results: The median PFS was 8.7 mo for Bev versus 7.3 mo for Bev/Tem (HR = 0.91; 95% CI, 0.68-1.23), 11.3 mo for Bev/Sor (HR = 0.84; 95% CI, 0.62-1.13), 7.7 mo for Sor/Tem (HR = 1.11; 95% CI, 0.83-1.49). The response rates (CR+PR) were 12% for Bev versus 28% for Bev/Tem, 30% for Bev/Sor and 27% for Sor/Tem. No difference in OS was observed. Common toxicities included hypertension, fatigue, hand-foot syndrome, and diarrhea. Grade 3/4 adverse events and dose reductions were more common on CTT. Conclusions: CTT was not superior to single-agent Bev for the PFS primary endpoint. Common severe toxicities were expected, but more prevalent with CTT than with Bev alone. The VEGF/VEGFR co-inhibition strategy may warrant further investigation possibly with more selective VEGFR inhibitors. Clinical trial information: NCT00378703.
Treatment benefit of tivozanib hydrochloride versus sorafenib on health-related quality of life (HRQoL) among patients (pts) with advanced/metastatic renal cell carcinoma (mRCC): TIVO-1 study results.
Authors: Cella David , Ivanescu Cristina , Skaltsa Konstantina , Casamayor Montserrat , Strahs Andrew Louis , Esteves Brooke , Berkenblit Anna , Motzer Robert John
Published: February 2017

355

Background: Tivozanib hydrochloride (T) was superior to sorafenib (S) in progression-free survival (medians of 11.9 vs. 9.1 months, respectively; 12.7 vs. 9.1 months, respectively, for metastatic treatment-naïve pts) in the phase III TIVO-1 study in pts with mRCC. T showed a differentiated safety profile with lower rates of dose interruptions/reductions v S (18/12 vs. 35/43, respectively; p<0.001). TIVO-1 also evaluated patient self-reported HRQoL. Methods: Pts with mRCC were randomized 1:1 to receive T (1.5 mg PO once daily for 3 weeks on, 1 week off) or S (400 mg bid, continuously). HRQoL was assessed on Cycle 1/Day1 (baseline [BL]) and at the beginning of each cycle, using the Functional Assessment of Cancer Therapy–General (FACT-G), FACT–Kidney Symptom Index Disease Related Symptoms (FKSI-DRS), and EuroQol 5-dimensional (EQ-5D) questionnaires; EQ-5D scores are not reported here. Pts with BL and ≥1 post-BL evaluable forms were analyzed. Changes from BL in FACT-G and FKSI-DRS scores over 18 treatment cycles were analyzed using repeated measures mixed-effects models. QoL improvement/deterioration was defined as an increase/decrease from BL of ≥3 points for FACT-G subscales and FKSI-DRS total score and 7 points for the FACT-G total score during the study. Results: In the mixed effects analyses, no significant differences in HRQoL (FACT-G and FKSI-DRS) were noted between T and S. More pts receiving T vs. S experienced a significant improvement during the study in physical well-being (PWB) (25.7% vs. 16.4%; p=0.011) and a favorable trend in all other FACT-G and FKSI scores (p values: 0.078–0.405). FKSI improvement was greater with T than S in treatment-naïve pts (34.1% vs. 23.6%; p=0.023), pts with ≥2 metastases (32.9% vs. 24.7%; p=0.054), or pts <65 years old (33.0% vs. 22.8%; p=0.022). Median time to QoL deterioration was usually longer with T (3.75-7.66 months) than S (2.04-8.80 months). Conclusions: HRQoL was generally similar for T and S. Non-significant numeric differences usually favored T over S, and PWB improvement occurred significantly more often with T. These results support the previously-reported PFS advantage of T over S. Clinical trial information: NCT01030783.
Overall survival (OS) of sorafenib (So) plus interleukin-2 (IL-2) versus So alone in patients with treatment-naive metastatic renal cell carcinoma (mRCC): Final update of the ROSORC trial.
Authors: Procopio Giuseppe , Verzoni Elena , Bracarda Sergio , Ricci Sergio , Ridolfi Laura , Sacco Cosimo , Miceli Rosalba , Porta Camillo , Bregni Marco , Bajetta Emilio
Published: February 2017

356

Background: A randomized phase II trial evaluating So plus IL-2 versus So alone as first-line treatment of mRCC, did not show any difference in progression-free survival (PFS) (primary endpoint) between the two groups. The final overall survival analysis is here reported. Methods: In this open-label phase II study, 128 patients with mRCC were randomized to receive either oral So 400 mg bid continuous dosing plus IL-2 4.5 MIU subcutaneously administered 5 times weekly for 6 weeks every 8 weeks (Arm A), or So alone (Arm B). At relapse, most patients of the two arms underwent treatment with other targeted therapies (TTs) including sunitinib, everolimus, and axitinib. Overall survival was estimated by Kaplan-Meier method and compared by two-sided log-rank test. Results: According to Motzer criteria 55 % of the patients were low risk in both arms, and 41% and 39% were intermediate risk in Arm A and B respectively. After a median follow-up time of 58 months (interquartile range: 28-63 months), the median OS was 38 and 33 months in Arm A and B, respectively (p = 0.667). Five-year OS was 26.3% (95% CI: 15.9-43.5) for the combination arm and 23.1% (95% CI: 13.2-40.5) for single agent arm. The overall number of death was 85, 42 of whom in the So monotherapy group. Median PFS survival was 7.3 and 6.9 months for Arm A and B, respectively (p = 0.109). Overall, 49 (77%) and 48 (75%) patients in Arm A and B, respectively, received at least one subsequent targeted therapy (TTs). The most common adverse events (AEs) in both arms were asthenia, hand-foot syndrome, hypertension and diarrhoea. Grade 3-4 AEs were documented in 38% of patients treated with the combination regimen and in 25% of those undergoing single agent treatment. Conclusions: The OS results suggest an improved outcome in patients with mRCC treated with TTs which appears independent of the treatment initially administered. This prospective study, regarding use of sorafenib in first line of treatment, was associated with a surprising median OS. Clinical trial information: NCT00609401.
Comparison of PFS and safety for Asian compared to North American and European populations in the phase III trial of pazopanib versus sunitinib in patients with treatment-naive RCC (COMPARZ).
Authors: Guo Jun , Jin Jie , Huang Yiran , Wang Jin-Wan , Lim Ho Yeong , Uemura Hirotsugu , Rha Sun Young , Wu Hsi Chin , Crescenzo Rocco , Deen Keith C. , McCann Lauren , Motzer Robert John
Published: February 2017

366

Background: Pazopanib (P) and sunitinib (S) are multi-kinase angiogenesis inhibitors that positively impact progression-free survival (PFS) in patients (pts) with metastatic renal cell carcinoma (mRCC) (NEJM 2007 356:115; JCO 2009 29:475). The safety profile of multi-kinase angiogenesis inhibitors has been shown to vary depending upon ethnic background (Oncology 2011 80:395). Methods: Treatment naïve pts with clear cell mRCC and measurable disease were randomized 1:1 to P, 800mg QD continuous dosing or S, 50 mg QD for 4 weeks followed by 2 weeks off treatment. Primary endpoint was PFS. A subgroup analysis compared PFS (Cox analysis with treatment as only covariate) and AEs between the Asian, North American (NA), and European (EU) populations. Of the 1,110 pts 367 were from Asia (188 P, 179 S). Results: PFS in the Asian subgroup was consistent with NA and EU. HR (95% CI): Asia 1.07 (0.81, 1.42); NA 1.18 (0.90, 1.53); EU 1.03 (0.79, 1.36). Median PFS mos (95% CI) P: Asia 8.4 (8.3,11.1); EU 8.5 (8.0, 11.0); NA 8.3 (6.6, 11.0); S: Asia 11.1 (8.2, 14.3); EU 9.0 (8.1, 12.9); NA 10.5 (8.2, 13.4). AEs in >25% of pts in any arm in any region and a difference of 15% between any region within an arm are shown. Conclusions: In both arms, PFS in the Asian population was similar to NA and EU. In the Asian population increased incidences of hematotoxicity, hypertension, HFS, LFT increase, proteinuria, and decreased incidences of GI symptoms, headache were observed in both arms. Consistent with NA and EU, more frequent AEs in the Asian population (>10% difference between arms): ALT increase (P); HFS, thrombocytopenia, neutropenia (S). [Table: see text]
Sequential use of targeted therapies for metastatic renal cell carcinoma: A physician survey and chart review of community oncology practices in the United States.
Authors: Vogelzang Nicholas J. , Signorovitch James E. , Lin Peggy L. , Liu Zhimei , Culver Kenneth W. , Scott Jeffrey A. , Pal Sumanta Kumar , Jonasch Eric
Published: February 2017

418

Background: Multiple targeted agents are available to treat metastatic renal cell carcinoma (mRCC) and no consensus has been reached for optimal treatment sequencing. This study describes physician-reported treatment preferences, reasons for treatment choices, and current treatment patterns for mRCC in the community setting. Methods: A physician survey and retrospective chart review was conducted during May and June 2012 among community-based oncologists or hematologists who had ≥5 mRCC patients under their care in 2011. Charts were reviewed for adult mRCC patients initiated on 2nd-targeted therapy after January 2010 to collect information on current treatment sequence in mRCC patients and reasons for treatment choices. A parallel survey collected physician treatment preferences for 1st-, 2nd-, and 3rd-targeted therapies for mRCC patients with good or poor prognosis. Results: The study included surveys from 36 physicians and charts from 433 mRCC patients. The majority of patients (77%) received a tyrosine kinase inhibitor (TKI) and the rest (23%) received a mammalian target of rapamycin inhibitor (mTOR) as the 1st-targeted therapy. Sunitinib was the most common TKI and temsirolimus was the most common mTOR in the 1st-line setting. Among patients receiving 1st-line TKI, 34% received TKI (pazopanib was most used TKI) and 66% received mTOR (everolimus was most used mTOR) in the 2nd-line. Among 1st-line mTOR users, 94% used TKI (sunitinib was most used) and 6% mTOR (everolimus was most used) for 2nd-line. TKI-mTOR-TKI was the most commonly observed treatment sequence. Physician-stated preferences for 1st and 2nd targeted therapies were largely consistent with the results from the chart review, though actual mTOR use in the 2nd-line was greater than expected. Treatment guidelines and evidence from clinical trials were the top-ranked factors impacting treatment choices. Conclusions: In this large, retrospective chart review, TKI-mTOR-TKI was the most commonly observed treatment sequence for mRCC in the community setting.
Comparision of the risk of cardiovascular events and death in patients treated with degarelix compared with LHRH agonists.
Authors: Albertsen Peter C. , Nilsson Jan , Klotz Laurence , Payne Heather , van der Meulen Egbert , Persson Bo-Eric , Olesen Tine Kold , Beckman Joshua
Published: February 2017

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Background: LHRH agonists are used to treat patients (pts) with advanced prostate cancer and have been associated with an increased risk of cardiovascular (CV) events and related deaths. Degarelix is a GnRH antagonist that appears to mitigate this risk. Methods: Results were pooled from 2328 pts participating in 6 prospective randomised trials. Most pts (n=1,686) received 1 year of GnRH antagonist or LHRH agonist treatment; the remainder (n=642) had 3–7 months’ treatment. Data were classified based on the MedDRA system and analysed using Kaplan Meier plots and a Cox proportional hazard model. Event analysis was based on death from any cause or CV event defined as arterial embolic/thrombotic; haemorrhagic or ischemic cerebrovascular; myocardial infarction or other ischemic heart disease. High risk pts were defined as men with a baseline CV disease (CVD) history. Results: Treatment groups (GnRH antagonist, n=1,491 [degarelix]; LHRH agonist, n=837 [goserelin, n=458; leuprolide, n=379]) were balanced for baseline characteristics and CVD history (31% vs. 29%). Characteristics associated with CVD (e.g. statin medication, elevated blood pressure, diabetes, cholesterol >6.2 mmol/L) were similar between groups. The risk of a CV event or death was significantly lower in pts receiving degarelix during the first year of treatment (see Table). In pts with baseline CVD the findings remained significant. In pts with no baseline CVD, there was no difference in subsequent CVD events or death in either group. In analysis by time to CV event only in all pts and pts with baseline CVD (see Table), men receiving GnRH antagonist had a significantly lower risk of CV events. Conclusions: In all pts treated with a GnRH antagonist (degarelix) risk of a CV event or death was significantly lower than in pts receiving an LHRH agonist over a treatment period of up to 1 year. In pts with baseline CVD, risk reduction remained significant at ~50%. [Table: see text]
ARN-509 in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Rathkopf Dana E. , Antonarakis Emmanuel S. , Shore Neal D. , Tutrone Ronald , Alumkal Joshi J. , Ryan Charles J. , Saleh Mansoor N. , Hauke Ralph J. , Maneval Edna Chow , Scher Howard I.
Published: February 2017

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Background: ARN-509 is a novel second-generation anti-androgen that binds directly to the ligand-binding domain of the androgen receptor, impairing nuclear translocation and DNA binding. The Phase II portion of a multicenter Phase I/II study is evaluating the activity of ARN-509 in 3 distinct patient populations of men with CRPC: 1) non-metastatic treatment-naïve CRPC; 2) mCRPC treatment-naïve (tx-naïve); and 3) mCRPC abiraterone acetate pre-treated (AA). Preliminary results for the 2 cohorts of patients with metastatic CRPC are presented here. Methods: All patients had metastatic CRPC with progressive disease based on rising PSA and/or imaging. No prior chemotherapy for metastatic prostate cancer was allowed. Patients on the AA pre-treated cohort had to have been treated with AA for at least 6 months. All patients received ARN-509 at the recommended Phase II dose of 240 mg/day (Rathkopf et al, GU ASCO 2012). The primary endpoint was PSA response rate at 12 weeks according to the Prostate Cancer Working Group 2 Criteria in each of the treatment groups. Secondary endpoints included safety, time to PSA progression and objective response rates. PSA assessments were collected every 4 weeks and tumor imaging was performed every 16 weeks. Results: A total of 46 patients were enrolled: 25 on the tx-naïve and 21 on the post-AA cohorts. The combined median age was 68 (range 48-91) and at baseline, patients presented with ECOG performance status 0 (57%), Gleason Score 8-10 (52%), and median PSA of 14.7 (tx-naïve) and 58.4 (post-AA) ng/mL. All patients received prior treatment with a LHRH analog with or without a first-generation anti-androgen. To date, 15 patients discontinued the study due to disease progression (11), adverse events (2) and consent withdrawn (2). The most common treatment-related adverse events (AE) were fatigue (30%), abdominal pain (24%), nausea (22%), and diarrhea (17). There was only 1 treatment-related Grade 3 AE of abdominal pain. At 12 weeks, the PSA response was 88% (tx-naïve) and 29% (post-AA). Conclusions: In men with mCRPC, ARN-509 is safe and well tolerated, with robust PSA response in the tx-naïve cohort. Post-AA data suggests that ARN-509 has activity in a subset of patients that developed resistance to abiraterone acetate. Clinical trial information: NCT01171898.
ODM-201, a new generation androgen receptor inhibitor for castration-resistant prostate cancer: Preclinical and phase I data.
Authors: Fizazi Karim , Massard Christophe , James Nicholas David , Culine Stephane , Jones Robert Hugh , Oksala Riikka , Moilanen Anu , Aho Eija , Ravanti Laura , Kallio Pekka
Published: February 2017

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Background: Castration resistant prostate cancer (CRPC) is characterized by persistent, high level androgen receptor (AR) expression and resistance to conventional AR inhibitors. ODM-201 is a novel AR inhibitor with unique pharmacologic properties that has shown promising results in preclinical and clinical studies. Methods: AR binding affinity of ODM-201 to wild type AR was determined in cytosolic lysates obtained from ventral prostates of castrated rats using a competition binding assay. Additionally, effects of ODM-201 on the growth of castration resistant VCaP tumors was evaluated. Tumors were established by subcutaneous injection of VCaP prostate cancer cells into male nude mice. After initial tumor growth, mice were castrated. ODM-201 (50 mg/kg QD or BID orally) was initiated upon tumor regrowth. Since the risk of seizures has been reported for some second generation AR inhibitors, ODM-201 concentrations in mouse brain homogenates were studied after repeated oral administration to assess the risk. The clinical effects of ODM-201 (100, 200, 300, 500, 700, 900 mg BID) was examined in a Phase I/II dose-escalation trial in patients (N=24) with progressive metastatic CRPC. Results: ODM-201 binds to wild type AR with superior affinity compared to enzalutamide (Ki of 9 and 39 nM, respectively). In the VCaP CRPC model, ODM-201 significantly (p<0.001 compared to castrated control), and more efficiently than enzalutamide, inhibited tumor growth. After oral administration, tissue/plasma ratio of ODM-201 in mouse brain homogenates was negligible in all studied doses. In the Phase I/II clinical study, ODM-201 (100 to 700 mg results available) was well tolerated, and most commonly reported adverse events were asthenia, diarrhea and nausea. A PSA response (defined as ≥ 50% decrease) was obtained in 13/15 patients evaluable at 12 weeks with all patients achieving partial response or stable disease by RECIST/PCWG2 criteria. Conclusions: ODM-201 is a new generation AR inhibitor with superior preclinical efficacy compared to enzalutamide and bicalutamide, it does not enter the brain in preclinical studies, and it shows very promising activity and no significant toxicity in patients with CRPC. Clinical trial information: NCT01317641.
Development and validation of a mutivariate model combining cell cycle progression score with CAPRA to predict prostate cancer mortality in a conservatively managed cohort.
Authors: Brawer Michael K. , Cooperberg Matthew R. , Freedland Stephen J. , Swanson Gregory P. , Stone Steven , Reid Julia E. , Gutin Alexander , Carroll Peter , Cuzick Jack M.
Published: February 2017

67

Background: Prostate cancer outcomes are variable and difficult to predict. Improved tools are needed to appropriately match treatment to a patient’s risk of progression. We developed and validated a multivariate model to predict disease−specific mortality (DSM) by combining clinical parameters (CAPRA score) with a score based on measuring the expression level of cell cycle progression (CCP) genes. Methods: A multivariate prediction model was trained using patients from 4 retrospective cohorts with median clinical follow up of 7.6 years. We used 200 men from the UK diagnosed after TURP, 353 from Scott & White and 388 from UCSF treated with radical prostatectomy, and 118 men from Durham VA treated with EBRT. CCP score was derived from fixed tumor tissue (biopsy or surgical resection). Outcome was either time from treatment to biochemical recurrence (US cohorts) or time from diagnosis to disease specific mortality (UK cohort). The model was validated for predicting time from diagnosis to DSM in 180 men from the UK diagnosed by needle biopsy with clinically localized prostate cancer and managed conservatively (mean/median CAPRA score = 6). Results: A model combining CAPRA with CCP score was fit in the training set by a Cox Proportional Hazards analysis stratified by cohort. The Combined score was defined as 0.39*CAPRA+0.57*CCP score. There were no significant interactions between cohort and CAPRA or CCP score. This suggests that both CCP score and CAPRA confer similar prognostic information regardless of cohort composition, treatment, or specific outcome. In the validation cohort the Combined score was highly prognostic (HR= 2.27, 95%CI: (1.63, 3.16), p = 1.2 x 10−7). By likelihood ratio testing, the Combined score was a better predictor of DSM than CAPRA alone (p = 0.0028). The c−index of the Combined score was 0.75, which was an improvement over CAPRA (c−index 0.71). Conclusions: This multivariate model predicts DSM in a conservatively treated cohort. The model provides prognostic information beyond clinical variables, and can be used to help differentiate aggressive from indolent cancer at diagnosis.
Degarelix versus LHRH agonists: Differential skeletal and urinary tract outcomes from an analysis of six comparative randomized clinical trials.
Authors: Crawford E. David , Shore Neal , Miller Kurt , Tombal Bertrand , Kathrup Cathrina , van der Meulen Egbert , Persson Bo-Eric
Published: February 2017

68

Background: The use of ADT in men with prostate cancer is well established. GnRH antagonists have a mode of action distinct to that of LHRH agonists and comparative trials have shown differences in efficacy and safety between these agents. Adverse events (AE) from the musculoskeletal and renal and urinary systems have now been analysed. Methods: Results were pooled from 6 prospective, comparative randomised trials (n=2328). Most patients (pts) received 1 year of degarelix or LHRH agonist treatment (n=1686); the remaining men had 3–7 months’ treatment (n=642). AEs were analysed using Kaplan Meier plots and a log-rank test for homogeneity on relevant groups of MedDRA terms. Results: Treatment groups (degarelix, n=1491; LHRH agonist, n=837) were balanced for baseline characteristics such as age, testosterone, PSA and disease stage. In men with metastatic disease alkaline phosphatase (ALP) was reduced to a greater extent with degarelix (p=0.0373) throughout the year. Overall probability of fracture (<1% vs. 2%, p=0.0411) and incidence of joint related AEs (4% vs. 6%, p=0.0116) were significantly lower for degarelix-treated men. Incidence of muscle or bone pain was lower for degarelix (9% vs. 12%, p=0.0822). Incidence of urinary infections (UI) was reduced (5% vs. 8% with agonists) and time to first UI was significantly increased (p=0.0010) with degarelix. Overall probability of any renal or urinary tract AEs, including lower urinary tract symptoms (LUTS), was significantly lower in pts receiving degarelix (p<0.0001). Consistent with fewer skeletal and urinary tract AEs indicating better disease control, men with baseline PSA >50 ng/mL had significantly higher PSA PFS compared to agonist treated pts. OS during 1 year of treatment was significantly higher for degarelix pts (98.3% vs. 96.7%, p=0.0329). Conclusions: This analysis of 2,328 men shows degarelix-treated men had lower ALP, significantly fewer fractures, a lower incidence of urinary tract symptoms and higher overall survival than pts receiving an LHRH agonist over one year. Control of such disease symptoms is consistent with previous data on a significantly lower risk of PSA PFS during the first year of treatment.
Axitinib versus sorafenib as first‑line therapy in patients with metastatic renal cell carcinoma (mRCC).
Authors: Hutson Thomas E. , Gallardo Jorge , Lesovoy Vladmir , Al-Shukri Salman , Stus Viktor , Bair A. H. , Rosbrook Brad , Bycott Paul W. , Tarazi Jamal Christo , Kim Sinil , Vogelzang Nicholas J.
Published: February 2017

LBA348

Background: In the phase III AXIS trial, second-line therapy with axitinib resulted in significantly longer progression-free survival (PFS) versus sorafenib for mRCC. We conducted a multicenter, randomized, open-label, phase III trial to compare PFS of axitinib vs sorafenib as first-line therapy. Methods: Patients with untreated, measurable (RECIST v1.0), clear‑cell mRCC and Eastern Cooperative Oncology Group performance status (PS) 0 or 1 were randomized 2:1 to axitinib 5 mg twice daily (BID) or sorafenib 400 mg BID. Randomization was stratified by PS. Primary endpoint was PFS per independent radiology committee. The study had 90% power to detect a 78% PFS improvement from 5.5 mo with sorafenib to 9.8 mo with axitinib, corresponding to a hazard ratio (HR) of 0.561 (overall 1-sided α=0.025). Results: Patients (N=288) were mainly from Eastern Europe (51%), Asia (25%), North America (14%), or South America (10%).Patient baseline characteristics for axitinib (n=192) vs sorafenib (n=96) included: median age, 58y vs 58y; male, 70% vs 77%; white, 71% vs 69%; favorable risk, 49% vs 55%; PS 0, 57% vs 57%; nephrectomy, 85% vs 90%. Median (m) PFS was 10.1 vs 6.5 mo with axitinib vs sorafenib (HR adjusted for PS, 0.767; 95% confidence interval [CI], 0.559–1.053; 1‑sided P=0.0377). In patients with PS 0 and 1, respectively, mPFS with axitinib vs sorafenib was 13.7 vs 6.6 mo (HR, 0.644; 95% CI, 0.419–0.991; 1‑sided P=0.022) and 6.5 vs 6.4 mo (HR, 0.931; 95% CI, 0.585–1.482; 1‑sided P=0.38). Objective response rates (ORRs) with axitinib vs sorafenib were 32.3% vs 14.6% (1‑sided P=0.0006 adjusted for PS). Overall survival data were not mature. All-grade all‑causality adverse events (≥20%) with axitinib vs sorafenib were diarrhea (50% vs 40%), hypertension (49% vs 29%), weight decreased (37% vs 24%), fatigue (33% vs 26%), decreased appetite (29% vs 19%), palmar-plantar erythrodysesthesia (26% vs 39%), dysphonia (23% vs 10%), asthenia (21% vs 16%), and hypothyroidism (21% vs 7%). Conclusions: The study did not achieve its primary endpoint statistically, but axitinib demonstrated numerically longer mPFS and significantly higher ORR vs sorafenib, with an acceptable safety profile, as first-line therapy for mRCC. Clinical trial information: NCT00920816.
Phase III trial (Prevention of Early Menopause Study [POEMS]-SWOG S0230) of LHRH analog during chemotherapy (CT) to reduce ovarian failure in early-stage, hormone receptor-negative breast cancer: An international Intergroup trial of SWOG, IBCSG, ECOG, and CALGB (Alliance).
Authors: Moore Halle C. F. , Unger Joseph M. , Phillips Kelly-Anne , Boyle Frances M. , Hitre Erika , Porter David James , Francis Prudence A. , Minasian Lori M. , Gelber Richard D. , Goldstein Lori J. , Gomez Henry Leonidas , Vallejos Carlos , Partridge Ann H. , Dakhil Shaker R. , Martino Silvana , Barlow William E. , Fabian Carol J. , Meyskens Frank L. , Hortobagyi Gabriel N. , Albain Kathy S.
Published: February 2017

LBA505

Background: Premature ovarian failure (POF) is a common toxicity of CT. Risk depends on type and amount of CT, age, and perhaps ovarian cycling at the time of CT. POEMS is a SWOG-coordinated phase III randomized study to evaluate whether LHRH analog administration with CT for early-stage breast cancer (BC) would reduce POF. Methods: Premenopausal patients (PT) age <50 with stage I-IIIA ER/PR-negative BC to be treated with CT were randomized to receive standard cyclophosphamide-containing CT with or without monthly goserelin (GN) 3.6 mg SQ starting 1 week prior to the first CT dose. The primary endpoint is 2-year POF, defined as amenorrhea for the prior 6 months and post-menopausal FSH. Other endpoints include pregnancies and survival. Endpoints were analyzed in multivariable regression adjusting for stratification factors (age and CT regimen). Results: Between 2/04 and 5/11, 257 PT enrolled. Among 218 evaluable PT, 62% had complete primary endpoint data. Dropouts (n=83) were mostly due to deaths (n=14) or lack of FSH data. There was no strong evidence of informative missing data by arm according to stratification factors (p>.05). POF rates were 22% in the standard arm and 8% in the GN arm (OR=0.30, 95% CI: 0.10-0.87, p=.03 [unadjusted analysis]; OR=0.36, 95%CI: 0.11-1.14, p=0.08 [adjusted logistic regression analysis]). In a sensitivity analysis defining 2-year POF more liberally as either amenorrhea or elevated FSH, 45% in the standard arm and 20% in the GN arm had POF (OR=0.29, 95% CI: 0.12-0.70, p=.006). There were 13 pregnancies in the standard arm and 22 in the GN arm (OR=2.22, 95% CI: 1.00-4.92, p=.05). DFS and OS were better in the GN arm (Cox regression, including stage: HR=0.49, 95% CI: 0.24-0.97, p=.04; HR=0.43, 95% CI: 0.18-1.00, p=.05, respectively). Conclusions: LHRH analog administration with CT was associated with less POF and more pregnancies. In an exploratory analysis, GN use in premenopausal ER-negative BC was associated with improved DFS and OS. Clinical trial information: NCT00068601.
A randomized phase 2 trial comparing efficacy of the combination of the PARP inhibitor olaparib and the antiangiogenic cediranib against olaparib alone in recurrent platinum-sensitive ovarian cancer.
Authors: Liu Joyce , Barry William Thomas , Birrer Michael J. , Lee Jung-min , Buckanovich Ronald J. , Fleming Gini F. , Rimel Bj , Buss Mary K. , Nattam Sreenivasa R. , Hurteau Jean , Luo Weixiu , Quy Philippa , Obermayer Elizabeth , Whalen Christin , Lee Hang , Winer Eric P. , Kohn Elise C. , Ivy S. Percy , Matulonis Ursula
Published: February 2017

LBA5500

Background: PARP inhibitors and anti-angiogenics are clinically active in recurrent ovarian cancer (OvCa). Preclinical studies suggest these agents can synergize, and a phase 1 study showed that the combination of cediranib (ced) and olaparib (olap) is well-tolerated. We therefore compared the activity of olap alone (Olap) to combined ced and olap (Ced/Olap) in treatment of recurrent platinum-sensitive (plat-sens) high-grade serous (HGS) or BRCA-related OvCa (NCT 01116648). Methods: Patients (pts) across 9 centers were randomized 1:1 in this Ph 2 open label study to Olap (olap 400 mg capsules BID) or Ced/Olap (olap 200 mg capsules BID; ced 30 mg daily), stratified by BRCA status and prior anti-angiogenic therapy. Eligibility included pts with recurrent plat-sens HGS or BRCA-related OvCa. Pts had measurable disease by RECIST 1.1, PS 0 or 1, and the ability to take POs. No prior anti-angiogenics in the recurrent setting or prior PARP inhibitor was allowed. Progression-free survival (PFS) was defined as time from randomization to radiographic progression or death. With a target N=90 pts, the study was powered to detect a hazard ratio (HR) of 1.75 (median PFS 6 vs 10.5 mo). Results: Pts were enrolled from Oct 2011 to Jun 2013: 46 to Olap, 44 to Ced/Olap. 48 pts were known BRCA carriers (25 Olap; 23 Ced/Olap). At a planned interim analysis the DSMB recommended release of data. As of Jan 7, 2014, 41 pts had a PFS event. Median PFS was 9.0 mos for Olap and 17.7 mos for Ced/Olap (HR 2.9, 95% CI 1.5-5.6, p = 0.001). There were 2 complete responses (CR) and 21 partial responses (PR) in pts on Olap (56% objective response rate, ORR) and 3 CRs and 33 PRs in pts on Ced/Olap (84% ORR, p = 0.008). The overall rate of Gr3/4 toxicity was higher for pts on Ced/Olap (70%) than on Olap (7%). Differentially occurring toxicities included fatigue (27% Ced/Olap vs 7% Olap), diarrhea (23% vs 0%), and hypertension (39% vs 0%). Updated efficacy and exploratory subgroup analyses will be presented. Conclusions: Combined Ced/Olap significantly extended PFS and ORR compared to Olap in plat-sens OvCa. Further studies of this oral combination in plat-sens OvCa are warranted. Clinical trial information: NCT01116648.
Survival, response duration, and activity by BRAF mutation (MT) status of nivolumab (NIVO, anti-PD-1, BMS-936558, ONO-4538) and ipilimumab (IPI) concurrent therapy in advanced melanoma (MEL).
Authors: Sznol Mario , Kluger Harriet M. , Callahan Margaret K. , Postow Michael Andrew , Gordon Ruth Ann , Segal Neil Howard , Rizvi Naiyer A. , Lesokhin Alexander M. , Atkins Michael B. , Kirkwood John M. , Burke Matthew M. , Ralabate Amanda L. , Rivera Angel L. , Kronenberg Stephanie Anne , Agunwamba Blessing , Feely William , Hong Quan , Krishnan Suba , Gupta Ashok Kumar , Wolchok Jedd D.
Published: February 2017

LBA9003^

Background: We report updated survival and clinical activity in initially enrolled cohorts and activity by BRAF MT status in a phase I trial of concurrent and sequenced NIVO + IPI. Methods: MEL pts (n=53, enrolled 2009-2012, data analysis Dec 2013) with ≤3 prior therapies received IV concurrent NIVO + IPI, Q3Wk × 4 doses, followed by NIVO Q3Wk × 4. At wk 24, NIVO + IPI continued Q12Wk × 8 in pts with disease control and no DLT. Tumor responses were evaluated by WHO and immune-related criteria. Results: Pt characteristics included stage M1c: 55% and prior systemic therapy: 40%. Across doses, 1- and 2-y OS rates were 82% and 75%. Clinical activity was similar to previous reports except CRs rose to 9/53 (17%). Pts with/without tumor BRAF MT (n=36) had similar activity (Table). By wk 36, 42% demonstrated ≥80% tumor reduction. Median duration of response (DOR) was not reached (NR). Of 22 pts with objective response, 14 (64%) had DOR ≥24 wk (range: 25+, 106+). Treatment-related adverse events were as reported previously: grade 3-4, 53% of pts; most common: ↑ lipase and AST (13% ea). Data for sequenced cohorts are shown (Table). Conclusions: Concurrent NIVO + IPI therapy showed encouraging survival and a manageable safety profile in advanced MEL pts. Responses were observed regardless of BRAF MT status and were durable in the majority of pts. Forty additional pts were enrolled (last pt: Nov 2013) on a cohort of NIVO 1 mg/kg + IPI 3 mg/kg Q3Wk × 4 doses, followed by NIVO 3mg/kg Q2Wk (the selected regimen for phase II/III trials). Clinical trial information: NCT01024231. [Table: see text]