bluuebunny/crossref_metadata_2025 huggingface dataset:
Understanding the expanding armamentarium for GIST: Engaged learning outcomes.
Authors: Worst Michelle Arielle , Van Laar Emily Sherene , Tanzola Mindy , Heinrich Michael C. , Villalobos Victor Manuel
Published: February 2020

837

Background: Gastrointestinal stromal tumors (GIST) are rare soft-tissue sarcomas that harbor specific genomic alterations, making GIST an ideal model for targeted therapy. Common oncogenic drivers include mutations in the KIT and PDGFR tyrosine kinase. Due to varying resistance patterns to existing TKIs, clinicians are challenged to stay current with new data and how best to integrate new agents into treatment paradigms. The objective of this study was to assess the changes in oncologists’ and gastroenterologists’ knowledge, competence, and confidence through participation in education regarding optimal GIST treatment. Methods: The educational activity consisted of a 30-minute online, 2 faculty, video discussion with synchronized slides. Educational effect was assessed with a repeated pairs pre-/post-assessment study with a 3-item, multiple choice, knowledge/competence questionnaire and one confidence assessment question. For all questions, each participant served as his/her own control. Pre- and post-assessment scores were compared to determine the relative changes in the proportion of correct responses. A chi-square test assessed statistical significance at the P < 0.05 level. The activity launched 25th June 2019; data were collected until 19th August 2019. Results: Overall significant improvements were seen after education for oncologists (N=52, P < 0.001) and gastroenterologists (N=127, P < 0.01). The relative improvement was 79% for oncologists and 44% for gastroenterologists (pre-/post-assessment average correct response rates were 24%/43% and 23%/33%, respectively). Following the activity, 44% of oncologists and 37% of gastroenterologists were more confident in their ability to select appropriate therapy for patients with metastatic GIST. Conclusions: Participation in an online, 30-minute video discussion CME intervention resulted in statistically significant improvements in knowledge, competence, and confidence of oncologists and gastroenterologists, that may lead to improvements in clinical care. As new data and agents emerge, new educational activities are necessary to reinforce knowledge, close persistent gaps, and increase oncologists’ confidence in this clinical setting.
New response evaluation criteria using early morphological change in imatinib treatment for patients with gastrointestinal stromal tumor.
Authors: Ishida Tomo , Takahashi Tsuyoshi , Saito Takuro , Kurokawa Yukinori , Yamashita Kotaro , Tanaka Koji , Makino Tomoki , Yamasaki Makoto , Nakajima Kiyokazu , Mori Masaki , Doki Yuichiro
Published: February 2020

838

Background: While the introduction of molecularly targeted drugs, including imatinib, has greatly improved the prognosis of gastrointestinal tumor (GIST), the response evaluation criteria have not been optimized. Early morphological change (EMC) was previously reported as a predictive marker for molecularly targeted drugs in metastatic colorectal cancer. The purpose of the present study was to verify the efficacy of EMC in predicting the outcome in patients with GIST receiving imatinib. Methods: We retrospectively reviewed 55 patients. EMC in computed tomography (CT) image was evaluated, and the patients were categorized into two groups; active MR (morphologic response) (+) group and active MR (-) group, judging from the morphological features including the sharpness of the outline and the attenuation of target lesion. We investigated the association between the presence of active MR and clinical outcomes. Similarly, clinical outcomes classified by response evaluated by RECIST and Choi criteria were analyzed respectively. Results: Thirty-two patients had active MR (+). The median Progression-free survival(PFS) was 7 months vs 31 months (active MR(-) vs active MR(+), P = 0.013) and the median overall survival (OS) was 58 months vs 91 months ( P = 0.086), respectively. Although PFS of RECIST PD (progression disease) or Choi PD patients was shorter than that for PR (partial response) or SD(stable disease) patients ( P = 0.0037 for RECIST, P = 0.0058 for Choi), the number of PD patients was very small (N = 3, both in RECIST and Choi). Conclusions: The evaluation criteria based on EMC could be a sensitive method to predict the clinical outcome of imatinib treatment for patients with inoperative GIST.
Comparing FOLFOXIRI plus bevacizumab with doublet chemotherapy plus anti-EGFR antibody: A systemic review and network meta-analysis.
Authors: Zhang Jianwei , Li Jianxia , Xie Xiaoyu , Cai Yue , Wu Zehua , Hu Huabin , Ding Miaomiao , Deng Yanhong
Published: February 2020

97

Background: FOLFOXIRI plus bevacizumab (Triplet+Bev) improved survival benefit when comparing with doublet chemotherapy plus Bev (doublet+Bev) as initial treatment in metastatic colorectal cancer (mCRC). Several trials also compared the efficacy of doublet plus EGFR antibody (doublet+EGFRi) with doublet+Bev. However, little is known about triplet+Bev comparing with doublet +EGFRi in mCRC. Methods: We did a systematic review and network meta-analysis with a systematic literature search on PubMed, EMbase, Web of Science, and international oncology conferences. We included phase 2 and 3 randomized controlled trials investigating FOLFOXIRI+Bev versus doublet+Bev or doublet+EGFRi versus doublet+Bev as first-line treatments in mCRC. A Bayesian network meta-analysis was done to compare hazard ratios (HRs) for PFS and OS in overall population, Ras wild type population, left or right side patients, left or right-side Ras wild-type population. And to compare relative risk (RR) for objective response rates. Results: Eight trials involving 3980 patients were included. In direct comparison, Triplet+Bev was superior to doublet+EGFRi both in OS (HR 0.83 0.72-0.97), PFS (HR 0.73, 0.65-0.83)and ORR (RR 1.5, 1.2-2.0). Doublet+EGFRi was beneficial in OS (HR 1.2, 1.1-1.5) and ORR (RR 0.74, 0.52-0.97) than doublet+Bev, but not PFS. In indirect comparison, Triplet+Bev showed no difference to doublet+EGFRi in OS (HR 1.0, 0.84-1.4) and ORR (RR 1.1, 0.73-1.6) in all population, and improved PFS (HR 0.71, 0.60-0.86). In left side RAS wild-type subgroup, Triplet+Bev showed similar efficacy in OS (HR 1.2, 0.6-2.5), PFS (HR 1.6, 0.59-4.3), and ORR (RR 0.63, 0.22-15). But in Right-side subgroup, Triplet+Bev was beneficial both in OS (HR 0.41, 0.18-0.93) and PFS (HR 0.55, 0.34-0.92). In right-side RAS wild-type subgroup, Triplet+Bev also showed trend of longer OS (HR 0.37, 0.12-1.1) and PFS (HR 0.43, 0.18-1.1) than doublet+EGFRi. Conclusions: In left-side RAS wild-type mCRC, FOLFOXIRI+Bev showed similar efficacy to doublet+EGFRi. While in right-side subgroup or right-side RAS wild-type population, Triplet+Bev is preferable as initial treatment for mCRC, in the meanwhile, in cautious of AE.
A phase III randomized controlled trial comparing surgery plus adjuvant chemotherapy with or without preoperative chemoradiotherapy for locally recurrent rectal cancer: A Japan Clinical Oncology Group study (JCOG1801).
Authors: Tsukada Yuichiro , Ito Masaaki , Nakamura Naoki , Ito Yoshinori , Bando Hideaki , Ando Masahiko , Onaya Hiroaki , Ikeda Masataka , Sekimoto Mitsugu , Kadota Tomohiro , Katayama Hiroshi , Mizusawa Junki , Fukuda Haruhiko , Kanemitsu Yukihide
Published: February 2020

TPS263

Background: Local recurrence is one of the most common forms of recurrence after curative resection for primary rectal cancer. Surgical resection is recommended for locally recurrent rectal cancer (LRRC) to achieve radical cure if the tumor is judged as resectable with negative margins. However, a high local re-recurrent risk after surgery is a major problem due to the difficulty of re-resection and the serious symptoms, such as pain or fistula, resulting from re-recurrence. Preoperative chemoradiotherapy (preCRT) is expected to improve local control after radical surgery for radiation naïve LRRC; however, high frequency of surgical complications after preCRT cannot be ignored. Due to the refractory nature and rarity of LRRC, the true impact of preCRT on oncological and surgical outcomes has not been clarified by clinical trials. The purpose of this study is to confirm the superiority of preCRT followed by surgery plus adjuvant chemotherapy over surgery plus adjuvant chemotherapy alone, in terms of local relapse-free survival for resectable LRRC. Methods: Eligibility criteria include resectable LRRC without distant metastasis, no prior pelvic irradiation, no prior surgery for LRRC, aged 20-80 years, and sufficient organ function. Eligible patients are randomized into the surgery and adjuvant chemotherapy (arm A) or preCRT followed by surgery and adjuvant chemotherapy (arm B). PreCRT consists of the standard dose of capecitabine and radiotherapy (50.4Gy). Adjuvant chemotherapy consists of mFOLFOX6, CAPOX, capecitabine, or 5FU+l-LV. The primary endpoint is local relapse-free survival (LRFS), and the secondary endpoints include overall survival, relapse-free survival, %R0 resection, incidence of adverse events, and quality of life after surgery. The 3-year LRFS of arm A is assumed to be 60% with a 13% increase expected in arm B. The sample size was calculated as 106 (53 per arm) with a one-sided alpha of 10%, power of 70%, and accrual period of 6 years. This trial was initiated on 19 August 2019. Clinical trial information: jRCTs031190076.
A phase II study of trifluridine/tipiracil, irinotecan, and bevacizumab in pretreated metastatic colorectal cancer (TABAsCO).
Authors: Gupta Medhavi , Fountzilas Christos , Vijayvergia Namrata , Attwood Kristopher , Hochster Howard S. , Mukherjee Sarbajit , Iyer Renuka V. , Boland Patrick McKay
Published: February 2020

TPS275

Background: Colorectal cancer (CRC) is the second leading cause of cancer-related death in US. The majority of US patients (pts) receive first-line therapy (Rx) with FOLFOX [Folinic acid (FA), 5-fluorouracil (5-FU) and oxaliplatin (Ox)] + a biologic, making FOLFIRI [FA+ 5-FU+ irinotecan (Iri)] + bevacizumab (Bev) a common second-line Rx. This regimen has a median progression-free survival (PFS) of approximately 6 months (mo) and overall survival (OS) of 12 mo. Further gains are desperately needed. Trifluridine/tipiracil (FTD/TPI) is an oral combination Rx of a thymidine-based nucleoside analogue, FTD, and a phosphorylase inhibitor, TPI. FTD/TPI has a distinct mechanism of action from 5-FU and in preclinical models can overcome 5-FU resistance via DNA incorporation, base excision repair pathway and glycosylation responses to DNA damage. Further, there is an additive effect in combination with Iri. FTD/TPI was FDA approved for use in refractory metastatic CRC (mCRC) based on phase III RECOURSE trial. Phase I data showed combination of FTD/TPI, Iri and Bev to be safe, and an efficacy signal was seen in dose-expansion cohort (NCT01916447). A 12.5% response rate, 83.4 % disease control rate and PFS of 7.9 mo was achieved. As this study largely assessed refractory pts, one might expect a greater efficacy in Iri naïve pts. To test this hypothesis, we are conducting a multi-center phase II study of FTD/TPI, Iri and Bev as second-line Rx in mCRC pts. Methods: Eligible pts have mCRC and received first-line Ox based Rx. Rx to be given in 28-day cycles: Iri (180 mg/m2) and Bev (5 mg/kg) on D1 & 15, and FTD/TPI (25 mg/m2) twice daily on D2-6 & 16-20. Response assessment via CT/MRI to be done q8 wks (RECIST 1.1). Rx to continue until disease progression or unacceptable toxicity. The primary objective is to estimate PFS. Secondary objectives include ORR, OS, and safety. Final analysis to be done either 12 mo after enrollment of the final pt or once all pts have progression, whichever occurs earlier. A total of 40 pts to be accrued, and enrollment to start in January 2020. This study was approved and funded by the National Comprehensive Cancer Network (NCCN) Oncology Research Program from general research support provided by Taiho Oncology, Inc.
A phase II trial of [fam-] trastuzumab deruxtecan (T-DXd, DS-8201a) in subjects with HER2-positive, unresectable, or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma.
Authors: Fuchs Charles S. , Shahidi Javad , Mathew Lijoy , Qin Amy , Van Cutsem Eric
Published: February 2020

TPS460

Background: Despite attempts, no HER2-directed therapies have been approved for gastric or GEJ cancer after disease progression on trastuzumab. [Fam-] trastuzumab deruxtecan (T-DXd, DS-8201a) is a novel HER2-targeted antibody-drug conjugate composed of a humanized monoclonal antibody specifically targeting HER2, a cleavable tetrapeptide-based linker (drug-to-antibody ratio of ≈8), and a potent topoisomerase I inhibitor payload. In a phase 1 study, T-DXd (5.4 or 6.4 mg/kg) showed promising antitumor activity in a variety of tumor types, including a confirmed objective response rate (ORR) of 43% among subjects with extensively pretreated HER2-positive gastric cancer (Shitara et al. Lancet Oncol. 2019;20(6):827-836). Here we describe the phase 2 trial evaluating the efficacy and safety of T-DXd in subjects with HER2-positive gastric/GEJ cancer previously treated with trastuzumab (NCT04014075). Methods: This is a single-arm, open-label, multicenter, phase 2 study in subjects with centrally confirmed, HER2-positive (immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization positive), unresectable or metastatic gastric/GEJ cancer that progressed on or after first-line therapy with a trastuzumab-containing regimen. HER2 status will be confirmed by a fresh biopsy before enrollment. Subjects are excluded if they received anticancer therapy after a first-line trastuzumab-containing regimen. The study began in August 2019 and will recruit ≈ 72 subjects from 25 to 30 sites in North America and Europe. T-DXd at 6.4 mg/kg will be administered intravenously once every 3 weeks until disease progression. The primary efficacy endpoint is confirmed ORR by independent central review (ICR) using RECIST v1.1 criteria. Secondary endpoints include duration of response and progression-free survival by ICR and investigator assessment, ORR by investigator assessment, and overall survival. Additional endpoints include safety, disease control rate, and pharmacokinetic analyses. Health-related quality of life will also be measured. Clinical trial information: NCT04014075.
Phase II study of the combination of abemaciclib and pembrolizumab in locally advanced unresectable or metastatic gastroesophageal adenocarcinoma: Big Ten Cancer Research Consortium BTCRC-GI18-149.
Authors: Uboha Nataliya Volodymyrivna , Eickhoff Jens C. , Chandrasekharan Chandrikha , Jalal Shadia Ibrahim , Benson Al Bowen , Deming Dustin A. , Lindemann Stephen , Hochster Howard S.
Published: February 2020

TPS461

Background: Metastatic gastroesophageal adenocarcinoma (GEA) has poor prognosis. Overall survival (OS) remains around 12 months (mo) with current therapies. Pembrolizumab is approved for advanced GEA that has progressed on at least 2 prior lines of systemic therapy. However, the majority of patients progress on this treatment, and less than 15% of patients experience objective response (OR). This study will evaluate efficacy of pembrolizumab in combination with cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, abemaciclib, in patients with advanced GEA. Preclinical studies have demonstrated that CDK4/6 inhibitors can increase anti-tumor immunity and can synergize with immune checkpoint inhibitors. Based on these data, we hypothesize that abemaciclib will augment response to pembrolizumab in GEA. Methods: This is a multi-institutional, single arm, open label, phase II study of abemaciclib in combination with pembrolizumab in patients with advanced GEA who have progressed or were intolerant to at least 2 prior lines of therapy. Patients previously treated with immune checkpoint inhibitors or with microsattelite unstable tumors will be excluded. Treatments will be given on a 21 day cycle until disease progression or intolerable toxicities. Pembrolizumab, 200 mg intravenously, will be given on day 1, and abemaciclib, 150 mg, will be taken orally twice a day on days 1-21. Primary endpoint is progression free survival (PFS). Secondary endpoints include PFS rate at 6 mo, disease control rate, OS and OR rate. Correlative endpoints will examine relationship between PDL1 status, genomic signature and treatment response. Saliva samples will be collected for microbiome analysis. Archival tumor tissue and blood samples will be banked for future studies. A total of 31 evaluable subjects will be enrolled to detect an anticipated increase in the median PFS from 2 months (null hypothesis) to 4 months with 80% power at the one-sided 0.05 significance level. The trial is open to enrollment. Clinical trial information: NCT03997448.
Phase II study of trifluridine/tipiracil (FTD/TPI) and oxaliplatin as induction chemotherapy (IC) in resectable esophageal and gastroesophageal junction adenocarcinoma (EGAC).
Authors: Mukherjee Sarbajit , Assi Hussein , Fountzilas Christos , Attwood Kristopher , Boland Patrick McKay , Iyer Renuka V. , Catenacci Daniel V.T. , Hatoum Hassan
Published: February 2020

TPS464

Background: Neoadjuvant chemoradiation (CRT) followed by surgery is a standard approach for localized EGAC. Despite multimodality treatment, 5-year overall survival (OS) is less than 50%, with pathologic complete response (pCR) rates of 20%. Achievement of pCR is associated with an improved OS. We propose to use a novel combination of FTD/TPI and oxaliplatin as IC. We hypothesize that IC before CRT will increase the pCR rate in localized EGAC. Methods: This is an open-label, multicenter phase II trial. Patients (pts) with potentially resectable loco-regional EGAC are eligible. Pts. should have adequate organ function, ECOG performance status of 0 –1, age < 76 years, and endoscopic ultrasound-determined node-positive disease with any T-stage, or T3-T4a with any N stage. Pts. with T4b or M1 disease will be excluded. Pts. will receive three cycles of IC with FTD/TPI and oxaliplatin. Based on the maximum tolerated dose (MTD) observed in a phase I trial, FTD/TPI will be administered 35 mg/m² BID, days 1–5 every 14 days, with a fixed dose of oxaliplatin 85 mg/m² (day 1). Pts will then undergo concurrent CRT (standard radiation dose of 5040 cGY will be utilized) with weekly Carboplatin (AUC 2) and Paclitaxel (50 mg/m2) for 6 weeks followed by surgery. Our primary objective is to evaluate the pCR rate. The secondary objectives include evaluation of 2-year disease-free survival (DFS), 2-year OS, and assessment of toxicities of the IC. As a correlative endpoint, circulating tumor DNA level will be correlated with disease recurrence and metabolic response on PET CT. Assuming a historic pCR rate of 20% with standard CRT, 41 pts (enrollment of up to 45 pts accounting for non-evaluable pts) are needed to show a 15% increase in pCR with IC with 80% power at one-sided significance level of α = 0.1. In stage 1, n1= 22 evaluable pts will be enrolled. If there is 5 or more pCRs, an additional n2= 19 pts will be enrolled in stage 2. If 12 or more pCRs are observed in the total n = 41 evaluable pts, then the proposed treatment regimen will be considered promising for further study. We anticipate accrual over a 2-year period from 3 sites. Clinical trial information: NCT04097028.
A phase I open-label study to investigate safety and tolerability, efficacy, pharmacokinetics, pharmacodynamics, and immunogenicity of MT-5111 in subjects with HER-2 positive tumors.
Authors: Van Tine Brian Andrew , Barve Minal A. , Hamilton Erika Paige , Brenner Andrew Jacob , Wainberg Zev A. , Burnett Christine , Pelham Josh , Brieschke Brigitte , Strack Thomas
Published: February 2020

TPS465

Background: Engineered toxin bodies (ETBs) are proprietarily engineered from a Shiga-like Toxin A subunit fused to antibody-like binding domains. ETBs can force receptor internalization, self-route to the cytosol, and induce cell-kill via inactivation of ribosomes. MT-5111 is a 55 kDa de-immunized ETB targeting HER2, and may not be subject to resistance mechanisms that exist for TKI, ADC, or antibodies. It binds a HER2 epitope distinct from trastuzumab or pertuzumab, could be combined with other HER2 targeting agents, and may have improved tumor penetration. Methods: MT-5111 is evaluated as monotherapy in subj with confirmed HER2+ locally advanced or metastatic cancers. The primary objective is to determine the maximum tolerated dose in subjects (subj) with advanced HER2-positive tumors. Secondary endpoints are PK, tumor response and immunogenicity. Part 1 will escalate doses to identify MTD in up to 42 subj. Part 2 will further evaluate MT-5111 at the MTD in up to 98 subj. All subj will receive MT-5111 on Days 1, 8, and 15 of each 21-day cycle until disease progression, unacceptable toxicity, death, withdrawal of consent or another reason for withdrawal. Part 1 will include subj with any HER2+ solid cancers. Part 2 will enroll 3 expansion cohorts: HER2+ breast (BC), HER2+ gastroesophageal cancer (GEA), and other HER2+ solid cancers. HER2+ must be demonstrated on metastatic lesions in case of metastases. Tumors tested by immunohistochemistry (IHC) must have IHC status of 2+ or 3+, regardless of in-situ hybridization (ISH) results; for BC and GEA, if no IHC is available, ISH per ASCO-CAP guidelines is used. Subj with HER2+ BC should have had at least 2 lines of HER2-directed therapy; subj with HER2+ gastric cancer should have received trastuzumab or have been intolerant to trastuzumab. Subj with evaluable disease may be included in Part 1; in Part 2, all subj must have at least 1 measurable lesion per RECIST 1.1. ECOG should be 0-1, and bone marrow, hepatic, renal, cardiac function should be adequate. Further details can be found on clinicaltrials.gov (NCT04029922). Enrollment has begun in September 2019. Clinical trial information: NCT04029922.
FIGHT-302: Phase III study of first-line (1L) pemigatinib (PEM) versus gemcitabine (GEM) plus cisplatin (CIS) for cholangiocarcinoma (CCA) with FGFR2 fusions or rearrangements.
Authors: Bekaii-Saab Tanios S. , Valle Juan W. , Van Cutsem Eric , Rimassa Lorenza , Furuse Junji , Ioka Tatsuya , Melisi Davide , Macarulla Teresa , Bridgewater John A. , Wasan Harpreet Singh , Borad Mitesh J. , Lihou Christine F. , Zhen Huiling , Féliz Luis , Asatiani Ekatherine , Jiang Ping , Vogel Arndt
Published: February 2020

TPS592

Background: For advanced CCA, standard of care 1L systemic treatment is GEM + CIS. Genetic alterations in intrahepatic CCA provide potential therapeutic targets. Fibroblast growth factor receptor (FGFR) 2 gene rearrangements driving CCA tumorigenesis were identified almost exclusively in intrahepatic CCA patients (pts) (incidence, 10–16%). In phase 2, PEM (INCB054828), a selective, potent, oral FGFR1–3 inhibitor elicited an objective response rate (ORR) of 35.5% and median progression-free survival (PFS) of 6.9 months (mo) in previously treated, locally advanced or metastatic CCA with FGFR2 rearrangements (NCT02924376). FIGHT-302, a randomized, open-label, phase 3 study will evaluate efficacy and safety of 1L PEM vs GEM + CIS in unresectable/metastatic CCA with FGFR2 fusions or rearrangements (NCT03656536). Methods: Eligible pts are adults with confirmed unresectable/metastatic CCA; no prior systemic therapy for advanced disease < 6 mo before enrollment; radiographically measurable/evaluable disease (per RECIST v1.1); ECOG PS ≤1; documented FGFR2 fusions or rearrangements. Exclusions include clinically significant corneal or retinal disorder; history of calcium and phosphate homeostasis disorder or systemic mineral imbalance with ectopic soft tissue calcification; untreated CNS metastases or history of uncontrolled seizures. Pts will be randomized (1:1; stratified by region and tumor burden) to PEM 13.5 mg QD on a 21-day (d) cycle or GEM (1000 mg/m2) + CIS (25 mg/m2) on D1 and D8 of 21-d cycles (max 8). Crossover to PEM allowed after confirmed progression. PEM titration to 18 mg from cycle 2 allowed for pts without hyperphosphatemia (serum phosphate > 5.5 mg/dL) and Grade ≥2 treatment-related adverse events during cycle 1. Hyperphosphatemia will be managed with diet modifications, phosphate binders, diuretics, or dose adjustments. Treatment will continue until progression or unacceptable toxicity. Primary endpoint is PFS (by independent review). Secondary endpoints are ORR, overall survival, duration of response, disease control rate, safety, and quality of life. Four pts (target N = 432) are enrolled as of Sep 25, 2019. Clinical trial information: NCT03656536.
Phase II study of fluorouracil (FU), leucovorin (LV), and nanoliposomal irinotecan (nal-IRI) in previously treated advanced biliary tract cancer (NAPOLI-2).
Authors: Weinberg Benjamin Adam , Wang Hongkun , Pedersen Katrina , Sehdev Amikar , Sung Max W. , Hwang Jimmy J.
Published: February 2020

TPS593

Background: Biliary tract cancers (BTCs) are rare and aggressive malignancies. The current standard of care for advanced BTC is gemcitabine (GEM) plus cisplatin . Although there is no established second-line treatment, regimens such as FOLFOX, XELOX, FOLFIRI, XELIRI, GEM, and capecitabine have activity. Nal-IRI contains IRI free base encapsulated in liposome nanoparticles which shelter IRI from conversion to its active metabolite (SN-38) and increase intratumoral levels of SN-38 compared with IRI. FU/LV/nal-IRI has shown overall survival benefit and acceptable toxicity in patients (pts) with metastatic pancreatic adenocarcinoma following GEM-based therapy in the NAPOLI-1 trial. Methods: This is a single arm, open label, multicenter phase II study of pts with advanced BTC previously treated with gemcitabine plus platinum chemotherapy. Pts will receive nal-IRI 70 mg/m2 IV over 90 minutes, LV 400 mg/m2 IV over 30 minutes, and FU 2400 mg/m2 over 46 hours, every 14 days. The primary objective is to determine progression-free survival (PFS) rate at 4 months (4mo) using RECIST v. 1.1 criteria and central radiology review. Response assessments will occur using imaging every 8 weeks. All pts who receive at least 1 dose of the study treatment will be eligible for the primary analysis. We will substitute pts who screen fail or do not begin treatment. Median PFS reported for pts receiving second-line 5-FU doublet chemotherapy is 3 months with a PFS4mo of 30%. FU/LV/nal-IRI would be of interest if it could increase the PFS4mo to 50% or higher. We will use a 2-stage Simon Minimax design. Using a one-sided α of 0.05 and 80% power, 39 pts will be required to detect a difference in PFS4mo between 30% and 50%. Assuming a dropout rate of 10%, 44 pts will be enrolled across the 5 study sites. Enrollment began in Q2 2019. Clinical trial information: NCT04005339.
Phase Ib/II study of sorafenib (SOR) and pembrolizumab (PEM) in advanced hepatocellular cancer (HCC).
Authors: Gosain Rohit , Mukherjee Sarbajit , Lee Sunyoung S. , Miller Austin , Minderman Hans , Maguire Orla , Matsuzaki Junko , Casucci Danielle , Mahalingam Devalingam , Iyer Renuka V.
Published: February 2020

TPS596

Background: SOR has been the backbone of advanced HCC therapy with poor outcome. Anti-PD-1 therapy is approved as a second-line treatment option in HCC due to its promising efficacy and safety. Our preclinical work showed that SOR is immunomodulatory and may be synergistic when combined with anti-PD-1 therapy. Guided by this data, we initiated this multicenter study of SOR and PEM in advanced HCC patients (pts). Methods: Pts who have Child-Pugh Class A, ECOG PS of 0/1, biopsy-proven measurable HCC that is unresectable or metastatic, are included. Pts must not receive either SOR or anti-PD-1 therapy before. A total of 27 pts will be enrolled from 2 sites. Pts must have the following lab values: ANC ≥ 1,500/ mc; Hgb ≥ 8.5 g/dL; Plts ≥75,000/ mcL; serum total bilirubin ≤ 2.0 mg/dL; AST/ALT ≤ 5 X ULN; serum creatinine ≤ 1.5 X ULN. Pts with active hep B must be on antiviral therapy. Pts would be on a 4-week run-in of SOR alone at 400mg BID to ensure tolerability and stable dose (minimum 200 BID) before beginning PEM 200mg IV q3 weeks. Both drugs would be administered until progression or unacceptable toxicity with response assessment q6 weeks by RECIST 1.1 criteria. Primary endpoint: response rate. Secondary endpoints: safety, overall survival, and progression-free survival. Correlative Endpoints: Pre-treatment levels of immunosuppressive cells and the functional activity of effector T cells would be compared to post-treatment blood and tumor samples. The first 6 pts who completed 4 weeks of SOR-only treatment and began the combination therapy (addition of PEM at a fixed dose of 200 mg Q3W) would comprise the safety lead-in. Pts who withdrew before initiation of combination therapy (for reasons other than DLT) would be replaced. Dose-Limiting toxicity was defined as any ≥ grade 3 clinically significant toxicity, which is deemed possibly treatment-related and occurs within the first cycle of combination therapy. Toxicity would be assessed by NCI CTCAEV4.0. Status: First patient enrollment on 12/19/2017. On 11/28/2018, our 6th patient completed the SOR lead-in phase and began combination treatment with SOR and PEM. As of Sept 12, 2019, thirteen pts have enrolled, and 9 pts have received combination treatment. Support: Merck. Clinical trial information: NCT03211416.
A phase II, randomized, controlled trial of nivolumab in combination with BMS-986253 or cabiralizumab in advanced hepatocellular carcinoma (HCC) patients.
Authors: Welling Theodore , Beri Nina , Siolas Despina , Cohen Deirdre Jill , Becker Daniel Jacob , Zhong Hua , Wu Jennifer J. , Oberstein Paul Eliezer , Karasic Thomas Benjamin
Published: February 2020

TPS598

Background: Tyrosine kinase inhibitors can prolong survival in advanced HCC patients, but response rates have been minimal. Recently, immune checkpoint inhibition with nivolumab (nivo) demonstrated objective response rates (ORR) of 15% (escalation phase) and 20% (expansion phase) in the Checkmate 040 study. Pre-clinical and translational studies have demonstrated that IL-8 and tumor associated macrophages (TAMs) contribute to HCC progression and recurrence following treatment. Therefore, rationale exists to evaluate combinatorial approaches to target TAM function combined with checkpoint inhibitory therapy. This phase II, randomized study will evaluate the safety and efficacy of combined anti-CSF1R (Cabiralizumab) or anti-IL-8 (BMS-986253) in combination with Nivo in advanced HCC. Methods: Advanced HCC patients without prior systemic treatment and disease measurable by RECISTv1.1 with Childs A liver function are eligible. Patients will be enrolled (n=25 per arm) to Nivo 240 mg IV Q2 weeks monotherapy, Nivo 240 mg IV + BMS-986253 1200 mg IV Q2 weeks, or Nivo 240 mg IV + Cabiralizumab 4 mg/kg IV Q2 weeks. Primary endpoints include safety and ORR determined by RECISTv1.1. Secondary endpoints include time to response, duration of response, progression free survival, and overall survival. Exploratory endpoints include analysis of tumor microenvironment immune and tumor cell profiling of pre- and on-treatment tumor tissue. Clinical trial information: NCT04050462.
A phase II trial of pembrolizumab in combination with cisplatin or carboplatin and etoposide in chemotherapy naive patients with metastatic or unresectable high-grade gastroenteropanncreatic or lung neuroendocrine carcinoma.
Authors: Ramirez Robert A. , Matrana Marc Ryan , Satti Suma , Griffin Ryan Patrick , Voros Brianne A , Bren-Mattison Yvette
Published: February 2020

TPS635

Background: Combination chemotherapy (CTx) is the mainstay of treatment for patients with advanced high-grade gastroenteropancreatic neuroendocrine carcinoma (GEPNECs) and large cell neuroendocrine carcinomas (LCNECs) of the lung. Pembrolizumab (PEM) is a humanized antibody to the programmed cell death receptor (PD-1), which blocks the interaction with its cognate ligands, PD-L1 and PD-L2. PEM blocks the protective mechanism of cancer cells and allows the immune system to destroy them. Combination Ctx and immunotherapy has shown efficacy in other malignancies including small cell lung cancer. The purpose of this study is to test the efficacy, safety, and tolerability of combination CTx with PEM in patients with high-grade GEPNEC or LCNEC of the lung who are CTx naïve. Methods: This is an open label, phase II, single institution, multi-site trial using PEM in combination with either cisplatin or carboplatin and etoposide in patients with high grade GEPNECs or LCNEC of the lung who are CTx naïve. Patients with a histologic diagnosis of a GEPNECs with a Ki-67 of 55% or higher or a LCNEC of the lung will be eligible. Patients must be metastatic or unresectable; chemotherapy naïve; have at least one measurable lesion per RECIST 1.1, have an ECOG performance score of 0-1; and have a predicted life expectancy > 3 months. Approximately 36 GEPNEC and 6 LCNEC of the lung patients will be enrolled. Patients will receive PEM 200mg IV in combination with cisplatin 80 mg/m2 or carboplatin AUC 6 on day 1 and etoposide 100mg/m2 on days 1-3 of a 21-day cycle. Tumor response will be assessed by CT scan every 6 weeks using RECIST 1.1. Those patients who have responsive or stable disease after 4-6 cycles of platinum-based CTx will move to maintenance PEM every 3 weeks for up to 2 years. The primary endpoint will be progression free survival. Results: This study is open to enrollment. Clinical trial information: NCT03901378.
Demoralization and depression in pancreatic cancer patients.
Authors: Liu Jar-Yee , Placencio-Hickok Veronica , Anderson Brian , Oberstein Paul Eliezer , Coveler Andrew L. , Denlinger Crystal S. , Gong Jun , Hendifar Andrew Eugene
Published: February 2020

TPS778

Background: Demoralization is a maladaptive coping response to stressful situations characterized by thoughts of hopelessness, helplessness, and loss of meaning and purpose. Psychometrically, it is measured using the Demoralization-Scale II (DS-II), a validated questionnaire that yields a patient-reported quantification (scale 0-32) of demoralization. Previous studies involving patients with progressive disease have uncovered a strong positive correlation between demoralization and depression, respectively measured by the DS-II and Patient Health Questionnaire-9 (PHQ-9) surveys. Here, we aim to characterize demoralization and its relationship to depression in pancreatic cancer patients, a unique patient population in terms of its poor prognosis. We hypothesize that demoralization is highly prevalent in the pancreatic cancer patient population and strongly correlated with depression. Methods: Eligible patients with an active pancreatic cancer diagnosis, after consenting to an IRB approved protocol, will be administered the DS-II and PHQ-9 surveys to yield psychometric measurements for analysis. The primary objective of this project is to determine the association between demoralization (DS-II) and depression (PHQ-9) in pancreatic cancer patients. Secondary objectives include associations between demoralization and ethnicity, sexual orientation, suicidal ideation, education, cancer stage, and disease progression. Data will be analyzed via simple linear regression. An ANOVA will also be conducted using DS-II groups as the categorical variable and PHQ-9 scores as the continuous variable, and vice versa. This is a multi-institutional study to be conducted at Cedars-Sinai Medical Center, New York University, University of Washington, UC San Francisco, and Lewis Katz Schools of Medicine.
Tyme-88-Panc Part 2: A randomized phase II/III of SM-88 with MPS as third-line in metastatic PDAC.
Authors: Pant Shubham , Chawla Sant P. , Chung Vincent , Del Priore Giuseppe , Kim Dae Won , Noel Marcus Smith , Oberstein Paul Eliezer , Ocean Allyson J. , Philip Philip Agop , Picozzi Vincent J. , Simeone Diane M , Wang-Gillam Andrea
Published: February 2020

TPS789

Background: Patients with metastatic pancreatic cancer who have progressed on two prior lines of therapy have a poor prognosis with an overall survival in the range of 2-2.5 months. (Manax, et al. J Clin Oncol 37, 2019 suppl 4; abstr 226). There is currently no standard of care for these patients that has demonstrated improved outcomes. SM-88 (D,L-alpha-metyrosine; racemetyrosine [USAN]) is a proprietary dysfunctional tyrosine derivative and is the backbone of SM-88 used with MPS (Methoxsalen 10mg, Phenytoin 50mg and Sirolimus 0.5mg; all administered daily). SM-88 monotherapy was relatively well tolerated, with improvement in survival in select patients with heavily pretreated PDAC who achieved stable disease on therapy (HR 0.08, p = 0.02). Circulating tumor cells (CTC’s) were prognostic and decreased on therapy with SM-88 potentially identifying a subgroup of PDAC that may be most likely to benefit from therapy (Noel et al. Annal Oncol V30, Suppl 4, 2019). Preliminary radiomic analysis of the largest metastases at baseline suggested the same benefits including a correlation with baseline CTCs, changes in CTCs on therapy and OS (Ocean et al, Annal Oncol, V30, Suppl 5, 2019). Here, we describe a randomized, open-label, phase 2/3 trial evaluating the efficacy of SM-88 + MPS vs physician’s choice treatment as third line therapy for patients with metastatic PDAC. Methods: This is a multi-center Phase 3 study of patients ≥18 years with metastatic PDAC that progressed after 2 lines of chemotherapy (gemcitabine [gem] and 5-fluorouracil [5-FU] based) with an ECOG <2. Randomization will be 1:1 with 250 patients being stratified by site, ECOG, and choice of chemotherapy. SM-88 will be administered at a dose of 460mg twice daily (920 mg/day). Primary end point is Overall Survival (OS). Secondary end points include progression free survival, response rate, duration of response, pharmacokinetics, safety and CTCs. Clinical trial information: NCT03512756.
Immune checkpoint inhibitor use in cancer patients with a pre-existing history of autoimmune disorders.
Authors: Tawagi Karine , Simenson Victoria , Yuan Helen , Velasco-Gonzalez Cruz , Johnson Daniel , Matrana Marc Ryan
Published: February 2020

100

Background: Patients with a history of autoimmune disorders (AID) were generally excluded from immune checking inhibitor (CPI) trials because of concerns that these individuals might be at greater risk for developing serious immune-related adverse events (irAEs). This presents a knowledge gap, because a significant proportion of cancer patients also carry a diagnosis of AID. Methods: We retrospectively collected data from patients with AID treated with CPI at a single institution. irAEs were assessed using the CTCAEv5 criteria. Response was assessed using RECIST v1.1. Results: Of 47 cancer patients with a broad spectrum of malignancies and AIDs, 45% had active AID symptoms at the time of CPI initiation, of which 19% were on steroid-sparing agents (SSAs), 11% were on steroids, and 9% were on simultaneous steroids and SSAs. A total of 12 patients (25%) developed an AID flare, of which 100% were grade 1 or 2. Of these patients, 11 required systemic steroids, with 6 patients (55%) requiring greater than 12 weeks of oral steroids, and 3 patients required discontinuation of their CPI. Conventional irAEs developed in 10 patients (21%), of which 4 patients required systemic steroids, and 3 patients (27%) required discontinuation of their CPI. Efficacy outcomes for these patients, including radiographic response, will be available at time of data presentation. Conclusions: AID exacerbations or new irAES occurred in 25% and 21% of patients with a history of AID respectively, and were generally manageable. Only a minority of patients required cessation of their CPI due to toxicity.
A digital therapeutic for proactive monitoring of patients on immune checkpoint inhibitor therapy for early detection of immune-related adverse events.
Authors: Singhal Shyamali Mallick , Dormady Shane , Li Jiali , Singhal Shiva , Chin Lynda
Published: February 2020

101

Background: Immune-related adverse events (irAEs) occur frequently in patients receiving immuno-oncology therapy. irAEs are heterogeneous and unpredictable. Experience at academic cancer centers has shown that (1) education of patients and families must be continuous; (2) experience of the care team can improve outcomes; and (3) close monitoring of patients in between visits translate into early detection and timely intervention. Most oncologists in lower volume community practices have not gained the experience nor have the resource for continuous education frequent proactive monitoring. Methods: In addition to self-monitoring by patients on chemotherapy to improve outcome (Basch ref), we hypothesized that adoption of evidence-based management is critical as well. Thus, we have developed ApricityRx, a digital therapeutic (DTx) for end-to-end irAE management, which not only engages patients in frequent self-nonitoring but also activates the oncology team for timely intervention. In brief, ApricityRx (i) enables intelligent monitoring by educating and guiding patients to track specific expert-prioritized symptoms in between clinic visits; (ii) facilitates early recognition by prompting triage at the right time and (iii) recommends evidence-based management based on consensus guidelines. Results: In a community cancer center, 16 patients have been enrolled (44% consent rate) in an IRB approved feasibility trial to evaluate the usability of ApricityRx as a tool for frequent monitoring and timely triage. Over 435 unique longitudinal records containing over 34K data points, including patient-reported outcome (PRO) and clinical care data (EMR), were generated. Interim analyses have shown that primary and secondary endpoints were met. Detailed results will be presented. Conclusions: ApricityRx has shown usability in a low-volume community-based oncology practice to facilitate proactive monitoring and tinely triage by the oncology team. Further, ApricityRx has enabled not only generation of high-resolution patient-reported outcome (PRO) data, but also aggregation of PRO and real-world EHRs data for downstream analyses.
Efficacy and safety of yttrium-90 ibritumomab tiuxetan in the treatment of non-Hodgkin lymphoma.
Authors: Doyle Catherine , Smith Johnna , Bello Celeste M. , Sokol Lubomir , El-Haddad Ghassan
Published: February 2020

103

Background: Yttrium 90-labeled ibritumomab tiuxetan (Zevalin) is a radioimmunotherapy agent which combines the action of a beta-emitting isotope, yttrium-90, with the anti-CD20 monoclonal antibody, rituximab. The purpose of this study was to evaluate the efficacy of Zevalin in the treatment of Non-Hodgkin Lymphoma (NHL) in terms of response to therapy, overall survival (OS) and progression free survival (PFS). Methods: A total of 171 patients with NHL referred for treatment with Zevalin between September 2005 and January 2017 were identified for retrospective analysis. Clinical characteristics, treatments, and outcomes were extracted from clinical chart review. Survival rates and survival curves were generated using Kaplan-Meier analysis. Chi-square and independent student t test were used for comparison of categorical variables. Multivariate analysis (MVA) Cox proportional hazards ratios (HR) model was used to assess OS and PFS. Results: Of the 171 patients referred for treatment, median age was 70 years old, 54% were male (n = 93), and each patient had received a median of 2 prior chemotherapy regimens. The majority of patients were treated for follicular lymphoma (n = 107) and diffuse large B-cell lymphoma (n = 34). Seventy-three patients (53%) achieved complete response, and 23 patients achieved partial response (17%). One-year progression free survival was 71%, and median PFS was 31 months. Adverse events included cytopenic events, GI side effects, and mucocutaneous toxicity. Conclusions: Use of Zevalin for treatment of NHL demonstrated a significant improvement in PFS. In addition to improved efficacy, Zevalin was well-tolerated in this study and demonstrated an adequate safety profile. Further considerations will be given as to which treatment factors are associated with a complete response and improved PFS.
Immune monitoring of blood in advanced gastroesophageal adenocarcinoma patients treated with an anti-MMP9 monoclonal antibody in combination with nivolumab.
Authors: Kitano Shigehisa , Yamashita Makiko , Muro Kei , Satoh Taroh , Yamaguchi Kensei , Kadowaki Shigenori , Sakai Daisuke , Ichimura Takashi , Mitani Seiichiro , Kudo Toshihiro , Chin Keisho , Fukui Masato , Bhargava Pankaj , Brachmann Carrie , Zavodovskaya Marianna
Published: February 2020

13

Background: A phase 1b study was conducted in Japanese patients with >2nd line advanced gastroesophageal adenocarcinoma (GEA) to evaluate the safety, tolerability and explore efficacy and biomarkers, of andecaliximab (ADX), an anti-MMP9 monoclonal antibody, in combination with nivolumab (nivo). In this study, 5 of the 10 enrolled patients had a partial response and the remaining 5 had progressive disease. A larger parallel study in western patients showed no improvement in response or survival for the addition of ADX to nivo. A biomarker study is reported here which explored the hypothesis that baseline levels or early changes in the frequency of peripheral immune cells might identify responders to immunotherapy. Methods: Blood samples were collected at screen, C1D1, C1D8, C1D15, C2D1, C2D15 and then at CXD1 until end of treatment and processed to viably-frozen PBMCs. Immune cell analysis was conducted by flow cytometry (FCM), and included evaluation of T cells, B cells, myeloid derived suppressor cells, NK cells, monocytes, and dendritic cells (DCs). Baseline status and on treatment changes were explored. Results: FCM analysis of peripheral blood showed that the 5 responders had higher frequency of LAG3+CD8+ T cells and myeloid DCs, and lower frequency of plasmacytoid DC than non-responders at baseline. The number of CD8+ T cells decreased at C1D8 and then recovered in responders. In contrast, no CD8+ T cell changes were observed in non-responders. CTLA-4+ CD4+ T cells also increased after treatment in responders but not in non-responders. Changes in other evaluated cell populations were not observed. Conclusions: The observation that baseline levels of LAG3+CD8+ T cells and DCs were higher in responders is consistent with a prior anti-tumor immune response. Transient decreased peripheral CD8+ T cells might reflect T-cell trafficking into tumor in response to immunotherapy, and increased peripheral CTLA-4+ CD4+ T cells may also relate to tumor-localized response. Although in a very small number of patients, the observations are consistent with early changes in peripheral immune cells that may relate to response to immunotherapy. Clinical trial information: NCT02862535.