bluuebunny/crossref_metadata_2025 huggingface dataset:
Individualization of high dose carboplatin based on therapeutic drug monitoring (TDM) for the treatment of testicular germ cell tumors (TICE protocol): Results of a multicenter phase II study.
Authors: Thomas Fabienne , Moeung Sotheara , Broutin Sophie , Guitton Jerome , Boisdron-Celle Michele , Ciccolini Joseph , Massard Christophe , Flechon Aude , Delva Remy , Gravis Gwenaelle , Lotz Jean-Pierre , Bay Jacques-Olivier , Gross-Goupil Marine , Paci Angelo , Poinsignon Vianney , Fizazi Karim , Lafont Thierry , Lochon Isabelle , Chevreau Christine , Chatelut Etienne
Published: September 2018

4554

Background: We conducted a national phase II multicenter trial that aimed at evaluating the efficacy and tolerance of Paclitaxel plus Ifosfamide followed by high-dose carboplatin plus etoposide treatment (TICE) in previously treated germ cell tumors. The particularity of our study (in comparison with the standard protocol [Motzer RJ, et al. J Clin Oncol 2000 Mar; 18(6): 1173-1180.]) is that the carboplatin dose was individualized for each patient according to therapeutic drug monitoring (TDM) in order to reach the target AUC of 24 mg.min/ml over 3 days. Methods: In total, 89 patients were evaluable for pharmacokinetic study. Blood samples were taken on day 1 to determine the carboplatin clearance using a Bayesian approach (NONMEM 7.2) and to adjust the dose on day 3 to reach the target AUC of 24 mg.min/ml over 3 days. On days 2 and 3, samples were taken for retrospective assessment of the actual AUC and the intra- and inter-cycle clearance variability. Secondly, a population pharmacokinetic analysis was also performed on 59 patients using NONMEM to develop a covariate equation for carboplatin clearance prediction adapted for future patients treated with the TICE protocol. The performance of this new equation was then prospectively evaluated on the other 30 patients along with different methods of carboplatin clearance prediction. Results: TDM allowed us to control the carboplatin exposure with a mean actual AUC of 24.5 mg.min/ml (22.2 and 28.0 for 5th and 95thpercentile respectively) per cycle. We observed a modest but significant decrease of carboplatin clearance over cycles (median value of change of -11.8% from cycle 1 to cycle 3, maximum value of -36%). The new covariate equation allows unbiased and more accurate prediction of carboplatin clearance in the prospective validation cohort compared to other equations. Conclusions: Carboplatin TDM allowed the target AUC to be accurately reached and thereby avoid over- or under-exposure. We propose a new equation to predict carboplatin clearance more adapted to these particular patients (young males) that could be used as an alternative if the TDM cannot be organized. Clinical trial information: 2008-005068-14.
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.
Phase 2 biomarker-driven study of ipilimumab plus nivolumab (Ipi/Nivo) for ARV7-positive metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Boudadi Karim , Suzman Daniel L. , Luber Brandon , Wang Hao , Silberstein John , Sullivan Rana , Dowling Donna , Harb Rana , Nirschl Thomas , Dittamore Ryan Vance , Carducci Michael Anthony , Eisenberger Mario A. , Haffner Michael , Meeker Alan , Eshleman James R. , Luo Jun , Drake Charles G. , Antonarakis Emmanuel S.
Published: September 2018

5035

Background: ARV7+ mCRPC is an aggressive phenotype with a median PFS of 3-4 mo and OS of 7-9 mo. We hypothesized that ARV7+ tumors would be enriched for DNA repair mutations, rendering them more responsive to combined immune checkpoint blockade. Methods: We enrolled 15 mCRPC pts with ARV7+ CTCs (using a CLIA-certified assay) into a single arm phase 2 study. Pts received Nivo 3 mg/kg plus Ipi 1 mg/kg every 3 wk x 4 doses, then maintenance Nivo 3 mg/kg every 2 wk. Targeted sequencing for DNA repair defects was performed on pretreatment tumor biopsies (n=11) or cell-free DNA (n=4). Primary endpoint: PSA50response rate. Secondary endpoints: objective response rate (ORR) in pts with measurable disease, durable PFS (lack of progression ≥24 wk), PSA‐PFS, radiographic (r)PFS, overall survival (OS), and frequency/intensity of AEs. Results: 15 ARV7+ men were enrolled, with median f/u 8.4 (range 1.9–10.5) mo. Median age was 65, 47% had ECOG ≥1, median PSA was 115 ng/mL, 67% had visceral/nodal mets, all had bone mets, and 60% had ≥4 prior regimens for mCRPC. Mean ARV7/AR ratio was 23% (range 3–75%). 6/15 men (40%) had pathogenic DNA repair gene mutations ( BRCA2, ATM, MSH6, FANCM, FANCA, POLH). Overall, the PSA50rate was 1/15 (7%), ORR was 2/8 (25%), durable PFS rate was 3/15 (20%), PSA-PFS was 3.0 (95%CI 2.1–4.9) mo, rPFS was 3.9 (95%CI 2.8–5.5) mo, and OS was 9.5 (95%CI 7.2–NA) mo. Outcomes appeared better in DNA repair deficient (DRD+) tumors vs. DNA repair proficient (DRD–) tumors (TABLE). 15 grade 3-4 treatment-related AEs occurred in 7/15 (46%) men (including 2 hepatitis, 2 colitis, 1 pneumonitis); there were no treatment-related deaths. Conclusions: In this first study targeting ARV7+ mCRPC, treatment with Ipi/Nivo had acceptable safety and encouraging efficacy, particularly in men with DRD+ tumors. DNA repair mutations may be enriched in ARV7+ prostate cancer. Clinical trial information: NCT02601014. [Table: see text]
Clinical implications of the 2012 US Preventive Services Task Force (USPSTF) PSA screening recommendation in prostate cancer diagnoses and 5-year survival at a Minnesota safety net health care system.
Authors: Gale Kevin , Pease Daniel Fellows , Guinness Joseph , Wiernik Andres
Published: September 2018

5051

Background: Prostate specific antigen (PSA) screening for prostate cancer has declined following the USPSTF 2012 recommendation. How screening rates and prostate cancer diagnoses have subsequently changed in a racially diverse patient population is not well defined. In this study, we aim to determine the impact of the USPSTF screening recommendation in the Hennepin Healthcare System (HHS) in the state of Minnesota. Methods: A single-institution retrospective analysis of data from our electronic health record, to identify the characteristics of PSA screening and new prostate cancer diagnoses for men ≥50 years between 2008 and 2015. Data before and after May 2012 were compared. P-values were calculated using binominal and generalized linear models. Results: Nearly 22,000 patients underwent PSA screening from 2008 to 2015. PSA screening rates decreased after May 2012 for the four largest demographics represented (p < 0.001). Hispanics and Blacks were more likely to be screened when compared to Whites and Asians (p < 0.05). 319 cases of prostate cancer were diagnosed from 2008 to 2015 with 87 cases (27.3%) diagnosed by PSA-screening. The number needed to screen to diagnose one patient with prostate cancer at HHS was 137.5, and 9.5% of patients (1146 patients) had a false positive PSA that led to further testing or a biopsy. $56,090 was spent in screening costs per diagnosis of early stage prostate cancer via screening. Patients diagnosed from screening were less likely to present with high Gleason scores (8-10) compared to non-screening diagnosis (8% vs 23.3%, p < 0.01). The 5-year survival percentage (prostate cancer mortality) was improved for those patients diagnosed by PSA screening vs the non-screened group (100% vs 89.3%, p < 0.05). Conclusions: PSA screening has declined at HHS since the USPSTF recommendation against prostate cancer screening. Implementation of PSA screening in our healthcare system is expensive and leads to a high number of false positives. Despite this, the 5-year survival from prostate cancer is significantly higher when patients are diagnosed by PSA screening.
PSA doubling time (PSADT) and proximal PSA value predict metastasis-free survival (MFS) in men with biochemically recurrent prostate cancer (BRPC) after radical prostatectomy (RP).
Authors: Markowski Mark Christopher , Suzman Daniel , Chen Yongmei , Trock Bruce J. , Cullen Jennifer , Feng Zhaoyong , Antonarakis Emmanuel S. , Paller Channing Judith , Han Misop , Partin Alan W. , Eisenberger Mario A.
Published: September 2018

5075

Background: We previously reported a relationship between PSADT and MFS in BRPC post RP (Pound 1999; Freedland 2007; Antonarakis 2012). In men with PSADT<12 months, who are at high risk of lethal PCa, we sought to identify a PSA cutpoint (proximal PSA; PP) that indicates the imminent emergence of metastasis (M+). In this report we combined Center for Prostate Disease Research and Johns Hopkins (CPDR/JHU) databases to investigate the association of the PP value on MFS in men with BRPC and PSADT <12 mos. Methods: In the CPDR/JHU RP database (31,296), 513 men with BCR (>0.2ng/ml) with PSADT <12 mos who received no adjuvant/salvage ADT/RT were prospectively followed until radiological evidence of M+ are included in this analysis. All patients were evaluated yearly with >1 PSA and scans at regular intervals until M+. Associations with MFS were compared using logrank test and Cox regression. The PP is the most recent value >6 months prior to M+/censor. Results: M+ occurred in 218 of 513 patients with BRPC (median follow up 9 years). Risk of M+ increased successively for PSADT 6.0-7.5, 4.5-6, 3.0-4.5, and <3.0 months, adjusted for pT stage and Gleason score. PP ≥10ng/ml significantly increased risk of M+ in pts with PSADT <12 mos, regardless of PSADT subgroup, hazard ratio=2.95, p<.0001. Median MFS was 4.0 years at PP >10ng/ml vs 20 years at PP <10ng/ml. Table 1 shows median MFS and 3, 5, and 7 year MFS rates in subgroups with PSADT <3 and 3.01-6 months representing the highest risk groups. Conclusions: In men with PSADT<12 months, PSADT subgroups <7.5 months and PP >10ng/ml are independent predictors of MFS, adjusted for pT stage and Gleason score. PP ≥10ng/ml further define risk of M+ in BRPC with PSADT<12 months. These data can assist physicians in patient counseling and clinical trial design. [Table: see text]
Survival impact of initial local therapy selection for men under 60 with high risk prostate cancer.
Authors: Kaiser Adeel , Bentzen Soren , Siddiqui Minhaj , Naslund Michael J , Kwok Young , Amin Pradip P. , Vujaskovic Zeljko , Mishra Mark Vikas , Badiyan Shahed Nicolas
Published: September 2018

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Background: The impact of initial local therapy selection on survival for high risk prostate cancer (PCa) patients remains uncertain. We sought to assess this effect, while limiting competing causes of death, through the examination of a younger PCa patient cohort within the National Cancer Database. Methods: We evaluated the overall survival (OS) of men under 60 with high risk PCa receiving either radiation therapy (RT) or radical prostatectomy (RP). All men in this age group were treated between 2004 and 2013, harbored cN0M0 disease, and presented with Gleason Scores (GS) of 8 to 10. The RT group included patients who received external beam radiation (EBRT) alone or EBRT in combination with brachytherapy (BT). Overall survival and covariates were evaluated using multivariable Cox regression analysis. Results: A total of 16,944 patients met inclusion criteria of which 12,155 underwent RP and 4,789 received RT as initial therapy. 82.5% of RT patients received hormonal therapy, and the median dose was 77.4 Gy. In the RP group, 17.2% of patients received postoperative radiation, and 87% of these cases received a dose exceeding 64.80 Gy. The RP group had a higher proportion of cases with Charlson-Deyo comorbidity score > 0 (15.2% v. 11.2%, p < 0.000001). At a median follow-up of 50 months (0 - 131 months), RP was associated with improved OS in comparison to RT (hazard ratio = 0.52; 95% CI (0.47, 0.58); p < 0.000001). The estimated 8-year OS (±1 standard error of the estimate) was 85.1±0.7% and 74.9±0.7%, after RP and RT, respectively. This benefit remained present when adjusting for age, year of treatment, race, comorbidity score, Gleason score, T stage, hormonal therapy, chemotherapy, form of radiation, PSA, or insurance status. Conclusions: Compared to RT, initial treatment of men under 60 with high risk PCa with RP results in a large, statistically significant improvement in overall survival that remains consistent over time and remains significant in a multivariable model adjusting for known prognostic variables. These results are limited by the retrospective nature of the database analysis, and the lack of cancer specific survival information.
Survival outcomes of the NeoALTTO study: Updated results of a randomized multicenter phase III neoadjuvant trial.
Authors: Huober Jens Bodo , Holmes Eileen McCormick , Baselga Jose , De Azambuja Evandro , Untch Michael , Fumagalli Debora , Sarp Severine , Lang Istvan , Smith Ian E. , Boyle Frances M. , Xu Binghe , Lecocq Christophe , De La Pena Lorena , Jackisch Christian , Gelber Richard D. , Piccart-Gebhart Martine J. , Di Cosimo Serena
Published: September 2018

512

Background: In the neoadjuvant NeoALTTO trial dual HER2 blockade with lapatinib (L) plus trastuzumab (T) combined with weekly paclitaxel significantly increased the pathologic complete response rate (pCR) compared with either anti-HER2 agent alone plus paclitaxel. At first analysis pts with pCR had a better event free survival (EFS) and overall survival (OS) after median follow-up of 3.84 yrs. Methods: 455 pts with operable HER2-positive breast cancer were randomized to receive either L (n=154) 1500mg/day, T 4mg/kg loading dose followed by 2mg/kg/wk (n=149) or L 1000mg/day plus T (n=152) for 6 weeks followed by the assigned anti-HER2 treatment combined with paclitaxel weekly x 12. Following surgery pts received 3 cycles fluorouracil, epirubicin and cyclophosphamide q 3 weeks. The assigned anti-HER2 treatment was continued for 34 weeks thereafter. Primary endpoint was pCR (ypT0/is), secondary endpoints were EFS and OS and the association between pCR and OS analyzed by landmark analysis 30 weeks after randomization. Median follow-up was 6.7 years. Results: 6-yrs EFS rate was 67%/ 67%/74% with L/T/TL, respectively (L vs T HR 0.98 [95% CI 0.64–1.51] p=0.93; TL vs T HR 0.81 [95% CI 0.52–1.26] p=0.35). In the hormone receptor negative group 6- yrs EFS rate was 61%/ 63%/74% for the 3 groups, respectively (L vs T HR 1.09 [95% CI 0.61–1.95] p=0.76; TL vs T HR 0.81 [95% CI 0.44–1.51] p=0.52). OS at 6 yrs was 82%/79%/85% for L, T and TL, respectively (L vs T: HR 0.85 [95% CI 0.49-1.46] p=0.56; TL vs T HR 0.72 [95% CI 0.41-1.27] p=0.26). In landmark analyses, pts with a pCR had significantly higher 6-yrs EFS (77% /65%) and OS (89% /77%) compared to those without pCR, both overall and for the hormone receptor negative cohort. Conclusions: The updated results of the NeoALTTO study confirm the sustained survival benefits for pts who achieve a pCR. EFS and OS after 6 yrs did not differ significantly between the 3 treatment groups. The combination of T and L showed numerically higher EFS compared to T, especially in the hormone-receptor negative group. Clinical trial information: NCT00553358. [Table: see text]
Chemotherapy (CT) for isolated locoregional recurrence (ILRR) of breast cancer in ER-positive (ER+) and ER-negative (ER-) cohorts: Final analysis of the CALOR trial.
Authors: Wapnir Irene , Price Karen N. , Anderson Stewart J. , Robidoux Andre , Martin Miguel , Nortier J. W.R. , Paterson Alexander H. G. , Rimawi Mothaffar F. , Lang Istvan , Baena Cañada José Manuel , Thurlimann Beat J. K. , Mamounas Eleftherios P. , Geyer Charles E. , Gelber Shari I. , Coates Alan S. , Gelber Richard D. , Rastogi Priya , Regan Meredith M. , Wolmark Norman , Aebi Stefan Paul
Published: September 2018

513

Background: ILRR is associated with a high risk of developing breast cancer distant metastases and death. The CALOR trial (NCT00074152) investigated the effectiveness of CT following local therapy for ILRR. Previously reported results at 5-yrs median follow-up (MFU) showed significant benefit of CT for ER- ILRR, but further follow-up was required in ER+ ILRR. This report presents results at 8.8 yrs MFU within ER status cohorts. Methods: CALOR is an open-label, randomized trial for patients with completely excised ILRR after unilateral breast cancer. Eligible patients were randomized to CT (selected by the investigator; multidrug for at least 3 months recommended) or No-CT, and stratified by prior CT, hormone-receptor (ER, PR) status, and location of ILRR. Patients with ER and/or PR positive ILRR received adjuvant endocrine therapy. Radiation therapy was mandated for patients with microscopically involved margins, and anti-HER2 therapy was optional. Endpoints are disease-free survival (DFS), overall survival (OS) and breast cancer-free interval (BCFI). Results: From August 2003 to January 2010, 162 patients were enrolled: 104 ER+ and 58 ER-. The results at 8.8 years MFU in ER status cohorts are summarized in the Table (40 and 27 DFS events, respectively). The reduction in the hazard of an event associated with CT for the ER- ILRR cohort was sustained, but no benefit was observed for the ER+ cohort; interactions were significant for DFS and BCFI. The reduction in the hazard of an event seen in the ER- cohort was not apparent in ER+, with significant interactions for DFS and BCFI. Results for the 3 endpoints were consistent in multi-variable analyses adjusting for location of ILRR, prior chemotherapy, and interval from primary surgery. Conclusions: The final analysis of CALOR confirms that CT benefits patients with resected ER- ILRR. Long-term CALOR trial results do not support the use of CT for ER+ ILRR. Clinical trial information: NCT00074152. [Table: see text]
Breast conservation after neoadjuvant chemotherapy for triple-negative breast cancer: Surgical results from an international randomized trial (BrighTNess).
Authors: Golshan Mehra , Loibl Sibylle , Huober Jens Bodo , O'Shaughnessy Joyce , Rugo Hope S. , Wolmark Norman , McKee Mark D. , Maag David , Sullivan Danielle Marie , Giranda Vincent L. , Liu Xuan , Von Minckwitz Gunter , Geyer Charles E. , Sikov William M. , Untch Michael
Published: September 2018

514

Background: Neoadjuvant systemic therapy (NST) increases the frequency of breast-conserving therapy (BCT) in stage II-III breast cancer, but there is little data on how often it converts patients (pts) from BCT-ineligible (BCT-I) to BCT-eligible (BCT-E) and on the impact of other factors on surgical choices. We collected surgical assessment and management data from an international randomized trial of NST in triple-negative breast cancer (TNBC). Methods: Women with operable TNBC were randomized to veliparib (V) with carboplatin (C) and paclitaxel (P), placebo with C and P or placebo with P followed by doxorubicin and cyclophosphamide. The surgeons assessed BCT candidacy by clinico-radiographic criteria before and after NST; surgical management was at surgeon and patient discretion. We assessed interactions between BCT eligibility pre- and post-NST, germline BRCA mutation ( gBRCA) status, continent of treatment and achievement of pathologic complete response(pCR) and percentage of pts who underwent BCT versus mastectomy. Results: Pre- and post-NST surgical assessments were available for 604 pts who underwent surgery. BCT rates are listed in the Table. The BCT rate was 68% among pts deemed BCT-E after NST. pCR rates were identical between BCT-E pts who chose BCT (55%) vs. mastectomy (53%). Of 141 pts deemed BCT-I at baseline, 75 (53%) converted to BCT-E but only 42 (56%) of these opted for BCT. pCR rates were 49% in BCT-E converts vs. 36% in those remained BCT-I. gBRCA pts (n = 84) were less likely to choose BCT even if they were BCT-E. Pts treated in North America (NA) were less likely to choose BCT (55% vs. 80% for Europe and Asia P<0.0001) even among non- gBRCA considered BCT-E post-NST (61% vs. 85% P<0.0001). Conclusions: This largest prospective analysis of the impact of NST in TNBC demonstrates a conversion rate from BCT-I to BCT-E of 53%. BCT rates were lower in pts with gBRCA; the much higher mastectomy rate among BCT-E pts in NA merits investigation. Clinical trial information: NCT02032277. [Table: see text]
Clinical outcomes in ER+ HER2-negative breast cancer (BC) where treatment decisions incorporated the 21-gene recurrence score (RS): Elderly (≥70 yrs) vs younger patients (Pts).
Authors: Stemmer Salomon M. , Steiner Mariana , Rizel Shulamith , Ben Baruch Noa , Soussan-Gutman Lior , Bareket-Samish Avital , Nisenbaum Bella , Isaacs Kevin , Fried Georgeta , Rosengarten Ora , Peretz Tamar , Svedman Christer , McCullough Debbie , Klang Shmuel , Zidan Jamal , Ryvo Larisa , Kaufman Bella , Shak Steven , Liebermann Nicky , Geffen David B
Published: September 2018

543

Background: Elderly BC pts are generally undertreated, despite evidence suggesting that they may benefit from adjuvant chemotherapy (CT). We compared treatments/clinical outcomes in elderly vs younger Clalit Health Services (CHS) pts undergoing RS testing. Methods: This exploratory analysis of the CHS registry included BC pts with N0/N1mi/N1 disease who were RS-tested from 1/2006 (CHS approval of the test) through 12/2010 (N0) or 12/2011 (N1mi/N1). Medical records were reviewed to verify treatments/recurrences/survival. Results: The analysis included 458 elderly and 2052 younger pts, with a median (range) follow-up of 5.7 (0.9-9.6) and 6.1 (0.1-10.3) yrs, respectively. In the elderly/younger pts, median age was 73/58 yrs, 48%/52% had grade 2 tumors, median tumor size was 1.6/1.5 cm, 70%/72% were N0 and 30%/28% were N1mi/N1. RS distribution (<18, 18-30, ≥31) among elderly pts was 56%, 33%, and 11%, respectively, compared to 49%, 41%, and 10%, respectively, in younger pts. In pts with RS 18-30 and RS≥31, CT use was significantly lower in the elderly ( P<.001). Kaplan-Meier estimates for 5-yr distant recurrence and BC death risk are presented (Table). Conclusions: In elderly pts, the proportion of those with RS≥31 was very similar to younger pts; however, overall CT use was significantly lower. Within each RS group, there was no statistically significant difference in clinical outcomes between the age groups; though, numerically, in RS 18-30 pts, outcomes were worse in the elderly. In pts with RS<18, outcomes were excellent regardless of age and despite very low rates of CT use. [Table: see text]
LION: Lymphadenectomy in ovarian neoplasms—A prospective randomized AGO study group led gynecologic cancer intergroup trial.
Authors: Harter Philipp , Sehouli Jalid , Lorusso Domenica , Reuss Alexander , Vergote Ignace , Marth Christian , Kim Jae Weon , Raspagliesi Francesco , Lampe Boern , Landoni Fabio , Meier Werner , Cibula David , Mustea Alexander , Mahner Sven , Runnebaum Ingo B. , Schmalfeldt Barbara , Burges Alexander , Kimmig Rainer , Wagner Uwe A. G. , Du Bois Andreas
Published: September 2018

5500

Background: So far, there is no level-1 evidence regarding the role of systematic pelvic and para-aortic lymphadenectomy (LNE) in patients with advanced ovarian cancer (AOC) with macroscopic complete resection und clinically negative lymph nodes (LN). Therefore, surgical management regarding LNE worldwide is very heterogeneous. Methods: Prospective randomized trial including patients with newly diagnosed AOC FIGO IIB-IV with macroscopic complete resection and pre- and intra-operatively clinical negative LN were randomized intra-operatively to LNE versus no-LNE. All centers had to qualify regarding surgical skills before participation in this trial. The primary endpoint was overall survival. Results: 647 patients were randomized between 12/08 and 1/12 to LNE (n=323) or no-LNE (n=324). The median number of removed LN in patients randomized to LNE was 57 (pelvic 35 and para-aortic22). Post-op platinum-taxane based chemotherapy was applied in 85% of the patients in the no-LNE arm and 80% in the LNE arm. Microscopic metastases were diagnosed in 56% of the pts in the LNE arm. Median OS in the no-LNE arm was 69 months and 66 months in the LNE arm (HR 1.06, 95%CI 0.83-1.34, p=0.65) and the median PFS was 26 months in both arms (HR 1.11, 95%CI 0.92-1.34 p=0.30). Surgery in the LNE arm was 64 minutes longer (means: 352 vs 288 min), resulted in a higher median blood loss (650 vs 500 ml), and a higher transfusion rate (67% vs 59%). Furthermore, serious post-operative complications occurred more frequently in the LNE arm (e.g. rate of re-laparotomies 12.1% vs 5.9% [p=0.006], hospital re-admittance rate 8.0% vs 3.1% [p=0.006] and deaths within 60 days after surgery 3.1 vs 0.9% [p=0.049]). Conclusions: Systematic pelvic and para-aortic LNE in patients with AOC with both intra-abdominal complete resection and clinically negative LN neither improve overall nor progression-free survival despite detecting (and removing) sub-clinical retroperitoneal lymph node metastases in 56% of the patients. Our data indicate that systematic LNE of clinical negative LN in patients with AOC and complete resection should be omitted to reduce post-operative morbidity and mortality. Clinical trial information: NCT00712218.