bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy and safety of larotrectinib in patients with TRK fusion gastrointestinal cancer.
Authors: Berlin Jordan , Hong David S. , Deeken John F. , Boni Valentina , Oh Do-Youn , Patel Jyoti D. , Nanda Shivani , Brega Nicoletta , Childs Barrett H. , Hyman David Michael , Drilon Alexander E.
Published: February 2020

824

Background: Tropomyosin receptor kinase (TRK) fusions arise from rearrangements of the neurotrophic tyrosine receptor kinase ( NTRK) 1, 2, or 3 genes and an unrelated gene, creating constitutively active oncogenic drivers that have been detected in a range of adult and pediatric malignancies, but are generally rare in patients with gastrointestinal (GI) cancer. Larotrectinib is a selective TRK inhibitor approved for the treatment of adult and pediatric patients with TRK fusion cancer. Here, we report efficacy and safety data for patients with TRK fusion GI tumors. Methods: Patients with a TRK fusion GI cancer treated with larotrectinib in a phase II clinical trial, NAVIGATE (NCT02576431), were included in this analysis. Larotrectinib was administered at 100 mg twice daily, until disease progression, unacceptable toxicity, death, or withdrawal. Response was assessed by the investigator using RECIST v1.1. Results: As of February 19, 2019, 14 patients with TRK fusion GI cancer (median age 68 y, range 32–84 y) were enrolled. GI tumor types were colon (8), cholangiocarcinoma (2), pancreas (2), appendix (1), and hepatic (1). Fusions involved NTRK1 (n = 12) and NTRK3 (n = 2). Nine patients had ≥2 prior lines of therapy. The best response on last prior therapy was 1 partial response (PR). Overall best responses on larotrectinib were: colon cancer, 4 patients had a PR and 4 had stable disease (SD); pancreatic cancer, 1 patient had a PR and 1 had SD; cholangiocarcinoma, 1 patient had a PR and 1 had progressive disease; appendix cancer, 1 patient had SD; response in 1 patient with hepatic cancer was not determined. Median time to response was 1.8 months (range 1.7–2.1). With 5 patients ongoing and censored, the median progression free survival was 5.3 months (95% CI 2.2–9.0). Median overall survival was 33.4 months (95% CI 2.8–36.5). Larotrectinib was well tolerated, with most adverse events being grade 1 or 2. Conclusions: Although the sample size is limited, there is evidence of clinical activity with larotrectinib in TRK fusion GI cancer, with a manageable safety profile. TRK fusion GI cancer may represent an under-diagnosed subset of patients with viable treatment options. Clinical trial information: NCT02576431.
An intersectional investigation of race and sex on receipt of adjuvant chemotherapy in stage III colon cancer.
Authors: Dhahri Amina , Carballido Estrella M. , Felder Seth , Dineen Sean Patrick , Powers Benjamin D
Published: February 2020

86

Background: Race and sex disparities exist for receipt of adjuvant chemotherapy (AC) for stage III colon cancer. However, most studies have not used an intersectional approach, which assesses the cumulative effects of different identities (e.g., Black women) instead of treating each as distinct, independent variables. Using this approach, we assessed the summative impact of these identities on receipt of AC for stage III colon cancer. Methods: The National Cancer Database was queried from 2004 to 2015 for patients who underwent surgery for stage III colon cancer and were healthy enough for AC. Receipt of AC was assessed chi-squared and multivariable logistic regression analyses. Results: 92,696 patients were identified. White patients had higher rates of care at community cancer centers. Black patients had higher rates of treatment at academic cancer programs (p < 0.001). Overall 83.5% received AC. Black males and females had higher rates of AC (86.5% and 86.2%, respectively) compared to White males and females (85.3% and 80.5%), respectively (p < 0.001). In adjusted analysis, Black males had the lowest odds of AC (OR 0.73), followed by Black females (OR 0.89) and White females (OR 0.91). When evaluated by age < 65 years and adjusting for potential confounders, Black men remained the least likely group to receive AC (OR 0.70). Black females had similar odds of receipt of AC (OR 0.99) and White females had increased odds (OR 1.22) relative to White males. Conclusions: Despite higher rates of treatment at academic centers, Black males and females had lower odds of receipt of AC after adjusting for confounders. Younger Black males persisted with the lowest odds of AC, although younger Black females had odds similar to younger White males. Additional research is necessary to identify drivers of these disparities and interventions to ameliorate them. [Table: see text]
How to improve toxicity evaluation in clinical trials? Testing new metrics from irinotecan or oxaliplatin-based treatments in metastatic colorectal cancer (mCRC): A pooled analysis from 2,349 patients in ARCAD database.
Authors: Tournigand Christophe , Lopes Guilherme , Olswold Curtis L. , Adams Richard , Zalcberg John Raymond , Van Cutsem Eric , Saltz Leonard B. , Goldberg Richard M. , Hurwitz Herbert , Bokemeyer Carsten , Fuchs Charles S. , Chibaudel Benoist , Grothey Axel , De Gramont Aimery , Shi Qian
Published: February 2020

89

Background: Monitoring of adverse events (AE) is crucial in clinical trials. Maximum grade per patient (pt) is commonly used but better metrics are needed to aid describing and comparing AE profiles. Methods: We developed and evaluated 2 longitudinal AE summary metrics. 1) Onset time of max grade refers to whether a pt has max grade within pre-specified timeframes for an AE, e.g. onset can be defined as “early” (max grade before the 6th cy) or “late” (≥ 6th cy). 2) Adverse effect load (AEL) is a longitudinal score of worst grade possible excluding death over the entire treatment for an AE. Higher AEL means worst overall experience of AE. We applied these metrics to real trial data. Pts were from 6 mCRC trials included in ARCAD database and received Irinotecan-based (n = 1,119) or Oxaliplatin-based (n = 1,230) treatments that did not include biologicals. AEs were diarrhea, nausea/vomiting, neutropenia/leukopenia, and neuropathy. We used linear model to AEL and logistic model to the other metrics, adjusting for age, sex, and number of metastases. Results: For nausea/vomiting, pts in Oxali-based chemo showed a higher AEL compared to patients in Iri-based (mean (M) [standard deviation (SD)] = 0.04 [0.06] vs. 0.02 [0.04]; p < 0.001) even though less pts had gr ≥ 3 (10.4% vs. 16.2%, resp.; p < 0.001), suggesting a lower-grade but persistent nausea/vomiting for Oxali-based. Among pts with diarrhea max gr 2, pts in Iri-based had higher AEL than with Oxali-based (M [SD] = 0.11 [0.11] vs. 0.08 [0.09]; p = 0.008), indicating more persistent diarrhea for Iri-based trts even among pts with same max grade. For neutropenia/leukopenia, pts in Oxali-based trts experienced higher AEL (M [SD] = 0.09 [0.13] vs. 0.05 [0.11], p < 0.001), and more pts in Oxali-based trts had gr ≥ 3 (70.1% vs. 64.4%; p = 0.002), suggesting that pts in Oxali-based trts experienced worst overall and max grade neutropenia/leukopenia compared to pts in Iri-based. Conclusions: To improve toxicity assessment in clinical trials, AEL and onset time of max grade are new measures that describe the evolution of adverse events over time. Further validation is warranted.
DPYD gene polymorphisms in patients with gastrointestinal tumors receiving chemotherapy with 5-fluorouracil.
Authors: Kit Oleg Ivanovich , Vladimirova Liubov Yu , Timoshkina Natalya N. , Storozhakova Anna E. , Petrusenko Natalia A. , Gvaldin Dmitry Yu. , Kabanov Sergey N. , Ryadinskaya Ludmila A. , Tikhanovskaya Natalia M. , Popova Irina L. , Abramova Natalia A. , Samaneva Natalia Yu. , Teplyakova Maria A. , Lyanova Aza A. , Novoselova Kristina A. , Kalabanova Elena Aleksandrovna , Svetitskaya Yana V. , Trifanov Vladimir , Kolesnikov Evgeniy N.
Published: February 2020

90

Background: Complete or partial deficiency of the DPD enzyme due to genetic polymorphisms of the DPYD gene causes acute toxicity of fluoropyrimidines, which are widely used in combination chemotherapy regimens for various malignant neoplasms. The purpose of the study: to identify polymorphisms of the DPYD gene significant for 5-fluorouracil-induced toxicity. Methods: Venous blood samples from Caucasian patients were used to identify alleles of *2А rs3918290, 5* rs1801159, *13 rs55886062 and rs67376798 DPYD by RT-PCR and direct sequencing. Inclusion criteria were: verified diagnosis of gastrointestinal tumors, age>18 years old, fluoropyrimidine-containing regimes of treatment. Results: 104 pts were included, 54% were female. Mean age-61 years. Colorectal cancer was found in 80.7% pts, non-colorectal in 19.3% pts. Hematological and non-hematological toxicity Gd.3-4 was found in 24% pts. Allele * 5rs18011595, which causes enzyme deficiency was found in 28% of patients, (frequency was 0.281) which is significantly higher than the population frequency of the allele charactering for Caucasoid population (p <0.05). Meanwhile genotyping did not reveal the *2A, *13 alleles and rs67376798 alleles in the DPYD gene. Conclusions: *5rs1801159 allele was found as the main DPYD polymorphism associated with fluoropyrimidine toxicity in Caucasian pts with gastrointestinal tumors.
Neoadjuvant mFOLFOXIRI chemotherapy-improved survival benefit comparing with CRT in locally advanced rectal cancer: A propensity score matched analysis from two prospective trials.
Authors: Zhang Jianwei , Li Jianxia , Xie Xiaoyu , Cai Yue , Hu Huabin , Wu Zehua , Ling Jiayu , Deng Yanhong
Published: February 2020

98

Background: Neoadjuvant chemoradiotherapy (CRT) is the standard of treatment for locally advanced rectal cancer, but it delays administration of systemic chemotherapy, leading to high incidence of distant metastases. To enhance systemic chemotherapy and avoid the damage of radiation, neoadjuvant chemotherapy with mFOLFOXIRI had been investigated. However, no randomized comparison assessing the efficacy of mFOLFOXIRI versus CRT in LARC. Methods: 145 LARC patients received CRT as neoadjuvant treatment in the phase III FOWARC study (NCT01211210) and 103 patients received mFOLFOXIRI alone preoperatively in a phase II study (NCT02217020). A propensity score-adjusted method was adopted to provide an estimation of the benefit from the enhancive chemotherapy regimen as neoadjuvant treatment in terms of survival and activity parameters. Results: In the original cohort, patients in the mFOLFOXIRI group were younger with the median age of 48 versus 56 years old in the CRT group. More patients with tumor length over 5 cm and cT3 or N2 disease in the mFOLFOXIRI group ( P< 0.05). After propensity score adjusted matching, 73 patients were comparable in each groups. The pCR rate was 23.3% in thd mFOLFOXIRI group versus 13.7% in the CRT group, respectively (P = 0.14). The proportion of ypStage 0-I was 45.2% versus 39.7%, respectively (P = 0.5). The local recurrence rate was comparable between the two groups (5.5% vs. 4.1%, P= 0.70). But mFOLFOXIRI decrease the incidence of distant metastasis (8.2% vs. 27.4%, P= 0.002). And the 3 year disease free survival was 86.8% in the mFOLFOXIRI group versus 75.8% in the CRT group, respectively ( P= 0.049). Lower incidence of anastomotic fistula was shown in mFOLFOXIRI alone group than that of CRT group (5.5% vs. 17.8%, P = 0.02). Grade 3/4 neutropenia was more commen in mFOLFOXIRI group (39.7% vs. 8.2%, P < 0.001). Conclusions: Comparing with CRT, preoperative mFOLFOXIRI decreased the incidence of distant metastasis and improved 3 year DFS, and led to less toxicity and fewer postoperative complications. The phase III randomized study comparing FOLFOXIRI with CRT is still ongoing. Clinical trial information: NCT01211210 and NCT02217020.
A randomized phase III study of mFOLFOX6/bevacizumab combination chemotherapy with or without atezolizumab or atezolizumab monotherapy in the first-line treatment of patients (pts) with deficient DNA mismatch repair (dMMR) metastatic colorectal cancer (mCRC): Colorectal Cancer Metastatic dMMR Immuno-Therapy (COMMIT) study (NRG-GI004/SWOG-S1610).
Authors: Rocha Lima Caio Max Sao Pedro , Yothers Greg , Jacobs Samuel A. , Sanoff Hanna Kelly , Cohen Deirdre Jill , Guthrie Katherine A , Henry Norah Lynn , Ganz Patricia A. , Kopetz Scott , Lucas Peter C. , Blanke Charles David , Wolmark Norman , Hochster Howard S. , George Thomas J. , Overman Michael J.
Published: February 2020

TPS260

Background: Deficient DNA mismatch repair (dMMR) colorectal cancer (CRC) is highly immunogenic. Preclinical data showed synergistic interactions among FOLFOX, anti-VEGF, and programmed cell death-1 (PD-1) pathway blockade. Prior phase I study of mFOLFOX6/ bevacizumab (bev) + atezolizumab (atezo) was well tolerated and enhanced intratumoral infiltration of CD8+ T cells. We hypothesize that the dMMR subset of CRC may be effectively targeted with combination of PD-1 pathway blockade and mFOLFOX6/bev. Methods: This is a prospective randomized phase III open-label trial. Pts (N=347) with mCRC dMMR will be randomized to three trial arms (1:1:1): mFOLFOX6/bev; atezo monotherapy; or mFOLFOX6/bev + atezo. Stratification factors include BRAFV600E status, metastatic site, and prior adjuvant CRC therapy. Primary endpoint is progression-free survival (PFS) assessed by study investigator of mFOLFOX6/bev/atezo and atezo monotherapy compared to mFOLFOX6/bev. Secondary endpoints include OS, objective response rate, safety profile, disease control rate, duration of response, and PFS by retrospective central review. Health-related quality of life is an exploratory objective. Archived tumor tissue and blood samples will be collected for correlative studies. Key inclusion criteria are: mCRC without prior chemotherapy for advanced disease; dMMR tumor determined by local CLIA-certified IHC assay (MLH1/MSH2/MSH6/PMS2); availability of archived tumor tissue for central confirmation of dMMR status; and measurable disease per RECIST. Activated 11-7-17. As of 9-11-19, enrollment continues with 44/347 pts enrolled. Clinical trial: NCT02997228. Support:U10CA180868, -180822, -180888, -180819, UG1CA189867, U24CA196067; Genentech, Inc. Clinical trial information: NCT02997228.
NSABP FC-10: Phase IB study of pembrolizumab in combination with premetrexed + oaliplatin in patients (pts) with chemo-refractory metastatic colorectal cancer (mCRC).
Authors: Lee James J. , Yothers Greg , George Thomas J. , Krauss John C. , Maalouf Bassam Nabih , Parekh Hiral D. , Krishnamurthy Anuradha , Vehec Kelly R. , Wolmark Norman , Allegra Carmen Joseph , Jacobs Samuel A.
Published: February 2020

TPS262

Background: The majority of mCRC pts are microsatellite stable (MSS), have poor intratumoral CD8+ T cell infiltration, and no clinical response to immunotherapy checkpoint inhibitors. Preclinical studies suggest that chemotherapy may synergize with anti-PD-1. In non-small cell lung cancer (NSCLC), the combination of pembrolizumab (PemB), pemetrexed (PemT), + carboplatin demonstrated synergistic activity. This study will combine PemB with PemT, then that combination + oxaliplatin (Ox). The rationale for addition of Ox to PemT is that enhanced immunogenic cell death may induce CD8+ T cell infiltration into CRC tumors and model the mechanism of cytotoxicity seen in NSCLC. Thus, the combination of PemB+ PemT + Ox may induce synergistic antitumor immune activity. Methods: This multi-center phase Ib trial is actively enrolling pts with incurable mCRC with prior treatment for mCRC including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, and if RAS wild-type, anti-EGFR therapy. Measurable disease by imaging (RECIST 1.1) is required. Standard ineligibility includes active infections, systemic steroid use, or other conditions contraindicating immunotherapy. Cohort 1 will receive PemB + PemT; Cohort 2 will receive PemB + PemT + dose-escalated Ox. Imaging will be performed every 6 wks. The primary aim of Cohort 1: to evaluate for safety and efficacy using doses of PemB and PemT that have been studied in NSCLC. The primary aim of Cohort 2: to evaluate the safety, tolerability, and efficacy of PemB in combination with PemT + Ox. The RP2D of the 3-drug combination will be at the MTD taking into account toxicity profiles of study therapy agents. Secondary aims: to evaluate the clinical benefit rate of the doublet and triplet combinations in pts with chemo-refractory MSS mCRC and to estimate progression-free survival and overall survival in pts with MSS mCRC treated with these combinations. The cohorts will be analyzed separately with descriptive intent only. Maximum enrollment is 33 pts. Support: Merck; Lilly; NSABP Foundation, Inc. Clinical trial information: NCT03626922.
MONARCC: A randomized phase II study of panitumumab monotherapy and panitumumab (pan) plus 5 Fluorouracil (FU) as first-line therapy for RAS and BRAF wild type metastatic colorectal cancer (mCRC): An AGITG clinical trial.
Authors: Tebbutt Niall C. , Steer Christopher B. , Sjoquist Katrin Marie , Chantrill Lorraine A. , Karapetis Christos Stelios , Nott Louise M. , Espinoza David , Oostendorp Martinus , Yip Sonia , Cuff Jeff , Burge Matthew E.
Published: February 2020

TPS271

Background: Pan added to combination chemotherapy is established first-line therapy for RAS and BRAF wild type mCRC. Elderly patients are not well represented in clinical trials and may be more suited to treatment protocols with lower toxicity risks; FU plus bevacizumab (bev) is commonly used. Treatment related efficacy, toxicity, impact on quality of life and other outcomes of pan based regimens in an elderly population have not been well studied. Methods: A prospective non-comparative randomized phase 2 study. Australian Clinical Trials Registry Number: ACTRN 12618000233224. Main inclusion criteria include: Untreated patients aged 70 years or older; RAS and BRAF wild type; ECOG performance 0-2. Randomisation 1:1, stratified by primary tumour side, performance status, number of metastatic sites; to pan 6mg/kg 2 weekly or panitumumab plus FU 400 mg/m² bolus; leucovorin 200mg/m²; FU 2400mg/m² 48 hour infusion 2 weekly. Primary endpoint is 6-month progression-free survival (PFS). Sample size is 80 patients based on expected 6-month PFS rate of 73% with FU and bev. Using the method of Metha-Cain, if 24 or more patients are progression free at 6 months, the one sided 95% confidence interval includes 73% and we declare similar activity. Secondary endpoints include overall survival; toxicity and overall treatment utility, a composite measure of treatment benefit based on radiology, clinical progress, toxicity and patient reflection of the impact of treatment on their daily lives. Patients undergo a comprehensive health assessment at baseline and limited health assessment at 4 months. Physical activity trackers are worn for 2 weeks at treatment commencement and again at week 16. Tumour tissue and blood samples (at baseline, cycle 3 day 1 and at 24 weeks) will be collected for translational research. First site opened in June 2018. Twelve patients have been recruited to date from 9 sites in Australasia. Eighteen sites were open as at September 2019. Clinical trial information: 12618000233224.
Circulating tumor DNA-based decision for adjuvant treatment in colon cancer stage II evaluation: (CIRCULATE-trial) AIO-KRK-0217.
Authors: Folprecht Gunnar , Reinacher-Schick Anke , Tannapfel Andrea , Weitz Juergen , Kossler Thibaud , Weiss Lukas , Aust Daniela Ellen , von Bubnoff Nikolas , Kramer Michael , Thiede Christian
Published: February 2020

TPS273

Background: The benefit of adjuvant chemotherapy in stage II colon cancer is unclear, and clear clinical or molecular marker are not available for decision making. Recently, postoperative circulating tumour (ct)DNA has been demonstrated to be prognostic in colorectal cancer and other tumours. Methods: For the CIRCULATE trial we enrol patients (pts) with colon cancer stage II in Germany (AIO), Austria (ABCSG) and Switzerland (SAKK). Microsatellite stable pts are screened after resection of the primary by analysing the tumour block with panel sequencing and measuring patient specific mutations in the postoperative plasma sample. MSI-H pts are excluded from the trial. ctDNA positive (ctDNApos) pts are randomised (2:1) to receive adjuvant capecitabine based chemotherapy or no chemotherapy. Oxaliplatin can be added according to investigator’s choice. ctDNA negative (ctDNAneg) pts are randomised (1:4) to be followed-up within the study or to receive standard follow-up outside the trial. Pts in the follow-up group and their investigators are blinded for the ctDNA result. The primary aim is to compare the disease free survival (DFS) in ctDNApos pts randomised to chemotherapy or to follow-up. Secondary aims are to compare the overall survival (OS) in ctDNApos pts with or without chemo, to compare the DFS and OS in ctDNApos vs. ctDNAneg follow-up pts, to describe the DFS and OS in ctDNAneg pts, to describe the location of recurrences/metastases according ctDNA status, the ctDNA clearance rate and time to ctDNA negativity during adjuvant chemotherapy, further translational endpoints, and safety. To demonstrate a treatment effect in the ctDNA group with a hazard ratio of 0.617 (3 year DFS rate of 42.5 % vs. 25 %), 231 ctDNApos will be randomised (approx. 2310 pts in total) from 2019 – 2022. Clinical trial information: NCT04089631.
Tislelizumab plus chemotherapy as first-line treatment for unresectable, locally advanced recurrent/metastatic esophageal squamous cell carcinoma.
Authors: Yoon Harry H. , Kato Ken , Hubner Richard , Raymond Eric , Tao Aiyang , Liu Sumei , Qazi Ibrahim , Xu Jian-Ming
Published: February 2020

TPS462

Background: Esophageal squamous cell carcinoma (ESCC) is the predominant histological subtype of esophageal cancer, particularly in Asian countries. Inhibition of the PD-1/PD-L1 axis has demonstrated antitumor activity in patients with advanced unresectable or metastatic ESCC. Tislelizumab, an investigational humanized IgG4 monoclonal antibody with high affinity and binding specificity for PD-1, was engineered to minimize binding to FcγR on macrophages in order to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy. Results from early phase clinical studies suggest tislelizumab, as a single agent or in combination with chemotherapy, was generally well tolerated and had antitumor activity in patients with solid tumors, including ESCC. Methods: This global, phase 3, randomized, placebo-controlled, double-blind study (NCT03783442) is designed to evaluate the efficacy and safety of tislelizumab plus chemotherapy as first-line treatment of unresectable, locally advanced recurrent or metastatic ESCC. Adult patients with histologically confirmed unresectable ESCC, or locally advanced recurrent/metastatic disease with a ≥6 month treatment-free interval, are eligible; palliative radiation administered > 4 weeks from study initiation is allowed. Patients who received prior anti-PD-(L)1, anti-PD-L2, or first-line therapy are ineligible. Patients (n≈480) will be randomized 1:1 to receive tislelizumab 200 mg IV every 3 weeks (Q3W) plus investigator-chosen chemotherapy (ICC) or placebo plus ICC. ICC options include: platinum (plat; cisplatin 60-80 mg/m2 or oxaliplatin 130 mg/m2 IV Q3W) + 5-FU 750-800 mg/m2 by continuous IV infusion over 24 hours for 5d Q3W; or plat + capecitabine 1000 mg/m2 orally BID for 14d Q3W; or plat + paclitaxel 175 mg/m2 IV Q3W. Progression-free and overall survival are primary endpoints; secondary endpoints include objective response rate, duration of response, and health-related quality of life. Safety will be assessed by monitoring adverse events, physical examinations, vital signs, and electrocardiograms. This study is actively enrolling. Clinical trial information: NCT03783442.
A phase II study of futibatinib (TAS-120) in patients (pts) with advanced (adv) solid tumors harboring fibroblast growth factor receptor (FGFR) genomic aberrations.
Authors: Hollebecque Antoine , Doi Toshihiko , Saavedra Omar , Takahashi Osamu , He Helen , Benhadji Karim A. , Shitara Kohei
Published: February 2020

TPS470

Background: FGFR genomic aberrations are known to drive oncogenesis in multiple tumor types via FGFR signaling pathway dysregulation. Futibatinib is an oral, highly selective, irreversible FGFR1–4 inhibitor that has shown potent antiproliferative activity against FGFR-deregulated tumors of diverse tissue origins in preclinical studies. In a phase 1 dose-escalation/expansion study, futibatinib showed promising antitumor activity and tolerability in previously treated pts with tumors harboring FGFR aberrations. This phase 2 study was designed to evaluate the efficacy and safety of futibatinib in pts with tumors harboring FGFR aberrations. The study will enroll pts in multiple cohorts based on diagnosis and FGFR aberration status; cohorts enrolling pts with adv solid tumors are reported here. Methods: In this global, open-label, phase 2 study, pts (≥18 years; Eastern Cooperative Oncology Group performance status of 0 or 1) will be enrolled in cohort A (~60 pts with metastatic/locally adv solid tumors, except primary brain tumors or intrahepatic cholangiocarcinoma, harboring FGFR1–4 rearrangements and with disease progression after standard treatment) or cohort B (~35 pts with metastatic/locally adv gastric tumors harboring FGFR2 amplifications and with ≥2 prior therapies). Key exclusion criteria are clinically significant alterations in calcium–phosphorus homeostasis, ectopic mineralization/calcification, and prior FGFR inhibitor treatment. Pts will receive 20 mg futibatinib once daily in a continuous 28-day cycle until disease progression, unacceptable toxicity, or other discontinuation criteria are met. The primary endpoint is objective response rate (ORR) per independent central review. Secondary endpoints include ORR per investigator, disease control rate, duration of response, progression-free survival, overall survival, and safety. The anticipated start date is in April 2020.
A phase II study evaluating safety and efficacy of niraparib in patients with previously treated homologous recombination (HR) defective or loss of heterozygosity (LOH) high-metastatic esophageal/GEJ/proximal gastric adenocarcinoma: A Big Ten Cancer Research Consortium study.
Authors: Mamdani Hirva , Mehta Rutika , Fountzilas Christos , Radovich Milan , Perkins Susan , Jalal Shadia Ibrahim
Published: February 2020

TPS472

Background: Adenocarcinoma of esophagus (EAC) and GEJ is the fastest rising cancer in the US. The outcomes are extremely poor with median overall survival (OS) being 12 mo in patients (pts) with metastatic disease. The standard first line treatment for metastatic EAC is platinum-based regimen with median progression free survival (PFS) of 6 mo. Second line options are associated with limited efficacy. An analysis of TCGA has shown 40% of EAC harboring abnormalities in HR genes, most likely resulting from chronic acid reflux induced DNA damage. HR dysregulation is commonly associated with high LOH. Sensitivity to PARP inhibition has been shown to be a surrogate for HR defects or BRCAness phenotype. Clinically PARP inhibitors have shown activity in HR defective prostate and ovarian cancers. These findings provide the basis for this study. Methods: Pts with metastatic esophageal/GEJ/proximal gastric adenocarcinoma, previously treated with 1 line of platinum containing chemotherapy, and harboring high LOH and/or deleterious alteration(s) in HR genes ( BRCA1/2, PALB2, ATM, BARD1, BRIP1, CDK12, CHEK2, FANCA, RAD51, RAD51B, RAD51C, RAD51D, RAD54L, NBN, ARID1A, GEN1) are eligible for this study. Pts can be prescreened at the time of diagnosis of locally advanced or metastatic disease by genomic analysis of the most recent available tumor tissue. Pts will receive oral niraparib until disease progression or unacceptable toxicity. Primary objective is response rate (RR). Secondary objectives are safety and tolerability, progression free survival (PFS), and disease control rate (DCR). Exploratory objectives include correlation between high LOH and response to niraparib, mechanisms of resistance to PARP inhibition, EZH2 expression and its correlation with response and resistance to PARP inhibition, and analysis of germline HR gene mutations and correlation with response to niraparib. Estimated sample size is 43. The study has recently opened to accrual at Indiana University with intended collaboration with 2 additional sites. Clinical trial information: NCT03840967.
A phase II clinical trial of the phosphatidylserine targeting antibody, bavituximab, in combination with pembrolizumab in patients with advanced hepatocellular carcinoma.
Authors: Beg Muhammad Shaalan , Zhu Hao , Hsieh David , Kazmi Syed Mohammad Ali , Sanjeevaiah Aravind , Singal Amit G. , Kainthla Radhika , Khosama Leticia , Crane Kimberli , Brekken Rolf A. , Yopp Adam Charles
Published: February 2020

TPS599

Background: Phosphatidylserine (PS) is an immunosuppressive lipid segregated to the inner leaflet of the plasma membrane of normal cells. PS is externalized to the outer leaflet of the plasma membrane on cells that line tumor blood vessels, tumor cells and exosomes in the tumor microenvironment creating a specific target for anticancer treatments. Bavituximab is a PS targeting antibody that binds to PS via β2 glycoprotein-1 (β2GP1), an abundant serum glycoprotein. Bavituximab can modulate the tumor immune microenvironment to promote anti-tumor immune activity. This clinical trial is evaluating the effect of combining bavituxumab and the checkpoint inhibitor pembrolizumab in patients with advanced hepatocellular carcinoma (HCC). Methods: This is a single arm phase 2 clinical trial for patients with histologically confirmed HCC which is not eligible for curative and/or loco-regional therapy. No prior systemic therapy for HCC is allowed. Patients should be > 18 years, have Child-Pugh Score A, ECOG 0-1 and meet the following laboratory criteria: total bilirubin ≤ 2.0, INR ≤ 1.7; Hgb ≥ 8.5 g/dl; AST, ALT ≤5 times ULN; platelet ≥ 50,000/mm3; and albumin ≥ 2.5 g/dl. Major exclusion criteria include thromboembolic event within the last 6 months, clinically evident ascites, GI bleeding within 2 months, uncontrolled hypertension, HIV and autoimmune disease (except DM1, childhood allergies and thyroid abnormalities if adequately controlled. Dosing is as follows: Bavituximab: 3 mg/kg IV weekly, pembrolizumab: 200 mg IV every 3 weeks. The primary objective is to determine the overall response rate (ORR) of therapy. Secondary objectives are to determine the safety, tolerability and other measures of clinical efficacy (overall survival, 6 month PFS, and duration of response). Tumor and blood samples are being collected to assess for pharmacodynamic biomarkers. A minimax two-stage method will be used to analyze ORR after the first 15 patients are accrued. If 3 or more of the first 15 patients have either a complete or partial response, 13 additional patients will be enrolled. ORR will be analyzed by RECIST 1.1 criteria. Clinical trial information: NCT03519997.
A phase III study of futibatinib (TAS-120) versus gemcitabine-cisplatin (gem-cis) chemotherapy as first-line (1L) treatment for patients (pts) with advanced (adv) cholangiocarcinoma (CCA) harboring fibroblast growth factor receptor 2 (FGFR2) gene rearrangements (FOENIX-CCA3).
Authors: Borad Mitesh J. , Bridgewater John A. , Morizane Chigusa , Shroff Rachna T. , Oh Do-Youn , Moehler Markus H. , Furuse Junji , Benhadji Karim A. , He Helen , Valle Juan W.
Published: February 2020

TPS600

Background: Pts with adv CCA have poor survival outcomes, and chemotherapy offers limited survival benefit (5-year survival rates, 5–10%; median overall survival [OS], 8–12 months). FGFR2 gene rearrangements are known to be early drivers of oncogenesis in ~15% of pts with intrahepatic (i) CCA. Futibatinib, an oral, highly selective, irreversible FGFR1-4 inhibitor has shown antitumor activity against a broad spectrum of FGFR-deregulated tumors in preclinical studies. In a previous study, futibatinib demonstrated clinical activity and tolerability in heavily pretreated pts with adv CCA harboring FGFR2 gene rearrangements. This phase 3 trial (FOENIX-CCA3) is designed to evaluate futibatinib vs gem-cis as 1L therapy for pts with adv iCCA harboring FGFR2 rearrangements. Methods: FOENIX-CCA3 is a multicenter, open-label, randomized phase 3 study that will be conducted in pts with metastatic or unresectable iCCA harboring FGFR2 rearrangements (assessed at screening by a central laboratory). Pts must have an ECOG performance status of 0 or 1 and should not have received previous systemic anticancer therapy for adv disease (adjuvant/neoadjuvant therapy ≥6 mo prior to randomization is permissible). Pts with clinically-significant alterations in calcium-phosphorus homeostasis or ectopic mineralization/calcification will be excluded. Approximately 216 pts will be randomized (1:1 ratio) to receive 20 mg futibatinib once daily until disease progression or other discontinuation criteria are met or gem-cis (on days 1 and 8 of a 21-day cycle) for 8 cycles or until disease progression, whichever occurs first. Pts will be stratified by prior surgical excision (yes vs no), geographic region, and locally adv vs metastatic disease. The primary endpoint is progression-free survival (PFS) assessed by independent central review (ICR). Secondary endpoints include objective response rate and disease control rate based on ICR, OS, PFS per investigator assessment, and safety. The anticipated start date is in April, 2020.
Improving cascade genetic testing for families with inherited pancreatic cancer (PDAC) risk: The GENetic Education, Risk Assessment and TEsting (GENERATE) study.
Authors: Yurgelun Matthew B. , Ukaegbu Chinedu I. , Furniss C. Sloane , Kenner Barbara , Klein Alison , Lowy Andrew M. , McAllister Florencia , Mork Maureen E , Nelson Scott H. , Robertson Alison , Stopfer Jill E. , Underhill Meghan , Ocean Allyson J. , Madlensky Lisa , Petersen Gloria M. , Garber Judy Ellen , Lippman Scott Michael , Goggins Michael , Maitra Anirban , Syngal Sapna
Published: February 2020

TPS779

Background: 4-10% of PDAC patients harbor pathogenic germline variants in cancer susceptibility genes, including APC, ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2, STK11, and TP53. For families with such pathogenic variants, the greatest potential impact of germline testing is to identify relatives with the same variant (cascade testing), thereby providing the opportunity for early detection and interception of PDAC and other associated cancers. Numerous factors limit cascade testing in real-world practice, including family dynamics, widespread geographic distribution of relatives, access to genetic services, and misconceptions about the importance of germline testing, such that the preventive benefits of cascade testing are often not fully realized. The primary aim of this study is to analyze two alternative strategies for cascade testing in families with inherited PDAC risk. Methods: 1000 individuals with a confirmed pathogenic germline variant in any of the above genes in a 1st/2nd degree relative and a 1st/2nd degree relative with PDAC will be remotely enrolled through the study website (www.GENERATEstudy.org) and randomized between two methods of cascade testing (individuals with prior genetic testing will be ineligible): Arm 1 will undergo pre-test genetic education with a pre-recorded video and live interactive session with a genetic counselor via a web-based telemedicine platform (Doxy.me), followed by germline testing through Color Genomics; Arm 2 will undergo germline testing through Color Genomics without dedicated pre-test genetic education. Color Genomics will disclose results to study personnel and directly to participants in both arms. All participants will have the option of pursuing additional telephone-based genetic counseling through Color Genomics. The primary outcome will be uptake of cascade testing. Secondary outcomes will include self-reported genetic knowledge, cancer worry, distress, decisional preparedness, familial communication, and screening uptake, which will be measured via longitudinal surveys. Enrollment is underway nationwide as of May, 2019. Clinical trial information: NCT03762590.
Vitamin D receptor agonist paricalcitol plus gemcitabine and nab-paclitaxel in patients with metastatic pancreatic cancer.
Authors: Perez Kimberly , Cleary James M. , Karasic Thomas Benjamin , Raghavan Srivatsan , Rahma Osama E. , Nowak Jonathan , Borazanci Erkut Hasan , Downes Michael , Drebin Jeffrey A. , Tuveson David A. , Ting David Tsai , Moffitt Richard , Yeh Jen Jen , Aguirre Andrew , Evans Ronald , Von Hoff Daniel D. , Odwyer Peter J. , Wolpin Brian M.
Published: February 2020

TPS784

Background: Patients(pts) with metastatic pancreatic cancer (PC) have a median survival of less than one year even with use of multiagent chemotherapy programs. Pancreatic tumors are composed of multiple cell types and a dense extracellular matrix that may support cancer cell proliferation and impede chemotherapy delivery. Cancer-associated fibroblasts (CAF’s) in the tumor microenvironment secrete pro-inflammatory factors and components of the extracellular matrix. In PC laboratory models, engagement of the vitamin D receptor (VDR) by VDR agonists shifts CAFs toward a more quiescent phenotype with reduced tumor growth and improved chemotherapy penetration (Sherman. Cell, 2014). Paricalcitol is a synthetic VDR agonist used in patients with secondary hyperparathyroidism due to chronic kidney disease. A prior pilot study evaluated IV paricalcitol with gemcitabine (G) and nab-paclitaxel (A) before surgical resection in patients with resectable PC (NCT02030860). Methods: Pts with previously-untreated metastatic PC will be enrolled in a two-stage study consisting of a safety run-in and a randomized phase 2 study (NCT03520790). In the run-in stage, 36 pts will be randomized 1:1:1 to G (1000 mg/m2) and A (125 mg/m2) given 3 weeks on and 1 week off plus: (a) paricalcitol 25mcg IV thrice weekly, (b) paricalcitol 16mcg oral daily, or (c) placebo oral daily. Grade 3/4 hypercalcemia or genitourinary stones will be considered dose limiting toxicities.Pts will undergo paired pre- and on-treatment tumor biopsies to examine pharmacodynamic (PD) markers by bulk and single cell RNA sequencing and multiplex immunofluoresence.Assuming safety and supportive PD assessments, the phase 2 study will randomize an additional 76 pts to two treatment arms with GA plus: (a) paricalcitol or (b) placebo.Paricalcitol formulation (IV or oral) will be determined based on data from the run-in stage.The primary endpoint of the phase 2 study is overall survival, with a total of 100 pts needed to identify a hazard ratio of 0.6 with 80% power and one-sided alpha of 0.10.Secondary endpoints include safety, response rate, and progression free survival.Trial funding provided by SU2C, CRUK,Lustgarten Foundation, and AACR. Clinical trial information: NCT03520790.
Stereotactic MR-guided on-table adaptive radiation therapy (SMART) for locally advanced pancreatic cancer.
Authors: Parikh Parag , Low Daniel , Green Olga L. , Lee Percy P.
Published: February 2020

TPS786

Background: Standard dose radiation therapy has been unsuccessful in inoperable pancreatic cancer; with a negative study (LAP07) for conventional chemoradiation and dropping of the stereotactic body radiation therapy arm in Alliance A021501. Recently, reports of using high dose ablative radiation therapy has been associated with increased survival in retrospective studies. Moreover, technological advances with MRI-guided radiation therapy offer improved targeting and the ability to change the radiation delivery on a daily fashion; allowing ablative radiation doses over one week. However, it is not clear whether this can be done safely on a multiinstitutional basis. Methods: We are conducting the largest prospective study of ablative radiation therapy in pancreatic cancer. The study is a single arm, multi-institutional phase II, industry sponsored study to investigate the safety and efficacy of Stereotactic, MR guided, on-table-Adaptive Radiation Therapy (SMART). Eligibility criteria include locally advanced and borderline resectable pancreatic cancer patients with ECOG PS of 0 or 1; who have non-metastatic disease after a minimum of 3 months of any systemic therapy; including investigational agents. Patients will receive MR-guided radiation therapy to a dose of 50 Gy / 5 fractions; with maximum tumor coverage delivered each fraction that allows keeping the gastrointestinal organs at risk to a dose of 33 Gy or less. Primary endpoint is grade 3 of higher gastrointestinal toxicity at 90 days. Secondary endpoints are overall survival at 2 years, distant progression free survival at 6 months, and changes in patient related quality of life at 3 and 12 months. Target sample size was calculated to show at a significance level 0.05, a reduction of the toxicity rate to 8% or lower by using SMART compared with 15.8%, the toxicity rate of conventionally delivered chemoradiation at a power level 0.8. Given an expected 15% drop-out, the enrollment goal is 133. Descriptive statistics will be used for secondary objectives. The study opened in January, 2019 and is currently opened at 4 centers; with other US and international sites pending. Sponsored by Viewray, Inc. Clinical trial information: NCT03621644.
A pilot study of liposomal irinotecan plus 5-FU/LV combined with paricalcitol in patients with advanced pancreatic cancer progressed on gemcitabine-based therapy.
Authors: Grierson Patrick , Wang-Gillam Andrea , Park Haeseong , Pedersen Katrina , Tan Benjamin R. , Amin Manik A. , Suresh Rama , Trikalinos Nikolaos , Liu Jingxia
Published: February 2020

TPS793

Background: Pancreatic ductal adenocarcinoma (PDAC) is predicted to be the second leading cause of cancer-related death by 2030, and is characterized by resistance to chemo- and radiotherapy and a highly fibrotic tumor microenvironment. Front-line therapies for advanced PDAC include FOLFIRINOX and gemcitabine/nab-paclitaxel with median overall survival ranging from 8.5 to 11 months. After progression on gemcitabine-containing therapy, 5-FU/LV/liposomal irinotecan is a standard second-line option, however outcomes are still poor. Retrospective studies demonstrate superior survival of advanced PDAC in patients with high serum levels of 25(OH) vitamin D. Notably, the PDAC tumor microenvironment is enriched in cancer-associated fibroblasts that favorably respond to vitamin D, prolonging survival in combination with chemotherapy in mouse models. Furthermore, vitamin D suppresses catabolism of irinotecan in gastrointestinal cancer cells, potentiating its efficacy. Therefore, we are conducing an investigator-initiated study of 5FU/LV/liposomal irinotecan with paricalcitol as second-line therapy in advanced PDAC. Methods: This is a pilot study of 5FU/LV/liposomal irinotecan combined with paricalcitol in patients with advanced PDAC progressed on gemcitabine-based therapy. All patients receive liposomal irinotecan, LV, 5-FU and paricalcitol. Liposomal irinotecan is given at 70 mg/m2 IV over 90 minutes, LV at 400 mg/m2 IV over 30 minutes, and 5-FU at 2400 mg/m2 continuous IV infusion over 46 hours, on Day 1 of each 14-day cycle. Paricalcitol IV infusion will precede the above, given according to assigned cohort (75 mcg weekly or 7 mcg/kg weekly). The primary objective of this study is to determine the tolerability between two different dose levels of paricalcitol added to the combination regimen of 5-FU/LV/liposomal irinotecan in patients with advanced PDAC. Secondary objectives are measures of efficacy (ORR, PFS, OS, CA19-9 biochemical response rate). Clinical trial information: NCT03883919.
Real-world data validation for differential expression of immunoregulatory molecules and targetable cancer genes may provide therapeutic insights into agnostic-driven trial designs.
Authors: Adashek Jacob J. , Szeto Christopher W. , Reddy Sandeep K. , Spiess Philippe E.
Published: February 2020

10

Background: Targeting actionable genes and using immunotherapy have increased treatment options. We previously reported that some immunoregulatory molecules are found differentially regulated in the presence of certain gene mutations regardless of cancer subtype. Here we validated a subset of these associations in an independent, real-world dataset with distinct clinicopathological characteristics. Methods: Previously, 2740 TCGA patients were identified to have at least one potentially oncogenic mutation (mt) within an established 50-gene hotspot panel. Differential expression of 10 immunoregulatory molecules (IRM) was analyzed between mutant (mt) vs. wild-type (wt). To ensure observed significant associations were not confounded by tumor-type, differential IRM expression within mt-enriched tumor-types was compared to that of mt vs. wt. Now, using the NantHealth external database of 2739 unselected clinical cases these associations were validated. Results: Within the TCGA cohort 19/50 gene mutations were found to be significantly associated with ≥1 IRM expression. In many, the mt effect-size was larger than that of tumor-type; e.g. head & neck carcinomas (HNSCC) are highly enriched for CDKN2A mt (OR = 4.9, p = 4.3e-9), yet CDKN2A mt are more associated with CTLA4 expression than HNSCC histology (t = 7.0 vs. 5.4). Of these 15 associations, 6 were validated within the independent later-stage NantHealth cohort. Most notably, CDKN2A mt was validated as associated with increased PD1 and CTLA4 expression while KRAS and APC mt were validated as associated with decreased PDL1/2 expression. Conclusions: The presented differential checkpoint expression patterns are strongly associated with mutation status and are not primarily driven by tissue-type, which have been further validated by an external database. Strategies combining genomic targets have been shown to yield success as well as using immunotherapies. Our data suggests there may be a role for combining NGS targets along with IRM expression patterns to better guide future design of clinical trials in combatting various cancers in a tissue-agnostic fashion.