bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I prospective trial of TAS-102 (trifluride and tipiracil) and radioembolization with 90Y resin microspheres for chemo-refractory colorectal liver metastases.
Authors: Fidelman Nicholas , Atreya Chloe Evelyn , Griffith Madeline J , Milloy Marion Alexandra , Carnevale Julia C. , Cinar Pelin , Venook Alan P. , Van Loon Katherine 
Published: February 2020

110 Background: Clinical efficacy of Yttrium-90 (90Y) radioembolization (TARE) for patients with chemotherapy-refractory metastatic colorectal cancer (mCRC) is limited by extrahepatic disease progression. TAS-102 (trifluride and tipiracil) has overall survival benefit for patients with refractory mCRC and may be a radiosensitizer. We aimed to evaluate the safety of the combination of TAS-102 and 90Y resin TARE in a Phase I dose-escalation trial. Methods: Adult patients with bilobar liver-dominant chemo-refractory mCRC were treated with sequential Y90 resin TARE (body surface area dosimetry) in combination with TAS-102 (20mg/m2, 27mg/m2, and 35mg/m2) in 28-day cycles according to 3+3 dose-escalation design. Beginning with cycle 3, TAS-102 was administered as monotherapy until disease progression or development of intolerable toxicity. Primary objectives were to determine maximum tolerated dose (MTD) of TAS-102, to assess toxicity, and to establish safety of TAS-102 in combination with 90Y TARE. Results: A total of 14 patients (10 women, 4 men) have been treated to date. Among 9 patients enrolled in the dose-escalation phase, no dose limiting toxicities were observed. The MTD of TAS-102 in combination with Y90 was 35mg/m2, which was selected for the dose expansion phase. Severe adverse events (AEs) included: neutropenia (46%); anemia (23%); and thrombocytopenia (8%), which were attributed to TAS-102. All other AEs were mild and transient. At least one follow-up imaging study has been obtained for 13 patients, and 10 patients have completed trial participation. Disease control rate in the liver was 100%. Conclusions: The combination of TAS-102 and 90Y TARE for patients with liver-dominant mCRC is safe and consistently achieved disease control within the liver. Severity and incidence of AEs is within the expected range of TAS-102 and 90Y TARE monotherapy. A dose-expansion phase with planned enrollment of 12 patients is ongoing. Clinical trial information: NCT02602327.
Safety and efficacy of trifluridine/tipiracil (FTD/TPI) plus bevacizumab in clinical practice for patients with chemorefractory metastatic colorectal cancer: A retrospective comparative study.
Authors: Kagawa Yoshinori , Nose Yohei , Hata Taishi , Kawai Kenji , Sakamoto Takuya , Murakami Kohei , Katsura Yoshiteru , Ohmura Yoshiaki , Masuzawa Toru , Takeno Atsushi , Takeda Yutaka , Murata Kohei 
Published: February 2020

112 Background: Trifluridine/tipiracil (FTD/TPI) significantly improves overall survival (OS) in patients with chemorefractory metastatic colorectal cancer (mCRC). The phase I/II C-TASKFORCE study of FTD/TPI + bevacizumab (Bev) for patients with mCRC who are refractory to standard chemotherapy demonstrated promising efficacy results. FTD/TPI + Bev were linked to significant and clinically relevant improvements in progression-free survival (PFS) and OS compared with FTD/TPI monotherapy and a favorable safety profile in a Danish randomized trial. This retrospective study investigated the safety and efficacy of FTD/TPI alone or in combination with Bev for patients with refractory mCRC in clinical practice. Methods: We reviewed the outcomes of patients with chemorefractory mCRC who received FTD/TPI alone (monotherapy; 35 mg/m2, twice daily on days 1–5 and 8–12 in a 28-day cycle) or FTD/TPI + Bev (combination; 5 mg/kg, days 1 and 15) in our institution since 2014. We compared the safety and efficacy of the monotherapy and combination regimens. Adverse events were evaluated using Common Terminology Criteria for Adverse Eventsv4.0. Median PFS and OS were analyzed using the Kaplan–Meier method. Results: In total, 56 patients received chemotherapy containing FTD/TPI. Twenty-four patients were treated with monotherapy, and 32 patients received the combination regimen. The median PFS was 1.8 months in the monotherapy arm, versus 4.7 months in the combination arm (hazard ratio [HR] = 0.28; 95% confidence interval [CI] = 0.15–0.51; P < 0.0001). The median OS was 6.3 months for the monotherapy arm, versus 11.7 months for the combination arm (HR = 0.25; 95% CI = 0.13–0.48; P < 0.0001). There was no significant difference in the rates of adverse events between the groups excluding neutropenia. Neutropenia (Grade 3 or worse) developed in five patients (20.8%) in the monotherapy arm and 17 patients (53.1%) in the combination arm ( P = 0.030). There were no treatment-related deaths. Conclusions: In patients with chemorefractory mCRC, FTD/TPI + Bev significantly improved PFS and OS versus FTD/TPI monotherapy.
Efficacy and safety of regorafenib as third-line therapy in metastatic colorectal cancer: An indirect meta-analysis.
Authors: WU Yinying , Fan Yangwei , Dong Dan Feng , Dong Xuyuan , Hu Yuan , Shi Yu , Jing Jiayu , Li En Xiao 
Published: February 2020

119 Background: The evidence base for optimum third-line therapy for metastatic colorectal cancer (mCRC) is not conclusive. Recent studies have demonstrated the efficacy of regorafenib as third-line therapy in mCRC. This indirect meta-analysis compared the efficacy and safety of regorafenib in comparison to other available third-line therapies in mCRC. Methods: Literature search for randomized controlled trials was conducted in PubMed, Embase and Cochrane library for studies evaluating the efficacy and safety of fruquintinib, regorafenib, TAS-102 and nintedanib as third-line therapies in mCRC patients. The primary outcomes included overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) and safety as the secondary outcome. Hazard ratio (HR) and relative risk (RR) with their respective 95% confidence interval (CI) were used for analysis of survival, clinical response and safety data, respectively. An adjusted indirect meta-analysis with placebo as the common comparator was performed. Results: We identified 8 RCTs studies comparing regorafenib (2 studies), fruquintinib (2 studies), TAS-102 (3 studies) and nintedanib (1 study) against placebo. The OS with regorafenib was significantly better when compared to nintedanib (HR= 0.66, 95% CI 0.45, 0.95, p=0.02), but was similar to that of fruquintinib (HR=1.01, 95% CI 0.67, 1.52, p=0.94) and TAS-102 (HR= 0.97, 95% CI 0.68, 1.38, p=0.88). The PFS and ORR for regorafenib were slightly better than TAS-102 (PFS: HR= 0.86, 95% CI 0.54, 1.37, p=0.5; ORR: RR= 1.13, 95% CI 0.11, 11.05, p=0.92) and nintedanib (PFS: HR= 0.68, 95% CI 0.42, 1.10, p=0.12, ORR: not reported) but was lower than fruquintinib (PFS: HR= 1.53, 95% CI 0.93, 2.52, p=0.08; ORR: RR= 0.68269, 95% CI 0.045, 10.32, p=0.79). Safety analysis showed that the relative risk of adverse events was lesser in patients treated with regorafenib in comparison to fruquintinib but was similar to that of nintedanib and TAS-102. Conclusions: Regorafenib with its efficacy and safety coupled with comprehensive continuously anti-angiogenic therapy, might be the first option in third-line mCRC. Head-on comparisons are required for further validation.
Phase I with expansion cohorts in a study of NEO-201 in adults with chemo-resistant solid tumors.
Authors: Morelli M. Pia , Houston Nicole D. , Lipkowitz Stan , Lee Jung-min , Zimmer Alexandra Dos Santos , Zia Farah Z. , Trewhitt Kathrine , Nichols Erin , Pavelova Mira , Hewitt Stephen M. , Fantini Massimo , Arlen Philip M. , Tsang Kwong Y. , Annunziata Christina M. 
Published: February 2020

129 Background: NEO-201 is a humanized IgG1 monoclonal antibody (mAb) generated against tumor-associated antigens (TAA) from colorectal cancer. Our preclinical data demonstrated that NEO-201 exerts anti-tumor activity by NK-mediated ADCC and CDC against several tumor types. We identified NEO-201 antigen as a tumor-associated form of CEACAM-5 and -6, which is expressed by tumor tissue but is not present in the surrounding healthy tissue. Methods: This is a first-in-human phase 1 study to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of NEO-201 in adults with advanced solid tumors that have high likelihood of expression NEO201 antigen and have progressed to standard of treatments. This is a classic 3+3 dose escalation, with cohort expansion at the MTD. NEO-201 is administered intravenously every two weeks, and at four dose levels (DL1 = 1mg/kg, DL2 = 2mg/kg, DL3 = 4mg/kg and DL4 = 6mg/kg). Patients are evaluated for safety according to CTCAEv5.0., and for response according to RECISTv1.1. Biological samples are collected to understand NEO-201 pharmacokinetics, the effects on immune profile and the correlation with treatment toxicity and response. Results: Here we report the safety data and pharmacokinetics from DL1 and 2. A total of 9 evaluable patients were enrolled. Prolonged neutropenia, defined as ³G2 neutropenia lasting for >7 days, was observed at DL2. The cohort was expanded to a total of 6 patients and no further DLTs were observed. Seven out of nine of the patients enrolled had colon cancer, two had pancreatic cancer and one had hormone positive breast cancer. The most frequent treatment-related AEs were infusion reaction which was observed in all patients, and moderate fatigue (33%). Best response was SD observed in two patients (one on each of DL1 and DL2). Dose escalation continues on DL3 and DL4. NEO201 antigen expression in patient tumor tissue, circulating CEACAM6/CEACAM5, and MICA will be evaluated to correlate with response and toxicity. Conclusions: NEO201 has shown some promising activity. PK and PD studies are ongoing to better understand dosing schedule, toxicity profile and to identify biomarkers for patient selection. Clinical trial information: NCT03476681.
Pembrolizumab (P) in patients (Pts) with colorectal cancer (CRC) with high tumor mutational burden (HTMB): Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study.
Authors: Meiri Eyal , Garrett-Mayer Elizabeth , Halabi Susan , Mangat Pam K. , Shrestha Sagun , Ahn Eugene R. , Osayameh Olufunlayo , Perla Venu , Schilsky Richard L. 
Published: February 2020

133 Background: TAPUR is a phase II basket study evaluating anti-tumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results in a cohort of CRC pts with HTMB treated with P are reported. Methods: Eligible pts had advanced CRC, no standard treatment (tx) options, measurable disease, ECOG PS 0-1, and adequate organ function. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Pts had HTMB, defined as ≥9 mutations/megabase (Muts/Mb) by a FoundationOne test (n=26) or other tests (n=2) approved by the Molecular Tumor Board. Pts with MSI-H tumors were ineligible. Dosing of P was 2 mg/kg (n=8) or 200 mg (n=20) IV over 30 mins, every 3 wks. Simon two-stage design was used to test a null rate of 15% vs. 35% (power = 0.85; α = 0.10). If ≥2 of 10 pts in stage 1 have disease control (DC) (objective response (OR) or stable disease at 16+ wks according to RECIST (SD16+)), 18 more pts enrolled. If ≥7 of 28 pts have DC, the tx is worthy of further study. Secondary endpoints are progression-free survival (PFS), overall survival (OS) and safety. Results: Twenty-eight pts enrolled from June 2017 to November 2018; 1 pt was ineligible and excluded. HTMB ranged from 9 to 54 Muts/Mb. Table (N=27) summarizes demographics and outcomes. Tumor MS status was reported stable for 25 pts, ambiguous for 1 pt, and not available for 1 pt. One PR (MS stable and 10 Muts/Mb) and 7 SD16+ were observed for DC and OR rates of 28% (90% CI, 16% to 45%) and 4% (95% CI, 0% to 19%), respectively. 2 pts each had grade 3 AEs at least possibly related to P including abdominal infection, anorexia, colitis, diarrhea, fatigue, nausea, and vomiting; 1 also had SAE of acute kidney injury. Conclusions: Monotherapy with P showed anti-tumor activity in heavily pre-treated CRC pts with HTMB . Additional study is warranted to confirm the efficacy of P in this population. Clinical trial information: NCT02693535. [Table: see text]
A phase II study of FOLFOXIRI plus bevacizumab (Bmab) as initial chemotherapy for patients (pts) with untreated metastatic colorectal cancer (mCRC): TRICC1414 (Be TRI).
Authors: Yamada Takeshi , Nishina Tomohiro , Nasu Junichiro , Matsumoto Toshihiko , Yuasa Yasuhiro , Shiraishi Takeshi , Nagano Hiroaki , Moriyama Ichiro , Fujiwara Toshiyoshi , Miguchi Masashi , Yoshida Ryosuke , Nosaka Kimiyasu , Tanioka Hiroaki , Nagasaka Takeshi , Kurisu Yasuro , Kobayashi Michiya , Tsuchihashi Kenji , Inukai Michio , Kikuchi Takashi , Shinozaki Katsunori 
Published: February 2020

134 Background: FOLFOXIRI-Bmab has been recognized as one of the standard first-line treatments for mCRC. We conducted a single arm, multicenter, phase II study to assess the efficacy and safety of FOLFOXIRI-Bmab in pts with untreated mCRC harboring UGT1A1(*6 and *28) wild or single hetero genotype. Methods: Pts received FOLFOXIRI-Bmab (irinotecan 165 mg/m2, oxaliplatin 85 mg/m2, l-leucovorin 200mg/m2, fluorouracil 3200 mg/m2 and Bmab 5mg/kg repeated biweekly) up to a maximum of 12 cycles, followed by the sequential therapy which consisted of the remaining drugs if any of the individual drugs were discontinued at the investigator’s discretion. Protocol therapy was continued until progressive disease, an unacceptable adverse event, tumor resection or consent withdrawal. The primary endpoint was ORR evaluated by central reviewers. Secondary endpoints include TTF, PFS, OS, R0 resection rate, relative dose intensity (RDI) and safety. The exploratory objectives were early tumor shrinkage (ETS), depth of response (DoR). Results: 47 pts were enrolled from 16 centers between April 2015 and May 2017, of whom 1 was excluded for not meeting the inclusion criteria. The full analysis set consisted of 44 pts because 2 had no target lesions that were considered measurable lesion by central reviewers. 46 pts had the following characteristics: median age 58 (29-68), 57% male, 76% PS0, 22% right-sided tumors and 52% UGT1A1 wild. RAS status was 37% wild, 52% mutant, 11% unknown. Primary endpoint was met. The ORR was 63.6% (95% CI, 47.8-77.6). ETS and DoR was 70.5%, 43.9%, respectively. R0 resection rate was 23%. Median PFS was 15.5mo (95% CI, 11.5-23.4). Median TTF was 8.1mo (95% CI, 5.3-10.1). Median OS was 34.4mo (95% CI, 26.4-not reached). The mean RDI of fluorouracil, irinotecan and oxaliplatin were 71%, 67%, and 64%, respectively. Grade 3 or higher adverse events (≥10%) were neutropenia (65.2%), febrile neutropenia (FN) (26.1%), anorexia (10.9%), nausea (10.9%), and diarrhea (10.9%). No treatment-related deaths were observed. Conclusions: Our results of FOLFOXIRI-Bmab in Japanese pts showed to be beneficial and manageable although caution to FN is required. Clinical trial information: NCT02497157.
Drug-drug interaction (DDI) potential of oral napabucasin in healthy adults.
Authors: Dai Xiaoshu , Karol Michael D. , Hitron Matthew , Hard Marjie , Goulet Matthew T. , Mclaughlin Colleen F. , Brantley Scott J. 
Published: February 2020

142 Background: Napabucasin is an NQO1-bioactivatable investigational agent hypothesized to affect multiple oncogenic cellular pathways including pSTAT3 through the generation of reactive oxygen species. This phase 1 open-label study evaluated the DDI potential of napabucasin and its major metabolite (M1) with respect to 7 major human drug cytochrome P450 (CYP) enzymes and the breast cancer resistance protein (BCRP) transporter. Methods: Healthy adult subjects who initially demonstrated they could tolerate administration of 240 or 480 mg twice daily (BID) napabucasin over 2-days (D) received single doses of the CYP and transporter substrates, followed by ≥7-day washout. In the DDI portion, subjects received napabucasin 240 mg BID on D1–11 with the phenotyping cocktail administered on D6 (omeprazole [CYP2C19] 20 mg, caffeine [CYP1A2] 100 mg, flurbiprofen [CYP2C9] 50 mg, bupropion [CYP2B6] 150 mg, dextromethorphan [CYP2D6] 30 mg, and oral midazolam [CYP3A] 2 mg), intravenous (IV) midazolam 2 mg on D7, repaglinide (CYP2C8) 0.25 mg on D8, and rosuvastatin (BRCP transporter) 10 mg on D9. Results: DDI potential was evaluated in 17 subjects. Exposure to omeprazole, flurbiprofen, and oral midazolam with (test) or without (reference) napabucasin 240 mg BID were similar. Napabucasin increased exposure (area under the curve to infinity) to caffeine (124%), IV midazolam (118%), repaglinide (127%), and rosuvastatin (213%); and decreased exposure to bupropion (79%) and dextromethorphan (71%). None of these changes were expected to be clinically meaningful. The exposure of the major metabolites of the probe drugs with or without napabucasin or M1 were similar. Of the 17 subjects, 12 (70.6%) reported adverse events (AEs); 58.8% reported gastrointestinal disorders. One patient had a grade 3 AE (neutrophil count low); no serious AEs were observed. Conclusions: The data suggest minimal in vivo DDI potential for napabucasin with respect to 7 major human drug CYP enzymes and the BCRP transporter. Napabucasin 240 mg BID was generally tolerable in healthy subjects. Co-administration of napabucasin with CYP and transporter substrates was safe and tolerable. Clinical trial information: NCT03411122.
Neoadjuvant chemotherapy followed by liver resection for patients with metastatic colorectal cancer.
Authors: Jin Rui , Jin Zhaohui , Cleary Sean P. , Nagorney David M. , Smoot Rory L. , McWilliams Robert R. , Mahipal Amit 
Published: February 2020

147 Background: Colorectal cancer is one of the leading causes of cancer related deaths with liver being most common site of CRC metastasis. More than 50% of the CRC patients will develop metastatic liver lesion that eventually leads to death in about 70% of them. In this retrospective review we reviewed the outcome of pts who received neoadjuvant chemotherapy followed by resection of liver lesion for metastatic colorectal cancer. Methods: 304 pts who had preoperative chemotherapy were identified from 1045 metastatic colorectal cancer patients who had liver metastasectomy at Mayo Clinic between 1997 and 2018. A retrospective review was conducted by using data from electronic medical records. Statistical analyses utilized Kaplan-Meier method, Log-rank test, and Cox proportional hazards models. Results: There were 113 (37%) female and 191 (63%) male pts. Median age at primary disease diagnosis was 56.5 yrs. Two hundred forty-nine pts presented with stage IV metastatic colorectal cancer. Primary tumor locations were: 53 right-sided, 117 left-sided and 133 rectum. 152 (50%) pts had extrahepatic metastases. Two pts were found to be MSI-H, 113 MSS, 189 unknown. BRAF mutation was found in 6 patients. RAS mutation was present in 84 patients, with 124 unknown. Pts received chemotherapy for median of 2.82 months. Single agent fluoropyrimidine was administered in 38 (12%) pts and rest receiving chemotherapy doublet or triplet with fluropyrimidine plus oxaliplatin being most common regimen. The median overall survival from primary diagnosis for the entire group was 74.5 months. Median overall survival from liver metastasectomy was 60.0 months. In univariate analysis, metachronous disease, age < 60 yrs, and an absence of extrahepatic lesions led to statistically significant improvement of overall survival from primary diagnosis. Metachronous and extrahepatic lesions remained statistically significant in multivariate analysis. Conclusions: Neoadjuvant chemotherapy followed by liver metastasectomy is beneficial for highly-selected metastatic colorectal cancer pts. Compared to a historical control of 30-36 months, our patient population had a median overall survival of about 5 years from resection.
A phase II study of durvalumab (MEDI4736) (anti-PD-L1) and trametinib (MEKi) in microsatellite stable (MSS) metastatic colorectal cancer (mCRC).
Authors: Johnson Benny , Thomas Jane V , Dasari Arvind , Raghav Kanwal Pratap Singh , Vilar Sanchez Eduardo , Kee Bryan K. , Eng Cathy , Parseghian Christine Megerdichian , Morris Van K. , Wolff Robert A. , Shureiqi Imad , Kopetz Scott , Overman Michael J. 
Published: February 2020

152 Background: Monotherapy with immune checkpoint blockade (ICB) is ineffective for patients (pts) with MSS mCRC. Novel approaches to modulate the tumor microenvironment (TME) are needed. Here, we investigate whether the combination of trametinib (T) with durvalumab (D) can alter the immune TME by successfully priming and activating T-cells. Methods: An open-label, single center phase II trial with primary endpoint of immune-related response rate for T+D in refractory MSS mCRC pts (NCT03428126). T is 2mg/day orally starting 1 week prior to D, which is given 1500mg intravenously every 4 weeks. Dose de-escalation strategy performed to identify maximum tolerated dose (MTD). Simon 2-stage design utilized with plans to enroll 29 pts into the first stage, requiring response in 2 or more pts to proceed to stage 2 (n = 15). Results: Demographics for 29 treated pts: 48% female, median age 48 years (range 28-75), and median prior therapies was 2 (range 1-5). No grade (G) 4 treatment-related adverse events (TRAE). The most common G3 TRAE included autoimmune hepatitis (14%) and acneiform rash (10%). G1/2 TRAE included acneiform rash (69%), fatigue (24%) and anemia (21%). No fatal TRAE and 4 pts discontinued treatment due to TRAE. 1 of 29 pts had confirmed partial response (PR) lasting 9.3 months (mo) for an ORR of 3.4%. This pt had an ATM E221fs*14 mutation. 7 pts had stable disease (SD) with median time to progression (TTP) of 5.4 mo (range 3.9-9.3 mo). 1 pt remains on active therapy with SD ( > 10 mo). 5 pts (1 PR, 4 SD) demonstrated decrease in total CEA ng/mL (best percentage reduction: 94%, 95%, 42%, 34% and 21.6% respectively). Median TTP for the entire cohort was 3.2 mo (range 1.1-9.3 mo). Consensus molecular subtypes (CMS) were performed on the primary CRC in 23 pts: 12 CMS2, 2 CMS3, and 9 CMS4. 4 SD pts were CMS2, 1 SD pt was CMS4 and the CMS status of the pt with a PR was unknown. Conclusions: The combination of T+D did not meet efficacy criteria to proceed to the second stage of the study. Analysis of 15 paired on-treatment biopsies is ongoing and will be presented. Utilization of CMS characterization in mCRC clinical trials is feasible and may provide an improved biological understanding of treatment activity. Clinical trial information: NCT03428126.