bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase I dose-escalation study of sorafenib plus S-1 in refractory solid tumors.
Authors: Tsai Hui-Jen , Chiang Nai-Jung , Shiah Her-Shyong , Chang Kwang-Yu , Su Wu-Chou , Chang Jang-Yang , Chen Li-Tzong
Published: February 2017

745

Background: S-1 is a new oral fluoropyrimidine-derived combo and has been shown activity in patients with various cancers in phase II/III studies. Sorafenib is an oral multikinase inhibitor with anti-proliferative and anti-angiogenesis activities and has been approved for the first-line treatment of advanced HCC, RCC and radioactive iodine-resistant thyroid cancer. In xenograft mouse models, sorafenib showed its activity to enhance the cytotoxicity of chemotherapeutic agents. Therefore, a phase I dose-escalation study to determine the dose-limiting toxicity and maximum dose of S-1 in combination with standard dosing of sorafenib in patients with refractory solid tumors was conducted. Methods: Eligible patients would receive escalating dose (30, 35 and 40 mg/m2, twice daily) of S-1 in a standard 3+3 phase I study design. Treatment was consisted of continuous sorafenib 400 mg bid plus S-1 30-40mg/m2 bid, D1-14, every 21 days per cycle. DLTs were assessed during the first two cycles of treatment, and treatment would be continued until disease progression, the occurrence of unacceptable toxicity or consent withdrawal. Results: A total of 13 patients were included, 7 in 30 mg/m2 dose level and 6 in 35 mg/m2 dose level. DLT occurred in 2 of 6 patients with 35 mg/m2 twice daily, manifested as grade 3 skin rash and prolonged grade 2 hand-foot-skin reaction in one each; while there was no DLT observed in 30 mg/m2 cohort. Seven patients achieved durable tumor control, included one pancreatic neuroendocrine tumor patient who had a sustained PR for 27.9 months, and durable stable diseases (>6 months of progression-free survival) in 3 out of 4 colorectal cancer patients, 2 of 2 biliary tract cancer patients and 1 of 2 pancreatic cancer patients. Conclusions: The recommended dose of S-1 in this combination was 30mg/m2 bid. Preliminary results suggested sorafenib/S-1 combination is feasible and deserves for further exploration in refractory advanced gastrointestinal tract cancers. Clinical trial information: NCT01128998.
Pre-treatment serum folate levels and toxicity in colorectal cancer patients treated with 5-fluorouracil and folinic acid.
Authors: Yan Michael , Vincent Mark David , Ho Cheryl , Winquist Eric , Jonker Derek J. , Rayson Daniel
Published: February 2017

755

Background: 5-fluorouracil (5-FU) chemotherapy is associated with severe and unpredictable toxicity in a significant proportion of patients.We hypothesized that susceptibility to 5-FU toxicity might be related to individual differences in components of reduced folate metabolism affecting intracellular 5,10-MTHF levels, detectable in blood prior to treatment. Methods: A prospective cohort of chemo-naive colorectal cancer patients planned to receive IV 5-FU and folinic acid for five consecutive days every four weeks were studied. Baseline clinical and laboratory data were collected prior to treatment. Biochemical data associated with folate metabolism was also collected and not revealed to treating physicians. The primary endpoint was occurrence of > grade 3 toxicity and/or toxicity mandating dose delay or reduction. Results: Of 78 eligible patients studied, 68% experienced > grade 3 toxicity, 69% had schedule modification, and 81% had either or both. Multivariable analyses identified only a higher pre-treatment serum folate level as an independent predictor of toxicity > grade 3 and/or mandating schedule modification (p = 0.016). An increasing toxicity trend was observed amongst folate-stratified patient cohorts, with an odds ratio of 2.87 (p = 0.09) comparing the highest and lowest quartiles. Concurrently, overall survival and relapse-free rates also increased with pretreatment folate levels in the adjuvant cohort with log rank values of 3.60 (p = 0.06) and 7.20 (p = 0.007) between the highest quartile and the lower quartiles, respectively. Conclusions: The incidence of severe toxicity with this schedule of 5-FU and folinic acid was high and positively correlated with the pretreatment serum folate level. Interestingly, a concurrent increase in overall and relapse free survival is observed with increasing serum folate levels. These results suggest that an optimal pretreatment folate level exists that balances chemotherapy treatment efficacy and toxicity.
A phase I study of combination of panitumumab and bevacizumab in KRAS wild-type colorectal cancer patients who were previously treated with fluoropyrimidine, oxaliplatin, irinotecan, and bevacizumab.
Authors: Takahashi Naoki , Iwasa Satoru , Tachikawa Masanori , Fukahori Masaru , Sudo Kazuki , Sasaki Yusuke , Shoji Hirokazu , Honma Yoshitaka , Okita Natsuko , Takashima Atsuo , Hamaguchi Tetsuya , Boku Narikazu , Shimada Yasuhiro , Yamagiwa Koki , Ebata Yuka , Uchida Yasuo , Honda Kazufumi , Terasaki Tetsuya , Yamada Yasuhide
Published: February 2017

759

Background: Clinical benefit of combination of panitumumab and bevacizumab (PB) based on the BBP strategy in third-line chemotherapy is unclear. There was no prospective data about the pharmacokinetic interaction between bevacizumab and panitumumab. Methods: This study composed two parts; 1) PB part: phase I study of PB to estimate its recommended dose, 2) CPB part: feasibility study to investigate the safety in combination of bevacizumab and panitumumab at the recommended dose in the phase I part with irinotecan (CPT-11) at the dose used in the prior chemotherapy. Inclusion criteria was as follows; 1) Age: ≥ 20 and < 76 years old, 2) performance status ≤ 1, 3) histologically colorectal adenocarcinoma with KRASwild-type, 4) patients who previously received fluoropyrimidine, oxaliplatin, CPT-11 and bevacizumab for unresectable metastatic disease. Three dose levels of panitumumab (Level 1: 6mg/kg, Level 0: 5mg/kg, Level -1: 4mg/kg) was set in PB part and starting dose level was Level 0. Bevacizumab was administered at fixed-dose of 5mg/kg regardless of dose levels of panitumumab. All drugs were administered on day1 and repeated every 2 weeks. Definition of dose limiting toxicity (DLT) was grade 4 hematological adverse events or ≥ grade3 non-hematological adverse events despite the supportive care observed in 28 days from day1 of cycle 1. Results: There were no cases showing DLT at level 0 (n = 3) and level 1 (n = 3) in the PB part and recommend dose was determined as panitumumab 6mg/kg and bevacizumab 5mg/kg. In the whole treatment course at level 1, grade 3 rash acneiform was observed in 2 patients and 2 patients achieved partial response. In six patients (CPT-11 150mg/m2, biweekly n = 3, 120mg/m2n = 3) enrolled in the CBP part, grade 3 toxicities were leukopenia/neutropenia (n = 1), mucositis (n = 1), diarrhea (n = 1), rash acneiform (n = 1), thromboembolic event (n = 1). Two out of 6 patients achieved partial response in CPB regimen. Conclusions: The recommended dose of PB regimen were panitumumab 6mg/kg and bevacizumab 5mg/kg. Combination of panitumumab and bevacizumab showed manageable toxicity. Clinical trial information: UMIN000009362.
Effect of regorafenib and TAS-102 in metastatic colorectal cancer (mCRC) patients on survival in salvage line with different toxicity profile.
Authors: Sugimoto Naotoshi , Yoshinami Tetsuhiro , Yamamoto Sachiko , Yagi Toshinari , Imamura Fumio
Published: February 2017

763

Background: In the CORRECT study, regorafenib has survival benefits in patients with metastatic colorectal cancer (mCRC) in salvage line. In the J-003 and RECOURSE study, TAS-102 has also survival benefit in them, too. But no randomized study is existed about the comparison between regorafenib and TAS-102. So we retrospectively compared the efficacy and toxicity of regorafenib and TAS-102 in patients with mCRC for salvage line in our hospital. Methods: The selection criteria were pathologically proven mCRC; 20 years or older; had a previous treatment history of two or more regimens of standard chemotherapy; no prior regorafenib and TAS-102 therapy; performance status 0-1; able to oral intake; and adequate organ functions. The patients in regorafenib group, regorafenib 160mg/body was given orally once daily for 21days followed by a 7-day rest. In TAS-102 group, TAS-102 35mg/m2 was given orally twice daily 5 days of treatment followed by a 2-day rest period, and then a 14-day rest period. Results: The analysis covered 51 patients over the period from October 2009 to June 2015.The median age was 67 years (range 33-79); 29 males and 22 females; PS 0/1 score 19/32; 23 patients were treated regorafenib and 28 patients were treated TAS-102.Progression-free survival and overall survival were 2.6 and 10.6 months with regorafenib and 3.2 and 9.7 months with TAS-102 (no significant difference). The rate of grade 3-4 toxicity were hypertension (35%), hand-foot syndrome(35%), AST/ALT increased(12%) in regorafenib group, and leucopenia (15%), neutropenia (35%), anemia(10%) in TAS-102 group. There was no treatment death in both groups. Conclusions: Both regorafenib and TAS-102 give mCRC patients survival benefit in salvage line with different toxicity profile.
Impact of blue 465nm LED on suppression of cancer growth.
Authors: Yoshikawa Kozo , Shimada Mitsuo , Higashijima Jun , Nakao Toshihiro , Nishi Masaaki , Kashihara Hideya , Takasu Chie
Published: February 2017

767

Background: Recent studies demonstrate the efficacy of irradiation from light emitting diodes (LED) for wound healing and anti-inflammation and anti-cancertherapies. In this study, the blue LED (465nm) suppressed the tumor growth in various cancers. Methods: < Experiment 1, Effect of blue LED on colon cancer > Human colon cancer cells (HT29 or HCT116) were seeded onto laboratory dishes that were put on LED irradiation equipment with a blue LED (465 nm). Irradiation at 15 or 30 mW was performed 10 min/day, each day for 5 days. Cell counting kit8 was then used to measure cell viability. Apoptosis and expression of several mRNAs (caspase, MAPK and autophagy pathway) in HT29 cultures irradiated with 465 nm LED were evaluated via AnnexinV/PI and RT-PCR, respectively. < Experiment 2, Effect of blue LED on pancreas cancer > Human colon cancer cells (SUIT2) were examined by same way and additionally cell cycle was checked. < Experiment 3, Effect of LED on CSCs > Cancer sphere were seeded onto laboratory dishes that were then put on LED irradiation equipment with a 465 nm-LED. Stemness gene and cell surface markers of CSCs expressions were analyzed by RT-PCR. Results: < Experiment 1 > Viability of HT29 and HCT116 cells was lower in blue LED irradiated cultures than in control cultures. Moreover, the expression of FAS, caspase3, capase8, and JUK were significantly higher in 465 nm-LED irradiated cultures than in control cultures, and expression of ERK1/2 and LC3 was lower in blue LED-irradiated cells. < Experiment 2 > Viability of SUIT2 cells was lower in blue LED irradiated cultures than in control cultures. And the CCND1 mRNA expression was significantly lower in blue LED group (p < 0.05). The cells of phase G2/M was decreased. < Experiment 3 > Cell viability of cancer sphere were significantly decreased by LED irradiation(p < 0.05). And, stemness gene and cell surface markers of CSCs expressions were significantly decreased by LED irradiation (p < 0.05) Conclusions: Blue LED irradiation inhibited tumor growth in various cancer cell lines.
Metastasectomy or radiofrequency ablation for treatment for colorectal cancer liver metastasis: Comparison of recurrence rates and identification of risk factors for local recurrence.
Authors: Vietti-Violi Naik , Bize Pierre E. , Duran Rafael , Demartines Nicolas , Halkic Nermin , Knebel Jean-Francois , Denys Alban
Published: February 2017

769

Background: Metastasectomy and radiofrequency ablation (RFA) are currently use for treatment of colorectal cancer (CRC) liver metastasis aiming for total tumor ablation with sparing liver parenchyma. Literature is lacking of studies comparing results and risk of recurrence between both techniques. We aim to compare recurrence rate after RFA and metastasectomy for CRC liver metastasis and to define which lesion is the best candidate for each treatment. Methods: By a lesion-by-lesion analysis, we reviewed 121 metastases treated by metastasectomy (43 patients, median follow up 798 days) and 110 metastases treated by RFA (60 patients, median follow up 590 days). Rate of local recurrence (LR) and hepatic recurrence (HR) were compared. We analyzed patients and primary tumor characteristics, looked for predictive factors for recurrence in metastasis data: size, deepness in liver, distance to hepatic veins, pathological resection margins in case of surgery. Analysis were performed using Chi Square and logistic regression in uni and multivariate analysis. Results: Patients and primary tumor characteristics were similar. Metastasis size was larger in metastasectomy group (18mm, range 2-90mm and 15mm, range 3-55mm; p = 0.03). Lesions were located deeper in the liver parenchyma in RFA group (20mm, range 3-51mm and 26mm, range 6-59mm; p < 0.001). Rate of LR and HR were nearly statistically different in favor of RFA: LR was 19% for metastasectomy group and 10% for RFA group (p = 0.06, delay: 245 and 289 days, p = 0.56), HR were 78% for metastasectomy and 66% for RFA (p = 0.054, delay: 226 and 235 days, p = 0.81). Predictive factors for recurrence in metastasectomy group: R1 status (p = 0.03) and metastasis deepness (p = 0.02). Metastasis deepness and proximity to hepatic veins increased risk for R1 (p = 0.04 and p < 0.001 respectively). We found no predictive factor for recurrence in RFA group. Conclusions: Pending proper selection (small lesions visible under imaging guidance), RFA tends to have a lower recurrence rate than metastasectomy. Lesions localized in depth in the liver parenchyma, close to hepatic veins are at risk of LR after metastasectomy.
Epidemiology and survival of metastatic gastrointestional stromal tumor: A Surveillance, Epidemiology, and End Results (SEER) database review.
Authors: Sundararajan Srinath , Kumar Abhijeet , Kanaan Mohammed Nawaf , Cui Haiyan , Elquza Emad , Patel Hitendra
Published: February 2017

86

Background: Metastatic gastrointestinal stromal tumor (MGIST) is a rare disease with limited data available on its epidemiology and survival. We aimed to study the epidemiology and survival pattern of M-GIST by reviewing the Survival, Epidemiology and End Result (SEER) database. Methods: SEER database was reviewed for patients (pts) with histologically confirmed GIST between 2002 and 2007. Variables included were age, race, gender, date of diagnosis (DOD), stage, location of primary tumor, and disease specific survival (DSS). The association between survival and race, gender, and site of disease for metastatic GIST patients was investigated. Primary outcome was 3-year DSS. Survival rate was estimated using the Kaplan–Meier method and the difference in 3-years survival was tested by log-rank test. Cox proportional hazard regression model was employed to test the association between survival and age. Results: A total of 653 patients with MGIST pts were identified and 602 were included for analyses. The distribution of MGIST according to primary site was as follows: gastric (42%), small intestine (26.2%), colorectal (4.6%), peritoneal (4.5%), NOS (17%) and other sites (5.9%). The mean age of diagnosis was 61 years. Caucasians to African-American (AA) ratio was 3.5:1 and male to female ratio was 1.3:1. Three-year DSS was 56.5% for Caucasians compared to 62.9% in AA (p = 0.25). Three-year DSS was 57.8% for males compared to 58.6% in females (p = 0.88). Small intestine MGIST had the best 3-Year DSS of 73.8% compared to gastric MGIST, which had a 3-year DSS of 50.7%(p < 0.0001). Peritoneal MGIST had the worst prognosis with 3-year DSS of 34.4%. Conclusions: MGIST had significant difference in survival based on the location of primary tumor. In contrary to the findings of previous studies, small intestine MGIST had superior 3-year DSS compared gastric primary M-GIST. There was no statistically significant difference in survival based on gender or race. [Table: see text]
Notch and wnt-beta catenin pathways as targets of γ-secretase inhibitor IX (GSI) mediated therapy in CD44+ gastric cancer (GC) cells.
Authors: Plentz Ruben R , Barat Samarpita , Chen Xi , Bui Cuong , Bozko Przemyslaw , Malek Nisar P
Published: February 2017

99

Background: GC is the second most common cause of cancer related death worldwide. New palliative therapeutic approaches to treat GC are of urgent need. Targeting cancer stem cells (CSC) could be an effective approach to treat GC. Recent studies have indicated that Notch signaling and wnt-beta-catenin pathways are crucial for CSC development. In this study, we mainly focused on inactivation of both Notch and wnt-beta-catenin pathways in CSC CD44+ GC cells using GSI. Methods: For our experiments we have used the GC cell line MKN45, as it showed expression of both targets (CD44,Hes1). For in vitro experiments proliferation, wound healing, invasion and tumorsphere assays were performed to analyze the migration, invasive and tumorigenic potential of CD44+ sorted GC initiating cells after GSI treatment. Western blot analyses of downstream signaling targets of Notch and wnt-beta catenin were tested after GSI treatment. SiRNA experiments for Notch1 and CD44 were also performed in order to confirm the Notch and wnt-beta-catenin pathway crosstalk. For in vivo analysis sorted CD44+ cells were subcutaneously injected into NMRI-nu/numice and were treated with vehicle or GSI. Results: CD44+ sorted MKN45 cells showed high expression of Hes1 as compared to the CD44- cell population. GSI treatment showed effective inhibition of cell proliferation, migration, invasion and tumor sphere formation of CD44+ cells. Interestingly, amongst all Notch receptors, Notch1 was found to be important in mediating the crosstalk between Notch and wnt-beta-catenin signaling cascades in CD44+ GC cells. Moreover, upon silencing of both CD44 and Notch1 by SiRNA showed effective inhibition of downstream targets and reconfirmed the proposed hypothesis of CD44 mediated Notch and wnt/beta-catenin crosstalk in GC cells. Conclusions: Our study highlights the crosstalk between Notch and wnt-beta-catenin in GC CD44+ cells. GSI could be an alternative drug to treat human GC as it effectively targets the CD44+ GC cells thus, completely reducing all the chances of relapse and metastasis associated with GC. Therefore, GSI therapy can open up new avenues for GC treatment with improved / better clinical outcome.
Phase II/III randomized trial of exclusive chemoradiotherapy with or without dose escalation in locally advanced esophageal carcinoma: The CONCORDE study (PRODIGE 26).
Authors: Crehange Gilles , Bonnetain Franck , Peiffert Didier , Le Prise Elisabeth , Etienne Pierre-Luc , Rio Emmanuel , Pereira Renata , Noel Georges , Benezery Karen , Seitz Jean Francois
Published: February 2017

TPS190

Background: INT 0123 failed to demonstrate an overall survival benefit with chemoradiotherapy dose escalation in locally advanced esophageal cancer. Nearly 45% of the patients had local persistent or recurrent disease. Several drawbacks surround the interpretation of the results of INT 0123. Improvements in target definitions with planning CT and 18F FDG PET/CT in keeping with improvements in radiation dose delivery that better protect healthy tissues with 3D conformal radiation therapy and/or IMRT should lead to the retesting of dose escalation in the modern era of new technologies. Methods: Patients are randomized into two groups: Experimental group: 40Gy ENI followed by a 26-Gy boost to the primary tumor and involved nodes (i.e. 33 daily fractions of 2Gy) with concomitant and adjuvant FOLFOX-4 weeks 1, 3, 5, 7, 9 and 11. Control group: 40Gy ENI followed by a 10-Gy boost to the primary tumor and involved nodes (in 25 daily fractions of 2Gy) with concomitant and adjuvant FOLFOX-4 weeks 1, 3, 5, 7, 9 and 11. Randomization using minimization to ensure balanced allocation across: Center / Adeno vs Squamous cell carcinoma / stage III vs I-II / weight loss / 3D-CRT vs IMRT. The principal hypothesis is that the rate of survival without locoregional relapse at 2 years will reach 50% in the reference arm and 65% in the experimental arm (Hazard ratio = 0.62). With a risk α = 0.05 (bilateral test) and β = 0.15 (power 85%). If we use a rate of 5% for lost to follow-up, it will be necessary to recruit 266 patients. The main inclusion criteria are: age < 75 years, WHO Status 0, 1 and 2, Enteral or parenteral feeding planned before the start of treatment if oral calorie intake < 1500 kcal, Histologically proven carcinoma of the esophagus, adenocarcinoma or squamous cell, T3, N0-N3, M0 (UICC 7thedition), T1-T2, N0-N3, M0 with a contra-indication for surgery, Absence of tracheo-esophageal fistula, Absence of thoracic or upper abdominal irradiation for another tumor, Written informed consent. 141 of the 160 patients required in phase II of the trial were included by September 22nd 2015. (ClinicalTrials.gov Identifier: NCT01348217). Clinical trial information: NCT01348217.
A phase I trial with cohort expansion of BYL719 in combination with gemcitabine and nab-paclitaxel in locally advanced and metastatic pancreatic cancer.
Authors: Soares Heloisa P. , Nguyen Danny , Springett Gregory M. , Kim Richard D. , Williams-Elson Irene , Miller Kara , Kothari Nishi , Mahipal Amit
Published: February 2017

TPS467

Background: The phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR pathway which is aberrantly stimulated in many tumors has emerged as a potential target for anticancer therapy. Although several class I PI3K inhibitors are under development, there is considerable evidence suggesting that targeting a single isoform of PI3K (p110α) would have sufficient antitumor activity and improved therapeutic window. The PI3K pathway is frequently activated and plays an important role in pancreatic cancer. Further, PI3KCA mutations, the gene encoding isoform p110α, are observed in this disease. BYL719 is an oral class I α-specific PI3K inhibitor that showed anti-tumor activity in different preclinical models. Recently, the first in human phase 1 trial of BYL719 defined the maximum tolerated dose (MTD) at 400 mg once daily. Methods: This is a single institution, open label, single group, phase I study with cohort expansion that utilizes the standard 3+3 design for dose. The primary objective is to determine the MTD of BYL719 in combination with gemcitabine and nab-paclitaxel as frontline therapy in patients with locally advanced, recurrent or metastatic pancreatic adenocarcinoma. Up to 24 patients will be enrolled in 4 dose escalation levels. The MTD is defined as the highest dose level at which 1 or less of 6 patients experience a dose limiting toxicity (DLT). Once the MTD is reached and/or the recommended dose for expansion is determined, an additional dose expansion cohort of 15 patients will be included. Secondary endpoints include characterizing the safety profile at the MTD and DLTs associated with it as well as obtaining pharmacokinetic data. Peripheral blood and pre-treatment tumor samples will be collected for evaluation of biomarkers that could predict treatment response, including levels of pAKT, p4EBP1 and pS6. BYL719 will be administered daily. Standard doses of gemcitabine and nab-paclitaxel will be given on days 1, 8 and 15 of the 28 days cycle. Patients will get restaging scans every 2 cycles. As per September 2015, twelve patients have been included in this study which is currently enrolling patients on cohort 3. Clinical trial information: NCT02155088 Clinical trial information: NCT02155088.
Perioperative stromal depletion by PEGPH20 in pancreatic ductal adenocarcinoma.
Authors: Ko Andrew H. , Cinar Pelin , Tempero Margaret A. , Nakakura Eric K. , Yeh Benjamin M , Chondros Dimitrios
Published: February 2017

TPS476

Background: Treatment with PEGylated recombinant human hyaluronidase (PEGPH20) depletes stromal HA in pancreatic tumors, resulting in increased intratumoral perfusion and improved drug delivery. This Phase 2 study evaluates the clinical, biologic, and radiographic effects of neoadjuvant PEGPH20, gemcitabine (GEM) and nab-paclitaxel (NAB) in patients (pts) with borderline resectable pancreatic ductal adenocarcinoma (PDAC). Methods: Therapy-naïve patients aged ≥ 18 years with histologically confirmed PDAC defined as borderline resectable by consensus national guidelines will be eligible. Pts must have ECOG PS of 0-1 and adequate renal, marrow and hepatic function. Co-primary endpoints include incidence of postoperative pancreatic fistula and pathologic complete response rate. The trial uses a 2-stage design. In Part 1 (n = 15), pretreatment endoscopic ultrasound-guided core biopsies and functional MRI (fMRI) will be obtained. After a 1-week run-in with PEGPH20 (3μg/kg on Days [D]1 and 4), pts will undergo repeat biopsy and fMRI. Pts will then receive PEGPH20 (3μg/kg), NAB (125 mg/m2) and GEM (1000mg/m2) on D1, 8 and 15 of a 28-day cycle. Enoxaparin (1mg/kg daily) and dexamethasone (8mg pre- and post- PEGPH20) will be administered prophylactically. CA 19-9 levels will be checked monthly. Restaging CT will be obtained at the end of Cycles 2 and 4, with repeat fMRI performed after Cycle 4. Pts who are judged to be appropriate operative candidates upon multidisciplinary tumor board review will go to surgery at that point. Tissue analyses will be performed on the serially collected tumor samples, including the resected pancreatic specimen, with a focus on HA expression and immune cell infiltrates. Upon recovery, pts will receive 2 adjuvant cycles of GEM and NAB. If the predefined safety threshold is met in Part 1, an additional 21 pts will be enrolled in Part 2, without the one-week PEGPH20 run-in or pre- and post-run-in biopsies. Assuming 25 of the 36 pts are evaluable (i.e., able to go to surgery), a post-operative fistula rate of 11% would be able to be estimated with 95% CI of 3.4%-23.1%. Study initiation has begun as of September 2015. Clinical Trial Information: NCT02487277 Clinical trial information: NCT02487277.
LAPACT: An open-label, multicenter phase II trial of nab-paclitaxel (nab-P) plus gemcitabine (Gem) in patients (pts) with locally advanced pancreatic cancer (LAPC).
Authors: Philip Philip Agop , Lacy Jill , Dowden Scot D. , Sastre Javier , Bathini Venu Gopal , Cardin Dana Backlund , Ma Wen Wee , Sobrero Alberto F. , Koski Sheryl L. , Borg Christophe , Tonini Giuseppe , Rivera Fernando , Hwang Jimmy J. , Knoble Jeanna L. , Al Baghdadi Tareq , Saif Wasif M. , Meiri Eyal , Kayitalire Louis , Li Jack , Hammel Pascal
Published: February 2017

TPS477

Background: In pts with LAPC, more effective systemic therapies may be associated with improved local control, delay of metastasis, and overall survival (OS). The phase III MPACT trial in pts with metastatic PC demonstrated longer OS (median, 8.7 vs 6.6 mos; HR, 0.72; P < 0.001) and an ≈ 3-fold greater shrinkage of primary tumors with nab-P + Gem vs Gem alone (−22.15% vs −7.02%), raising the possibility of improved local PC control with nab-P + Gem. LAPACT will assess the efficacy and safety of nab-P + Gem in LAPC. Methods: LAPACT will enroll treatment-naive pts (planned n ≈ 110) in the United States, Canada, and Europe with Eastern Cooperative Oncology Group performance status ≤ 1, confirmed unresectable LAPC, no distant metastases, and adequate organ function. Pts with mixed-origin tumors, any other malignancy within 5 years, peripheral neuropathy grade > 1, or clinically significant ascites are ineligible. Pts will receive nab-P 125 mg/m2 + Gem 1000 mg/m2 on days 1, 8, and 15 of each 28-day cycle. Pts without progressive disease (PD) or unacceptable toxicity after 6 cycles will receive investigator’s choice of surgery, chemoradiotherapy, or continued nab-P + Gem. If a major response is observed, surgery may occur prior to completing 6 cycles of nab-P + Gem. The primary endpoint is time to treatment failure (TTF; time from first therapy dose to discontinuation due to PD, start of a new non–protocol-defined anti-cancer therapy, or death). The study design allows for 80% power at a 1-sided α of 0.05 to detect a 30% increase over the 5.1-month median TTF observed for nab-P + Gem in the MPACT study. The secondary endpoints are disease control rate (DCR) after 6 cycles, overall response rate, progression-free survival, OS, safety, and quality of life. The exploratory endpoint is correlation of changes in circulating nucleic acids with PD and treatment response. An interim DCR analysis will occur after all pts have completed 6 cycles of nab-P + Gem, discontinued therapy due to PD, died, or started a new non–protocol-defined therapy before completing 6 cycles of therapy. Enrollment is ongoing (first pt enrolled in April 2015). Clinical trial information: NCT02301143.
Phase I study of veliparib with gemcitabine and radiation therapy in patients with borderline resectable and locally advanced unresectable pancreatic cancer.
Authors: Tuli Richard , Nissen Nicholas N. , Annamalai Alagappan , Hoffman David M. J. , Bryant Miranda , Tighiouart Mourad , Rogatko Andre , Rokhsar Sepehr , Scher Kevin S. , Jamil Laith , Lo Simon , Hendifar Andrew Eugene
Published: February 2017

TPS487

Background: Targeted inhibition of PARP1/2 is one way to further exploit the well-known synergy between gemcitabine (G) and radiotherapy (RT) in locally advanced pancreatic cancer (LAPC). PARP1/2 inhibitors, such as veliparib (V), have shown excellent anti-tumor activity when used with other cytotoxic therapies. This synergy may be further exploited in pancreatic cancer by targeting tumors with pre-existing defects in double- strand DNA repair. Extrapolating from our own laboratory findings (Tuli et al, Transl Oncol, 2014) and based on our hypothesis that PARP1/2 inhibition with G and RT will result in enhanced tumor control, we are conducting an IRB- approved phase I study in patients with borderline resectable and LAPC. Methods: The primary objective of this study is to determine the maximum tolerated dose (MTD) of V, which is defined as the dose level resulting in a probability (θ = 0.4) that a dose limiting toxicity (DLT) will occur within six weeks. Treatment cycle is 3 weeks followed by weekly evaluation for an additional 3 weeks. G (1000 mg/m2) is administered on days 1, 8, 15. RT (36 Gy) is given in 15 fractions (2.4 Gy/day). V is administered BID in 20 mg increments beginning at a dose of 20 mg. Inclusion criteria: histolopathological diagnosis of borderline resectable or LAPC, age > 18 years, KPS > 70%, life expectancy > 6 months, normal organ and marrow function, and negative pregnancy test. Dose escalation follows a Bayesian escalation without control (EWOC) design, where time to DLT is modeled using a proportional hazards model with constant baseline hazard rate. Secondary objectives: 1) measure clinical activity using RECIST 1.1 for PFS, OS; 2) evaluate pre-treatment tumor biopsy specimen and longitudinal blood samples for baseline levels of DNA repair proteins (ERCC1, XRCC1, PAR, etc.) as potential prognostic, predictive and correlative biomarkers; and 3) assess BRCA1/2, PALB2, PTEN germline and somatic mutations using validated gene sequencing, immunohistochemical and quantitative PCR methods. Since December 2013, 26 patients have consented with 22 enrolled. Clinical trial information: NCT01908478.
HER2 amplification as a ‘molecular bait’ for trastuzumab-emtansine (T-DM1) precision chemotherapy to overcome anti-HER2 resistance in HER2 positive metastatic colorectal cancer: The HERACLES-RESCUE trial.
Authors: Siena Salvatore , Bardelli Alberto , Sartore-Bianchi Andrea , Martino Cosimo , Siravegna Giulia , Magri' Alessandro , Leone Francesco , Zagonel Vittorina , Lonardi Sara , Amatu Alessio , Tosi Federica , Racca Patrizia , Ponzetti Agostino , Ciardiello Fortunato , Marsoni Silvia
Published: February 2017

TPS774

Background: We previously documented HER2 amplification in 5% of KRAS wild-type metastatic colorectal cancer (mCRC; Valtorta E. et al, Modern Pathology, 2015). Despite refractoriness to standard chemotherapy and to cetuximab, patients with HER2 amplified mCRC achieve 30% response rate (RR) and long lasting objective responses (median duration 8.5 mos.) when treated with lapatinib (L) and trastuzumab (T) [HERACLES trial - EudraCT 2012-002128-33; Siena et al. J Clin Oncol 33, 2015 (suppl; abs 3508)]. We sampled responding HERACLES patients at progression, and found persistent high levels of HER2 tested by IHC and FISH on tissue re-biopsies, or by droplet digital liquid biopsy in plasma ctDNA (LB). We reasoned that HER2 in these tumors could still be exploited as “molecular bait” for T-DM1, an antibody-drug conjugate of trastuzumab linked to the cytotoxic agent emtansine. We thus conducted a preclinical trial in a patient-derived xenograft (PDX) model generated from the viable biopsy of a acquired-resistant HERACLES patient. In a 2-arm trial against control (6 PDXs per arm), we compared T-DM1 to pertuzumab, and found that only T-DM1 treated animals achieved tumor responses. We therefore designed a proof-of-concept trial of T-DM1 in HER2 amplified mCRC patients progressing or relapsing after T+L treatment. Methods: HERACLES-RESCUE is an independent phase II trial assessing the efficacy of T-DM1 in HER2 amplified mCRC progressing after anti-HER2 (L+T) therapy within the HERACLES trial. Response rate is the primary endpoint. Using the A’Hern approach to retrofit the sample size from the constrained sample size of patients treated in HERACLES, and assuming α = 0.15, β = 0.85 and H0 = 5%, if 2 responses will be observed in 13 patients we would be able to define a clinically relevant true response rate of 25% (H1). Eligibility: progression/relapse within HERACLES L+T treatment, lack of KRAS mutations by LB, measurable disease (RECIST v1.1), ECOG PS ≤ 1, and adequate organ function. Treatment: T-DM1: 3,6 mg/kg q21d. A first patient was treated on August 2015. EudraCT number: 2015-003275-30; Funded by AIRC Grant # 9970. Clinical trial information: 2015-003275-30.
Neoadjuvant chemotherapy alone with mFOLFOXIRI in locally advanced rectal cancer: A single-arm phase II study.
Authors: Deng Yanhong , Zhang Jianwei , Cai Yue , Hu Huabin , Ling Jiayu , Xiao Jian , Huang Meijin , Kang Liang , Wang Lei , Lan Ping , Wang Jianping
Published: February 2017

TPS783

Background: Pre-operative 5-Fu based chemoradiation is still the standard of treatment for locally advanced rectal cancer (LARC). Although local recurrence rate had been controlled, about 30% of patients will develop distant metastases, which is the main obstacle for improving survival of LARC. Besides, preoperative radiation causes lots of concerns about anal and sexual functions. Whether systemic chemotherapy alone is effective enough in treating rectal cancer is not yet known. In our previous study of neoadjuvant mFOLFOX6 with or without radiotherapy in LARC, about 30% of patients in the arm with chemotherapy alone showed good response. And FOLFOXIRI had showed higher response rate in metastatic colorectal cancer. This phase II study is to explore whether pre-operative FOLFOXIRI could further improve the ratio of tumor downstaging (ypT0-2N0) in LARC. Methods: The primary endpoint is the ratio of tumor downstaging to ypT0-2N0M0 (pCR and stage I).The secondary endpoint included pathologic complete response rate, 3-year disease free survival rate, 3-year local recurrence rate, and safety. We hypothesized that FOLFOXIRI could improve the downstaging rate from 30% to 50% with 5% type I error and 80% power. 84 patients met inclusion criteria will be enrolled in the trial. All patients will receive the study regimen every 2 weeks for 4-6 cycles. MRI of the pelvic will be performed every 2 cycles of the therapy to assess clinical response. If the tumor response over 20% after 4 cycles of treatment, the patient will go to surgery (TME) directly or 2 more cycles of treatment before surgery under the decision of MDT. On the contrary, if the tumor show poor response (< 20%), short-term radiotherapy will be performed before operation. After surgery, 6-8 cycles of mFOLFOX6 will be given as adjuvant chemotherapy. Clinical trial information: NCT02217020 Clinical trial information: NCT02217020.
Phase III double-blinded, placebo-controlled study of MABp1 for improving survival in metastatic colorectal cancer.
Authors: Goel Sanjay , Wyrwicz Lucjan , Choi Minsig , Coveler Andrew L. , Ucar Antonio , Brown Alexander Ward , Sarosiek Tomasz , Wong Lucas , Stecher Michael , Fisher George A. , Hendifar Andrew Eugene
Published: February 2017

TPS784

Background: Interleukin 1 alpha (IL-1a) is a pro-inflammatory cytokine that initiates and propagates sterile inflammatory responses. IL-1a is present on the surface of tumors, and released from necrotic cells within the microenvironment, where it upregulates MMPs, VEGF, chemotactic cytokines, and IL-6 contributing to tumor growth and infiltration of the microenvironment by T-regulatory cells and tumor associated macrophages. IL-1a is also found on the surface of platelets and activates vascular endothelium allowing for circulating tumor cells to establish new areas of metastasis. Specific blockade of IL-1a with the true human IgG1k antibody MABp1, is expected to deprive the tumor of its ability to grow, spread, and evade immune surveillance. A phase I/II study showed radiographic evidence of tumor response in mCRC patients, as well as clinically meaningful improvement in cancer associated symptoms, with no significant toxicity. In the context of this therapy, the improvement in key cancer symptoms, including reversal of lean body mass loss, fatigue, and anorexia, is the direct result of an anti-neoplastic effect and is expected to correlate with an overall survival benefit. Methods: This “Phase III Study of MABp1 in Patients With Advanced Colorectal Cancer (XCITE)” is a global study of 600 patients, ECOG-PS 0-2, metastatic CRC refractory to oxaliplatin, irinotecan, fluoropyrimidine, and EGFR-inhibitors if KRAS wildtype. Patients are randomized 2:1 to receive MABp1 7.5 mg/kg iv every two weeks plus best supportive care (BSC) versus placebo (iv Q2 week) plus BSC. BSC does not include any other therapy with proven anti-cancer activity. The primary endpoint is OS, with secondary endpoints of PFS, ORR, change in lean body mass, and QoL. Patients continue on trial until clinical or radiographic progression as defined by the immune related response criteria (irRC). The study is powered to show a clinically meaningful improvement in OS, evaluated by log-rank test with a one-sided alpha of 0.025. As of September 2015, enrollment is currently underway in the United States and Europe, and results of the first interim analysis are expected in 2016. [NCT01767857]. Clinical trial information: NCT01767857.
Measuring value in bundled payments for head and neck cancer.
Authors: Lee Seohyun , Spinks Tracy E. , Guzman Alexis B. , Weber Randal S. , Hanna Ehab Y. , Hessel Amy Clark , Beadle Beth Michelle , Hutcheson Kate A. , Incalcaterra James , Wood Nancy M. , Jones Delrose , Feeley Thomas W.
Published: February 2017

11

Background: Value, defined as outcomes relative to costs, cannot be improved without rigorous long-term measurement. To assess value within a bundled payment pilot for head and neck cancer, we aim to generate timely, patient-centered outcomes and robust, near-real time financial tracking (Porter and Teisberg, Redefining health care. Creating value-based competition on results; Harvard Business School Press, 2006). Methods: Clinical and quality experts created an outcome measure set for head and neck cancer, using a three-tiered outcomes hierarchy from Michael Porter of Harvard Business School as a framework. Process measures were identified to evaluate compliance with standards of care. Data sources were verified and patient-reported outcomes were collected via a patient portal. A REDCap database was created to aggregate all longitudinal outcomes. The project managers and financial leaders identified key financial metrics to be tracked for enrolled patients. Outcomes and financial data were built into a dashboard to deliver timely, actionable information on value. Patients will be tracked for 2 years post-treatment completion. Results: 22 outcome measures and 6 process measures are being collected for all enrolled patients. Financial indicators, such as cumulative costs and fee-for-service payment vs. bundled payment, are being tracked for each patient. Currently, most outcomes and financial data are extracted manually. Implementation of a new electronic health record (EHR) should alleviate much of this administrative burden (Table). Conclusions: The project demonstrates the feasibility of value measurement for bundled payment. With provider and patient input, the outcome measures direct attention to what is important to patients and is actionable by clinicians. Additionally, near real-time financial tracking offers insights into the financial implications of this alternative payment model for cancer care. With automation via the EHR, this value measurement methodology can be scaled for other disease sites and additional payers. [Table: see text]
Implementing psychosocial distress screening across a health system: Herding cats or herding cats?
Authors: Sheaffer Heather
Published: February 2017

113

Background: With the American College of Surgeons Commission on Cancer 2015 Standards in hand, Penn Medicine embarked on a project to formulate an entity-wide plan for the provision of psychosocial distress screening. Identifying psychosocial distress and providing resources to meet those needs is an essential component of quality cancer care. Penn Medicine and the Abramson Cancer Center provided more than 91,000 chemotherapy treatments, 121,000 radiation treatments, and 14,000 proton therapy treatments in FY 15 in urban, suburban and rural settings with wide variations in resources. Methods: The establishment of the Psychosocial Distress Task Force was the key to the success of the project. Participants from multiple disciplines were invited from each facility including identified stakeholders and those with experience screening patients. After reviewing the literature, the task force set the agenda for the project including what tool to utilize for screening, when to screen, who will respond and what metrics would be evaluated. Results: Penn Medicine successfully developed a process for psychosocial distress screening across the health system by the 2015 deadline. The process includes screening all first return medical oncology patients for distress using the PHQ-4 and documenting the results in either the EMR or in the paper chart depending on the facility. The screening results then trigger a consult to social work where the patients are assessed using a standardized social work assessment developed by the task force for use by all oncology social workers across the system to standardize care. Conclusions: Given the scope of Penn Medicine oncology and the diversity of locations and staff models, formulating a plan for the provision of psychosocial distress screening presented a major challenge to the organization. This challenge was met through the establishment of a system-wide task force who planned and implemented distress screening across entity in a cohesive, coordinated way meeting the 2015 Standard.
Factors associated with toxicity-related service use among community oncology patients.
Authors: Harrison Jordan M , Lavasseur Beth , Stella Philip J. , Adams Paul T. , Swafford Lauren , Lewis JoAnn , Mendelsohn-Victor Kari , Friese Christopher Ryan
Published: February 2017

133

Background: Chemotherapy-associated toxicities occur often, yet sparse data are available to correlate toxicities with related service use. Toxicities may disrupt treatment, impair quality of life, and induce unplanned service use. We sought to understand the frequency and correlates of unplanned service use among patients receiving first-cycle chemotherapy at 5 community-based ambulatory oncology practices in southeast Michigan. Methods: A prospective survey examined the dichotomous outcome of toxicity-related unplanned service use. Newly-diagnosed patients were recruited before the first chemotherapy cycle. At the second cycle visit, patients completed a questionnaire that measured severity of nausea, vomiting, diarrhea, constipation, mouth sores, IV catheter problems, pain, fever/chills, extremity edema, and dyspnea on a 5-point scale (1 = did not experience to 5 = disabling). They also rated distress on a 10-point scale (0 = none, 10 = worst). Patients reported unplanned oncologist visits, emergency department visits, and unplanned hospitalizations, all of which were treated as unplanned service use. Mixed-effects logistic regression was used to identify factors associated with unplanned service use, with random effects for each clinic. Results: Among 106 patients (98% white, 74.5% women, mean age 60+11), common diagnoses were breast, lung, and colorectal cancer and non-Hodgkin lymphoma. Frequent toxicities were pain, nausea, diarrhea, and constipation. Thirty-six patients (34%) reported unplanned service use: 29% reported oncologist visits, 14% reported ED visits, and 8% reported hospitalizations. 45% of the total sample and 89% of patients with unplanned service use reported at least one toxicity that was severe or disabling. Factors associated with unplanned service use were high patient-reported distress and receipt of colony-stimulating factor. Conclusions: Toxicity-related service use was common in this community oncology population. Proactive symptom assessment tools may help clinicians manage toxicities between visits. A deeper understanding of toxicity patterns and correlates can inform clinical practice guidelines in community oncology practices.
The standardization of skin cancer treatment recommendations through the analysis of clinical pathways data and an evidence-based, physician-driven committee process.
Authors: Heron Dwight Earl , Barry Amanda , Benson Hans , Lorinc Zach , Lokay Kathleen
Published: February 2017

147

Background: Clinical pathways (CP) have the potential to improve the quality and safety of care and lead to more predictable outcomes and costs through standardization. Via Oncology’s CP program aims to standardize care at radiation centers across its nationwide network. Created through an evidence-based, physician-driven committee process, CP recommend the best treatment plan for specific patient populations based on a hierarchy of efficacy, toxicity, and cost. In the absence of definitive data, reaching a consensus on the best treatment recommendation is difficult, particularly for disease states such as melanoma, squamous cell carcinoma, and basal cell carcinoma for which a wide range of radiation doses and schedules are considered effective and regional and institutional preferences may vary. Methods: After initial implementation of CP, radiation disease committees meet semiannually to review treatment recommendations and utilization data collected for the prior six months. Data reflect treatment plans selected by physicians for individual patients. At the January 2015 skin pathway committee meeting, committee members reviewed data for each patient presentation to determine which doses and schedules were used most frequently. Results: After reviewing the utilization data, the committee narrowed the recommendations to one or two treatment plans per presentation, typically including standard and hypofractionated schedules. In scenarios where multiple treatment plans were selected at a similar frequency, the committee standardized to the lower dose and fewer fractionation plan. This reduced the number of treatment plans on the pathway from 34 to 15. A decrease in pathway adherence rates was not observed following this change. Conclusions: Data gathered from CP can be used to further standardize clinical care when there are several effective and accepted treatment regimens but a lack of published data. Through a dynamic process of assessing and modifying physician practice and patterns of care, CP provide cancer centers with a platform to ensure delivery of consistent, high-quality care to patients throughout their network.