bluuebunny/crossref_metadata_2025_split huggingface dataset:
High-dose chemotherapy (HDCT) plus peripheral-blood stem-cell transplant (PBSCT) for patients (pts) with relapsed germ-cell tumors (GCT) and active brain metastases (mets).
Authors: Kalra Maitri , Adra Nabil , Mckay John , Abonour Rafat , Hanna Nasser H. , Einhorn Lawrence H. 
Published: September 2018

4558 Background: The optimal management of progressive brain mets in pts with GCT remains unsettled. Treatment options include chemotherapy, stereotactic or whole brain radiation (XRT), surgery, or a combination thereof. Global germ cell cancer group analysis suggested multimodality therapy improves survival probabilities in pts with brain mets at relapse (JCO.2016;1;34(4):345-51). We report our experience on managing 25 consecutive pts with relapsed GCT and progressive brain mets undergoing HDCT with PBSCT at Indiana University from 2006-2016. Methods: All pts received HDCT consisting of carboplatin 700 mg/m2 days 1-3 and etoposide 750 mg/m2 i.v. days 1-3 followed by PBSCT on day 5 for upto 2 cycles. Pts were treated with craniotomy, XRT, chemotherapy alone, or a combination of modalities. Patient and disease characteristics, management of brain mets, and outcomes were measured. Platelet transfusions were given to maintain platelet counts > 30,000 and goal of > 50,000 in those with signs of hemorrhage. Results: Patient characteristics and outcomes are summarized in Table 1. Median age was 27.7 years (range, 16-48). All pts had progressive brain mets at time of starting HDCT. AFP ranged 1.6 to 1130, hCG 0.5 to 25601. At median follow-up of 24.8 months (range 2.5 to 118.5 months), 11 pts (44%) were alive with NED, 2 pts were alive with relapsed disease, and 12 pts died of disease progression. 17/18 patients developed progressive CNS mets despite radiation and/or craniotomy and of those, 8 are alive with NED. Toxicity was as previously published with this regimen (N Engl J Med 2007;357:340-8). Conclusions: Patients with relapsed GCT with progressing brain mets, including those with prior locoregional therapy, are curable with HDCT. [Table: see text]
Safety and usefulness of patient-centered shared survivorship care after chemotherapy for testicular cancer.
Authors: Boer Hink , Lubberts Sjoukje , Bunskoek Sophie , Nuver Janine , Lefrandt Joop D. , Steursma Gerrie , Sluiter Wim J. , Siesling Sabine , Berendsen Annette J. , Gietema Jourik A. 
Published: September 2018

4561 Background: Testicular cancer (TC) survivors are at risk to develop early cardiovascular morbidity. Close collaboration between oncologists and primary care physicians (PCPs) is mandatory for optimal cardiovascular risk management. We designed a simple shared survivorship care program in which TC patients regularly visit their PCP instead of their oncologist. The primary aim of this study was to test safety and feasibility of shared-care follow-up after chemotherapy for metastatic TC. Methods: TC patients with complete remission after chemotherapy and age ≥18 years were eligible. Participants received a personalized survivorship care plan with scheduled visits to the oncologist and PCP, which was available both on paper and as a mobile application. During PCP visits, signals indicating cancer recurrence, cardiovascular risk and psychosocial issues were assessed. Safety boundaries were defined for the occurrence of failed response to signals indicating cancer recurrence. Patient data were monitored real-time to check if the shared-care follow-up was carried out within these boundaries. Secondary outcomes were satisfaction among TC patients and PCPs, measured with an evaluation questionnaire, and anxiety levels, measured with the Hospital Anxiety and Depression Scale. Results: 64% of eligible TC patients and 99% of the approached PCPs were willing to participate; 162 patients were enrolled in the shared-care program and 241 primary care visits took place. No failures occurred in the detection of relapsed TC. Therefore, the safety boundary was crossed, indicating that shared-care follow-up is a safe alternative to hospital-only follow-up. Four primary care visits were deemed as failed visits because of logistic issues.Anxiety levels did not increase during shared-care follow-up (3.6 vs 3.3 (p = 0.38). Patients were satisfied with the knowledge of PCPs and appreciated this regular contact. 78% of the PCPs would like to extend their role in shared-care follow-up. Conclusions: This easy to use shared survivorship care program is safe and feasible in the follow-up of TC patients. Communication within this patient-centered follow-up program may be further supported with e-health tools. Clinical trial information: NCT01783145.
A phase I study of cabozantinib plus nivolumab (CaboNivo) and cabonivo plus ipilimumab (CaboNivoIpi) in patients (pts) with refractory metastatic (m) urothelial carcinoma (UC) and other genitourinary (GU) tumors.
Authors: Apolo Andrea B. , Mortazavi Amir , Stein Mark N. , Davarpanah Nicole N. , Nadal Rosa Maria , Parnes Howard L. , Ning Yangmin M. , Francis Deneise C , Cordes Lisa M , Berniger Marilise Anne , Steinberg Seth M. , Agarwal Piyush K. , Bagheri Mohammadhadi H. , Nanda Swati , Monk Paul , Lancaster Tiffany , Moore Tina , Costello Rene , Bottaro Donald P. , Pal Sumanta K. 
Published: September 2018

4562 Background: We report the safety and clinical activity of the combination of CaboNivo and CaboNivoIpi in pts with mUC and other mGU tumors (NCT02496208). Methods: In this phase I trial 30 pts were treated in 4 dose levels (DL) for part 1 (CaboNivo) and 18 pts were treated in 3 DL for part 2 (CaboNivoIpi). Pts received Cabo PO daily and Nivo IV (part 1) with Ipi 1mg/kg x 4 doses q3wks (part 2). A mUC and a renal cell carcinoma (RCC) expansion cohort of CaboNivo has initiated enrollment. Tumors were assessed for overall response rate (ORR) q8wks (RECIST 1.1). Adverse events (AEs) were graded (G) by NCI-CTCAE v4.0. Results: From 7/22/15 to 12/31/2016, 48pts (CaboNivo N = 30; CaboNivoIpi N = 18) (mUC N = 19; bladder urachal N = 4; bladder squamous cell carcinoma (bSCC) N = 2; germ cell tumor (GCT) N = 4; castrate-resistant prostate cancer (CRPC) N = 9; RCC N = 2, sarcomatoid RCC N = 2, Sertoli cell N = 1, and trophoblastic tumor N = 1 were treated. Median age was 58 (range 35-77), 41 (85%) were male. Common treatment-related G1/2 AEs for CaboNivo: ALT increase (67%), fatigue (63%), diarrhea (60%), hypothyroidism (57%); CaboNivoIpi: fatigue (72%), diarrhea (61%), anorexia (61%); Grade 3 AEs for CaboNivo: hypertension (23%), neutropenia (17%), hypophosphatemia (13%), lipase increase (10%), fatigue (7%), aseptic meningitis (3%); CaboNivoIpi: hypophosphatemia (19%), hypertension (19%), fatigue (13%), hyponatremia (13%), nausea (13%), lipase increase (11%), colitis (6%); G4 CaboNivo: lipase increase (7%) thrombocytopenia (3%); CaboNivoIpi lipase increase (6%) There were no G5 toxicities, no DLTs. 43 pts were evaluable for response: ORR was 30% 13/43 [3 CR (2 mUC, 1 bSCC); 10 PRs (4 mUC, 2 penile, 1 sarcomatoid RCC, 1 urachal, 1 CRPC, 1 bSCC)]. ORR for CaboNivo 39% (mUC 44%); CaboNivoIpi 18% (mUC 29%). 11/13 (85%) of responses were ongoing at cutoff. Conclusions: CaboNivo and CaboNivoIpi combinations were well tolerated with no DLTs and have durable efficacy in mGU tumors particularly mUC. Rare tumors such as bSCC, urachal, and penile cancers demonstrated response to the combination. Larger cohorts of mUC and rare GU tumors are ongoing. Clinical trial information: NCT02496208.
Efficacy and safety of pegylated human IL-10 (AM0010) in combination with an anti-PD-1 in renal cell cancer.
Authors: Naing Aung , Infante Jeffrey R. , Wong Deborah Jean Lee , Korn Wolfgang Michael , Aljumaily Raid , Papadopoulos Kyriakos P. , Autio Karen A. , Pant Shubham , Bauer Todd Michael , Drakaki Alexandra , Daver Naval Guastad , Hung Annie , Van Vlasselaer Peter , Brown Gail Linda , Oft Martin , Tannir Nizar M. 
Published: September 2018

4567 Background: IL-10 has anti-inflammatory activity and stimulates the cytotoxicity and proliferation of CD8+ T cells at higher concentrations. IL-10 receptors and PD1 are expressed on activated CD8 T cells, providing a rationale for combining AM0010 and an anti-PD1. The efficacy and safety profile for AM0010 alone was established in poor to intermediate risk RCC pts treated in 3rdLOT. Objective responses were observed in 4 of 15 pts with RCC. In the dose escalation of AM0010 plus pembrolizumab, 4 of 8 patients had an objective response. The mPFS was 16.7 months and the mOS has not been reached, median follow up (mFU) is 19.3 mo. Methods: In this Phase 1b, 29 pts. with metastatic RCC were enrolled until Nov. 18 2016 on AM0010 (10 ug/kg daily SC) and nivolumab (3mg/kg, q2wk IV). 2 had favorable, 20 had intermediate and 4 had poor IMDC risk (3 were not available). Pts. had a median of 1 prior therapy (range 1-3). All pts. had received a VEGFR-TKI. Tumor responses were assessed with irRC. Immune responses were evaluated by serum cytokines, activation of blood derived T cells and peripheral T cell clonality. Results: AMO010 plus nivolumab was well tolerated. TrAEs were reversible. There were no autoimmune colitis, pneumonitis, or endocrine disorders. 14 patients had at least 1 G3/4 TrAE, including anemia (9), thrombocytopenia (5), hypertriglyceridaemia (4). 2 pts had a reversible cytokine release syndrome with splenomegaly and increased immune mediated red blood cell phagocytosis most likely precipitated by T-cell activation, as both pts had tumor responses. As of Jan 31 2017, partial responses (PR) were observed in 8 of 26 evaluable pts (31%). An additional 13 of 26 pts had stable disease (41%), 7 pts had tumor reductions of more than 30%. The mPFS and mOS has not been reached with a mFU of 5.2 mo. (range 0.3-10.3). AM0010 + anti-PD1 increased Th1 cytokines in the serum while decreasing TGFb, an expansion of proliferating PD1+ Lag3+ activated CD8 T cells and de-novo oligoclonal expansion of T cell clones in the blood. Conclusions: AM0010 in combination with nivolumab is well-tolerated in RCC pts. The efficacy and the observed CD8 T cell activation is promising and encourages the continued study of AM0010 in combination with nivolumab. Clinical trial information: NCT02009449.
Clinical factors associated with AR-V7 detection in ARMOR3-SV, a randomized trial of galeterone (Gal) vs enzalutamide (Enz) in men with AR-V7+ metastatic castration-resistant prostate cancer (mCRPC).
Authors: Taplin Mary-Ellen , Antonarakis Emmanuel S. , Ferrante Karen J. , Horgan Kerry , Blumenstein Brent A. , Saad Fred , Luo Jun , De Bono Johann S. 
Published: September 2018

5005 Background: Presence of the AR-V7 splice variant may predict resistance to Enz and abiraterone in men with mCRPC. Gal is an oral agent that disrupts AR signaling via AR degradation, CYP17 lyase inhibition, and AR antagonism. ARMOR3-SV was designed to test the hypothesis that in mCRPC patients with AR-V7+ CTCs, Gal could improve radiographic progression-free survival (rPFS) versus Enz. Methods: In this randomized, open-label, multicenter phase 3 study (NCT02438007), men with treatment-naïve mCRPC were screened for CTC-specific AR-V7 (Qiagen), and AR-V7+ men were randomized 1:1 to Gal or Enz. rPFS (by independent blinded central review) was the primary endpoint. Planned sample size was 148, with 120 rPFS events to achieve 90% power to detect a hazard ratio of ≤0.55. Results: 953 patients were screened globally for AR-V7 from Sept 2015 through study closure; 73 men (8%; 95% CI 6-10%) were AR-V7+, 250 (26%) AR-V7–, and 630 (66%) had no CTCs/AR present (unevaluable). AR-V7 detection was associated with higher PSA levels ( > vs < median; P < 0.01), more bone metastases ( > 20 vs 11-20 vs 6-10 vs 0-5; P < 0.01), presence of M1 disease at diagnosis (dx) (yes vs no; P = 0.04), shorter time from dx to screening ( < vs > median; P < 0.01), higher ECOG (≥1 vs 0; P = 0.02), prior antiandrogen use (yes vs no; P < 0.01) and prior docetaxel use (yes vs no; P < 0.01). Among the AR-V7+ men, 38 were randomized (19 Gal, 19 Enz), 31 screen failed, and 4 were discontinued from screening at study halt. Baseline characteristics were balanced. On the recommendation of the DSMB, the study was closed early as it was unlikely to meet its primary endpoint. At the time of the study closure, in the Gal and Enz arms respectively, median time on therapy was 2.0 vs 2.8 mo, median time to PSA progression (PCWG1) was 3.9 vs 3.8 mo, PSA50 response rates in evaluable patients were 2/16 (13%) and 8/19 (42%), and there were no new safety signals. Conclusions: In treatment-naïve mCRPC patients, AR-V7 detection is more common in men with higher disease burden and portends a poor prognosis. Novel study designs and alternative treatment approaches are urgently needed for AR-V7+ mCRPC patients. Clinical trial information: NCT02438007.
Phase II study of bipolar androgen therapy (BAT) in men with metastatic castration-resistant prostate cancer (mCRPC) and progression on enzalutamide (enza).
Authors: Teply Benjamin A. , Wang Hao , Sullivan Rana , Rifkind Irina , Bruns Ashley , Decarli Morgan , Sinibaldi Victoria J. , Pratz Caroline F. , Luo Jun , Carducci Michael Anthony , Paller Channing Judith , Antonarakis Emmanuel S. , Eisenberger Mario A. , Denmeade Samuel R. 
Published: September 2018

5017 Background: Androgen receptor (AR) overexpression is a common adaptive resistance mechanism in mCRPC. High dose testosterone in this setting may induce tumor responses and restore normal AR expression. To evaluate BAT, we enrolled men with mCRPC progressing on enza to assess (1) responses to BAT and (2) enza re-challenge after BAT. Methods: Eligible men had minimally symptomatic mCRPC with progression on enza. Subjects received testosterone cypionate 400mg IM every 28d and continued gonadal suppression, until progression. Subjects were evaluated with PSAs each cycle, and CT/bone scans every 3 cycles. Upon progression on BAT, men were re-challenged with enza. The co-primary endpoints were > 50% PSA responses (PSA50) to BAT and PSA50 to enza re-challenge. The null hypothesis was a PSA50 rate of 5% for both endpoints, with alternative hypotheses of 20% to BAT and 25% to enza. 30 subjects were required for 90% and 83% power, respectively, with overall type 1 error of 0.1. Secondary endpoints were safety, objective response, progression-free survival (PFS), and effect on circulating tumor cell-based AR and AR-V7 expression. Results: 30 eligible subjects were accrued (2014-2016). No dose limiting toxicities were seen. 2 subjects had transient pain flares after BAT initiation. Common grade 1-2 adverse events (AE) were musculoskeletal pain (40%), increased hemoglobin (37%), breast tenderness (17%) and rash (17%). 3 Grade 3-4 AE potentially attributable to BAT occurred (pulmonary embolism, NSTEMI, and urinary obstruction). 9/30 men (30% [95% CI: 17-48%]) achieved a PSA50 to BAT. 5/14 men (36%) with measurable disease had an objective response by RECIST 1.1. The median clinical/radiographic PFS on BAT was 8.6 months. 21 subjects proceeded to enza re-challenge, yielding 15 PSA50 responses (54% by intention to treat [95% CI: 34-69%]), with a PFS of 4.8 months. 1/3 AR-V7+ subjects responded to BAT, and all had decreased AR-V7/AR ratios (2 converted to AR-V7-) after 3 cycles. Conclusions: The study met its primary endpoints, demonstrating preliminary efficacy of BAT in men with progressive mCRPC after enza. A randomized study comparing BAT to enza in mCRPC is ongoing. Clinical trial information: NCT02090114.
Updated results from the phase III ALTTO trial (BIG 2-06; NCCTG (Alliance) N063D) comparing one year of anti-HER2 therapy with lapatinib alone (L), trastuzumab alone (T), their sequence (T→L) or their combination (L+T) in the adjuvant treatment of HER2-positive early breast cancer.
Authors: Moreno-Aspitia Alvaro , Holmes Eileen McCormick , Jackisch Christian , De Azambuja Evandro , Boyle Frances M. , Hillman David W. , Korde Larissa A. , Fumagalli Debora , Izquierdo Miguel A. , McCullough Ann E. , Wolff Antonio C. , Pritchard Kathleen I. , Untch Michael , Lang Istvan , Xu Binghe , Smith Ian E. , Barrios Carlos H. , Gelber Richard D. , Baselga Jose , Piccart-Gebhart Martine J. 
Published: September 2018

502 Background: Pre-specified 5-year analyses of the phase III Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO) Trial defined in Amendments 11&12. Methods: From June 2007 to July 2011, 8381 patients (pts) were randomised from 946 sites in 44 countries to receive either L+T, T→L, L, or T. In 2011, due to futility the L arm was closed and is not included in this analysis. The primary end point is disease-free survival (DFS). Secondary objectives include treatment comparisons with respect to overall survival (OS), time to recurrence (TTR), time to distant recurrence (TDR), cardiac and overall safety and tolerability. Primary analysis results of the study were published in JCO 2015 34:1034-1042. This updated analysis occurs at a 6.9 yrs median follow up (MFU). Results: All patients have reached 5-years of follow-up. 705 DFS events for L+T vs T have been observed. HR for DFS was 0.86 (95% CI, 0.74-1.00; 6-yr DFS%=85% vs 82%) for L+T vs T and 0.93 (95% CI, 0.81-1.08; 6-yr DFS%=84% vs 82%) for T→L vs. T. The 6-year OS was 93%, 92%, and 91% for L+T, T→L, and T, respectively. HR for OS was 0.86 (95% CI, 0.70-1.06) for L+T vs. T and 0.88 (95% CI, 0.71-1.08) for T→L vs. T. DFS differences for L+T vs. T were slightly higher for the hormone-receptor(ER)-negative [HR 0.80 (95% CI, 0.64-1.00; 6-yr DFS%=84% vs. 80%)] and the sequential chemotherapy [HR 0.83 (95% CI, 0.69-1.00; 6-yr DFS%=83% vs.79%)] subgroups. There were no differences in sites of first DFS events according to treatment arm for CNS, loco-regional, or distant recurrences. There were more AEs related to study treatment (L+T 93% vs T 64%). The incidence of primary cardiac end points was low: 1% for L+T, 0.5% for T→L and 0.9% for T. Conclusions: The HRs for this updated analysis are similar to those from the Primary Analysis and the event rate remains lower than anticipated (705 vs 850 planned). Cardiac toxicity remains low. This analysis suggests that HER2+/ER- tumors may have a different biology than HER2+/ER+ and may benefit more from dual HER2 blockade. Long-term follow up continues. Clinical trial information: NCT00490139.
Outcomes of metastatic castration-resistant prostate cancer (mCRPC) patients (pts) treated with different new agents (NAs) sequence in post-docetaxel (DOC) setting: Final analysis from a multicenter Italian study.
Authors: Caffo Orazio , Bria Emilio , De Giorgi Ugo , Tucci Marcello , Galli Luca , Fratino Lucia , Rossetti Sabrina , Iacovelli Roberto , Lo Re Giovanni , Mosillo Claudia , Gasparro Donatello , Guglielmini Pamela Francesca , Damiani Azzurra , Procopio Giuseppe , De Lisi Delia , Ruatta Fiorella , Scagliarini Sarah , Donini Maddalena , Sperduti Isabella , Basso Umberto 
Published: September 2018

5030 Background: Abiraterone acetate (AA), cabazitaxel (CABA), and enzalutamide (ENZ) may prolong survival in mCRPC pts progressing after DOC, although it is not clear how to use NAs to best exploit their efficacy and avoiding their possible cross resistances. In 2015, we reported the outcomes of a series of 260 mCRPC pts, receiving at least 2 NAs, after DOC progression in routine clinical practice (Eur Urol. 2015;68:147-53). In the present study we updated the analysis with longer follow-up and by assessing a larger series of pts. Methods: Based on a multi-institutional collaboration, we collected data of pts who received at least 2 NAs after DOC: we assessed biochemical (bRR) and objective response rates (oRR) and progression free survival (PFS) of each NA by treatment line; moreover, we evaluated the overall survival (OS) from the second line start by sequence strategy. For the OS analysis we differentiated three different types of NAs sequences after DOC: one new hormone agent (AA or ENZ) followed by CABA (NHA→CABA); CABA followed by AA or ENZ (CABA →NHA); one NHA followed by the other NHA (NHA →NHA). Results: A consecutive series of 476 mCRPC pts with bone (86%), nodal (56%) or visceral (15%) mets, was collected. All received NAs as 2nd and 3rdline after DOC. The outcomes by both treatment lines and NAs are detailed in the table. We observed a statistically significant difference in terms of OS when compared the three sequence strategies: the median OS of pts treated with NHA→CABA, CABA→NHA, and NHA→NHA was respectively 12.9 mos, 14.2 mos, and 8.8 mos, respectively (p = 0.01). Conclusions: At our knowledge this retrospective study reports the highest number of pts treated post-DOC with at least 2 NAs. Our data confirmed that the activity of NAs decreased in the 3rd line compared to the 2nd line and suggested a cumulative OS advantage when CABA is used in the sequence. [Table: see text]
Efficacy, safety, tolerability, and pharmacokinetics of EPI-506 (ralaniten acetate), a novel androgen receptor (AR) N-terminal domain (NTD) inhibitor, in men with metastatic castration-resistant prostate cancer (mCRPC) progressing after enzalutamide and/or abiraterone.
Authors: Chi Kim N. , Vaishampayan Ulka N. , Gordon Michael S. , Smith David C. , Rudsinski Erin , De Haas-Amatsaleh Angela , Thapar Neil , Perabo Frank , Montgomery Robert B. 
Published: September 2018

5032 Background: EPI-506 (ralaniten acetate) is a first-in-class small molecule transcription inhibitor of the AR NTD. Nonclinical studies demonstrated activity against both full length and resistance-related AR species, including AR-v7. Methods: Open-label, single-arm, Phase 1/2 study evaluating EPI-506 administered orally once-daily. The Phase 1 is a 3+3 design to establish the safety, pharmacokinetic (PK) profile, and recommended phase 2 dose of EPI-506. Anti-tumor activity is also evaluated. Inclusion criteria included: mCRPC with progression after ≥1 line of hormonal therapy or chemotherapy, and progression on enzalutamide and/or abiraterone. Results: Eighteen patients (pts) have been enrolled in the dose escalation phase over 5 dose levels (80, 160, 320, 640, 1280 mg). Median age was 71 (range 58-87). Prior treatments included enzalutamide only (N = 7), abiraterone only (N = 2) or both (N = 9). Six pts have had prior chemotherapy. Seven pts have discontinued due to disease progression and 2 pts due to adverse events (AEs): Grade 4 elevated amylase (related) and Grade 4 gastrointestinal bleeding (unrelated). Median exposure was 98.5 days (range 26-338). Most frequently reported treatment emergent AEs were diarrhea (N = 7), nausea (N = 5) and fatigue (N = 3). One Grade 3 AE (AST elevation) at 1280 mg and one Grade 4 AE (increased amylase) at 640 mg were reported. PK data demonstrate a dose-proportional profile for Cmax and AUC coupled with an initial negative food effect up to 640 mg. At week 4 of continuous dosing, 3 of 18 evaluable pts demonstrated PSA declines ranging from 9 to 18% receiving doses ≥640 mg. Conclusions: EPI-506 is well-tolerated with a favorable safety profile. PK indicates dose-proportionality. PSA declines have been observed at doses associated with sub-therapeutic exposure in preclinical studies. This study is the first to evaluate targeting the AR NTD, a region critical for transcriptional function of all known AR species. Clinical trial information: NCT02606123.