bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase 1b (open-label)/phase 2 (randomized, double-blinded) study evaluating nab-paclitaxel and gemcitabine with or without olaratumab in first-line treatment of metastatic pancreatic cancer.
Authors: Bendell Johanna C. , Pelzer Uwe , Womack Mark S. , Borazanci Erkut Hasan , Bahary Nathan , Garrido-Laguna Ignacio , Maur Michela , Prater Tyler , Levy Donna Elise , Cronier Damien , Ramage Sam , Macarulla Teresa
Published: January 2019

TPS524

Background: Olaratumab is a human IgG1 monoclonal antibody that specifically binds human platelet-derived growth factor receptor (PDGFR)-α and blocks PDGF-mediated signaling pathways. Increased PDGFRα expression is observed in pancreatic cancer tissue, and has been suggested to play a role in the mesenchymal transition of pancreatic cancer. An ongoing trial designed to evaluate the safety and efficacy of olaratumab in combination with nab-paclitaxel/gemcitabine (nPG) in patients with unresectable metastatic pancreatic cancer not previously treated for metastatic disease is currently being conducted. Methods: JGDP (NCT03086369) is a global Phase 1b/Phase 2 study being conducted to evaluate the safety and efficacy of olaratumab in combination with nPG as first-line therapy in patients with Stage IV pancreatic cancer (ECOG PS ≤1). In the Phase 1b portion of the study, patients will receive intravenous (iv) olaratumab following a 3+3 dose escalation scheme at two different schedules: on Days 1, 8 and 15 at doses of 15 mg/kg and 20 mg/kg, or on Days 1 and 15 at 20 mg/kg and 25 mg/kg. Olaratumab will be given in combination with nPG (125 mg/m2 iv/1000 mg/m2 iv) on Days 1, 8, and 15 of a 28-day cycle. After the maximum tolerated dose has been identified, additional patients will be enrolled in a cohort expansion to confirm the safety of the combination prior to proceeding to the Phase 2 portion of the study. In the Phase 2 study, approximately 162 patients will be randomized at a 1:1 ratio to receive olaratumab at the recommended Phase 2 dose regimen or placebo, both in combination with nPG (125 mg/m2 iv/1000 mg/m2 iv). Treatment will continue until disease progression or other discontinuation criteria are met. The primary end point of the Phase 2 study is overall survival; a 2-sided α level of 0.20 will be applied. Assuming OS HR = 0.67, there is ≥80% power to show a significant difference in OS between study arms. Secondary end points include progression free survival, duration of response, objective response rate, patient-reported outcomes, and safety. As of September 2017, enrollment for the Phase 1b study is currently ongoing. Clinical trial information: NCT03086369.
A single arm phase II study of rucaparib maintenance in patients with advanced pancreatic adenocarcinoma and a known deleterious BRCA1, BRCA2 or PALB2 mutation who have achieved stability on platinum therapy.
Authors: Reiss Kim Anna , Maxwell Kara Noelle , Nathanson Katharine , Teitelbaum Ursina R. , O'Hara Mark H. , O'Dwyer Peter J. , Schneider Charles , Carpenter Erica L. , Mick Rosemarie , Domchek Susan M.
Published: January 2019

TPS531

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a median overall survival of < 1 year. A subset of PDAC is characterized by a homologous recombination deficiency (HRD). The most well-defined patients within this group are those with deleterious mutations in BRCA1, BRCA2 and PALB2. This subset of tumors respond exceptionally well to treatment with platinum agents, leading to durable responses. However, cumulative toxicity can complicate or even prevent continued therapy, and there is an unmet need to establish maintenance strategies for such patients.Prior studies have shown that BRCA1 and BRCA2 associated PDACs respond to PARP inhibitors. Cross-resistance to platinum and PARP inhibitors exists, so initiating PARP inhibitor therapy after the development of platinum-resistance is an inferior approach. In this setting, we have designed a phase II trial of rucaparib as maintenance therapy for patients with deleterious BRCA1, BRCA2 or PALB2 who have sustained stability on platinum-based treatment. Methods: We have enrolled 2 of 42 planned patients on study NCT03140670. Eligibility criteria include inoperable PDAC, a known somatic or germline deleterious mutation in BRCA1, BRCA2 or PALB2 and stability on platinum-based chemotherapy for ≥16 weeks. Patients who have progressed on platinum-based treatment or who have received prior therapy with PARP inhibitors are excluded. Patients will receive oral rucaparib twice daily continuously in 28-day cycles. The primary endpoint is progression-free survival at 6 months. Secondary endpoints include response rate, duration of response and overall survival. A pre-treatment tumor biopsy and biopsy at progression will be obtained, as well as serial blood collections for circulating tumor material. Correlative assays will include tumor and circulating tumor DNA sequencing to identify genomic predictors of outcome and study resistance mechanisms. Clinical trial information: NCT03140670.
A study of ramucirumab (LY3009806) versus placebo in patients with hepatocellular carcinoma and elevated baseline alpha-fetoprotein (REACH-2).
Authors: Zhu Andrew X. , Galle Peter R. , Kudo Masatoshi , Finn Richard S. , Qin Shukui , Xu Yihuan , Abada Paolo , Llovet Josep
Published: January 2019

TPS538

Background: Ramucirumab (RAM), a human IgG1 mAb, inhibits ligand activation of VEGFR2. In REACH, while improvement in overall survival (OS) in the overall population was not statistically significant, meaningful improvement was observed in a patient subgroup with baseline alpha-fetoprotein (AFP) ≥400 ng/mL (N = 250) (HR = 0.67, p = 0.006; median OS [months] RAM 7.8 vs placebo [pbo] 4.2). RAM treatment was generally well tolerated in patients with advanced hepatocellular carcinoma (HCC) after prior sorafenib (SOR). Methods: REACH-2 is a randomized, double-blind, pbo-controlled, global phase 3 study of RAM+best supportive care (BSC) vs pbo+BSC in patients with HCC and elevated baseline AFP following therapy with SOR. Eligibility includes Child-Pugh < 7; Barcelona Clinic Liver Cancer Stage C or B disease not amenable/refractory to locoregional therapy; AFP ≥400 ng/mL; ECOG PS 0 or 1; ≥1 measurable lesion; and disease progression during/after SOR, or SOR intolerance. Patients with history of hepatic encephalopathy, clinically meaningful ascites, liver transplant, or hepatic locoregional therapy after SOR are not eligible. Eligible patients will be randomized 2:1 to 8 mg/kg RAM or pbo (14-day cycle) and treated until radiographic/clinical disease progression or discontinuation criteria are met. The primary objective is OS; secondary objectives include progression-free survival (PFS), objective response rate, safety, and patient-focused outcomes. Recognizing expanding treatment options for HCC, a second, single arm, open-label cohort of ~44 patients will be enrolled with the same eligibility and treatment as the main cohort except a requirement for prior treatment other than SOR (eg, mTKIs, immune checkpoint inhibitors) and some exclusions of checkpoint inhibitor-related adverse events. The primary objective is safety; secondary objectives include OS, PFS, and patient-focused outcomes. Additionally, a third randomized cohort of ~65 Chinese patients will be enrolled with the same objectives, eligibility, treatment, and evaluations as the main cohort. Analysis of Open-Label and Chinese cohorts will be independent of the main REACH-2 cohort. Clinical trial information: NCT02435433.
Randomized phase III study of observation versus adjuvant capecitabine and oxaliplatin in curatively resected small bowel adenocarcinoma: A Japan Clinical Oncology Group study (JCOG1502C).
Authors: Honma Yoshitaka , Ueno Makoto , Kanemitsu Yukihide , Ohkawa Shinichi , Kitahara Hideaki , Mizusawa Junki , Katayama Hiroshi , Nakamura Kenichi , Furuse Junji , Shimada Yasuhiro
Published: January 2019

TPS539

Background: Small bowel adenocarcinoma (SBA) is extremely rare tumor. Surgery is broadly applied as a standard treatment for localized SBA. However, the patients with localized SBA have poor prognosis even after curative resection (5-year survival: 40-65%), and most of them experience relapse. To prevent relapse, postoperative therapies are considered as most promising. However, there is no prospective study of postoperative therapies for curatively resected SBA patients and which regimens improve prognoses is unknown. For metastatic SBA, fluoropyrimidine and oxaliplatin is now regarded as global standard chemotherapy. Therefore, Japan Clinical Oncology Group (JCOG) planned a multicenter randomized phase III trial to confirm the superiority of postoperative capecitabine and oxaliplatin (CAPOX) to observation for curatively resected SBA under the Advanced Medical Care System of the Ministry of Health, Labour and Welfare, Japan. This study is a counterpart trial of BALLAD trial conducted in International Rare Cancer Initiative (IRCI) (clinical trials gov; NCT02502370), and the integrated analysis of BALLAD trial and JCOG1502C is planned. Methods: Eligibility criteria include histologically proven adenocarcinoma located in the duodenum (except Ampulla of Vater) / jejunum / ileum, curatively resected with regional lymph nodes dissection, pathological stage I (T1b-2N0M0) / stage II / stage III. Eligible patients are randomized into observation arm or CAPOX arm. CAPOX (130 mg/m2 of oxaliplatin on day 1, and 1000 mg/m2 of capecitabine twice a day for 14 days) is repeated every 3 weeks for 6 months (total 8 courses). The primary endpoint is RFS. The 3-year RFS of observation arm is assumed to be 70% and expected a 10% increase in CAPOX arm. The sample size was calculated as 150 (75 per arm) with a one-sided alpha level of 10%, a statistical power of 70%, an accrual period of 6.5 years. This study has been registered in the UMIN Clinical Trials Registry (UMIN000027280). This trial was activated in 9 May 2017, and no patients was enrolled as of Sep 2017. We will increase the number of participating sites up to 20 throughout Japan. Clinical trial information: UMIN000027280.
A phase I/II trial of NBTXR3 nanoparticles activated by SBRT in the treatment of liver cancers.
Authors: Chajon Enrique , Pracht Marc , De Baere Thierry , Nguyen France , Bronowicki Jean-Pierre , Vendrely Veronique , Baumann Anne-Sophie , Croisé-Laurent Valérie , Deutsch Eric
Published: January 2019

TPS551

Background: A new class of material with high electron density, hafnium oxide, was designed at the nanoscale (NBTXR3) to efficiently enhance the energy dose deposit from within the tumor cells and increase lethality of tumors, when exposed to radiotherapy (RT). The physical mode of action of NBTXR3 may represent a breakthrough approach for the local treatment of liver cancers, as it does not engage liver and renal functions, i.e. nanoparticles are not metabolized and not excreted by kidney. A phase I/II trial has been implemented for the treatment of hepatocellular carcinoma and liver metastasis [NCT02721056]. The study is currently recruiting patients. Methods: Patients (pts) receive a single intralesional (IL) injection of NBTXR3 (53.3g/L) at Volume levels equivalent to 10%, 15%, 22% and 33% of the baseline tumor volume, followed by RT (SBRT, 45Gy / 3 fractions / 5 to 7 days). For the Phase I part, primary endpoints include determination of the Recommended Dose and Dose Limiting Toxicities (DLT). The Phase II part will test three different groups of patients, HCC with portal vein thrombus, HCC without portal vein thrombus and a third cohort with liver metastases. Primary endpoints are complete response rate and safety. Results: Enrollment was completed for Volume levels 10% (6 pts) and 15% (4 pts) and is currently recruiting patients at 22% level. The NBTXR3 injections were successful in all cases. Radiotherapy has been delivered as planned without any DLT occurrence. No serious adverse event (SAE) related to NBTXR3 or the treatment procedure occurred. Three adverse events related to the injection were reported and no adverse event related to NBTXR3. Importantly, NBTXR3 nanoparticles did not have any impact on the reliability of image-guided radiation therapy (IGRT). Conclusion: The injection of NBTXR3 was safe and well tolerated at these levels. Patients received the planned RT. No DLT occurred. Enrollment is now opened at the 22% level. NBTXR3 shows promising results in terms of safety and antitumor activity and is also currently evaluated in other six clinical studies. Clinical trial information: NCT02721056.
A prospective biomarker trial of microbiome, immune, and genomic markers as predictors of radiation response in anal squamous cell carcinoma.
Authors: Colbert Lauren Elizabeth , Lin Daniel , Minsky Bruce D. , Holliday Emma Brey , Klopp Ann , Das Prajnan , Eng Cathy , Morris Van Karlyle , Taniguchi Cullen M.
Published: January 2019

TPS869

Background: Preclinical evidence suggests that the microbiome plays a significant role in carcinogenesis and in response to immunotherapy and chemotherapy, but little is known about the role of the microbiome in response to radiation. Our group previously demonstrated that in patients with cervical squamous cell carcinoma (SCC), radiation response and immune response to radiation are improved with increased rectal microbial diversity. Methods: We are currently enrolling patients with local anal SCC undergoing definitive chemoradiation on a prospective biomarker trial evaluating changes in the gastrointestinal microbiome, immune microenvironment, and whole genome sequencing using a novel, non-invasive swab biopsy technique in addition to serial blood collections. This biopsy technique allows novel evaluation of dynamic changes throughout the course of chemoradiation. Microbiome sequencing is performed using 16s rRNA sequencing. Immune profiling is done using multiparametric flow cytometry for T-cell activation and exhaustion phenotypes and T-cell receptor sequencing. Inclusion criteria are biopsy proven HPV-related SCC of the anus, with no evidence of metastatic disease, and undergoing definitive chemoradiation. Our population is uniquely treated with cisplatin/5-FU based chemotherapy, rather than lymphotoxic mitomycin-C, allowing unique evaluation of immune populations. The primary endpoint of this study is complete tumor response based on pelvic MRI and digital rectal exam at three weeks. Secondary endpoints include FDG-avid diseases at 3 months and disease recurrence. To date we have accrued 10 patients out a planned 30 patient pilot cohort. We expect the remainder of these patients to be accrued by December 2017.
Phase 1b/2 study of binimetinib (BINI) in combination with nivolumab (NIVO) or NIVO plus ipilimumab (IPI) in patients (pts) with previously treated microsatellite-stable (MSS) metastatic colorectal cancer (mCRC) with RAS mutation.
Authors: Bendell Johanna C. , Kopetz Scott , Middleton Mark R. , Eves P. Taylor , Bozon Viviana , Boyd Adam P. , Schellens Jan H.M.
Published: January 2019

TPS870

Background: Approximately 96% of CRCs have an MSS phenotype, which results in more immunologically quiescent tumors for which immunotherapies are largely ineffective (Lee et al. 2015; Overman et al. 2016). Pts with MSS CRC and activating RAS mutation (35%–45% of CRCs) have treatment options limited still further because anti-EGFR monoclonal antibodies (eg, cetuximab) are ineffective owing to dominant activation of RAS in the MAPK pathway (Douillard et al. 2014). However, preclinical and preliminary clinical data suggest that MAPK pathway inhibition enhances antigen presentation and T-cell cytotoxicity to positively modulate the efficacy of checkpoint inhibitors (Brea et al. 2016; Bendell et al. 2014). The main objective of this open-label multicenter phase 1b/2 study is to evaluate whether the potential positive modulation of NIVO or NIVO plus IPI, when combined with BINI, translates into clinically meaningful overall response in pts with MSS mCRC and RAS mutation. Methods: The study will enroll ~90 previously treated pts (1 or 2 prior regimens), ~42 in phase 1b and ~48 in phase 2. The primary objective of phase 1b will be to determine the recommended phase 2 dose (RP2D) of BINI in combination with NIVO ± IPI. Dose finding in the doublet arm will begin with BINI 45 mg BID + NIVO 480 mg Q4W; the triplet arm will begin with the BINI RP2D from the doublet arm + NIVO 480 mg Q4W + IPI 1 mg/kg Q8W. In phase 2, pts will be randomized 1:1 to doublet or triplet arms, incorporating the BINI RP2Ds found in phase 1b; treatment will continue in 28-day cycles until disease progression, unacceptable toxicity, withdrawal of consent, initiation of subsequent anticancer therapy, loss to follow-up, or death. The primary objective for phase 2 will be to assess response by RECIST version 1.1. The study will also characterize safety and PK. CT.gov Identifier: Clinical trial information: NCT03271047.
A randomized phase III clinical trial of sequential capecitabine or 5-FU plus bevacizumab (Cape/5-FU+Bmab) followed by Cape/5-FU plus oxaliplatin plus Bmab (CapeOX/mFOLFOX6+Bmab) versus combination CapeOX/mFOLFOX6+Bmab in advanced colorectal cancer: The C-cubed (C3) study.
Authors: Ojima Hitoshi , Mishima Hideyuki , Sawaki Akira , Nagasaka Takeshi , Shimokawa Mototsugu , Inukai Michio , Shinozaki Katsunori , Tanioka Hiroaki , Nasu Junichiro , Nishina Tomohiro , Hazama Shoichi , Okajima Masazumi , Tsuji Akihito , Tsuji Yasushi , Munemoto Yoshinori , Yamaguchi Shigeki , Yamaguchi Yoshiyuki
Published: January 2019

TPS872

Background: Less intensive regimens, focusing on survival and disease control, may be better first-line treatments in unresectable metastatic colorectal cancer (mCRC). Several randomized trials suggested that sequential cytotoxic agents in mCRC may improve overall survival compared with combination chemotherapy. This study investigated whether sequential treatment with Bmab-based first-line therapy with oxaliplatin has superior efficacy to combination treatment for unresectable mCRC. Methods: This study is a two-arm, multicenter, open-label, randomized phase III trial in Japan, comparing the efficacy and safety of sequential Cape/5-FU+Bmab with escalation to CapeOX/mFOLFOX6+Bmab versus combination CapeOX/mFOLFOX6+Bmab as the first-line treatment of mCRC. The primary endpoint is Time to failure of strategy (TFS). In the sequential arm (Arm A: oxaliplatin ‘wait-and-go’), treatment escalation from Cape/5-FU+Bmab to CapeOX/mFOLFOX6+Bmab is recommended for progressive disease. In the combination arm (Arm B: oxaliplatin ‘stop-and-go’), de-escalation from CapeOX/mFOLFOX6+Bmab to Cape/5-FU+Bmab is possible after 12 weeks of treatment. Re-escalation to CapeOX/mFOLFOX6+Bmab after progressive disease is considered only for patients who received de-escalation of oxaliplatin, not caused by oxaliplatin-associated toxicity, after 12 weeks of treatment. A target sample size of 304 evaluable patients is considered sufficient to detect a hazard ratio of 0.69 for the TFS of the sequential ‘wait-and-go’ approach compared with the combination ‘stop-and go’ approach with 80% power and a 2-sided significance level of 5%. From December 2014 to September 2016, 311 patients were enrolled across 81 centers in Japan. The follow-up period is until March 2018, and results are expected in 2019, and results are expected in 2019. Clinical trial information: 000015405.
BACCI: A phase II randomized, double-blind, placebo-controlled study of capecitabine bevacizumab plus atezolizumab versus capecitabine bevacizumab plus placebo in patients with refractory metastatic colorectal cancer.
Authors: Mettu Niharika B. , Niedzwiecki Donna , Boland Patrick McKay , Fakih Marwan , Arrowood Christy , Bolch Emily , Hurwitz Herbert , Grothey Axel
Published: January 2019

TPS873

Background: Initial treatment of metastatic colorectal cancer (mCRC) involves a 5-fluorouracil based chemotherapy regimen, often in combination with anti-VEGF therapy. Upon disease progression, multiple studies have suggested a benefit for continued anti-VEGF therapy. There is increasing evidence that VEGF plays a role in cancer immune evasion. Targeting of inflammatory and immune checkpoints are attractive approaches to enhance the benefits of anti-VEGF therapy. The safety and activity of the anti-PD-L1 antibody atezolizumab with bevacizumab and with 5-FU, oxaliplatin, and bevacizumab have been recently reported; the combinations were well-tolerated and suggested clinical activity. Therefore, bevacizumab may increase the immunogenicity of colorectal cancers, and the combination of atezolizumab plus bevacizumab may be associated with clinically meaningful response rates and disease control. Furthermore, there may be candidate biomarkers that may identify those patients most likely to benefit from this combination. Methods: In this randomized, double-blind, multicenter, placebo-controlled phase II study, 135 patients with mCRC will be randomized 2:1 to receive capecitabine/bevacizumab/atezolizumab or capecitabine/bevacizumab/placebo. Patients with prior PD-L1/PD-1 therapy are ineligible. Primary and secondary efficacy will be conducted using ITT analysis. Safety analyses will include all randomized patients who receive at least one dose of study treatment. The primary objective is PFS. The secondary objectives are ORR, OS, safety, and tolerability. The primary comparison will be superiority of the active treatment for the PFS endpoint, atezolizumab versus placebo testing at 1-sided α = 0.1 (log rank test). A PFS hazard ratio of 0.618 (active treatment versus placebo) is detectable with 86% power (1 sided α = 0.1). No interim analyses for futility or efficacy will be conducted. A subset analysis will be performed in the microsatellite-high patients looking at potential differences in PFS and OS. Trial is active and currently recruiting patients. Clinical trial information: NCT02873195.
NRG-GI002: A phase II clinical trial platform for sensitization testing using total neoadjuvant therapy (TNT) in rectal cancer.
Authors: George Thomas J. , Yothers Greg , Hong Theodore S. , Russell Marcia McGory , You Y. Nancy , Parker William , Jacobs Samuel A. , Pogue-Geile Katherine L. , Gollub Marc Jeffrey , Hall William Adrian , Rahma Osama E. , Kachnic Lisa A. , Vijayvergia Namrata , Wolmark Norman
Published: January 2019

TPS876

Background: Locally-advanced rectal cancer (LARC) improvements have plateaued due to an inability to consistently deliver adjuvant therapy and effective novel therapies. Systematic testing of new chemotherapy and radiation sensitizers are needed to advance treatment outcomes. This randomized phase II modular clinical trial platform utilizes Total Neoadjuvant Therapy (TNT) with parallel experimental arms (EA) in LARC. The EAs are not intended for direct comparison, but rather to test a variety of sensitizers or hypotheses in a consistent and homogenous high-risk patient (pt) population with correlative biomarkers. Success of any EA will be determined by achievement of pathologic endpoints compared to a control arm. Methods: This NCTN multi-arm randomized phase II trial serves as a modular platform to assess novel sensitizers to neoadjuvant chemotherapy and/or chemoradiotherapy (chemoRT) in LARC. Eligibility includes LARC with any ONE of the following criteria: distal location (cT3-4 ≤5cm from the anal verge, any N); bulky (any cT4 or tumor within 3mm of the mesorectal fascia); high risk for metastatic disease (cN2); or not a candidate for sphincter-sparing surgical resection. After randomization, all pts receive neoadjuvant FOLFOX x 4mo → chemoRT (capecitabine with 50.4Gy) → surgical resection 8-12 wks later. The first EA will assess the activity of veliparib with standard chemoRT. A second EA, testing pembrolizumab concurrently with and following chemoRT, is in development. Primary endpoint is a demonstrated improvement in Neoadjuvant Rectal Cancer (NAR) score for the EA vs control representing a 20% relative risk reduction in DFS HR and 3-4% absolute OS improvement. Secondary endpoints include comparisons of OS, DFS, toxicity, pCR, cCR, therapy completion, negative surgical margins, sphincter preservation, sphincter function including quality of life, and exploratory assessments of molecular and radiographic predictors of response and distant failure. Target accrual is 79 evaluable pts per arm with additional EAs added through protocol amendments. NCT02921256. Support: U10 CA-180868, -180822, UG-189867, U24CA196067; AbbVie Clinical trial information: NCT02921256..
KEYNOTE-177: Phase 3, open-label, randomized study of first-line pembrolizumab (Pembro) versus investigator-choice chemotherapy for mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) metastatic colorectal carcinoma (mCRC).
Authors: Diaz Luis A. , Le Dung T. , Yoshino Takayuki , André Thierry , Bendell Johanna C. , Rosales Minori , Kang S. Peter , Lam Bao , Jäger Dirk
Published: January 2019

TPS877

Background: Approximately 5% of mCRCs are dMMR, leading to high levels of MSI. CRCs with MSI-H have abundant lymphocyte infiltrates and strong expression of immune checkpoints. In the phase 2 KEYNOTE-016 study, the anti–programmed death 1 (PD-1) antibody pembro provided an ORR of 40% in patients (pts) with progressive dMMR mCRC vs 0% in pts with MMR-proficient mCRC. KEYNOTE-177 (ClinicalTrials.gov, NCT02563002) is an international, randomized, open-label, phase 3 study to evaluate the efficacy and safety of pembro vs standard-of-care (SOC) chemotherapy as first-line therapy for dMMR or MSI-H mCRC. Methods: Pts aged ≥18 years with locally confirmed dMMR or MSI-H stage IV CRC, measurable disease per RECIST v1.1 by local site assessment, ECOG performance status 0-1, adequate organ function, no active autoimmune disease or brain metastases, and no prior systemic therapy for mCRC are eligible. Pts will be randomized 1:1 to receive pembro 200 mg every 3 weeks (Q3W) or investigator’s choice of SOC chemotherapy (options include mFOLFOX6 or FOLFIRI alone or in combination with bevacizumab or cetuximab; must be chosen prior to randomization). Treatment will continue until disease progression, unacceptable toxicity, pt/investigator decision to withdrawal, or completion of 35 cycles (pembro only). Response will be evaluated Q9W per RECIST v1.1 by central imaging vendor review and per immune-related RECIST. Pts in the SOC arm who have disease progression and meet crossover criteria may be eligible to receive pembro for up to 17 treatment cycles. Eligible pts may continue pembro after initial RECIST-defined progression. AEs will be assessed throughout treatment and for 30 days thereafter (90 days for serious AEs) and graded per NCI CTCAE v4.0. Pts are to be followed up for survival Q9W. Primary end point is PFS per RECIST v1.1 by central imaging vendor review. Secondary end points include ORR per RECIST v1.1 by central imaging vendor review, OS, and safety and tolerability. Other end points include DOR and HRQoL. Planned enrollment in KEYNOTE-177 is 270 pts across 23 countries. Clinical trial information: NCT02563002.
VOLTAGE: Multicenter phase 1b/II study of nivolumab monotherapy and subsequent radical surgery after preoperative chemoradiotherapy with capecitabine in patients with locally advanced rectal cancer.
Authors: Tsukada Yuichiro , Bando Hideaki , Inamori Koji , Fukuoka Shota , Sasaki Takeshi , Nishizawa Yuji , Kotani Daisuke , Kojima Motohiro , Togashi Yosuke , Nakamura Naoki , Akimoto Tetsuo , Komatsu Yoshito , Yuki Satoshi , Homma Shigenori , Hatanaka Yutaka , Matsuno Yoshihiro , Sato Akihiro , Nishikawa Hiroyoshi , Ito Masaaki , Yoshino Takayuki
Published: January 2019

TPS878

Background: Fluoropyrimidine-based chemoradiotherapy (CRT) and subsequent radical surgery (SRS) are widely accepted as standard treatment for patients (pts) with locally advanced rectal cancer (LARC). Pathological complete remission (pCR) rates are associated with improved clinical outcomes. An important target, high-frequency microsatellite instability (MSI-H), was identified for which anti-PD-1 antibodies confirmed robust antitumor activity in metastatic colorectal cancer (mCRC). Recently, improved therapeutic effects by combining an immune checkpoint inhibitor with radiotherapy (RT) have been reported in pts with other cancer types. Furthermore, sequential use of an anti-PD-1 antibody after RT has demonstrated synergistic effects in in vivo models. The purpose of this study is to investigate safety, efficacy, and proof-of-concept (POC) of nivolumab (Nivo) monotherapy plus SRS after pre-CRT in non-MSI-H and MSI-H pts with LARC. Methods: The inclusion criteria are: LARC in the lower/middle rectum; clinical stage, T3–4 N-any M0; age ≥20 years; and 50.4 Gy of concurrent pre-CRT completed with daily 1,650 mg/m2 of capecitabine. Within 2 weeks after pre-CRT, 240 mg of Nivo is administered every 2 weeks 5 times before SRS, which is performed at least 2 weeks after Nivo treatment. The purpose of P1b is to evaluate dose-limiting toxicity and determine the recommended P2 dose (RP2D). In P2, the efficacy and safety of Nivo at RP2D are evaluated. The primary endpoint is the pCR rate by independent central assessment in pts with non-MSI-H LARC. Secondary endpoints include disease-free and overall survival and adverse events. Fifty pts including 40 non-MSI-H and 10 MSI-H pts will be enrolled. As an exploratory biomarker study, repeated biopsies from primary sites and blood collections will be performed 4 times during the treatment courses (before and after pre-CRT, during Nivo treatment, and at SRS), and phenotypes of immune-competent cells, neoantigens, T cell receptor repertoire, and enteric bacteria will be evaluated. As of September 2017, P1b has been completed and P2 is ongoing. Clinical trial information: NCT02948348.
TRUSTY: A randomized multicenter phase II/III study of trifluridine/tipiracil and bevacizumab versus irinotecan, fluoropyrimidine, and bevacizumab as second-line treatment in patients with metastatic colorectal cancer progressive during or following first-line oxaliplatin-based chemotherapy.
Authors: Yoshino Takayuki , Oki Eiji , Nozawa Hiroaki , Nakajima Takako Eguchi , Taniguchi Hiroya , Morita Satoshi , Takenaka Naruhito , Ozawa Daisuke , Shirao Kuniaki ,   The TRUSTY Study Group
Published: January 2019

TPS881

Background: Trifluridine/tipiracil is an oral combination preparation approved for the treatment of patients with metastatic colorectal cancer (mCRC). Trifluridine is a thymidine analog, and tipiracil is a thymidine phosphorylase inhibitor that improves the bioavailability of trifluridine. Phase I/II C-TASK FORCE study of trifluridine/tipiracil plus bevacizumab (Bev) for patients with refractory mCRC demonstrated a promising efficacy results with mild toxicity profile (Kuboki Y, et al. Lancet Oncology, 2017). Methods: We are conducting a randomized multicenter phase II/III non-inferiority study (JapicCTI-173618) to compare trifluridine/tipiracil plus Bev versus FOLFIRI plus Bev (in the control arm, S-1 can replace 5-FU) in second-line mCRC patients who have failed first-line oxaliplatin-based chemotherapy. Key eligibility criteria are a histologically confirmed colorectal adenocarcinoma, refractory to first-line chemotherapy including a fluoropyrimidine, oxaliplatin, and either Bev or an anti-EGFR antibody (if RAS wild-type), an age of 20 years or older, ECOG performance status of 0-1, and adequate oral intake. Patients are randomized in a 1:1 ratio to receive trifluridine/tipiracil plus Bev or FOLFIRI plus Bev using the minimization method stratified by RAS status, prior therapy (Bev/anti-EGFR antibody), and primary tumor sidedness. The primary endpoint is overall survival. The non-inferiority hypothesis will be achieved if the upper limit of the two-sided 95% CI of the HR is below 1.33 (as HR scale, power 0.80). If achieved, the non-inferiority hypothesis with the margin of 1.25 (as HR) and the superiority will be consequently tested. Secondary endpoints include progression-free survival, time to treatment failure, response rate, disease control rate, subsequent treatment, time to post-study treatment failure, the quality of life, and adverse events. The target sample size is 524 patients. Patients will be enrolled from October 2017. Clinical trial information: 173618.
Trial in progress: A phase II study of second-line FOLFIRI plus panitumumab after first-line FOLFOX plus panitumumab for RAS wild-type colorectal cancer with evaluation of circulating tumor DNA.
Authors: Maeda Hiromichi , Nagata Naoki , Nagasaka Takeshi , Oba Koji , Mishima Hideyuki , Kato Takeshi , Yoshida Kazuhiro , Muro Kei , Sakamoto Junichi
Published: January 2019

TPS886

Background: The mechanisms underlying the acquired resistance of metastatic colorectal cancer (mCRC) against panitumumab treatment is not fully understood. The efficacy and safety of FOLFIRI with panitumumab as the second-line chemotherapy after failure of FOLFOX with panitumumab treatment has yet to be determined. To address these two points, a multicenter single-arm Phase II clinical trial is being conducted with evaluation of circulating tumor DNA (ctDNA). Methods: The major inclusion criterion is that the patient has refractory measurable tumor that has progressed after the first-line therapy with FOLFOX plus panitumumab. After registration, treatment with the FOLFIRI and panitumumab will be continued in 2-week cycles until disease progression, unacceptable toxicity and/or patients’ refusal. The primary endpoint for this study is six-month progression-free survival (PFS) rate, a simple surrogate endpoint of PFS. According to a clinical trial revealing the median PFS of 4.6 months for FOLFIRI alone and 6.4 months for panitumumab plus FOLFIRI treatment in RAS wild-type patients (Peeters et al. Clin Cancer Res. 2015; 21: 5469-79), we assume the threshold and expected 6-month PFS rate as 35% and 50%, respectively. Under the settings of one-sided alpha = 0.10 and power = 80%, the required sample size is 53 patients. The target number of cases in this study is 55 patients, considering a dropout rate of 5%. The secondary endpoint includes the tumor-related gene mutation status assessed by liquid biopsy. Primary tumor and/or metastatic site tissue samples will be collected by formalin-fixed paraffin-embedded specimens at the time of registration. Blood samples will be collected at 3 time-points: (1) before second-line treatment, (2) at 6 ± 2 weeks after initiation of the treatment protocol, and (3) after confirmation of acquired resistance to this second-line therapy. The multiple evaluation of ctDNA will provide the meaningful information concerning relationship between the tumor resistance against treatment and alterations in gene mutation status. Clinical trial information: UMIN000026817.
Blastemal progenitors modulate immune signaling during early limb regeneration
Authors: Tsai Stephanie L. , Baselga-Garriga Clara , Melton Douglas A.
Published: January 2019

Blastema formation, a hallmark of limb regeneration, requires proliferation and migration of progenitors to the amputation plane. Although blastema formation has been well described, the transcriptional programs that drive blastemal progenitors remain unknown. We transcriptionally profiled dividing and non-dividing cells in regenerating stump tissues, as well as the wound epidermis, during early axolotl limb regeneration. Our analysis revealed unique transcriptional signatures of early dividing cells and, unexpectedly, repression of several core developmental signaling pathways in early regenerating stump tissues. We further identify an immunomodulatory role for blastemal progenitors through interleukin 8 (IL-8), a highly expressed cytokine in subpopulations of early blastemal progenitors. Ectopic il-8 expression in non-regenerating limbs induced myeloid cell recruitment, while IL-8 knockdown resulted in defective myeloid cell retention during late wound healing, delaying regeneration. Furthermore, the il-8 receptor cxcr-1/2 was expressed in myeloid cells, and inhibition of CXCR-1/2 signaling during early stages of limb regeneration prevented regeneration. Altogether, our findings suggest that blastemal progenitors are active early mediators of immune support, and identify CXCR-1/2 signaling as an important immunomodulatory pathway during the initiation of regeneration.
The cell biology of quiescent yeast – a diversity of individual scenarios
Authors: Sagot Isabelle , Laporte Damien
Published: January 2019

Most cells, from unicellular to complex organisms, spend part of their life in quiescence, a temporary non-proliferating state. Although central for a variety of essential processes including tissue homeostasis, development and aging, quiescence is poorly understood. In fact, quiescence encompasses various cellular situations depending on the cell type and the environmental niche. Quiescent cell properties also evolve with time, adding another layer of complexity. Studying quiescence is, above all, limited by the fact that a quiescent cell can be recognized as such only after having proved that it is capable of re-proliferating. Recent cellular biology studies in yeast have reported the relocalization of hundreds of proteins and the reorganization of several cellular machineries upon proliferation cessation. These works have revealed that quiescent cells can display various properties, shedding light on a plethora of individual behaviors. The deciphering of the molecular mechanisms beyond these reorganizations, together with the understanding of their cellular functions, have begun to provide insights into the physiology of quiescent cells. In this Review, we discuss recent findings and emerging concepts in Saccharomyces cerevisiae quiescent cell biology.
Income and capital breeding in males: energetic and physiological limitations on male mating strategies
Authors: Soulsbury Carl D.
Published: January 2019

Income and capital breeding describe two dichotomous breeding strategies that characterise the allocation of resources to reproduction. Capital breeders utilise stored endogenous resources (typically lipids) to finance reproduction, whereas income breeders use exogenous resources (typically carbohydrates). The basis for such characterisation has mainly come from studying females, yet for many species, male and female reproductive success may be determined by substantially different factors. Females allocate resources to offspring production, whereas males typically allocate resources to accessing mating opportunities, e.g. from contests or displays. The primary metabolic fuel (lipids or carbohydrates) in males appears to be dependent on the type of activity being performed (i.e. high versus low intensity or long versus short duration), rather than capital or income breeding strategy per se. Males performing sustained, long-duration effort typically utilise lipids, whereas those undergoing intense activity more often utilise carbohydrates. As a result, either fuel type can be used in either strategy. Breeding season duration can constrain strategy choice; lipids and carbohydrates can be used in short breeding season species, but only lipids provide a viable fuel source for long breeding season capital breeders. Both capital- and income-breeding males must manage their resource use during the breeding season, but capital breeders must also cope with physiological stressors associated with extended fasting. Overall, the capital–income breeding concept applies equally to male reproduction, but compared with females, there are different physical and physiological constraints that shape choice of strategy. This Commentary also highlights some key future areas that need to be investigated to further understand how capital–income breeding strategies shape male mating strategies.
A Spatial Knowledge Economy
Authors: Davis Donald R. , Dingel Jonathan I.
Published: January 2019

Leading empiricists and theorists of cities have recently argued that the generation and exchange of ideas must play a more central role in the analysis of cities. This paper develops the first system of cities model with costly idea exchange as the agglomeration force. The model replicates a broad set of established facts about the cross section of cities. It provides the first spatial equilibrium theory of why skill premia are higher in larger cities and how variation in these premia emerges from symmetric fundamentals. (JEL J24, J31, O31, R12, R23)
Some Causal Effects of an Industrial Policy
Authors: Criscuolo Chiara , Martin Ralf , Overman Henry G. , Van Reenen John
Published: January 2019

We exploit changes in the area-specific eligibility criteria for a program to support jobs through investment subsidies. European rules determine whether an area is eligible for subsidies, and we construct instrumental variables for area eligibility based on parameters of these rule changes. Areas eligible for higher subsidies significantly increased jobs and reduced unemployment. A 10-percentage point increase in the maximum investment subsidy stimulates a 10 percent increase in manufacturing employment. This effect exists solely for small firms: large companies accept subsidies without increasing activity. There are positive effects on investment and employment for incumbent firms but not Total Factor Productivity. (JEL E24, G31, H25, L25, L52, R23)
Are Low Interest Rates Deflationary? A Paradox of Perfect-Foresight Analysis
Authors: García-Schmidt Mariana , Woodford Michael
Published: January 2019

We argue that an influential neo-Fisherian analysis of the effects of low interest rates depends on using perfect-foresight equilibrium analysis under circumstances where it is not plausible for people to hold expectations of that kind. We propose an explicit cognitive process by which agents may form their expectations of future endogenous variables. Perfect foresight is justified by our analysis as a reasonable approximation in some cases, but in the case of a commitment to maintain a low nominal interest rate for a long time, our reflective equilibrium implies neither neo-Fisherian conclusions nor implausibly strong predicted effects of forward guidance. (JEL D84, E12, E31, E43, E52)
The Long-Term Effects of Management and Technology Transfers
Authors: Giorcelli Michela
Published: January 2019

This paper examines the long-run causal effects of management on firm performance. Under the United States Technical Assistance and Productivity Program (1952–1958), the United States organized management training trips for Italian managers to US firms and granted technologically advanced machines to Italian companies. I exploit an unexpected budget cut that reduced the number of participating firms and find that, compared to businesses excluded by the budget cut: performance of Italian firms that sent their managers to the United States increased for at least fifteen years after the program; performance of companies that received new machines increased, but flattened out over time; management and new machines were complementary. (JEL F23, L25, M16, M54, N34, N64, O33)
The Cyclicality of Sales, Regular and Effective Prices: Business Cycle and Policy Implications: Reply
Authors: Coibion Olivier , Gorodnichenko Yuriy , Hong Gee Hee
Published: January 2019

We address how using different censoring thresholds and imputation procedures affects the baseline results of Coibion, Gorodnichenko, and Hong (2015). Higher censoring thresholds introduce measure ment error and outliers that generate wide variability in results across weighting schemes, but methods that explicitly control for outliers confirm the results of Coibion, Gorodnichenko, and Hong (2015) for all censoring thresholds. We also illustrate how the BLS’s approach to imputing missing prices can introduce a cyclical bias into measures of posted price inflation when store-switching is present in the data. (JEL D12, E31, E32, L25, L81)
Case Report: Ocular toxoplasmosis in a WHIM syndrome immunodeficiency patient
Authors: McDermott David H. , Heusinkveld Lauren E. , Zein Wadih M. , Sen H. Nida , Marquesen Martha M. , Parta Mark , Rosenzweig Sergio D. , Fahle Gary A. , Keller Michael D. , Wiley Henry E. , Murphy Philip M.
Published: January 2019

A patient with WHIM syndrome immunodeficiency presented with sudden painless right eye blindness associated with advanced retinal and optic nerve damage. Toxoplasma gondii was detected by PCR in vitreous fluid but not serum.  The patient was treated with trimethoprim-sulfamethoxazole.  Vision did not return; however, the infection did not spread to involve other sites.  Toxoplasmosis is rare in primary immunodeficiency disorders and is the first protozoan infection reported in WHIM syndrome.
Inequalities of Hermite–Hadamard type for HH-convex functions
Authors: Dragomir Sever Silvestru
Published: January 2019

Some inequalities of Hermite–Hadamard type for HH-convex functions defined on positive intervals are given. Applications for special means are also provided.
Asymptotics of approximation of conjugate functions by Poisson integrals
Authors: Kharkevych Yu. I. , Pozharska K. V.
Published: January 2019

We obtain a decomposition of the upper bound for the deviation of Poisson integrals of conjugate periodic functions. The decomposition enables one to provide the Kolmogorov–Nikol'skii constants of an arbitrary order.
Abbreviations
Authors: Editors Editors
Published: January 2019

Abbreviations
An Approximation Algorithm for Capacity Allocation Over a Single Flight Leg with Fare-Locking
Authors: Sumida Mika , Topaloglu Huseyin
Published: January 2019

In this paper, we study a revenue management model over a single flight leg, where the customers are allowed to lock an available fare. Each customer arrives into the system with an interest in purchasing a ticket for a particular fare class. If this fare class is available, the customer immediately purchases the ticket by paying the fare or locks the fare by paying a fee. If the customer locks the fare, then the airline reserves the capacity for the customer for a certain duration of time. At the end of this duration of time, the customer makes her ultimate purchase decision at the locked fare. The goal of the airline is to find a policy to decide which set of fare classes to make available at each time period to maximize the total expected revenue. Such fare locking options are commonly offered by airlines; the dynamic programming formulation of the revenue management problem with the option to lock an available fare has a high-dimensional state variable that keeps track of the locked fares. We develop an approximate policy that is guaranteed to obtain at least half of the optimal total expected revenue. Our approach is based on leveraging a linear programming approximation to decompose the problem by the seats on the flight and solving a dynamic program that separately controls the capacity on each seat. We also show that our results continue to hold when the airline makes pricing decisions instead of fare class availability decisions. Our numerical experiments show that the practical performance of our approximate policy is remarkably good compared to a tractable upper bound on the optimal total expected revenue.

The online supplement is available at https://doi.org/10.1287/ijoc.2018.0816 .