bluuebunny/crossref_metadata_2025 huggingface dataset:
Pilot study of vemurafenib and panitumumab combination therapy in patients with BRAF V600E mutated metastatic colorectal cancer.
Authors: Yaeger Rona D. , Cercek Andrea , O'Reilly Eileen Mary , Reidy Diane Lauren , Kemeny Nancy E. , Wolinsky Tamar , Gollub Marc J. , Lacouture Mario E. , Rosen Neal , Vakiani Efsevia , Saltz Leonard
Published: February 2017

611

Background: BRAF mutant metastatic colorectal cancer (mCRC) is an aggressive subset of colorectal cancer that exhibits minimal response to selective RAF inhibitors. Preclinical data suggest that epidermal growth factor receptor (EGFR) reactivation with RAF inhibition attenuates the efficacy of RAF inhibitors in mCRC and that combined EGFR and RAF inhibition may be a promising therapeutic strategy. Methods: We undertook a pilot trial to assess the response rate and safety of the combination of the selective RAF inhibitior vemurafenib and anti-EGFR antibody panitumumab in patients with BRAF mutant mCRC. Patients received panitumumab 6 mg/kg IV every 14 days starting on day 1 and vemurafenib 960 mg orally twice daily continuously starting on day 8, with treatment staggered for planned correlative studies. Results: Fifteen patients received treatment. Median age was 62 years (range 22-83 years), seven patients (47%) were male, and 11 patients (73%) had a right-sided primary tumor. Performance status was ECOG 0 in four patients (27%) and ECOG 1 in 11 patients (73%). All patients had progressed through at least one standard treatment regimen, and eight patients (53%) had received previous fluoropyrimidine, oxaliplatin, and irinotecan chemotherapy. Acneiform rash (all grade 1 or 2) (53%), fatigue (53%), and arthralgias (40%) were the most frequently observed treatment-related adverse events. Treatment response was assessed in 12 patients because two patients died from disease progression before the first scan and one patient withdrew consent soon after starting treatment. Two patients (13%) had confirmed partial responses (100% and 64% regression) lasting 40 and 24 weeks, respectively. Eight patients (53%) had stable disease (SD) with tumor regression of >15% by RECIST measurement in six of these patients, including two of whom achieved stable disease lasting over six months. Conclusions: Combined RAF and EGFR inhibition is well tolerated and leads to tumor regression in a subset of patients with BRAF mutant mCRC. Planned correlative studies will evaluate degree of pathway inhibition and reactivation of other upsteam pathways with vemurafenib and panitumumab treatment. Clinical trial information: NCT01791309.
Loss of human epidermal growth factor receptor 2 (HER2) expression in HER2-overexpressing esophagogastric (EG) tumors treated with trastuzumab.
Authors: Janjigian Yelena Yuriy , Riches Jamie Cathleen , Ku Geoffrey Yuyat , Imtiaz Tooba , Capanu Marinela , Chou Joanne F. , Kelsen David Paul , Ilson David H. , Berger Michael F. , Vakiani Efsevia
Published: February 2017

63

Background: Trastuzumab-based therapy is the standard therapeutic approach for patients with metastatic HER2+ esophagogastric (EG) tumors. While trastuzumab prolongs survival in this population, responses are rarely complete and resistance invariably develops. Loss of HER2 and presence of co-occurring molecular alterations may impact the efficacy of HER2 targeted agents in second line setting. Methods: We reviewed clinical and pathologic data of patients (pts) with metastatic HER2+ (IHC 3+ or FISH >2.0) EG adenocarcinoma undergoing trastuzumab/chemotherapy treatment at MSKCC. Samples with ample tissue were analyzed using an on-site 341 cancer-associated gene bait capture, next generation sequencing (NGS) assay. When available, biopsy at the time of disease progression on trastuzumab was tested for HER2 by IHC and FISH. Results: Eighty four pts with Stage IV HER2+ EG adenocarcinoma (57 IHC 3+, 27 IHC2+/FISH+) treated with trastuzumab with chemotherapy. Median progression free survival on 1stline trastuzumab therapy 9.4 months (mos) [95%CI: 6.9-13.3 mos]. Median overall survival 20.3 mos [95%CI: 14.7-22.4 mos]. Post-trastuzumab biopsy available in 23 of 84 (27%) pts, of those 35% (8 of 23) lost HER2 positivity (4-IHC 0, 4 FISH negative). NGS performed on 24 of 84 (28%) samples. Alterations were observed in EGFR (13%), TP53 mut (92%), cell cycle mediators such as cyclin dependent kinases (42%) and the phosphoinositide 3-kinase/AKT/mTOR axis (21%). Conclusions: Loss of HER2 expression occurs in patients with HER2+ EG cancer treated with trastuzumab and presents a possible mechanism for trastuzumab resistance. Our data suggest the need for repeat biopsies to accurately determine appropriate use of second-line HER2 directed therapy.
FOLFOXIRI plus bevacizumab (bev) versus FOLFIRI plus bev as first-line treatment of metastatic colorectal cancer (mCRC): Updated survival results of the phase III TRIBE trial by the GONO group.
Authors: Cremolini Chiara , Loupakis Fotios , Masi Gianluca , Zagonel Vittorina , Bergamo Francesca , Salvatore Lisa , Cortesi Enrico , Tomasello Gianluca , Ronzoni Monica , Pinta Francesco , Zaniboni Alberto , Tonini Giuseppe , Buonadonna Angela , Amoroso Domenico , Sonaglio Claudia , De Stefano Alfonso , Boni Corrado , Allegrini Giacomo , Boni Luca , Falcone Alfredo
Published: February 2017

657

Background: The phase III TRIBE trial met its primary endpoint, by demonstrating that first-line FOLFOXIRI plus bev significantly prolongs PFS, as compared to FOLFIRI plus bev. Also RECIST response rate, early response rate and deepness of response were significantly increased. At the first statistical analysis, with a median follow-up of 32.2 months, OS results were considered preliminary. Methods: Between July 2008 and May 2011, 508 patients were randomized to either FOLFIRI plus bev (arm A, n=256) or FOLFOXIRI plus bev (arm B, n=252). Both treatments were administered for a maximum of 12 cycles followed by 5FU/bev until progression. Results: At a median follow-up of 48.1 months, 374 deaths were recorded (Arm A=200 vs. Arm B=174). Median OS for Arm B vs. Arm A was 29.8 vs. 25.8 months (HR=0.80, 95% CI, 0.65-0.98, p=0.030). Long-term survival rates are reported in Table 1. Treatment effect was consistent across all analyzed subgroups. Among clinical variables, ECOG performance status of 1 or 2, right-sided primary tumor, synchronous metastases, disease not confined to the liver, unresected primary tumor, high Kohne score negatively affected prognosis at univariate analyses. At an exploratory model accounting for these variables, adjusted HR for treatment effect on OS was 0.77 (95% CI, 0.61-0.96, p=0.020). Conclusions: FOLFOXIRI plus bev improves survival of mCRC patients, as compared to FOLFIRI plus bev. The estimated 5-years OS rate of patients treated with FOLFOXIRI plus bev was equal to 24.9%, with an absolute benefit of 12.5% compared to controls. FOLFOXIRI plus bev represents a valuable option for the upfront treatment of mCRC. Clinical trial information: NCT00719797. [Table: see text]
Trial-level association between response-based endpoints (RBEs) and progression-free (PFS)/overall survival (OS) in first-line therapy for metastatic colorectal cancer (mCRC) in the ARCAD database.
Authors: Coart Elisabeth , Saad Everardo D. , Shi Qian , Sommeijer Dirkje Willemien , Zalcberg John Raymond , Maughan Tim , Goldberg Richard M. , Schmoll Hans-Joachim , Punt Cornelis J. A. , Van Cutsem Eric , Douillard Jean-Yves , Hoff Paulo Marcelo , Tebbutt Niall C. , Fuchs Charles S. , Falcone Alfredo , Tournigand Christophe , De Gramont Aimery , Sargent Daniel J. , Burzykowski Tomasz , Buyse Marc E. ,   ARCAD Group
Published: February 2017

666

Background: Early tumor shrinkage (ETS; ≥20% decrease from baseline) and early objective tumor response (EOTR; CR/PR by RECIST) are associated with improved PFS/OS to a similar extent than best overall response (BOR), confirmed response (ConfR) and non-progression rate (NPR; CR/PR/SD by RECIST) at the individual level in first-line mCRC (ASCO 2014, abstr 3538/3578). We assessed these RBEs at the trial level. Methods: Data were available on 12,185 pts enrolled in a total of 17 randomized trials of chemotherapy (CT) alone or with targeted agents (TAs). ETS, EOTR and NPR were assessed at 6/8/9 and 12 weeks (wks), whereas BOR and ConfR were ascertained within 26 wks from randomization. Association between treatment effects on RBEs and on PFS/OS was assessed by coefficients of determination (R2, adjusted for estimation errors) using a copula model). Results: None of the RBEs had consistently strong correlations with PFS or OS (Table). The number of trials was insufficient to obtain reliable estimates for antiangiogenics and anti-EGFR separately. Conclusions: Despite their individual-level associations with PFS and OS, RBEs do not appear to be surrogate endpoints in first-line mCRC, given their poor predictive ability. [Table: see text]
A post-hoc health-related quality of life (HRQoL) analysis of patients with metastatic colorectal cancer (mCRC) in the phase III CONCUR trial.
Authors: Chang Jane , Odom Dawn , Radder Christina , Kappeler Christian , Xu Rui-hua , Qin Shukui , Kim Tae Won , Li Jin
Published: February 2017

667

Background: CONCUR (NCT01584830) showed that regorafenib (REG) significantly improves overall survival (OS) and progression-free survival (PFS) vs. placebo (PBO) in Asian patients with mCRC who progressed after standard therapy (J Li, et al. WCGI 2014). Post hoc exploratory analyses were conducted to assess the effect of treatment on HRQoL. Methods: Patients were randomly assigned 2:1 to treatment with either REG (n=136) or PBO (n=68). The HRQoL analyses included all 204 patients and were selected a priori based on clinical relevance; the global health status/QoL (QL) and the physical functioning (PF) scales of the EORTC QLQ-C30 questionnaire were used. A linear mixed-effects model (LMM) was used to examine the treatment effect on HRQoL and trends over time, assuming that data were missing at random. A pattern-mixture model (PMM) was applied to assess the treatment effect while accounting for potentially informative missing data. Time-to-deterioration (TTD) of HRQoL and responder analyses were conducted to determine the treatment effect based on timing and proportion of patients reaching a minimal important difference (MID) change in QL/PF (≥10 points). Results: The QL and PF changes over time were numerically similar between REG and PBO based on the LMM. The PMM grouped patients based on timing of last HRQoL assessment (<3 or ≥3 cycles) and had results similar to the LMM, demonstrating little impact of informative missing data. For the TTD analysis, when an event was defined as the earliest MID decrease in QL/PF, disease progression, or death, REG showed significantly different TTD curves from PBO (QL: median 8.0 vs. 7.0 weeks, hazard ratio (HR)=0.54; PF: median 7.9 vs. 7.0 weeks, HR=0.59, respectively; all p<0.01). Median TTD was comparable between treatments after removing progression/death from the definition. The responder analyses showed that a similar proportion of patients achieved an improvement in MID in REG vs. PBO (QL: 27.2% vs. 29.4%; PF: 14.0% vs.16.2%, respectively). Conclusions: The findings of this exploratory analysis demonstrate that HRQoL is similar for the REG and PBO groups, indicating that REG prolongs OS and PFS vs. PBO while maintaining a comparable HRQoL. Clinical trial information: NCT01584830.
Preoperative infusional 5-FU and sorafenib with external radiation therapy in locally advanced rectal cancer: Results of a phase I study.
Authors: Prithviraj Gopi Kesaria , Jiang Kun , Zhao Xiuhua , Chen Dung-Tsa , Campos Tiffany , Shridhar Ravi , Hoffe Sarah E. , Almhanna Khaldoun , Shibata David , Kim Richard D.
Published: February 2017

683

Background: The standard of care in locally advanced rectal cancer (T3, T4, or N1) is preoperative treatment with fluoropyrimidine-based chemotherapy. Sorafenib works synergistically with radiation (RT), and inhibits ras/raf, PDFGR and VEGFR. This phase I study evaluated the safety and efficacy of sorafenib with infusional 5-FU and RT in patients with locally advanced rectal cancer. Methods: Patients with confirmed stage II or III rectal cancer were recruited in 4 cohorts of 3 patients per dose level (DL), with an expansion cohort at the MTD. A 3+3 dose escalation design was used. RT was given in 25 fractions at 1.8Gy (45 Gy) day 1-5 at all dose levels. 6-10 weeks following neoadjuvant therapy, patients underwent surgery. Results: 17 patients were enrolled at Moffitt Cancer Center, including 10 females and 7 maleswith a median age of 54years (range: 31-72).After observing toxicity in the first cohort (2 patients with G2 and G3 skin toxicity and 1 patient with G2 mucositis) requiring dose interruptions, an amendment was made to change the schedule of chemotherapy and sorafenib to days 1-5 instead of daily.Following this, the primary G3 toxicity was hypertension, in 2 patients at 200 mg adjusted DL (day 1-5) and 1 patient at the 400 mg PO BID DL. 1 patient had G3 ALT elevation at the 400 mg PO BID DL, and no grade IV toxicities were observed. G1 and G2 toxicities included diarrhea, mucositis, nausea, fatigue, proctitis, and thrombocytopenia. No perioperative complications were seen. One patient is awaiting surgery. Due to patient refusal, 2 patients did not undergo surgery.The pCR rate was 35.7% and downstaging was observed in 85.7% of patients.KRAS status was available for 12 patients. The pCR was 40% in those with KRASmutant tumors (2/5 pts). Median NAR (neoadjuvant rectal cancer) score was 8.4. Conclusions: This regimen was very well tolerated after changing the dosing schedule. The pCR and downstaging rate is encouraging, and supports further clinical investigation of this regimen. Clinical trial information: NCT01376453. [Table: see text]
Effects of regorafenib therapy on health-related quality of life (HRQoL) in patients with metastatic colorectal cancer (mCRC) in the phase III CONCUR trial.
Authors: Qin Shukui , Kim Tae Won , Yau Thomas Cheung , Ma Brigette , Pan Hongming , Xu Jian-Ming , Bai Yuxian , Wang Liwei , Yeh Kun-Huei , Bi Feng , Cheng Ying , Le Tuan Anh , Lin Jen-Kou , Liu Tianshu , Dong Ma , Kappeler Christian , Chang Jane , Xu Rui-hua , Li Jin ,   on behalf of CONCUR Investigators
Published: February 2017

697

Background: The CONCUR trial (NCT01584830) showed that the multikinase inhibitor regorafenib (REG) significantly improved overall survival and progression-free survival vsplacebo (PBO) in Asian patients with mCRC who had progressed on approved standard therapies. HRQoL was an exploratory endpoint. Methods: In this international multicenter trial conducted in Asia, patients were randomized 2:1 to receive REG 160 mg (n=136) or PBO (n=68) once daily for the first 3 weeks of each 4-week cycle. Prespecified QoL analyses were conducted on all 204 patients using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and the EuroQol-five dimension questionnaire (EQ-5D). HRQoL outcomes were expressed as time-adjusted area under the curve (AUC) to allow descriptive evaluations of QoL in the REG and PBO groups across the entire treatment period. Individual domains were also compared using descriptive statistics. Results: Overall, changes in HRQoL were similar in the REG and PBO groups. Difference in least-squares (LS) mean time-adjusted AUC of the EORTC QLQ-C30 global health status/QoL (GH) score: −0.40 (95% CI: −3.53 to 2.72); differences in LS mean time-adjusted AUC for EQ-5D index and visual analog scale (VAS) scores: −0.03 (95% CI: −0.08 to 0.01) and −1.18 (95% CI: −4.01 to 1.66), respectively. The PBO group had <5 patients after cycle 3, so results should be interpreted with caution. Changes from baseline scores in cycles 2 and 3 did not appear to differ between REG and PBO on the 15 domains of the EORTC QLQ-C30, the EQ-5D index, and the VAS. Conclusions: No substantial differences in overall changes in HRQoL were seen between patients treated with REG and PBO in the CONCUR trial. Clinical trial information: NCT01584830. [Table: see text]
Trends of clinical staging for cancer patients at primary presentation: Have we improved over time?
Authors: Reddy Sanjay S. , Handorf Elizabeth , Smaldone Marc C. , Ridge John A. , Farma Jeffrey M. , Sigurdson Elin R.
Published: February 2017

737

Background: The efficacy of non-surgical and of neoadjuvant therapy for cancer cannot be determined without appropriate clinical staging. The absence of staging data has been a persistent problem. Methods: Using the National Cancer Database from 1998-2011 we reviewed patients diagnosed with cancers of three disease sites, head and neck (HNC), rectal (RC), and bladder (BC). Rates of clinical staging were assessed by institution type, either community (COM) or academic (ACA). Patients treated with surgery alone were excluded from analysis. Results: 166,670 patients with HNC, 125,699 patients with RC, and 15,433 patients with BC were identified. Prior to induction therapy, 91% and 92% of HNC patients were clinically staged in COM versus ACA, and 73% and 78% of RC patients, respectively (p<0.0001). BC patients were clinically staged 79% of the time in both institutions (p=0.43). Among HNC patients, clinical staging was assigned to 90% in 1998, which increased to 94% in 2011 (p<0.0001). For RC, clinical staging rates increased from 62% in 1998 to 89% in 2011 (p<0.0001). In BC, 74% were staged in 1998, which declined to 66% in 2007. However, the trend reversed, and 92% received a clinical stage by 2011 (p<0.0001). When comparing trends between COM and ACA, in 1998 stage was reported in 90% and 91% for HNC, respectively. By 2011, the proportions rose to 93% and 94%(p<0.0001). In 1998, 60% of RC patients were staged in the COM versus 66% in ACA. By 2011, 88% and 91% had staging reported (p<0.0001). For BC in 1998, 75% of patients were assigned a stage in both center types, which fell until 2007, when a steady increase was observed. By 2011, 92% of patients were staged in both center types (p<0.0001). Conclusions: Clinical staging improved in all classes of patients with time, although a substantial number still lack staging information. Clinical stage reporting varied by type of institution as well as disease sites. Patients with HNC had the highest rate of clinical staging prior to treatment and RC had the lowest. Between 1998 and 2011, RC has seen the most significant upward trend in recording clinical stage. Despite this, thousands of patients have received treatment without documentation of their clinical stage.
Liver resectability following S-1+L-OHP with cetuximab as the first-line treatment of unresectable liver limited metastases from KRAS exon 2 wild-colorectal cancer in Japanese patients (KSCC 1002).
Authors: Miyamoto Yuji , Emi Yasunori , Tokunaga Shoji , Beppu Toru , Kakeji Yoshihiro , Oki Eiji , Saeki Hiroshi , Mori Shinichiro , Inomata Masafumi , Akagi Yoshito , Baba Hideo , Natsugoe Shoji , Ogata Yutaka , Maehara Yoshihiko ,   Kyushu Study Group of Clinical Cancer (KSCC)
Published: February 2017

755

Background: There is no data concerning liver resectability following S-1+L-OHP (C-SOX) with cetuximab (Cmab) as the first-line treatment of unresectable liver limited metastases from KRAS exon 2 wild-colorectal cancer by prospective, multi-center study in Japan. The Kyushu Study group of Clinical Cancer (KSCC) conducted phase II trials in this setting. Methods: Eligibility criteria included unresectable liver limited metastases from histologically confirmed advanced colorectal cancer, ECOG PS 0-1 and adequate general condition. Patients (pts) received 4-6 cycles of C-SOX (oxaliplatin 130 mg/m2, day 1 followed by S-1 80 mg/m2 po [days 1-14] every 3 weeks) with weekly durable intravenous (DIV) Cmab administration at 400 mg/m2 (day 1) and 250 mg/m2/week (except day 1), followed by evaluating the liver resectability. Results: Of the 33 pts enrolled from March 2010 to July 2013; M/F, 20/13; median age, 64 years (range 48-83); ECOG PS 0/1, 27/6; primary lesion -/+, 18/15; number of liver metastasis 1-4/5 or more, 10/23; uni-/bi-lobular liver meta. 5/28; synchronous/metachronous 30/3. The number of FAS and SAS cases was 33. Response without confirmation for CR, PR, SD, PD and NE were 1 (3.0%), 20 (60.6%), 6 (18.2%), 3 (9.1%) and 3 (9.1%), respectively. An overall response rate was 63.6% (95% CI: 46.3–81.0%). The liver resectability for all time treatment was 16/33 (48.5%). The number of R0 cases was 13 pts (39.4%). Median progression free survival (liver resection was not censored and not event, events = relapse, progression, secondary cancer, and death) for 16 liver resection cases and 17 not-resection cases were 25.0 months (8.1-not reached), 4.5 months (3.0-10.8), respectively. Median overall survival (mOS) for all 33cases was 31.6 months (14.8, not reached). Median OS for 17 not-resection cases was 14.0 (6.4-not reached), and mOS for 16 liver resection cases was not reached and 3-year survival rate was 51.4%. Conclusions: C-SOX + Cmab regimen is safe and effective for unresectable liver limited metastases from KRAS exon 2 wild-colorectal cancer, and might be to lead the high liver resectability. Clinical trial information: UMIN000004331.
A phase I, dose-escalation, multicenter study of ACT-PFK-158, 2HCl in patients with advanced solid malignancies explores a first-in-human inhibitor of glycolysis.
Authors: Redman Rebecca Ann , Pohlmann Paula Raffin , Kurman Michael R. , Tapolsky Gilles , Chesney Jason
Published: February 2017

TPS494

Background: In human cancers, loss of PTEN, stabilization of hypoxia inducible factor-1α, and activation of Ras and AKT converge to increase the activity of a regulator of glycolysis, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3). This enzyme synthesizes fructose-2,6-bisphosphate (F2,6BP), which is an activator of 6-phosphofructo-1-kinase, a crucial step of glycolysis that is tightly controlled by multiple metabolic feedback mechanisms and dictates the rate of glycolytic flow. The vast majority of pancreatic ductal adenocarcinomas and approximately 50% of colon adenocarcinomas harbor activating mutations in Ras and these tumors have been reported to be highly glycolytic. PFK158 is a potent small molecule inhibitor of PFKFB3 that is selectively cytotoxic to Ras-transformed epithelial cells and displays broad anti-tumor activity causing ~80% growth inhibition in several mouse models of human-derived tumors and syngeneic murine models of colon cancer. Importantly, IND-enabling safety and toxicity studies have demonstrated that PFK158 is well tolerated in rats and dogs with an expected good therapeutic index, lending support for a phase 1 trial that is now underway. Methods: The primary objective of the study is to describe the dose limiting toxicity and to determine either the maximum tolerated dose or biological effective dose of PFK-158 in a “3+3” cohort-based dose escalation design that follows a modified Fibonacci scheme. Multiple secondary endpoints have been incorporated to assess the effects of PFK-158 on peripheral blood mononuclear cell F2,6BP activity and on glucose uptake using FDG-PET imaging. This trial is currently enrolling at two US sites; Cohort 1 has been completed without dose-limiting toxicity and Cohort 2 is enrolling with two subjects under treatment as of September 2014. In conclusion, PFK158 is the first-in-man and first-in-class PFKFB3 inhibitor to be examined in a phase I trial and may have significant clinical utility either as a monotherapy or when combined with other targeted agents. Clinical trial information: NCT02044861.
A phase II clinical trial of carbon-ion radiotherapy and concurrent S-1 chemotherapy for locally advanced pancreatic cancer.
Authors: Shinoto Makoto , Shioyama Yoshiyuki , Suefuji Hiroaki , Matsunobu Akira , Toyama Shingo , Kudo Sho
Published: February 2017

TPS504

Background: Despite recent advances in chemotherapy and radiotherapy, prognosis of unresectable locally advanced pancreatic cancer (LAPC) patients remains poor. To improve the outcome, a phase I/II clinical trial of carbon-ion radiotherapy (CIRT) with concurrent gemcitabine for LAPC was started in National Institute of Radiological Sciences in Japan.When compared to photon beams, carbon ion beams offer improved dose distribution, enabling us to concentrate a sufficient dose within a target volume while minimizing the dose in the surrounding radiosensitive normal tissue. In addition, carbon ions being heavier than protons provide a higher biological effectiveness, which increases with depth reaching the maximum at the end of the beam’s range. Although CIRT is expected to offer powerful local effect, whereas the potential risk of distant metastasis represent a critical problem for LAPC. To control distant metastases and subsequently prolong patient survival, a more effective systemic treatment might be essential. Recently, S-1 has shown favorable antitumor activity in several clinical trials for pancreatic cancer. Oral S-1 also has a great clinical advantage because the risks of complications associated with intravenous administration are avoided.We considered oral S-1 to be an attractive alternative to gemcitabine in the CIRT for LAPC. Thus, we planned a phase II clinical trial to evaluate the efficacy and safety of CIRT with concurrent S-1, which is the first trial in the world. Methods: Eligibility included pathological confirmation of pancreatic invasive ductal carcinomas and radiographically unresectable disease without metastasis. Concurrent S-1 is administered orally twice a day at a dose of 80mg/m2/day for 28 days every 6 weeks. Carbon-ion radiotherapy is prescribed with 55.2GyE at 12 fractions in 3 weeks. The primary endpoint is two year overall survival. Clinical trial information: UMIN000013803.
Physical activity in patients with unresectable pancreatic adenocarcinoma: A multicentric randomized controlled study (APACaP study).
Authors: Neuzillet Cindy , Vergnault Mathieu , Foucaut Aude-Marie , Touillaud Marina , Bonnetain Franck , Hammel Pascal ,   GERCOR
Published: February 2017

TPS506

Background: Exercise during chemotherapy (CT) is a promising strategy to reduce fatigue and improve health-related quality of life (QoL). It has been shown feasible and efficient in various cancers, including at advanced stage. Effects of physical activity in advanced pancreatic ductal adenocarcinoma (PDAC) have never been explored to date. We aim to evaluate the effects of a physical activity intervention in this setting. Methods: Randomized national multicentric interventional study to test the efficacy of an unsupervised home-based 16-week physical exercise program. Specificities of PDAC for physical activity program implementation will be taken into account (physical activity partner instead of patients groups, nutritional management). Main inclusion criteria: histologically confirmed, unresectable PDAC; scheduled for CT; WHO PS 0-2; age ≥ 18; physical activity partner. Two study arms: intervention group invited for the exercise program (aerobic and resistance exercises) in addition to usual care; control group receiving usual care alone. Primary objective: effects on fatigue (MFI-20) and health-related QoL (EORTC-QLQ-C30) at week 16, unified as co-primary endpoint. Secondary objectives: effects on pain, anxiety and depression, nutritional status, insulin resistance, CT tolerance, survival; adherence to the program. Number of patients: 200. PDAC patients are strongly affected by fatigue, thus they are expected to benefit from a physical activity intervention. Moreover, exercise may have a beneficial effect on tumor outcomes, by reducing insulin resistance and insulin/IGF-1 secretions. Such intervention may appear challenging because of multiple cancer-related symptoms (fatigue, depression, pain, denutrition) that can appear as barriers to physical activity. Conversely, we hypothesize that a physical exercise program, by taking into account PDAC specificities, may improve symptoms and health-related QoL. If this intervention is proven to be feasible and effective, such standardized physical exercise programs might be proposed in complement to CT in patients with advanced PDAC as a logical next step. Clinical trial information: NCT02184663.
A pilot study of AMP-224—a PD-1 inhibitor—in combination with stereotactic body radiation therapy (SBRT) in patients with metastatic colorectal cancer.
Authors: Duffy Austin G. , Makarova-Rusher Oxana V. , Fioravanti Suzanne , Walker Melissa , Venkatesan Aradhana , Abi-Jaoudeh Nadine , Wood Bradford J. , Citrin Deborah E. , Greten Tim F.
Published: February 2017

TPS788

Background: AMP-224, a B7-DC Fc fusion protein, binds to PD-1, an inhibitory receptor that is present on the cell surface of exhausted, activated, effector, and memory T cells. AMP-224 has a unique mechanism of action in that it binds specifically to PD-1HI T cells (chronically stimulated / exhausted T cells) but not to PD-1LOcells which represent the normal activated T cell population. Several preclinical studies have documented an increase in peripheral antitumor immunity following radiation, a phenomenon known as the “abscopal effect”. Tumor PD-L1 expression has also been shown to be induced by radiation, which can suppress the anti-tumor immune response. Inhibition of PD-1/PDL-1 axis has been shown to improve anti-tumor immunity by blocking the tumor-mediated suppression of cytotoxic T cells. The aim of the study is to evaluate whether the anti-tumor immunity of anti-PD1 therapy (with AMP-224) can be enhanced by radiation therapy. Methods: Patients with histologically confirmed metastatic colorectal cancer to liver are being enrolled to this pilot study. The objectives are to determine the safety, tolerability and feasibility of AMP-224 in combination with stereotactic body radiation therapy (SBRT) to metastatic hepatic metastasis in patients with advanced colorectal cancer. Select eligibility are as follows: at least 1 measurable metastatic hepatic lesion by RECIST 1.1 criteria and amenable to SBRT. Patient must have progressed on or been intolerant of at least one prior oxaliplatin- and/or irinotecan-containing regimen and have metastatic lesions that are not amenable to curative resection; ECOG ≤ 1; Life expectancy of greater than 3 months. Acceptable organ and bone marrow function. No active or prior documented autoimmune or inflammatory disorders. Clinical trial information: awaited.
Disparities in baseline magnetic resonance imaging (MRI) utilization and imaging characteristics for prostate cancer (PCa) patients.
Authors: Ajayi Ayobami , Rosen Mark Alan , Vapiwala Neha , Both Stefan , Agawu Atu , Christodouleas John Paul , Bekelman Justin E. , Tochner Zelig , Deville Curtiland
Published: February 2017

119

Background: Blacks with low risk PCa more likely to have adverse pathologic features at prostatectomy and larger dominant intraprostatic lesions (DIPL) with high anterior foci prevalence. Whether pretreatment MRI identifies these differences is unknown. The aim of this study was to determine whether disparities exist in MRI utilization and imaging characteristics for PCa patients. Methods: An institutional database of 617 PCa patients treated with proton and/or intensity modulated radiotherapy from 2005-2013 identified patients with pelvic MRI (T2 weighted, diffusion weighted, and/or dynamic contrast-enhanced sequences, 91% with endorectal coil). DIPL presence, size, extracapsular extension (ECE) and seminal vesicle invasion (SVI) were reviewed. Whites vs. Blacks overall and stratified by risk group were compared using Fishers exact test for categorical and student’s t-test for continuous variables (P<0.05 significant). Results: Race was 367 White (59%), 208 Black (34%), and 42 Asian/Other (7%). Age (mean 67±8), Gleason score, and risk group did not differ significantly for Whites vs Blacks; clinical stage and mean PSA (ng/mL) did (White 8±11 vs Black 14±22, P<0.001). Overall, 472 (77%) patients underwent baseline MRI, with Blacks (67%) less likely than Whites (81%), P<0.001. The disparity was greatest for low-risk Blacks (47% vs 90%, P<0.001), not significant in the intermediate-risk group (70% vs 78%, P=0.205), and reversed in high-risk (94% vs 75%, P=0.007). There were no significant differences in DIPL presence, diameter, area, ECE, or SVI overall or within low- and intermediate-risk groups. For high-risk, Blacks demonstrated smaller DIPL in maximum diameter 17 ± 8 mm (vs 21 ± 10; P=0.042) and area 185 ± 156 mm2(vs 295 ± 285; P=0.042), with no differences in DIPL presence, additional IPLs, ECE, or SVI. Conclusions: In this urban, academic center cohort, Black PCa patients were significantly less likely to undergo staging MRI. No differences were found in DIPL presence, area, ECE, or SVI, except in the high-risk group. Further investigation is required to better understand how pretreatment MRI utilization and imaging characteristics differ by race.
Radiogenomics of prostate cancer: Association between qunatitative multiparametric MRI features and PTEN.
Authors: VanderWeele David James , McCann Stephanie , Fan Xiaobing , Antic Tatjana , Jiang Yulei , Oto Aytekin
Published: February 2017

126

Background: Better methods are needed to assess prior to prostatectomy the risk of aggressive prostate cancer. Radiogenomics is a promising new paradigm that aims to gain molecular and genomic insights from clinical images. Loss of PTEN expression correlates with clinically aggressive disease and is associated with a 7-fold increase in the risk of prostate cancer death. Methods: From 38 patients who had undergone multi-parametric prostate MRI prior to prostatectomy, a pathologist and a radiologist simultaneously identified 45 peripheral-zone cancer regions of interest (ROIs). Histologic sections of the cancer foci underwent immunohistochemical analysis and were scored according to percent of tumor cells expressing PTEN as: negative (0-20%), mixed (20-80%), or positive (80-100%). From the MRI ROIs, the average and 10th percentile ADC values, T2-weighted signal-intensity histogram skewness, and quantitative perfusion parameters were calculated. Both dynamic perfusion two-compartment model and an empirical mathematical model (EMM) were used to fit the average contrast concentration curves within the ROIs as a function of time. Associations between the quantitative image features and PTEN expression were analyzed with Pearson's correlation coefficient (r). Results: The PTEN scores were: positive (n = 21, 47%), mixed (n = 12, 27%), and negative (n = 12, 27%). Two perfusion imaging contrast uptake parameters obtained from EMM correlated with PTEN scores (r = 0.25, p < 0.1 and r = 0.43, p < 0.01), and T2-weighted signal-intensity skewness also showed some correlation tendency (r = −0.25, p < 0.1). No correlation was seen between mean ADC and 10th percentile ADC values and PTEN score. Conclusions: This preliminary study of radiogenomics of prostate cancer suggests that fast contrast uptake of cancer on DCE-MR imaging and a T2-weighted imaging feature are potentially associated with prostate cancer PTEN expression, which warrants further studies and validation.
Effect of radium-223 dichloride (Ra-223) on pain from US EAP.
Authors: Morris Michael J. , Sartor A. Oliver , Vogelzang Nicholas J. , Shore Neal D. , Cislo Paul , Bangerter Keith , Sweeney Christopher
Published: February 2017

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Background: Ra-223, a first-in-class alpha-emitting radiopharmaceutical, has shown pain palliation in phase 2 trials (Parker 2013; Nilsson 2012). Here we present the results of Ra-223 effect on pain from US EAP. Methods: Pain was assessed at baseline, during treatment (trt) , and follow up (up to 6 mos after last trt visit) using the Brief Pain Inventory (BPI-SF) Questionnaire. The pain severity assessment was based on the worst pain item from the BPI-SF. The analysis was restricted to those not on opioids at baseline due to missing data for those on opioids. Hypotheses tests were based on changes from baseline. A meaningful change in score was defined as >2 points from baseline (Atkinson 2010). Results: Of 177 treated patients (pts) with baseline pain scores, 109 were not on opioids at baseline (6% had a score of 0 [no pain], 46% had 1-4 [mild pain], 34% had 5-7 [moderate pain], 14% had 8-10 [severe pain]). A significant decrease in mean pain severity from baseline (P<0.05) was observed at all trt visits. Among 97 pts who could have pain improvement (baseline score ≥2), 57 (59%) experienced a reduction in pain during at least one on-trt visit. Among all pts not on opioids at baseline and had baseline pain assessment, 46/109 (42%) had improved pain without worsening (decrease of ≥2 points), 20/109 (18%) had stable pain (no change of ≥2 points), 30/109 (28%) had worsening of pain (increase of ≥2 points or initiation of opioids) at some point and never had improvement, 11/109 (10%) had improvement and worsening at different times during trt, and 2/109 (2%) had no post baseline data. (Table presents data at each trt visit). Conclusions: Radium-223 was associated with meaningful pain relief in 42% of pts, whereas 28% had worse pain and 18% no change. The confounding effect of change in opioids after initiation prevents adequate interpretation of this finding for pts on opioids at baseline. Clinical trial information: NCT01516762. [Table: see text]
Preliminary activity of veliparib (V) in BRCA2-mutated metastatic castration-resistant prostate cancer (mCRPC).
Authors: Pahuja Shalu , Appleman Leonard Joseph , Belani Chandra Prakash , Chen Alice , Chu Edward , Beumer Jan Hendrik , Puhalla Shannon
Published: February 2017

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Background: Male BRCA mutation carriers have a 2-8-fold increased risk of prostate cancer when compared to the general population, and up to 3% of patients (pts) with prostate cancer carry an inherited mutation in BRCA1 or 2. The therapeutic implications of germline BRCA mutations in prostate cancer are largely unknown. BRCA mutation enhances sensitivity to inhibition of the PARP1 and PARP2 enzymes, due to a synthetic lethal effect on DNA repair. We therefore conducted a phase 1 study of the PARP 1, 2 inhibitor, veliparib (V), in 2 cohorts of pts- BRCA germline mutated (BRCA+) and BRCA-wild type (BRCA-wt; consisting of serous ovarian cancer and triple-negative breast cancer). Methods: A 3+3 dose escalation phase I trial was performed to determine a maximum tolerated dose (MTD) and recommended phase II dose (RP2D). V was administered orally continuously on a 28-day cycle. Results: A total of98 (70 BRCA+ and 28 BRCA-wt) pts were enrolled. The maximum administered dose (MAD) was 500 mg BID and the MTD/RP2D was 400 mg BID. In BRCA+ cohort at doses ≥ 400 mg BID, overall response rate (ORR) defined as complete response (CR)+ partial response (PR) was 37%, and clinical benefit rate (CBR) defined as CR+PR+stable disease (SD) > 6 cycles was 40%. Three pts with BRCA2+ metastatic castration-resistant prostate cancer (mCRPC) were enrolled on the RP2D and were evaluable for response. In these pts, the ORR was 2/3 (66%) and CBR 3/3 (100%) (summarized in table). One pt with rapidly progressive mCRPC involving liver and bone achieved PR and undetectable serum PSA, and remains on therapy at 19+ cycles. The most common adverse effects in these pts were grade 1/2 nausea/vomiting, fatigue, and leukopenia consistent with the overall study population. Conclusions: Single-agent V demonstrates evidence of activity in BRCA2+ mCRPC. These data support the role of genotype-directed therapy in prostate cancer. Clinical trial information: NCT00892736. [Table: see text]
Quantitative total bone imaging (QTBI) in patients with metastatic castration-resistant prostate cancer (CRPC) using NaF PET/CT.
Authors: Liu Glenn , Perlman Scott , Perk Tim , Harmon Stephanie , Simmons Kelly , Staab Mary Jane , Jeraj Robert
Published: February 2017

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Background: CRPC is frequently associated with the development of osseous metastases. While imaging allows treatment response determination in soft tissue metastasis, its application in bony metastasis is limited to staging. Methods: QTBI is an innovative tool that allows extraction of comprehensive functional information in all osseous metastases, as well as treatment response in individual lesions, using 18F-Sodium Fluoride (NaF) PET/CT. We completed a multi-center trial assessing the performance characteristics (test-retest) and responsiveness of QTBI as an imaging biomarker of treatment response in men with metastatic CRPC to bone treated with either a taxane-based or androgen-signaling pathway directed therapy. Results: 54 patients have been enrolled from three academic centers. Potential imaging biomarkers of treatment response have been identified. Here we present initial data regarding the inter-lesional response heterogeneity and implications. Conclusions: Changes in SUVmax, SUVtotal, and SUVmean reflect quantifiable PET measurements that are complementary, but may have different meaning depending on the treatment administered (cytotoxic vs cytostatic). Relying on one measure alone can be misleading, particularly when assessing treatment response. For example, some lesions may experience a decrease in SUVmax, while simultaneously having an increase in SUVtotal. This implies that the therapy decreased the max functional activity of the lesion, but the overall functional burden of the lesion increased analogous to “slowing down” progression. This is in contrast with lesions that decrease (increase) in both SUVmax and SUVtotal, which would imply decreased activity and burden (increased activity and burden). We will show data representative of the above along with clinical outcomes in support of this conclusion, as well as the implications of treatment response heterogeneity in the clinical outcome. In summary, QTBI provides a unique tool in understanding the dynamics of treatment response, allowing newer trial designs that can explore combination, sequence, and the issue of continuing treatment beyond progression with existing therapies. Clinical trial information: NCT01516866.
Response to taxane chemotherapy as first subsequent therapy after abiraterone acetate (AA) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): Post-hoc analysis of COU-AA-302.
Authors: De Bono Johann Sebastian , Smith Matthew Raymond , Saad Fred , Rathkopf Dana E. , Mulders Peter F.A. , Small Eric Jay , Shore Neal D. , Fizazi Karim , De Porre Peter , Kheoh Thian San , Li Jinhui , Todd Mary Beth , Griffin Thomas W. , Ryan Charles J.
Published: February 2017

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Background: In study COU-AA-302 of chemotherapy-naïve men with mCRPC, AA plus prednisone (AA) significantly improved radiographic progression-free survival and overall survival vs placebo plus prednisone (P). There is limited information about response to subsequent therapy after AA. In this post hoc analysis of pts in the AA treatment arm who progressed, we evaluated the clinical outcome to chemotherapy as first subsequent therapy. Methods: In COU-AA-302, 546 pts were randomized and received AA. Clinical outcome and discontinuation data from pts receiving chemotherapy as first subsequent therapy after progressing on AA were collected retrospectively and source verified. Median time to prostate-specific antigen (PSA) progression was estimated using the Kaplan-Meier method. Results: 73% (365/502; 44 still continuing on AA) of pts in the AA treatment arm received ≥ 1 subsequent therapy. Chemotherapy, docetaxel (DOC) or cabazitaxel (CBZ), was the most common first subsequent therapy. As of March 2014, following AA on study 53% (265/502) of pts received taxane chemotherapy (261 DOC, 4 CBZ) as first subsequent therapy. Median duration of first subsequent chemotherapy, mainly DOC, was 3 months (IQR, 1.0-5.0). Results are summarized (Table). Conclusions: This post hoc analysis describes antitumor activity in pts who progressed with AA and received taxane chemotherapy as first subsequent therapy. Despite the limitations of a retrospective analysis, these data support further assessment of subsequent therapies following AA treatment for mCRPC. Clinical trial information: NCT00887198. [Table: see text]
The oral CYP17-Lyase (L) inhibitor VT-464 in patients with CRPC.
Authors: De Bono Johann Sebastian , Pezaro Carmel Jo , Gillessen Silke , Shore Neal D. , Nordquist Luke T. , Efstathiou Eleni , Araujo John C. , Berry William R. , Liu Glenn , Vogelzang Nicholas J. , Omlin Aurelius Gabriel , Schotzinger Robert J. , Eisner Joel Robert , Moore William R.
Published: February 2017

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Background: VT-464 is an oral, non-steroidal inhibitor of CYP17-L and an antagonist of androgen receptor (AR) variants F876L and T877A which are associated with resistance to enzalutamide (ENZ) and abiraterone/prednisone (AA), respectively. INO-VT-464-CL-001 is a Phase (Ph) 1/2 study of VT-464 in treatment-naïve (TN) and treatment-failure (TF) patients with CRPC. Results are reported for Ph 1 (TN patients) and early results from Ph 2 patients. Methods: Phase 1: safety, tolerability, PK and initial efficacy (PSA and steroid concentrations) in M0 and M1 TN patients in escalated dose-cohorts from 50 to 600 mg bid in 28-day continuous dosing cycles. Phase 2: preliminary efficacy in M0 and M1 TN and TF (post-AA, -ENZ, and/or CHEMO) patients at 450 mg bid. Results: In Ph 1, 26 TN patients received VT-464 at 50 mg bid (n=1), 100 mg bid (n=1), 200 mg bid (n=4), 300 mg bid (n=8), 450 mg bid (n=9) and 600 mg bid (n=3) with 2 patients currently on study (15 and 29 months). Another 10 TN patients received VT-464 in Ph 2 at 450 mg bid. Most Ph 1 adverse events (AEs) were grade 1 or 2 and not considered drug related. There were 18 grade 3 AEs and 1 grade 5 AE considered not related to study drug, plus 4 grade 3 AEs (vasovagal/syncope) considered at least possibly related. For a single oral 450 mg dose, t½ was 6.8±0.8h (mean±SEM), Cmax was 8.6±1.2uM and Tmax was 3.4±0.7h. 19 of 26 Ph 1 and Ph 2 TN patients who received from 300 to 600 mg bid had PSA responses (6 PSA30%, 2 PSA50% and 1 PSA90% response). Preliminary PSA responses in Ph 2 TF patients included a PSA90% response in a prior-ENZ pre-chemo patient and a PSA50% response in a prior-ENZ and -chemo patient. No mineralocorticoid excess syndrome (MES) or changes in ACTH response or LFTs were observed. Plasma testosterone concentrations were reduced to near or below the limit of quantification in most patients at ≥ 450 mg bid, with normal progesterone and cortisol concentrations. No supplemental steroids were used. Conclusions: Clinical results at the doses evaluated support VT-464 CYP17 L-selectivity. The PSA50% and PSA90% responses in 2 of 7 prior Xtandi patients, combined with a lack of MES despite no supplemental steroids, warrants further investigation in the ongoing Ph 2 study, particularly in prior ENZ and AA patients. Clinical trial information: NCT02012920.