bluuebunny/crossref_metadata_2025 huggingface dataset:
Radiation exposure from diagnostic CT for young patients with colon cancer in the first 5 years after diagnosis.
Authors: Lumish Melissa Amy , Tan Gary , Mahmood Usman , Dauer Lawrence , Cercek Andrea , Bates David
Published: January 2023

90

Background: Given the rise in colorectal cancer (CRC) in younger patients, this study aims to analyze the radiation exposure received by early onset colorectal cancer patients from diagnostic imaging performed in the first 5-years from diagnosis. Methods: A retrospective review of all patients (age ≤ 50 y) with stage I-III CRC who received at least 5 surveillance or staging body computed tomography (CT) scans in the 5 years from diagnosis was performed beginning in October 2015. The volume CT dose index (CTDIvol) and dose length product (DLP) were extracted; a previously validated Monte Carlo (MC) based software, VirtualDose (Virtual Phantoms, Inc., Albany, NY), was used to estimate organ dose to 19 organs based on the imaging mode parameters. The effective doses were calculated based on methods set forth in the International Commission on Radiological Protection ICRP No. 103 Publication. Results: A total of 107 patients were included (age range 25-50 years, median 44 years). The average effective dose per CT scan was 15.0 mSv range: 11.6 to 22.6 mSv) for male (n = 62) and 13.4 mSv (8.04 to 17.5 mSv) for female (n = 45) patients. The cumulative effective dose was greater than 100 mSv for 9 (8.4%) of patients and between 50 to < 100 mSv for 28 (26.2%) of the patients in this study. Of the 107 patients, 23% (n = 25) of the patients recurred during the first 5 years. Conclusions: The majority of early-onset colorectal cancer patients in this study received a cumulative dose under 100 mSv, which is considered low risk according to a policy statement by the International Organization for Medical Physics. Since the majority of patients in this study received what is considered a low cumulative radiation dose from repeated CT imaging during the 5-year period after diagnosis, this may provide reassurance that repeated CT imaging, particularly for surveillance, is warranted. Individual risk will vary but the clinical benefits of clinical imaging outweigh the small, if any, risk of radiation-induced cancers in this patient cohort. [Table: see text]
Phase 1 dose-finding trial of cabozantinib (cabo) and trifluridine/tipiracil (FDT/TPI) in metastatic colorectal carcinoma (mCRC).
Authors: Dayyani Farshid , Balangue Jasmine , Valerin Jennifer Brooke , Zell Jason A. , Taylor Thomas H , Cho May Thet
Published: January 2023

98

Background: Salvage treatments for refractory mCRC are an unmet need. This study determined the safety and Recommended Phase 2 Dose (RP2D) of the multi-kinase inhibitor Cabo in combination with FDT/TPI in mCRC. Methods: Single institution investigator-initiated phase 1 study using 3+3 design. Patients (pts) with mCRC previously treated with a fluoropyrimidine, oxaliplatin, irinotecan and appropriate biologics were eligible. Cabo was given orally (p.o.) at 20 mg (dose level [DL] 0) or 40 mg (DL 1) daily on days 1-28, and FTD/TPI p.o. at 35 mg/m2 on days 1-5 and 8-12 every 28 days. Prophylactic growth factors were allowed. The primary endpoint was Dose Limiting Toxicity (DLT) at 28 days. Secondary endpoints included overall survival (OS), progression-free survival (PFS), objective response rate and CEA response. Results: 12 pts were enrolled. Median age 57 years (31-80), male (9/12), ECOG 0/1 = 7/5, Caucasian/Hispanic/Asian = 7/4/1. 3 pts were treated at DL 0 with no observed DLT. Another 9 pts (n = 6 pts to determine RPD2 and additional n = 3 pts in expansion) were treated at DL 1, none exhibiting a DLT. The most common any grade (G) treatment related adverse events (TRAE) were diarrhea (50%), nausea (42%), neutropenia (42%), fatigue (33%) and rash (25%). G3-4 TRAE in > 5% of patients were neutropenia (25%) and thrombocytopenia, hypokalemia, weight loss (each 8%). No serious TRAE or G5 were reported. The RP2D was determined to be DL 1. Median PFS and OS were 4.1 (95% CI 1.9-6.8) and 6.7 (95% CI 2.2-not evaluable) months, respectively. The disease control rate was 75%. 5/12 (42%) pts had a CEA decline > 30%. Conclusions: The combination of Cabo and FTD/TPI is feasible and tolerable and showed encouraging clinical activity in refractory mCRC. Additional pts are being enrolled at DL 1 and will be presented at the meeting. Clinical trial information: NCT04868773 .
TRIDENTE trial: A phase II study of rechallenge with encorafenib, binimetinib, and cetuximab in patients with RAS wild-type/BRAF V600E–mutant metastatic colorectal cancer.
Authors: Kotani Daisuke , Kagawa Yoshinori , Matsubara Yuki , Bando Hideaki , Harada Kazuaki , Takahashi Naoki , Mihara Yoshiaki , Nakayama Izuma , Izawa Naoki , Kawakami Takeshi , Masuishi Toshiki , Hasegawa Hiroko , Ohta Takashi , Wakabayashi Masashi , Yoshino Takayuki
Published: January 2023

TPS264

Background: The BEACON CRC trial demonstrated survival benefit of combination therapy with encorafenib (ENCO) + cetuximab (CET) +/- binimetinib (BINI) in patients with RAS wild-type (WT)/ BRAF V600E mutant metastatic colorectal cancer (mCRC). However, prognosis of those patients still be poor after the refractoriness to the BEACON combination therapy. One of resistant mechanisms to BRAF inhibitor has been reported as MAPK alterations including RAS mutation, similar to those for anti-EGFR antibody in patients with RAS/ BRAF V600E WT mCRC. Promising results of rechallenge therapy with anti-EGFR antibody in patients with RAS/ BRAF V600E WT mCRC and with combination of BRAF inhibitor + MEK inhibitor in patients with BRAF V600 mutant melanoma suggest the treatment strategy of rechallenge therapy with the BEACON triplet therapy in patients with RAS WT/ BRAF V600E mutant mCRC. Methods: TRIDENTE trial is a multicenter phase II trial to assess efficacy and safety of rechallenge therapy with ENCO + BINI + CET in patients with RAS WT/ BRAF V600E mutant mCRC after the refractoriness to either the BEACON doublet or triplet therapy. Key eligibility criteria includes RAS WT/ BRAF V600E mutant mCRC; ≥ 20 years old; ECOG PS 0-1; refractory or intolerant to at least one fluoropyrimidine-based regimen (including irinotecan or oxaliplatin); refractory or intolerant to anti-PD-1 antibody if patients with MSI-high; history of previous combination therapy containing ENCO + CET with at least partial response by RECIST v1.1; confirmed disease progression within 4 weeks after last administration of previous ENCO; ≥ 4 months of period between the last administration of previous ENCO and the start of study treatment. Enrolled patients receive the combination therapy with ENCO (300 mg, QD), BINI (45 mg, BID), and CET (initially 400 mg/m2, and subsequently 250 mg/m2, QW) as the study treatment. Primary endpoint is the objective response rate (ORR) by investigators’ assessment in patients receiving at least one dose of study treatment. A target sample size is calculated to be 21 on the hypothesis that the threshold ORR is 3% and expected ORR is 20%, with a significant level of 5% (one-sided) and power of 80%. Secondary endpoint includes progression-free and overall survivals, disease control rate, and safety. Exploratory molecular analysis is performed using targeted next-generation sequencing in circulating-tumor DNA at the timepoints of baseline and discontinuation of study treatment. As of September 19, 2022, 8 patients have been enrolled. Clinical trial information: jRCTs031210511 .
STELLAR-303: A phase 3 study of XL092 in combination with atezolizumab versus regorafenib in patients with previously treated metastatic colorectal cancer (mCRC).
Authors: Hecht J. Randolph , Tabernero Josep , Parikh Aparna Raj , Wang Yijia , Wang Zhong , Schwickart Martin , Curran Dominic , Saeed Anwaar
Published: January 2023

TPS267

Background: The prognosis of patients with mCRC is poor, with a 5-year survival rate of 14% (American Cancer Society 2020). Patients who have progressed after front-line chemotherapy have limited treatment options. Regorafenib or trifluridine-tipiracil are approved for patients in the third- or later-line setting, but survival benefit is limited. While immune checkpoint inhibitor (ICI) therapy is approved (nivolumab ± ipilimumab, and pembrolizumab) in patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) mCRC, the MSI-H phenotype is limited to ~5% of mCRC patients. In phase 1/2 trials, ICIs in combination with VEGFR2 multi-kinase inhibitors (MKIs) have demonstrated encouraging clinical activity in mCRC, including atezolizumab and durvalumab (ICIs) in combination with the MKI cabozantinib, with data suggesting a greater benefit in RAS wild-type (wt) vs mutant (mut) disease (Abrams TA, et al. ASCO GI 2022:Abs 121; Saeed A, et al. ASCO GI 2022:Abs 135). XL092 is a novel MKI, targeting MET, VEGFR2, and the TAM kinases AXL and MER; the relatively short half-life (~21 hours) of XL092 is favorable for once-daily (QD) dosing and dose modification to manage tolerability. STELLAR-303 is a phase 3 study evaluating the efficacy and safety of XL092 + atezolizumab versus regorafenib in patients with previously treated RASwt or RASmut mCRC. Methods: STELLAR-303 (XL092-303; NCT05425940) is a global, open-label, randomized phase 3 study. Eligible patients are ≥18 years old and have mCRC that is measurable per RECIST v1.1, are documented not to have MSI-H or dMMR disease, and have an ECOG performance status of 0–1 and adequate organ function. RAS and MSI/dMMR status must be determined by a tissue-based analysis. Patients must have progressed during/after or be intolerant to standard-of-care treatments for mCRC; prior regorafenib, trifluridine/tipiracil, or PD-L1/PD-1 ICIs are not allowed. Patients are randomized 1:1 to XL092 100 mg PO QD + atezolizumab 1200 mg IV Q3W or to regorafenib 160 mg PO QD (21 days of 28-day cycle); randomization is stratified by geographic region (Asia vs other), RAS status (wt vs mut), and liver metastases (yes/no). The study plans to enroll 600 patients (400 RASwt and 200 RASmut). The primary endpoint is overall survival in the RASwt population, with additional efficacy endpoints of progression-free survival, objective response rate, and duration of response per RECIST v1.1 by investigator; efficacy endpoints will also be assessed in the overall study population and in patients with RASmut mCRC. Additional endpoints will assess safety, quality of life, changes in biomarkers, pharmacokinetics, immunogenicity of atezolizumab, and healthcare utilization. Enrollment is ongoing. Clinical trial information: NCT05425940 .
SEAMARK: Randomized phase 2 study of pembrolizumab + encorafenib + cetuximab vs pembrolizumab alone for first-line treatment of BRAF V600E–mutant microsatellite instability–high (MSI-H)/mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC).
Authors: Kopetz Scott , Bekaii-Saab Tanios S. , Yoshino Takayuki , Chung Chin-Hee , Zhang Xiaosong , Tabernero Josep
Published: January 2023

TPS268

Background: Among patients with MSI-H/dMMR CRC, BRAF mutations occur in approximately 30%. MSI-H/dMMR and BRAF mutations are both associated with poor prognosis; in patients who have both biomarkers, poor prognosis is thought to be driven by the BRAF mutation. Pembrolizumab is indicated for the treatment of patients with MSI-H/dMMR unresectable or metastatic CRC (mCRC). The BRAF inhibitor encorafenib, in combination with cetuximab, an anti-EGFR antibody, is indicated for previously treated patients with BRAF V600E-mutant mCRC. Currently, there are no first-line treatment options indicated specifically for patients with both MSI-H/dMMR and BRAF V600E-mutant mCRC. To assess the safety and efficacy of combining pembrolizumab with encorafenib + cetuximab, the SEAMARK study will evaluate this combination vs pembrolizumab alone in patients with previously untreated BRAF V600E-mutant MSI-H/dMMR mCRC. Methods: SEAMARK (NCT05217446) is an open-label, multicenter, randomized, phase 2 study. Approximately 104 patients (randomized 1:1; stratified by Eastern Cooperative Oncology Group Performance Status [ECOG PS] 0 vs 1) will receive either pembrolizumab + encorafenib + cetuximab or pembrolizumab. Enrolled patients must be aged ≥16 or ≥18 years (per country-specific regulations) and have previously untreated BRAF V600E-mutant MSI-H/dMMR mCRC; measurable disease (Response Evaluation Criteria in Solid Tumors 1.1); ECOG PS 0 or 1; and adequate bone marrow, hepatic, and renal function. Patients who received prior treatment with BRAF/EGFR inhibitors or immune checkpoint inhibitors, or who have brain metastases (unless radiologically stable) or RAS mutation (or unknown RAS status), will be excluded. The primary endpoint is investigator-assessed progression-free survival. Secondary endpoints include safety and tolerability, overall survival, objective response rate, duration of response, and quality of life. Enrollment started in July 2022. Clinical trial information: NCT05217446 .
Durvalumab (MEDI 4736) with extended neoadjuvant regimens in rectal cancer: A randomised phase II trial (PRIME-RT).
Authors: Roxburgh Campbell SD , Hanna Catherine Ruth , Graham Janet , Saunders Mark P. , Samuel Leslie M. , MacLeod Nicholas James , Devlin Lynsey , Edwards Joanne , Hillson Lily , McMahon Ross K , Jones Leia Ashleigh , Kelly Caroline , Lewsley Liz-Anne , Morrison Paula , Atherton Peter , Walker Nicola , Gourlay Jacqueline , Tiplady Ellie , Adams Richard , O'Cathail Sean Michael
Published: January 2023

TPS282

Background: Advances in multi-modality treatment of locally advanced rectal cancer (LARC) have resulted in low local recurrence rates, but many patients still die from distant disease. There is increasing recognition that with neoadjuvant treatment some patients achieve a complete response and may avoid surgical resection. PRIME-RT tests the inclusion of neoadjuvant immunotherapy with the aim of enhancing complete response rates, improving stoma-free survival and reducing distant relapse. Methods: PRIME-RT is a multi-centre, open label, phase II, randomised trial for patients with newly diagnosed LARC. Eligible patients are randomised to Arm A: short course radiotherapy (25 Gray in 5 fractions) with concomitant durvalumab, followed by durvalumab and FOLFOX chemotherapy, or Arm B: long course chemoradiotherapy (50 Gray to primary tumour, 45 Gray to elective nodes, in 25 fractions with capecitabine) with concomitant durvalumab followed by FOLFOX and durvalumab. The primary endpoint is complete response rate in each arm. Bio-specimens including serial tumour biopsies and peripheral blood samples are collected prior to, during, and following treatment to explore the molecular and immunological factors underpinning treatment response. The main trial will recruit up to 42 patients and commence after a safety run-in which is recruiting patients with metastatic disease. After opening in January 2021, the four patients completed the safety run in and the main trial commenced in March 2022. The trial is currently open across 5 UK sites. Up to date recruitment details will be provided at the time of presentation but at the time of writing this is ahead of target. Early recruitment to PRIME-RT has shown that adding immunotherapy in the neoadjuvant setting for LARC is feasible. Furthermore, on treatment biospecimen collection is also feasible across multiple sites. The expectation is that the trial will provide efficacy and safety information which allows the optimal treatment approach to be tested within a larger phase clinical trial. Core funding (Glasgow CRUK CTU) and trial-specific funding (Astrazeneca). Clinical trial: NCT04621370; ISRCTN18138369. Clinical trial information: ISRCTN18138369 .
Trial in progress: A phase II, multicenter, open-label study of PolyPEPI1018 in combination with atezolizumab in participants with relapsed or refractory microsatellite-stable metastatic colorectal (MSS mCRC) cancer (Oberto-301).
Authors: Hubbard Joleen M. , Ahn Daniel H. , Jones Jeremy Clifton , Wittenberger Kathleen , Molnar Levente , Lorincz Orsolya , Somogyi Eszter , Csiszovszki Zsolt , Youssoufian Hagop , Toke Eniko Rita
Published: January 2023

TPS283

Background: Colorectal cancer (CRC) is among the top three most commonly occurring cancers globally. CRC is now routinely classified as MSI-high (MSI-H) or microsatellite-stable (MSS) based on the detection or absence of molecular markers of genetic instability, respectively. The efficacy of checkpoint inhibitor immunotherapy in MSI-H CRC has not been replicated in MSS CRC. Therefore, additional interventions are needed to convert immunologically “cold” MSS CRC to “hot” tumors resembling MSI-H tumors. PolyPEPI1018 is an off-the-shelf, multi-peptide vaccine containing 12 immunogenic epitopes derived from 7 cancer testis antigens (CTAs) frequently expressed in patients with CRC. PolyPEPI1018 successfully restored and boosted pre-existing anticancer immunity of MSS mCRC subjects and triggered recruitment and infiltration of cytotoxic T cells into the tumor. In first line metastatic MSS CRC, PolyPEPI1018 in combination with fluoropyrimidine/bevacizumab vaccine was safe and demonstrated early evidence of clinical activity. Therefore, we hypothesized that the combination of PolyPEPI1018 and atezolizumab will convert a “cold” MSS mCRC to a “hot” tumor and may increase the likelihood of inducing favorable antitumor immunity and subsequent clinical benefit. Methods: The study is a phase 2, multicenter, single-arm clinical trial of PolyPEPI1018 vaccine (1.2 mg, sc, every 3 weeks) and atezolizumab (1200 mg, iv, every 3 weeks) for patients with advanced or metastatic MSS CRC who have progressed on 2 or 3 lines of prior standard regimens. 28 patients will be enrolled at 3 US sites with a primary objective to assess the safety and tolerability of multiple doses of PolyPEPI1018 in combination with atezolizumab. Secondary endpoints include objective response rate (ORR) assessed by RECIST v1.1, vaccine induced immunological response rate (IRR), progression-free survival and overall survival. Correlative aims include assessing blood and tissue biomarkers (PD-L1, Immunoscore®IC, ctDNA, clinical tumor markers) for association with clinical benefit. An exploratory study is being conducted for co-development of a companion diagnostic based on HLA-genotype and computational personal epitope (PEPI) prediction test. A Simon 2-stage design will be used for the initial assessment of ORR. If pre-specified activity goal for the first stage of accrual (n = 18) is met, additional 10 participants will be enrolled to the second stage. A formal review of safety will be performed after the initial 6 participants have received at least 2 cycles of study therapy. The study is open with 10 patients enrolled at time of submission. Clinical trial information: NCT05243862 .
TST001 (a high affinity humanized anti-claudin18.2 monoclonal antibody) in combination with nivolumab plus capecitabine and oxaliplatin as first-line or with nivolumab as late-line treatment in locally advanced and metastatic gastric/gastroesophageal junction (G/GEJ) cancer: Design of cohorts from a phase I/IIa study (TST001-1002).
Authors: Guo Weijian , Germa Caroline , Qi Chuan , Qian Chunhua , Yao Jenny , Wang Jianming , Zhang Lijuan , Qian Xueming , Xia Zhenzhong
Published: January 2023

TPS476

Background: TST001 (osemitamab) is a high affinity recombinant humanized ADCC enhanced antibody that can specifically bind to the extracellular structure of claudin 18.2 protein and eliminate cancer cells by antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Pre-clinical studies have shown that TST001 has potent single agent anti-tumor activity and synergistic effect when used in combination with immune checkpoint inhibitors in claudin 18.2 positive tumors. In the ongoing phase I/IIa clinical trial (NCT04495296), TST001 alone or in combination with capecitabine and oxaliplatin (CAPOX) in the treatment of G/GEJ adenocarcinoma has revealed encouraging preliminary efficacy (IGCC 2022, ESMO 2022). The combination of TST001 with nivolumab (in 2nd/3rd line treatment) or nivolumab + standard of care chemotherapy (in 1st line) are being explored in the same study. Methods: Each cohort includes a dose escalation phase in CLDN18.2 non-selected patients and a dose expansion phase in CLDN18.2 positive patients, aiming to identify the recommended Phase 2 dose and evaluate the safety, tolerability and preliminary efficacy of TST001 in combination with nivolumab plus CAPOX or nivolumab in patients with G/GEJ adenocarcinoma. First line, treatment naïve patients with HER2 negative or unknown, locally advanced or metastatic G/GEJ adenocarcinoma will receive 21 days cycles of TST001 combined with CAPOX plus nivolumab until disease progression or unacceptable toxicity, with oxaliplatin for a maximum of 8 cycles and capecitabine per investigator’s discretion after that; 2nd or 3rd line patients with locally advanced or metastatic G/GEJ adenocarcinoma will receive 21 days cycles of TST001 combined with nivolumab. AEs will be categorized by CTCAE v5.0. Efficacy will be evaluated every 6 weeks per RECIST1.1. These two cohorts will be initiated in September 2022 from about 40 sites in China. Combinations with nivolumab are being explored in the US study too (NCT04396821). Clinical trial information: NCT04495296 .
Combined intraperitoneal and systemic chemotherapy as adjuvant or perioperative chemotherapy for patients with type 4 scirrhous gastric cancer: PHOENIX-GC2 trial.
Authors: Ishigami Hironori , Omori Takeshi , Tsuji Yasushi , Shinohara Hisashi , Yabusaki Hiroshi , Kobayashi Daisuke , Takahari Daisuke , Hata Hiroaki , Kusumoto Tetsuya , Kanda Mitsuro , Oba Koji , Kitayama Joji , Seto Yasuyuki ,   Japan Intraperitoneal Chemotherapy Study Group
Published: January 2023

TPS477

Background: Despite recent progress in adjuvant and perioperative chemotherapy, the prognosis of patients with type 4 scirrhous gastric cancer remains poor due to a high risk of peritoneal metastasis. We have previously developed combination chemotherapy regimens of intraperitoneal (IP) paclitaxel (PTX) and systemic chemotherapy, and promising clinical efficacy was reported in gastric cancer with peritoneal metastasis. Herein, a multicenter, open-label, randomized, phase III study is proposed to verify the efficacy of IP PTX to prevent peritoneal recurrence. Methods: Gastric cancer patients with type 4 tumors and without apparent distant metastasis, including peritoneal metastasis, will be randomized for standard systemic chemotherapy or combined IP and systemic chemotherapy based on peritoneal lavage cytology findings. Those with negative peritoneal cytology will receive radical gastrectomy and adjuvant chemotherapy of S-1 plus docetaxel (control arm), or S-1 plus intravenous and IP PTX (experimental arm). Those with positive peritoneal cytology will receive three courses of S-1 plus oxaliplatin (control arm), or S-1 plus oxaliplatin and IP PTX (experimental arm). Subsequently, they undergo gastrectomy and receive postoperative chemotherapy of S-1 plus docetaxel (control arm), or S-1 plus intravenous and IP PTX (experimental arm). The primary endpoint is disease free survival after a 3-year follow-up period. Secondary endpoints are overall survival, survival without peritoneal metastasis, safety, completion rate, curative resection rate, and histological response of preoperative chemotherapy. A total of 300 patients are to be enrolled from 40 hospitals throughout Japan. Clinical trial information: jRCT2031200087 .
Single-arm phase II trial to evaluate the safety of laparoscopic/robotic total gastrectomy with spleen-preserving splenic hilar dissection for locally advanced proximal gastric cancer that invades the greater curvature: JCOG1809.
Authors: Kinoshita Takahiro , Yoshikawa Takaki , Ojima Toshiyasu , Omori Takeshi , Cho Haruhiko , Honda Michitaka , Nunobe Souya , Kurokawa Yukinori , Kuroda Shinji , Mizusawa Junki , Fukuda Haruhiko , Boku Narikazu , Terashima Masanori
Published: January 2023

TPS479

Background: The standard treatment for locally advanced proximal gastric cancer invading the greater curvature is “open total gastrectomy combined with splenectomy” (OTG+S) aiming for whole clearance of the splenic hilar lymph nodes. However, its pertinent postoperative severe complication (e.g. pancreatic fistula) is problematic. An objective of this study is to evaluate the safety of “laparoscopic or robotic total gastrectomy with spleen-preserving splenic hilar dissection” (LRSHD) as a new treatment option which has a potential to reduce surgical morbidity, subsequently to replace the current standard treatment, OTG+S. Methods: This is a multicenter single-arm phase II trial. The main eligibility criteria are as follows; clinical T2-4a resectable locally advanced proximal gastric adenocarcinoma that invades the greater curvature; without obvious lymph node metastasis at the splenic hilum nor direct invasion to the spleen/splenogastric ligament. Protocol treatment is laparoscopic or robotic total gastrectomy with splenic hilar lymph node dissection (D2 + No.10 lymphadenectomy according to the Japanese guidelines) in which the spleen is preserved with skeletonizing the splenic vessels. Quality control of surgery is assured by surgeon’s qualification and central peer review of intraoperative photo at the splenic hilum after dissection. The primary endpoint is the proportion of postoperative pancreatic fistula and/or intra-abdominal abscess formation with Clavien-Dindo Grade III or higher (within 30 days after surgery). Secondary endpoints are intraoperative blood loss, operation time, mortality, overall postoperative complication, number of yield splenic hilar nodes, number of metastatic splenic hilar nodes, conversion to splenectomy, conversion to laparotomy, relapse-free survival, and overall survival. Sample size was set as 85 patients to obtain 80% power considering that 15% of patients are judged as unresectable intraoperatively, with the hypothesis that the primary endpoint would have an expected value of 7% and a threshold value of 16% in one-sided alpha of 0.1. Planned accrual period is 5 years. The accrual began in August 2019. As of August 2022, 53 of the planned 85 patients (62.4%) have been enrolled. When the safety of LRSHD is proved by this study, a non-inferiority phase III trial will be consequently launched. Clinical trial registry number: UMIN000037580. Clinical trial information: UMIN000037580 .
A phase II study to evaluate anlotinib plus TQB2450 as adjuvant therapy in patients with esophageal squamous cell carcinoma (ALTER-E005).
Authors: Guo Changying , Chen Shengjia , Ye Yongqiang , Mao Wei-Min
Published: January 2023

TPS488

Background: About 30.3-58.0% of patients who undergo esophagectomy may experience recurrence. The efficacy of postoperative chemoradiation has not been demonstrated in a randomized trial in patients with esophageal squamous cell carcinoma (ESCC) compared to surgery along. Therefore, it is urgent to explore more effective and safer postoperative regimen for resectable ESCC. Checkmate 577 has demonstrated immunotherapy can prolong disease free survival (DFS) for patients who have residual disease following preoperative chemoradiation and R0 resection. Anlotinib is an orally administered tyrosine kinase inhibitor that targets VEGFR1-3, FGFR1-4 and PDGFRα/β. In a randomized, double-blind phase 2 trial, the use of anlotinib in previously treated metastatic ESCC patients significantly improved progression-free survival (PFS) compared with placebo ( NCT02649361 ). TQB2450 is a novel humanized monoclonal antibody against PD-L1, which has shown encouraging activity in combination with anlotinib in the treatment of multiple tumors, such as biliary tract cancer (NCT03996408) and ovarian cancer (NCT04236362). The ALTER-E005 study is designed to evaluate the efficacy and safety of anlotinib combined with TQB2450as adjuvant therapy in ESCC patients. Methods: ALTER-E005 is a multi-center, single-arm, phase II study. A total of 30 patients will be enrolled. Eligible pts (≥18 years) must be histologically confirmed T1-2N1-3M0 or T3-4NanyM0 ESCC; received radical (R0) resection of ESCC with no recurrence in imaging examination within 6-12 weeks after surgery; ECOG PS 0–1. Patients enrolled will receive oral anlotinib 12 mg on days 1-14 and intravenous TQB2450 1,200 mg on day 1 every 3 weeks until disease recurrence. The primary endpoint is DFS. The secondary endpoints include safety, 1-year DFS rate, 3-year DFS rate, 1-year overall survival (OS) rate, and 3-year OS rate. Enrollment to the ALTER-E005 trial is currently ongoing in China. Clinical trial information: NCT05252078 .
Phase 1/2 trial of vesicular stomatitis virus expressing human interferon-β and NIS (VSV-IFNβ-NIS), with pembrolizumab, in patients with neuroendocrine carcinoma.
Authors: McGarrah Patrick Walsh , Naik Shruthi , Halfdanarson Thorvardur Ragnar , Leventakos Konstantinos , Peng Kah Whye , Russell Stephen J. , Adjei Alex A. , Molina Julian R.
Published: January 2023

TPS657

Background: Poorly differentiated neuroendocrine carcinoma (NEC) is an aggressive malignancy comprising both pulmonary and extrapulmonary primary sites. NEC includes both small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC), as well as other neuroendocrine carcinomas arising from any primary organ. A substantial portion (~40%) of NEC arises from gastrointestinal primary sites. The optimal systemic therapy beyond first line platinum and etoposide is not established. There is a critical need to improve upon the median survival in the second line, as most patients do not survive more than 6 months. The efficacy of single agent immune checkpoint inhibitors (ICIs) in NEC has been disappointing. One possible explanation for this is that the tumor microenvironment in NEC is non-inflamed. VSV-IFNβ-NIS is a vesicular stomatitis virus (VSV)-based oncolytic virus being tested in multiple early phase clinical trials. Preliminary studies of immune responses in patients receiving VSV-IFNβ-NIS therapy suggest some patients develop T cell responses to viral antigens and known tumor antigens. We hypothesize that VSV-IFNβ-NIS therapy may convert a non-inflamed or immune-excluded phenotype in NEC to a highly inflamed phenotype that sensitizes the tumor to ICIs. Methods: This is a phase 1-2 safety run-in study designed to determine the safety of VSV-IFNβ-NIS in combination with a single agent ICI, pembrolizumab, followed by dose expansion in patients with refractory non-small cell lung cancer (NSCLC) or NEC. The safety run-in portion of this study has been completed, and we are presently testing the recommended phase 2 dose (RP2D) of VSV-IFNβ-NIS in an expansion cohort of patients with SCLC or NEC of any primary site. Patients must have previously progressed on at least one line of systemic therapy. Prior treatment with checkpoint inhibitors is permitted. Patients are treated one time with the RP2D of 1.0x10^11 TCID50 VSV-IFNβ-NIS on day 1, followed by pembrolizumab on day 8 and then pembrolizumab every 21 days until progression, up to 2 years. The primary objective is to estimate the response rate by RECIST 1.1. Secondary objectives include estimation of disease-control rate, duration or response, progression-free survival, overall survival, and safety signals. The NEC expansion cohort will seek to enroll 10 patients. If at least one objective response is observed, and safety is confirmed, the regimen will be considered for future study. Clinical trial information: NCT03647163 .
Natural history study and tissue procurement of neuroendocrine neoplasms (NENs).
Authors: Mallorson Rosa , Cortez Briana N. , Varghese Diana Grace , Naimian Amirkia , Magee Tamika , Kelley Sarah , Kumar Suresh , Roper Nitin , Pommier Yves , Del Rivero Jaydira
Published: January 2023

TPS659

Background: Neuroendocrine neoplasms (NENs) are a rare spectrum of malignant neoplasms originating from neuroendocrine cells, most commonly affecting the gastrointestinal tract, pancreas, and lungs. Tumors may vary from low grade neuroendocrine tumors (NET) to high grade neuroendocrine carcinomas (NEC). The annual occurrence of NENs is increasing worldwide and currently the incidence in the US is about 6 cases per 100,000 people per year. A variety of therapeutic options are available for advanced NENs, however, when to apply a given option, what combination therapeutic approach should be used, how long treatment should be continued is unclear and controversial. Moreover, unlike common cancers, pre-clinical models for NENs are sorely limited. Without robust pre-clinical models our understanding of tumor pathophysiology and novel drug development can be challenging. Methods: A prospective study to evaluate the natural history and sample acquisition of NENs comprehensively and longitudinally. Patients ≥ 18 years old with histological confirmation of NENs, biochemical evidence of NENs, or by imaging studies of NENs are eligible. Participants are invited to NIH for biannual evaluations or as clinically indicated. Patients complete individual medical history, family history, and laboratory assessments including blood, saliva, and tumor for RNA/DNA analysis. A tumor analysis via a 500+ gene panel (Illumina TruSight Oncology 500 Panel) is performed for comprehensive genomic and epigenomic analysis. When feasible, fresh tissue is collected to develop pre-clinical models for drug testing. If clinically indicated, anatomic and functional imaging is performed. We aim to 1) create a repository of biological samples and conduct future investigations to understand the basic biology of NENs with the goal to develop novel treatment approaches, biomarkers of treatment response, and new prognostic and diagnostic models, 2) acquire clinical data so that the overall genomic, proteomic, and metabolomic alternations can be correlated to clinical parameters, 3) establish organoid cultures, cell line models, and xenograft models corresponding to NENs of various grades for drug screening. This protocol will evaluate the natural history of NENs, allow tissue acquisition, and study this heterogenous group of neoplasms with unique tumor biology, and current clinical management to stabilize correlations with clinical outcomes and develop novel therapies. Clinical trial information: NCT05237934 .
APOLLO: A randomized phase II double-blind study of olaparib versus placebo following curative intent therapy in patients with resected pancreatic cancer and a pathogenic BRCA1, BRCA2 or PALB2 mutation—ECOG-ACRIN EA2192.
Authors: Reiss Kim Anna , Hong Sung Chul , Kasi Anup , O'Reilly Eileen Mary , Maithel Shishir K. , Yao Xin , Hamilton Stanley R. , Boursi Ben , Pishvaian Michael J. , Klempner Samuel J , Domchek Susan M. , Catalano Paul J. , Chiorean E. Gabriela , Philip Philip Agop , O'Dwyer Peter J.
Published: January 2023

TPS763

Background: A meaningful subset of PDAC is characterized by a homologous recombination deficiency (HRD). The most well-defined patients within this group are those with pathogenic variants in BRCA1, BRCA2 and PALB2. In the metastatic setting, PARP inhibitor maintenance provides a progression-free survival benefit after a period of platinum based chemotherapy1,2, but the role of PARP inhibitors in the curative intent setting is undefined. The OlympiA study established one year of olaparib as the standard of care for patients with BRCA-related, early stage breast cancer who completed all other curative-intent treatment3. Therefore, we have designed a randomized, phase II double-blind study of one year of olaparib vs placebo in patients with pancreatic cancer and a germline or somatic variant in BRCA or PALB2 who have completed all curative intent therapy. Methods: We have enrolled and treated 23 of 152 planned patients on study NCT 04858334/EA2192. Eligibility criteria include: a pathogenic germline or somatic variant in BRCA1, BRCA2 or PALB2 as determined by local laboratory (central review required); completion of curative-intent resection and ≥ three months of multi-agent chemotherapy; no evidence of recurrent disease. At enrollment, patients must be within 12 weeks of their last anti-cancer intervention. Patients are randomized 2:1 to receive oral olaparib 300 mg twice daily or placebo for 12 28-day cycles. The primary endpoint is relapse-free survival. Overall survival is a secondary endpoint. Tumor tissue, fecal material (for microbiome analysis) and serial ctDNA samples are being collected. 1.Golan T, Locker GY, Kindler HL: N Engl J Med 381:1492-1493, 2019. 2. Reiss KA, Mick R, O'Hara MH, et al: J Clin Oncol 39:2497-2505, 2021. 3. Tutt ANJ, Garber JE, Geyer CE, Jr.: N Engl J Med 385:1440, 2021. Clinical trial information: NCT04858334 .
A phase I dose escalation study of carbon-ion radiotherapy for pancreatic cancer.
Authors: Shinoto Makoto , Takiyama Hirotoshi , Isozaki Tetusro , Yamada Shigeru
Published: January 2023

TPS768

Background: Despite recent advances in chemotherapy and radiotherapy, the prognosis of unresectable locally pancreatic cancer (LAPC) patients remains poor. To improve the outcome, we have developed carbon ion radiotherapy (C-ion RT) for pancreatic cancer and have shown good results against conventional photon therapy. Compared to conventional photon therapy, C-ion RT can safely administer higher doses, and we find the possibility of long-term survival for some unresectable LAPC. Currently, C-ion RT is performed using 55.2 Gy (RBE) in 12 fractions. However local control is not satisfactory. Further dose escalation needs to be safely administered to further improve outcomes. We have developed a new treatment strategy: intensity-modulated ion therapy using the simultaneous integrated boost method and the linear transfer energy (LET) optimization method. We believe that these cutting-edge technologies will allow for a more intensive effect on pancreatic cancer. Thus, we started a clinical trial to evaluate the safety of dose escalation using these novel techniques. Methods: Eligibility included pathological or clinical confirmation of pancreatic cancer without distant metastasis. Carbon ion radiotherapy is given in 12 fractions over 3 weeks. The radiation doses are set in four steps, with increases ranging from 55.2 Gy (RBE) to 67.2 Gy (RBE). A minimum of three patients is enrolled in each cohort, and if there is no dose limiting toxicity (DLT), a dose escalation is performed. The primary endpoint is acute adverse events; the secondary outcomes are late adverse events, local control rate, and overall survival. We started this trial in September 2021. Cohort 1 has been completed without DLT. Cohort 2 is now starting enrollment. Clinical trial information: jRCTs032210292 .
Casper: A phase I, open-label, dose finding study of calaspargase pegol-mnkl (cala) in combination with cobimetinib (cobi) in locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC).
Authors: Lopez Charles D. , Kardosh Adel , Chen Emerson Yu-sheng , Pegna Guillaume Joe , Goodyear Shaun , Taber Erin , Rajagopalan Brindha , Edmerson Exodus , Vo Johnson , Jackson Anna , Gingerich Tasha , Fahlman Anne , Ventura Diane , Roy Preeyam , Keith Dove , Mills Gordon B. , Brody Jonathan , Sheppard Brett C. , Sears Rosalie C. , Ronai Ze'ev
Published: January 2023

TPS772

Background: Metabolic adaptation provides rapidly dividing cancer cells the flexibility to maintain homeostasis as nutrient supplies are continuously exhausted in the tumor microenvironment. Asparagine synthetase (ASNS) catalyzes ATP-dependent biosynthesis of the non-essential amino acid asparagine from aspartate and glutamine. Cells lacking ASNS, however, are auxotrophic for asparagine. Use of L-asparaginase (ASNase) to promote asparagine starvation in PDAC and other solid tumors with low ASNS levels is a rationale treatment strategy; however, aberrant RAS/MAPK signaling can circumvent effects of ASNase. Preclinical data shows that targeted inhibition of MAPK signaling along with ASNase is active against PDAC; however, this has not been tested in patients to date. Methods: CASPER is an open-label, phase IB, single-arm, dose-escalation study to evaluate the safety and tolerability of combining cala and cobi in patients with locally-advanced or metastatic PDAC. Participants receive cala and cobi at assigned dose level. The study uses a Bayesian Optimal Interval (BOIN) design to determine the maximum tolerated dose (MTD) for the combination of study agents. Up to 15 participants will be enrolled and treated, with a cohort of 3 participants assessed before a decision is made to escalate, de-escalate, or maintain the current dose level before initiating the next cohort. MTD is defined as the dose level where dose-limiting toxicity (DLT) probability is closest to the target toxicity rate of 30% after applying isotonic regression to the observed dose-level-specific DLT rate. Per BOIN, the dose level is escalated, maintained, or de-escalated based on comparisons of the observed DLT rate and pre-specified boundaries (0.236, 0.359). Starting in Cycle (C) 1, patients receive cobi (at assigned dose level) for Days (D) 1-14, and their assigned dose of cala on D1 of each 21-day cycle. If the combination of cala and cobi is tolerated and does not incur DLTs, participants will continue receiving their assigned dose of cala and cobi until evidence of disease progression, unacceptable toxicity, or study withdrawal. The DLT period starts on C1D1 and ends C2D21. Secondary endpoints include preliminary assessment of overall response rate (ORR), disease control rate (DCR), and mean levels of plasma ASNase. Paired tumor biopsies and serial blood will be used for exploratory objectives combining deep multi-omic analytics with clinical data. The trial is currently open with 1 patient enrolled at time of submission. Clinical trial information: NCT05034627 . [Table: see text]
The SHARON trial: A study of melphalan, BCNU, hydroxocobalamin, ascorbic acid, and autologous stem cell rescue for metastatic pancreatic cancer with an inherited BRCA mutation.
Authors: Yu Kenneth H. , Weekes Colin D. , Chen Yi-Bin Albert , Glazier Jeffrey Aaron , Glazier Arnold , Dahi Parastoo , Giralt Sergio , O'Reilly Eileen Mary
Published: January 2023

TPS774

Background: SHARON is a phase 1, single-arm trial to assess the safety and preliminary efficacy of 2 cycles of melphalan, BCNU, hydroxocobalamin (vitamin B12b), dose-escalated vitamin C, and autologous stem cells in patients with stage IV pancreatic cancer and an inherited, deleterious BRCA1/2 mutation. Cancers that evolve in patients with a germline BRCA1/ 2 mutation generally have loss or inactivation of the wild type allele, which results in hypersensitivity to melphalan. The melphalan dose-response is log-linear: doubling the melphalan area under the curve (AUC) doubles the log reduction in clonogenic survival. The melphalan AUC that can safely be achieved with melphalan followed by stem cell rescue has the potential to provide major log reductions in cancer cell survival in BRCA-deficient cancers. However, reversion mutations in BRCA can cause resistance to DNA-crosslinking agents such as melphalan. Studies have shown that oxidizing cellular glutathione (GSH) to glutathione disulfide (GSSG) can inhibit DNA repair and hypersensitize wild-type cancer cells to melphalan. In this trial, BCNU, vitamin B12b, and vitamin C are used to increase cancer cell GSSG levels. Methods: Eligibility criteria include stage IV pancreatic cancer, an inherited deleterious BRCA1/2 mutation, life expectancy of at least 6 months, measurable or non-measurable disease, and suitability for apheresis, chemotherapy, and stem cell infusion. Prior treatment with PARP inhibitors is allowed. Stem cells are collected by apheresis. Participants receive 2 cycles of melphalan 100 mg/m2, BCNU 150 mg/m2, vitamin B12b 1.45 g/m2, and vitamin C 3, 6, or 8 g/m2 on Day −2. Stem cell infusion administered on day 0. A 2 + 4 dose-escalation schedule is employed for vitamin C. Adverse reactions summarized by CTCAE 5.0. The primary endpoint is safety, and secondary endpoints are objective response rate (overall and for metastatic lesions) and overall and progression-free survival. Amendment pending to include stage IV, BRCA-related, HER2-negative breast cancer and PALB2 mutations. The trial is enrolling at Memorial Sloan Kettering Cancer Center and Massachusetts General Hospital. Clinical trial information: NCT04150042 .
Sonoporation for disrupting the pancreatic cancer microenvironment to enhance chemotherapy delivery and improve outcomes.
Authors: Posey James , Machado Priscilla , Eisenbrey John R. , Bashir Babar , Mille Patrick Johnston , Basu Mallick Atrayee , Singla Rajan , Kotopoulis Spiros , Nordaas Ingrid K. , Trelsgård Audun M. , Jouleh Tæraneh , Dimcevski Georg Gjorgji , Gilja Odd-Helge , Forsberg Flemming
Published: January 2023

TPS777

Background: Pancreatic ductal adenocarcinoma (PDAC) is 3% of cancers diagnosed in the United States and it is the fourth leading cause of cancer-related deaths. Hence, there is a considerable clinical need to develop innovative strategies for effective drug delivery and treatment. Sonoporation is a novel method that can enhance the therapeutic efficacy of co-administered chemotherapy by localized contrast-enhanced ultrasound imaging (CEUS) of gas-filled microbubbles (ultrasound contrast agent UCA), which temporarily changes tumor vascular microenvironment by increasing angiogenic vessel leakage through microstreaming, shockwaves and the activation of various intracellular signaling responses. Our Phase I clinical trial of sonoporation in 10 PDAC patients treated with Gemcitabine demonstrated no additional toxicity and an increase in median survival compared to 63 historical controls (8.9 vs 17.6 months; p = 0.011). Animal studies investigated 4 commercial UCAs under 2 different acoustic regimes and established the optimal UCA (Sonazoid, GE Healthcare, Oslo, Norway) as well as acoustic settings for sonoporation of PDAC. Methods: This Phase II clinical trial aims to improve standard of care (SoC) chemotherapy treatment by adding sonoporation (i.e., augmenting the SoC treatment with CEUS and microbubbles). Two sites (one in USA and one in Norway) will enroll 120 subjects with PDAC stage III or IIV prior to starting SoC chemotherapy. Exclusion criteria include known allergies to the UCA. The primary objective is to evaluate the safety and therapeutic efficacy of sonoporation on PDAC SoC treatment based on local progression-free and overall survival. Two groups: SoC chemotherapy or SoC chemotherapy followed by sonoporation. The optimal CEUS and microbubble conditions will be applied to a single PDAC tumor imaged by ultrasound. Treatment delivered day of SoC chemotherapeutic treatment for PDAC when the concentration of drugs is maximum. Gehan-Breslow-Wilcoxon test and Log-rank test will be used to compare survival. All clinical variables (e.g., concomitant imaging results, blood tests, etc.) will also be compared between groups with and without sonoporation. Clinical trial information: NCT04821284 .
Self-Sourced Medication Abortion, Physician Authority, and the Contradictions of Abortion Care
Authors: Karlin Jennifer , Joffe Carole
Published: January 2023

The growing acknowledgment of the phenomenon of individuals terminating their pregnancies by obtaining the medications necessary for an abortion—which this article refers to as “self-sourced medication abortion” (SSMA)—has shed light on the current contradictions in the world of abortion provision. This article offers a brief historical overview of the relationship between abortion provision and mainstream medicine, pointing to the factors that have led to the marginalization of abortion care. It then discusses interviews with 40 physicians who provide abortions about their perspectives on SSMA, and it explores how this group responds to the contradictions presented by SSMA. In doing so, it interrogates the changing meaning of “physician authority” among this subset of physicians. The authors suggest that these interviewees represent an emergent sensibility among this generation of abortion physicians, a sensibility strongly tied to a commitment to social justice.